Researchers have successfully used a DNA-editing technique to extend the lifespan of mice with the genetic variation associated with progeria, a rare genetic disease that causes extreme premature aging in children and can significantly shorten their life expectancy. The study was published in the journal Nature, and was a collaboration between the National Human Genome Research Institute (NHGRI), part of the National Institutes of Health; Broad Institute of Harvard and MIT, Boston; and the Vanderbilt University Medical Center, Nashville, Tennessee.

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Base editing for progeria treatmentProgeria is caused by a mutation in the nuclear lamin Agene in which one DNA base C is changed to a T. Researchers used the base editing method, which substitutes a single DNA letter for another without damaging the DNA, to reverse that change. Credit: Ernesto Del Aguila, NHGRI.

DNA is made up of four chemical bases A, C, G and T. Progeria, which is also known as Hutchinson-Gilford progeria syndrome, is caused by a mutation in the nuclear lamin A(LMNA) gene in which one DNA base C is changed to a T. This change increases the production of the toxic protein progerin, which causes the rapid aging process.

Approximately 1 in 4 million children are diagnosed with progeria within the first two years of birth, and virtually all of these children develop health issues in childhood and adolescence that are normally associated with old age, including cardiovascular disease (heart attacks and strokes), hair loss, skeletal problems, subcutaneous fat loss and hardened skin.

For this study, researchers used a breakthrough DNA-editing technique called base editing, which substitutes a single DNA letter for another without damaging the DNA, to study how changing this mutation might affect progeria-like symptoms in mice.

"The toll of this devastating illness on affected children and their families cannot be overstated," said Francis S. Collins, M.D., Ph.D., a senior investigator in NHGRI's Medical Genomics and Metabolic Genetics Branch, NIH director and a corresponding author on the paper. "The fact that a single specific mutation causes the disease in nearly all affected children made us realize that we might have tools to fix the root cause. These tools could only be developed thanks to long-term investments in basic genomics research.

The toll of this devastating illness on affected children and their families cannot be overstated.The fact that a single specific mutation causes the disease in nearly all affected children made us realize that we might have tools to fix the root cause. These tools could only be developed thanks to long-term investments in basic genomics research.

The study follows another recent milestone for progeria research, as the U.S. Food and Drug Administration approved the first treatment for progeria in November 2020, a drug called lonafarnib. The drug therapy provides some life extension, but it is not a cure. The DNA-editing method may provide an additional and even more dramatic treatment option in the future.

David Liu, Ph.D., and his lab at the Broad Institute developed the base-editing method in 2016, funded in part by NHGRI.

"CRISPR editing, while revolutionary, cannot yet make precise DNA changes in many kinds of cells," said Dr. Liu, a senior author on the paper. "The base-editing technique we've developed is like a find-and-replace function in a word processor. It is extremely efficient in converting one base pair to another, which we believed would be powerful in treating a disease like progeria.

To test the effectiveness of their base-editing method, the team initially collaborated with the Progeria Research Foundation to obtain connective tissue cells from progeria patients. The team used the base editor on theLMNAgene within the patients cells in a laboratory setting. The treatment fixed the mutation in 90% of the cells.

The Progeria Research Foundation was thrilled to collaborate on this seminal study with Dr. Collinss group at the NIH and Dr. Lius group at Broad Institute, said Leslie Gordon, M.D., Ph.D., a co-author and medical director of The Progeria Research Foundation, which partially funded the study. These study results present an exciting new pathway for investigation into new treatments and the cure for children with progeria.

Following this success, the researchers tested the gene-editing technique by delivering a single intravenous injection of the DNA-editing mix into nearly a dozen mice with the progeria-causing mutation soon after birth. The gene editor successfully restored the normal DNA sequence of theLMNAgene in a significant percentage of cells in various organs, including the heart and aorta.

Many of the mice cell types still maintained the corrected DNA sequence six months after the treatment. In the aorta, the results were even better than expected, as the edited cells seemed to have replaced those that carried the progeria mutation and dropped out from early deterioration. Most dramatically, the treated mice's lifespan increased from seven months to almost 1.5 years. The average normal lifespan of the mice used in the study is two years.

As a physician-scientist, its incredibly exciting to think that an idea youve been working on in the laboratory might actually have therapeutic benefit, said Jonathan D. Brown, M.D., assistant professor of medicine in the Division of Cardiovascular Medicine at Vanderbilt University Medical Center. Ultimately our goal will be to try to develop this for humans, but there are additional key questions that we need to first address in these model systems.

Funding for the study was supported in part by NHGRI, the NIH Common Fund, the National Institute of Allergy and Infectious Diseases, the National Institute of Biomedical Imaging and Engineering, the National Institute of General Medical Sciences, the National Heart, Lung and Blood Institute and the National Center for Advancing Translational Sciences.

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DNA-editing method shows promise to treat mouse model of progeria - National Human Genome Research Institute

ST. PAUL, Minn. & LAKE ZURICH, Ill.--(BUSINESS WIRE)--ScaleReady, a joint venture between Bio-Techne (NASDAQ: TECH), Fresenius Kabi, and Wilson Wolf, launches today. The new company brings together proven tools and technologies for cell culture, cell activation, gene editing, and cell processing from its founding partners.

ScaleReady provides leading therapeutic developers with the most simple, scalable, and versatile manufacturing platform in the industry, enhancing the prospects of success for cell and gene therapy organizations. The new company will accelerate innovation in cell and gene therapy manufacturing, building on the R&D pipelines of its founding partners and through global technology partnerships with industry and academic leaders.

ScaleReadys mission is to accelerate the groundbreaking advances in cell and gene therapy by satisfying the longstanding need for a truly scalable, cost-effective and practical manufacturing platform, said Adam Bryan, General Manager of ScaleReady. Its exciting to see the commitment that our industry-leading partners have made to this mission. Their dedication to combine resources, expertise and decades of experience, position us to make a meaningful contribution to this industry now and in the future through rapid advancement of platform technologies that lead the industry to greater efficiency, practicality and simplicity.

Through this partnership, ScaleReady provides sales, marketing, and application support for tools and technologies used in cell and gene therapy manufacturing worldwide. Wilson Wolfs G-Rex cell culture technology, Fresenius Kabis Lovo and upcoming Cue cell processing systems, and Bio-Technes range of GMP proteins, reagents, media, and gene editing technologies, are all part of the ScaleReady manufacturing platform.

With this venture, Wilson Wolf is adding tremendous wherewithal in our quest to provide the field of cell and gene therapy with a disruptive manufacturing platform that cost-effectively accelerates the delivery of potential life-saving therapies to a wide segment of society, said John Wilson, Chief Executive Officer of Wilson Wolf. Our G-Rex technology is uniquely positioned to address the scale limitation issues facing the industry. Our partners at Bio-Techne and Fresenius Kabi share our common purpose and bring complementary technologies that will accelerate our work.

With cell and gene therapies showing great potential for a wide range of diseases, the need for reliable and consistent raw material supply has never been more important. At Bio-Techne, we recently opened a new large-scale GMP reagent facility, increasing manufacturing capacity for animal-free raw materials, including E. coli-derived recombinant proteins, to ensure sustainable supply for future needs, said David Eansor, President Protein Sciences Segment, at Bio-Techne.

Dean Gregory, President Global Commercial Operations, Transfusion Medicine and Cell Therapies at Fresenius Kabi added, Cell therapies hold promise for patients and are a major area of focus for Fresenius Kabi. Through the partnership represented by ScaleReady, we will be able to make a greater contribution to this field at an accelerated pace. We are thrilled to share our expertise in automated cell processing and closed-system development to this important collaboration.

ScaleReady is owned equally by the three partners Bio-Techne, Fresenius Kabi, and Wilson Wolf. Separately, the three companies do business globally and have combined revenues of more than $7 billion. No other financial terms were disclosed at this time.

About ScaleReady

ScaleReady is bringing the future of cell and gene therapies to life with the most powerful and versatile manufacturing platform in the industry. ScaleReady delivers rapid expansion of T-cells at scalereducing complexity and cost, while providing superior repeatability and cell quality. Founded in 2020, ScaleReady is a joint venture between Bio-Techne, Fresenius Kabi and Wilson Wolf that brings together tools and technologies for cell culture, cell activation, gene editing and cell processing from each founding partner. Learn more at http://www.scaleready.com.

About Bio-Techne

Bio-Techne Corporation (NASDAQ: TECH) is a global life sciences company providing innovative tools and bioactive reagents for the research and clinical diagnostic communities. Bio-Techne products assist scientific investigations into biological processes and the nature and progress of specific diseases. They aid in drug discovery efforts and provide the means for accurate clinical tests and diagnoses. With thousands of products in its portfolio, Bio-Techne generated approximately $739 million in net sales in fiscal 2020 and has over 2,300 employees worldwide. For more information on Bio-Techne and its brands, please visit http://www.bio-techne.com.

About Fresenius Kabi

Fresenius Kabi (www.fresenius-kabi.com/us) is a global health care company that specializes in medicines and technologies for infusion, transfusion and clinical nutrition. The companys products and services are used to help care for critically and chronically ill patients. The companys U.S. headquarters is in Lake Zurich, Illinois. The companys global headquarters is in Bad Homburg, Germany. Fresenius Kabi is part of Fresenius SE(ETR: FRE), a global health care group with more than 305,000 employees in more than 100 countries, and annual sales exceeding $30 billion.

About Wilson Wolf

Based in St. Paul, Minnesota, Wilson Wolf (www.wilsonwolf.com) was founded in 1998 to pioneer the development of innovative cell culture technologies and has created patented products and protocols for numerous applications including monoclonal antibody production, corneal transplants, porcine heart valve testing, mesenchymal cell production, and islet transplants for type 1 diabetes. Over the last 5 years, its G-Rex product line has experienced an average annual sales growth rate of nearly 100%.

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ScaleReady Launches With the Mission to Revolutionize T Cell Therapy Manufacturing - Business Wire

The argument for continued investment

C> is a high potential and maturing sector, and is an already crowded environment, playing host to numerous start-ups and now, through M&A, recognised big pharma firms. Much like the rush to find a COVID-19 vaccine that dominates headlines worldwide, not every company involved will be able to succeed.

But finnCaps finnLife watch list of 50 leading AIM-listed biotech companies demonstrates that there is room for numerous companies to contribute to, and profit from, C>. Examining three entirely different approaches to CAR-T therapy, it is possible to see just how much space there is for this exciting sector, therefore displaying the case for continued investment.

Innovative CAR-T therapy demonstrates the depth of C> potential

CAR-T therapy in its existing form is a relatively new and specialised approach at treating cancer. It takes T cells from a patients bloodstream and genetically modifies them in a laboratory. These T cells are then injected back into the bloodstream with the aim of targeting and killing cancer cells.

While it has been shown to be an effective treatment, there are risks and side effects. One is the two-step autologous process (the slow time it takes for cell expansion sometimes as long as two weeks) while another is cytokine release syndrome (CRS), which occurs when cytokine molecules are inadvertently released, but too quickly to target just the tumours and instead target healthy cells.

The next generation of CAR-T treatments shows that there is space for a multitude of start-ups to be active in the C> space as they all help find varied solutions to these problems without negating the effectiveness of CAR-T.

One example is Horizon Delivery, a company that is developing its CYAD-02 project, which will help transport T cells more effectively to the tumour via the use of SMARTvector products.

The product underwent its first phase 1 trial test in January 2020 with a patient who was suffering from acute myeloid leukaemia. Horizon Delivery is also an industry leader in CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) screenings, meaning they can identify key genes or genetic sequences that draw out specific functions of a cell type from thousands of potential variants.

In a cancer context, this means they can route out and exclusively eliminate problematic cells that may have shown signs theyd resist a future cancer treatment.

Another example is Maxcyte, a global cell- based therapies and life sciences company that is developing its CARMA process, where a patients peripheral blood mononuclear cells (PBMCs) are removed and modified. The modified cells can then be used to target an array of different cancers.

Currently the company is conducting a phase 1 trial for advanced ovarian cancer in a dose escalation trial that will treat four separate cohorts the fourth of which was administered in March 2020.

Another example which shows the versatility of new CAR-T innovation is provided by Oxford Biomedica, a gene and cell therapy company specialising in the development of gene-based medicines.

Rather than a contained project or platform, its contribution to CAR-T is through a contract manufacturing development organisation. Collaborating with pharma companies, Oxford Biomedica uses its infrastructure to produce other companies licensed products, including Novartis Kymriah treatment (alongside other undisclosed CAR-T-related products).

With fast-moving innovation finally allowing multiple C> treatments to gain regulatory approval, along with a huge pipeline of upcoming therapies and an influx of funding and M&A activity, investing in C> no longer entails taking a bet on potential the future is finally here.

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After years of potential, cell and gene therapy is ready for the pharmaceutical mainstream - PMLiVE

Figure 1

Remaining Lifetime Risk for ATM PV Carriers

SALT LAKE CITY, Dec. 11, 2020 (GLOBE NEWSWIRE) -- In a spotlight poster discussion at the 2020 San Antonio Breast Cancer Symposium (SABCS), Myriad Genetics (NASDAQ: MYGN), a global leader in molecular diagnostics and precision medicine, today presented a new study that shows how its myRisk Hereditary Cancer and riskScore tests can better inform individualized clinical screening and prevention strategies for women at risk of developing breast cancer. The new Myriad study highlights how riskScore, a proprietary tool used to evaluate a womans risk of developing breast cancer, can accurately provide breast cancer risk information into a personalized assessment model for women carrying a pathogenic variant (PV) in the ATM gene.

This new study will enable a highly personalized risk calculation for patients who carry mutations in the ATM gene, said Nicole Lambert, president of Myriad Genetic Laboratories. As a result, women carrying gene mutations will be able to make more informed choices about how to manage their risk; if increased surveillance is sufficient or if they would consider surgical options.

Myriads riskScore test combines data from 20 years of genome-wide association studies with a validated algorithm that uses personal and family history. riskScore is performed in conjunction with Myriads myRisk Hereditary Cancer test, where myRisk identifies people who carry specific cancer-linked genetic mutations.

Asummary of the study is below. Follow Myriad on Twitter via @myriadgenetics and keep up to date with SABCS meeting news and updates by using the #SACBS20 hashtag.

riskScore Poster at SABCS Title: Development of a breast cancer risk assessment model for ATM mutation carriers incorporating Tyrer-Cuzick and a polygenic risk score Program Number: PD10-09 Session Title: Spotlight Poster Discussion 10 This study highlights the development of a comprehensive breast cancer risk model for ATM PV carriers incorporating an 86-variant PRS, along with family history and clinical information captured by Tyrer-Cuzick (a tool used to calculate the risk of breast cancer). The study found that with ATM PV carriers (N=216), a comprehensive model allowed for differentiation of carriers into low, moderate, and high breast cancer risk categories (See figure 1 below).

To view Figure 1. Remaining Lifetime Risk for ATM PV Carriers, please visit the following link:https://www.globenewswire.com/NewsRoom/AttachmentNg/d77da35a-714a-41f4-8a8a-dd79a79dc644

AboutriskScore riskScore is a clinically validated personalized medicine tool that enhances Myriads myRisk Hereditary Cancer test. riskScore helps to further predict a womens lifetime risk of developing breast cancer using clinical risk factors and genetic markers throughout the genome. The test incorporates data from more than 80 single nucleotide polymorphisms identified through 20 years of genome wide association studies in breast cancer and was prospectively validated in our laboratory to predict breast cancer risk in women of European descent. This data is then combined with a personal history and family history algorithm, the Tyrer-Cuzick model, to provide an individualized breast cancer risk assessment. Myriad is committed to advancing the validation of risk-assessment tools and making them available to all women, regardless of ancestry.

About Myriad myRisk Hereditary Cancer The Myriad myRisk Hereditary Cancer test uses an extensive number of sophisticated technologies and proprietary algorithms to evaluate 35 clinically significant genes associated with eight hereditary cancer sites including: breast, colon, ovarian, endometrial, pancreatic, prostate and gastric cancers and melanoma.

About Myriad Genetics Myriad Genetics Inc., is a leading personalized medicine company dedicated to being a trusted advisor transforming patient lives worldwide with pioneering molecular diagnostics. Myriad discovers and commercializes molecular diagnostic tests that: determine the risk of developing disease, accurately diagnose disease, assess the risk of disease progression, and guide treatment decisions across six major medical specialties where molecular diagnostics can significantly improve patient care and lower healthcare costs. Myriad is focused on three strategic imperatives: transitioning and expanding its hereditary cancer testing markets, diversifying its product portfolio through the introduction of new products and increasing the revenue contribution from international markets. For more information on how Myriad is making a difference, please visit the Company's website:www.myriad.com.

Myriad, the Myriad logo, BART, BRACAnalysis, Colaris, Colaris AP, myPath, myRisk, Myriad myRisk, myRisk Hereditary Cancer, myChoice, myPlan, BRACAnalysis CDx, Tumor BRACAnalysis CDx, myChoice CDx, Vectra, Prequel, Foresight, GeneSight, riskScore and Prolaris are trademarks or registered trademarks of Myriad Genetics, Inc. or its wholly owned subsidiaries in the United States and foreign countries. MYGN-F, MYGN-G.

Safe Harbor Statement This press release contains "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995, including statements related to the Company building ATM status into a clinically validated risk assessment tool that will create a more comprehensive, highly personalized report for patients seeking to understand their risk of developing breast cancer; and the Companys strategic directives under the caption "About Myriad Genetics." These "forward-looking statements" are based on management's current expectations of future events and are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in or implied by forward-looking statements. These risks and uncertainties include, but are not limited to: uncertainties associated with COVID-19, including its possible effects on our operations and the demand for our products and services; our ability to efficiently and flexibly manage our business amid uncertainties related to COVID-19; the risk that sales and profit margins of our molecular diagnostic tests and pharmaceutical and clinical services may decline; risks related to our ability to transition from our existing product portfolio to our new tests, including unexpected costs and delays; risks related to decisions or changes in governmental or private insurers reimbursement levels for our tests or our ability to obtain reimbursement for our new tests at comparable levels to our existing tests; risks related to increased competition and the development of new competing tests and services; the risk that we may be unable to develop or achieve commercial success for additional molecular diagnostic tests and pharmaceutical and clinical services in a timely manner, or at all; the risk that we may not successfully develop new markets for our molecular diagnostic tests and pharmaceutical and clinical services, including our ability to successfully generate revenue outside the United States; the risk that licenses to the technology underlying our molecular diagnostic tests and pharmaceutical and clinical services and any future tests and services are terminated or cannot be maintained on satisfactory terms; risks related to delays or other problems with operating our laboratory testing facilities and our healthcare clinic; risks related to public concern over genetic testing in general or our tests in particular; risks related to regulatory requirements or enforcement in the United States and foreign countries and changes in the structure of the healthcare system or healthcare payment systems; risks related to our ability to obtain new corporate collaborations or licenses and acquire new technologies or businesses on satisfactory terms, if at all; risks related to our ability to successfully integrate and derive benefits from any technologies or businesses that we license or acquire; risks related to our projections about our business, results of operations and financial condition; risks related to the potential market opportunity for our products and services; the risk that we or our licensors may be unable to protect or that third parties will infringe the proprietary technologies underlying our tests; the risk of patent-infringement claims or challenges to the validity of our patents or other intellectual property; risks related to changes in intellectual property laws covering our molecular diagnostic tests and pharmaceutical and clinical services and patents or enforcement in the United States and foreign countries, such as the Supreme Court decisions in Mayo Collab. Servs. v. Prometheus Labs., Inc., 566 U.S. 66 (2012), Assn for Molecular Pathology v. Myriad Genetics, Inc., 569 U.S. 576 (2013), and Alice Corp. v. CLS Bank Intl, 573 U.S. 208 (2014); risks of new, changing and competitive technologies and regulations in the United States and internationally; the risk that we may be unable to comply with financial operating covenants under our credit or lending agreements; the risk that we will be unable to pay, when due, amounts due under our credit or lending agreements; and other factors discussed under the heading "Risk Factors" contained in Item 1A of our most recent Annual Report on Form 10-K for the fiscal year ended June 30, 2020, which has been filed with the Securities and Exchange Commission, as well as any updates to those risk factors filed from time to time in our Quarterly Reports on Form 10-Q or Current Reports on Form 8-K. All information in this press release is as of the date of the release, and Myriad undertakes no duty to update this information unless required by law.

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New Study Provides Personalized Breast Cancer Risk Information for Women with ATM Gene Mutations - GlobeNewswire

Jos-Alain Sahel was on a rare vacation in Portugal in the spring of 2018 when his phone rang with grim news: The gene therapy he had worked on for a decade, a potential cure for a rare form of blindness, had failed in a pivotal trial.

In the first minute, I was very disappointed, Sahel says. I said, well OK, its not working.

A failed trial in drug development is crushing but not unexpected, a tradeoff of doing business in biology. You examine the full data, go back to the drawing board and either abandon the effort or tweak and try again. Sahel, founder of four companies and the longtime head of the Vision Institute of Paris, was used to the process. But this time, when the full data came, he was bewildered.

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They thought their gene therapy failed. Instead, it spawned a medical mystery - Endpoints News

Maryland, US headquartered company, Orgenesis, is championing a model that aims to bring down those costs it works with partner hospitals throughout the commercialization process.

The companys CGT platform, consisting of a pipeline of licensed cell and gene therapies, scientific expertise, customised processing systems, and an ecosystem of healthcare providers and research institutes, is designed to provide a pathway for groundbreaking autologous therapies to become commercially available on an industrial scale and at prices accessible to large populations.

Orgenesis business model is one focused on decentralization, enabling precision medicines to be prepared on-site at hospitals. In this way, we can really expedite cell and gene therapy development, said Orgenesis CEO, Vered Caplan.

With operations in the US, Europe, Israel and South Korea, Orgenesis has now created an international network of point of care (POCare) centers to serve patients directly in the hospital setting.

Beyond the US, we have POCare centers in many countries in Europe such as Greece, the Netherlands, Belgium, Slovenia, Italy and Spain; we also have centers in Israel, in Korea and in India and we will be starting up soon in Dubai,said the CEO.

The goal is to make gene and cell therapies feasible for large numbers of patients, said Caplan. We used to work as a contract development and manufacturing organization (CDMO) but we sold that business to Catalent at the beginning of the year.

The centralized processing and supply chain model only served to create a frustrating working environment, with plenty of constraints, said the Orgenesis lead.

We realized very quickly that we couldnt really ramp up to large scale relying on that kind of centralized model, particularly for autologous products, which represent most of the market today. It takes six months to train someone to work in a high-grade cleanroom there is a lot of work and expense involved in that and there is a limited number of patients that can be treated in such cleanrooms the utilization rate is very low - it [centralized processing and supply] is a very inefficient and costly way to supply and to develop medicine there is so much manual work involved, she told BioPharma-Reporter.

The company had been working for a number of years, investing a huge amount of effort in developing a range of automation solutions to supplant those manual processes, as well as building its mobile CGT processing labs and units (OMPULs), she said.

We had been fielding so many requests from hospitals that wanted to collaborate with us, asking us to make or scale up their CAR-T and other therapies. We realized that in order to get this done, we needed to take a decentralized approach and that we needed to provide a solution, not only for one hospital, but for every hospital that wanted these type of therapies; and we saw that such a model brings down the price of the therapy tremendously.

A hospital gives Orgenesis a license to work on the therapy, on the processing; production of the final product is automated and supplied via an on-site point-of-care processing unit. Orgenesis then sets about democratizing the treatment,making it available to any hospital in its POCare network.

The company says the final customized, automated processing system it has developed, with the integrated specific therapy, solves a variety of processing and cost hurdles. It results in a lower required grade of cleanroom, it simplifies facility management requirements, it enables multi-batch processing per cleanroom, which means reduced technical staffing. Moreover, the localized processing eliminates the many logistical difficulties associated with traditional, centralized manufacturing and transport.

Overall, it is said to provide faster turnaround, increased safety, and improved quality control management on-site.

Hospitals really want to supply CGTs, while patients are reading about such treatments and making inquiries of healthcare providers, she added.

Ours is really a combined licensing and service model.

We are like Uber. If you have a car, you want to make some extra revenue, you call up Uber and it gives you the network, the technology and all the operating procedures to be a taxi driver. That is very much what we do in terms of hospitals we give them the ability to be biotech companies, because this is not the standard thing they do, they dont want to take responsibility for cell and gene therapy it is too much for them. They want to treat patients, but they want to have that local supply, so we give them the technology and the capabilities to do that. We give them regulatory support for clinical trials, we give them CRO support, we give them a network - so they can function and do what they need to do, which is to undertake research and treat patients.

Orgenesis intends to leverage its network of regional partners to advance the development and commercialization of its therapeutic pipeline. Towards this end, it said its partners have committed to funding the clinical programs. In turn, the company typically grants its partners geographic rights in exchange for future royalties, and a partnership with Orgenesis to support the supply of the targeted therapies. Through this model, Orgenesis has already signed contracts, which it expect to generate over US$40M in revenue over the next three years, if fully realized.

On the therapeutic front, Orgenesis is focused on several key verticals, including immuno-oncology, anti-viral, and metabolic/auto-immune diseases.

It recently acquired Koligo Therapeutics, with the aim of leveraging Koligos 3D-V bioprinting technology across its POCare Platform. That technology, which utilizes 3D bioprinting and vascularization with autologous cells to create biodegradable and shelf-stable three-dimensional cell and tissue implants, is being developed for diabetes and pancreatitis, with longer term applications for neural, liver, and other cell/tissue transplants.

In February this year, Orgenesis announced that it has entered into a collaboration agreement with the John Hopkins University to utilize the POCare platform to develop and supply a variety of CGTs including cell-based immunotherapy technologies.

And the University of California, Davis (UC Davis) joined its POCare network in January. The collaboration will involve the scale up and integration of UC Davis lentiviral vector process.

Today we are very much in validation mode. Most of the therapies in this space, and the ones we have licensed from the hospitals I think we have about 25 today are all at different stages of clinical development. Some have been used to treat patients but that has all been done under hospital exception.

When we adopt a therapy into the network, we run it through the entire R&D, formal clinical and regulatory processes as [our goal] is a harmonized process, to have the same standard [in our closed systems] at our [POCare] centers, whether that is in Germany or Korea, said the CEO.

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Orgenesis CEO talks disruption: 'We are the Uber of the cell and gene therapy space' - BioPharma-Reporter.com

ZUG, Switzerland and CAMBRIDGE, Mass. and BOSTON, Nov. 04, 2020 (GLOBE NEWSWIRE) -- CRISPR Therapeutics (Nasdaq: CRSP) and Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX) today announced data in seven patients from two ongoing Phase 1/2 clinical trials of the investigational CRISPR/Cas9 gene-editing therapy CTX001 in severe hemoglobinopathies has been accepted for an oral presentation during the Plenary Scientific Session at the annual ASH Meeting and Exposition, which will take place virtually from December 5-8, 2020. Haydar Frangoul, M.D., Medical Director of Pediatric Hematology and Oncology at Sarah Cannon Research Institute, HCA Healthcares TriStar Centennial Medical Center, will deliver the presentation on behalf of all the authors on December 6, 2020.

An abstract posted online today includes data from five patients with three months to 15 months of follow-up after CTX001 infusion in the ongoing Phase 1/2 CLIMB-111 trial in transfusion-dependent beta thalassemia (TDT) and data from two patients with three months and 12 months of follow-up in the ongoing Phase 1/2 CLIMB-121 trial in severe sickle cell disease (SCD). Additional data will be presented at ASH, including longer-duration follow-up data for the patients included in the abstract and data for additional patients with greater than three months of follow-up.

CTX001 is being investigated in these two ongoing clinical trials as a potential one-time curative therapy for patients suffering from TDT and severe SCD.

The accepted abstract is now available on the ASH conference website.

About CTX001CTX001 is an investigational, autologous, ex vivo CRISPR/Cas9 gene-edited therapy that is being evaluated for patients suffering from TDT or severe SCD, in which a patients hematopoietic stem cells are engineered to produce high levels of fetal hemoglobin (HbF; hemoglobin F) in red blood cells. HbF is a form of the oxygen-carrying hemoglobin that is naturally present at birth, which then switches to the adult form of hemoglobin. The elevation of HbF by CTX001 has the potential to alleviate transfusion requirements for TDT patients and reduce painful and debilitating sickle crises for SCD patients.

Based on progress in this program to date, CTX001 has been granted Regenerative Medicine Advanced Therapy (RMAT), Fast Track, Orphan Drug, and Rare Pediatric Disease designations from the U.S. Food and Drug Administration (FDA). CTX001 has also been granted Orphan Drug Designation from the European Commission for both TDT and SCD, as well as Priority Medicines (PRIME) designation from the European Medicines Agency (EMA) for SCD.

CTX001 is being developed under a co-development and co-commercialization agreement between CRISPR Therapeutics and Vertex. Among gene-editing approaches being investigated/evaluated for TDT and SCD, CTX001 is the furthest advanced in clinical development.

About CLIMB-111The ongoing Phase 1/2 open-label trial, CLIMB-Thal-111, is designed to assess the safety and efficacy of a single dose of CTX001 in patients ages 12 to 35 with TDT. The trial will enroll up to 45 patients and follow patients for approximately two years after infusion. Each patient will be asked to participate in a long-term follow-up trial.

About CLIMB-121The ongoing Phase 1/2 open-label trial, CLIMB-SCD-121, is designed to assess the safety and efficacy of a single dose of CTX001 in patients ages 12 to 35 with severe SCD. The trial will enroll up to 45 patients and follow patients for approximately two years after infusion. Each patient will be asked to participate in a long-term follow-up trial.

About the Gene-Editing Process in These TrialsPatients who enroll in these trials will have their own hematopoietic stem and progenitor cells collected from peripheral blood. The patients cells will be edited using the CRISPR/Cas9 technology. The edited cells, CTX001, will then be infused back into the patient as part of a stem cell transplant, a process which involves, among other things, a patient being treated with myeloablative busulfan conditioning. Patients undergoing stem cell transplants may also encounter side effects (ranging from mild to severe) that are unrelated to the administration of CTX001. Patients will initially be monitored to determine when the edited cells begin to produce mature blood cells, a process known as engraftment. After engraftment, patients will continue to be monitored to track the impact of CTX001 on multiple measures of disease and for safety.

About the CRISPR-Vertex CollaborationCRISPR Therapeutics and Vertex entered into a strategic research collaboration in 2015 focused on the use of CRISPR/Cas9 to discover and develop potential new treatments aimed at the underlying genetic causes of human disease. CTX001 represents the first potential treatment to emerge from the joint research program. CRISPR Therapeutics and Vertex will jointly develop and commercialize CTX001 and equally share all research and development costs and profits worldwide.

About CRISPR TherapeuticsCRISPR Therapeutics is a leading gene editing company focused on developing transformative gene-based medicines for serious diseases using its proprietary CRISPR/Cas9 platform. CRISPR/Cas9 is a revolutionary gene editing technology that allows for precise, directed changes to genomic DNA. CRISPR Therapeutics has established a portfolio of therapeutic programs across a broad range of disease areas including hemoglobinopathies, oncology, regenerative medicine and rare diseases. To accelerate and expand its efforts, CRISPR Therapeutics has established strategic collaborations with leading companies including Bayer, Vertex Pharmaceuticals and ViaCyte, Inc. CRISPR Therapeutics AG is headquartered in Zug, Switzerland, with its wholly-owned U.S. subsidiary, CRISPR Therapeutics, Inc., and R&D operations based in Cambridge, Massachusetts, and business offices in San Francisco, California and London, United Kingdom. For more information, please visit http://www.crisprtx.com.

CRISPR Therapeutics Forward-Looking StatementThis press release may contain a number of forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, as amended, as well as statements regarding CRISPR Therapeutics expectations about any or all of the following: (i) the status of clinical trials (including, without limitation, the expected timing of data releases) related to product candidates under development by CRISPR Therapeutics and its collaborators, including expectations regarding the data and plans to present data at the annual ASH meeting and exposition; (ii) the expected benefits of CRISPR Therapeutics collaborations; and (iii) the therapeutic value, development, and commercial potential of CRISPR/Cas9 gene editing technologies and therapies. Without limiting the foregoing, the words believes, anticipates, plans, expects and similar expressions are intended to identify forward-looking statements. You are cautioned that forward-looking statements are inherently uncertain. Although CRISPR Therapeutics believes that such statements are based on reasonable assumptions within the bounds of its knowledge of its business and operations, forward-looking statements are neither promises nor guarantees and they are necessarily subject to a high degree of uncertainty and risk. Actual performance and results may differ materially from those projected or suggested in the forward-looking statements due to various risks and uncertainties. These risks and uncertainties include, among others: the potential for initial and preliminary data from any clinical trial and initial data from a limited number of patients (as is the case with CTX001 at this time) not to be indicative of final trial results; the potential that CTX001 clinical trial results may not be favorable; the potential impacts due to the coronavirus pandemic, such as the timing and progress of clinical trials; that future competitive or other market factors may adversely affect the commercial potential for CTX001; uncertainties regarding the intellectual property protection for CRISPR Therapeutics technology and intellectual property belonging to third parties, and the outcome of proceedings (such as an interference, an opposition or a similar proceeding) involving all or any portion of such intellectual property; and those risks and uncertainties described under the heading "Risk Factors" in CRISPR Therapeutics most recent annual report on Form 10-K, quarterly report on Form 10-Q, and in any other subsequent filings made by CRISPR Therapeutics with the U.S. Securities and Exchange Commission, which are available on the SEC's website at http://www.sec.gov. Existing and prospective investors are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date they are made. CRISPR Therapeutics disclaims any obligation or undertaking to update or revise any forward-looking statements contained in this press release, other than to the extent required by law.

CRISPR THERAPEUTICS word mark and design logo and CTX001 are trademarks and registered trademarks of CRISPR Therapeutics AG. All other trademarks and registered trademarks are the property of their respective owners.

About VertexVertex is a global biotechnology company that invests in scientific innovation to create transformative medicines for people with serious diseases. The company has multiple approved medicines that treat the underlying cause of cystic fibrosis (CF) a rare, life-threatening genetic disease and has several ongoing clinical and research programs in CF. Beyond CF, Vertex has a robust pipeline of investigational small molecule medicines in other serious diseases where it has deep insight into causal human biology, including pain, alpha-1 antitrypsin deficiency and APOL1-mediated kidney diseases. In addition, Vertex has a rapidly expanding pipeline of genetic and cell therapies for diseases such as sickle cell disease, beta thalassemia, Duchenne muscular dystrophy and type 1 diabetes mellitus.

Founded in 1989 in Cambridge, Mass., Vertex's global headquarters is now located in Boston's Innovation District and its international headquarters is in London. Additionally, the company has research and development sites and commercial offices in North America, Europe, Australia and Latin America. Vertex is consistently recognized as one of the industry's top places to work, including 11 consecutive years on Science magazine's Top Employers list and a best place to work for LGBTQ equality by the Human Rights Campaign. For company updates and to learn more about Vertex's history of innovation, visit http://www.vrtx.com or follow us on Facebook, Twitter, LinkedIn, YouTube and Instagram.

Vertex Special Note Regarding Forward-Looking StatementsThis press release contains forward-looking statements as defined in the Private Securities Litigation Reform Act of 1995, including, without limitation, statements regarding the expectations and plans to present data at the annual ASH meeting and exposition, the development, including expected timeline for development, and potential benefits of CTX001, our plans and expectations for our clinical trials and clinical trial sites, and the status of our clinical trials of our product candidates under development by us and our collaborators, including activities at the clinical trial sites and potential outcomes. While Vertex believes the forward-looking statements contained in this press release are accurate, these forward-looking statements represent the company's beliefs only as of the date of this press release and there are a number of risks and uncertainties that could cause actual events or results to differ materially from those expressed or implied by such forward-looking statements. Those risks and uncertainties include, among other things, that data from the company's development programs, including its programs with its collaborators, may not support registration or further development of its compounds due to safety, efficacy or other reasons, and other risks listed under Risk Factors in Vertex's most recent annual report and subsequent quarterly reports filed with the Securities and Exchange Commission and available through the company's website at http://www.vrtx.com. You should not place undue reliance on these statements or the scientific data presented. Vertex disclaims any obligation to update the information contained in this press release as new information becomes available.

(VRTX-GEN)

CRISPR Therapeutics Investor Contact:Susan Kim, +1 617-307-7503susan.kim@crisprtx.com

CRISPR Therapeutics Media Contact:Rachel EidesWCG on behalf of CRISPR+1 617-337-4167reides@wcgworld.com

Vertex Pharmaceuticals IncorporatedInvestors:Michael Partridge, +1 617-341-6108orZach Barber, +1 617-341-6470orBrenda Eustace, +1 617-341-6187

Media:mediainfo@vrtx.comorU.S.: +1 617-341-6992orHeather Nichols: +1 617-839-3607orInternational: +44 20 3204 5275

Originally posted here:
CRISPR/Cas9 Gene-Editing Therapy CTX001 for Severe Hemoglobinopathies Accepted for Plenary Presentation at the 62nd American Society of Hematology...

Petros Grivas, MD, PhD, discusses the phase 3 KEYNOTE-045 trial and the association between gene expression signatures and pembrolizumab in patients with advanced urothelial cancer.

Petros Grivas, MD, PhD, physician, Seattle Cancer Care Alliance; associate professor, Department of Medicine, Division of Oncology, and clinical director, Genitourinary Cancers Program, University of Washington School of Medicine; and associate member, Clinical Research Division, Fred Hutchinson Cancer Center, discusses the phase 3 KEYNOTE-045 trial and the association between gene expression signatures and pembrolizumab (Keytruda) in patients with advanced urothelial cancer.

All the patients receiving pembrolizumab on the KEYNOTE-045 trial appeared to benefit in terms of progression-free survival and overall survival, according to Grivas. There are no biomarkers with clinical utility that can guide selection of which patients should get pembrolizumab or not, based on the data presented the 2020 European Society for Medical Oncology. Therefore, these data show no impact on practice when using pembrolizumab to treat patients with platinum-refractory disease.

Grivas says that the utilization of pembrolizumab based on potential biomarkers needs to be researched further to evaluate the clinical advantage of gene expression signatures. At the moment, patients with platinum-refractory advanced urothelial cancer are all treated able to be treated with pembrolizumab.

Visit link:
Further Research Required to Find Biomarkers for Urothelial Cancer - Targeted Oncology

NEW YORK, Nov. 04, 2020 (GLOBE NEWSWIRE) -- Fortress Biotech, Inc. (NASDAQ: FBIO) (Fortress), an innovative revenue-generating company focused on acquiring, developing and commercializing or monetizing promising biopharmaceutical products and product candidates cost-effectively, today announced that data from two of its clinical programs have been accepted for presentation at the 62nd American Society of Hematology (ASH) Annual Meeting, which is being held virtually from December 5 8, 2020.

Phase 2 data on Caelum Biosciences (Caelum) CAEL-101 for the treatment of relapsed or refractory amyloid light chain AL amyloidosis will be presented by the Cleveland Clinic during oral and poster sessions. CAEL-101, which is being developed in a collaboration between Caelum, a company founded by Fortress, and Alexion Pharmaceuticals, Inc., recently progressed into Phase 3 development. In addition, interim Phase 1/2 data on Mustang Bios (Mustang) MB-106, a CD20-targeted, autologous chimeric antigen receptor (CAR) T cell therapy for patients with relapsed or refractory B-cell non-Hodgkin lymphomas, will be presented by Mustangs research partner Fred Hutchinson Cancer Research Center (Fred Hutch) during a poster session.

Lindsay A. Rosenwald, M.D., Fortress Chairman, President and Chief Executive Officer, said, We are looking forward to data from two of our clinical programs being presented in oral and poster sessions at the ASH Annual Meeting. CAEL-101 and MB-106 are important product candidates that are poised to fill the urgent need for new treatment options and make a meaningful difference for patients.

Details of the presentations are as follows:

CAEL-101 Oral Presentation:

Title: Safety, Tolerability and Efficacy of CAEL-101 in AL Amyloidosis Patients Treated on a Phase 2, Open-Label, Dose Selection Study to Evaluate the Safety and Tolerability of CAEL-101 in Patients with AL AmyloidosisSession: 653. Myeloma/Amyloidosis: Therapy, excluding Transplantation; Novel Approaches for Relapsed/Refractory Myeloma and AmyloidosisAbstract: 729Date and Time: Monday, December 7, 2020, 5:45 p.m. ETPresenter: Jason Valent, M.D., Clinical Assistant Professor of Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University; Staff Department of Hematology and Oncology, Director Multiple Myeloma Program, Taussig Cancer Institute, Co-Director Amyloidosis CenterCleveland Clinic

CAEL-101 Poster Presentation:

Title: CAEL-101 Is Well-Tolerated in AL Amyloidosis Patients Receiving Concomitant Cyclophosphamide-Bortezomib-Dexamethasone (CyborD): A Phase 2 Dose-Finding Study (NCT04304144)Session: 653. Myeloma: Therapy, excluding Transplantation: Poster II Abstract: 2277Date and Time: Sunday, December 6, 2020, 10:00 a.m. - 6:30 p.m. ETPresenter: Jason Valent, M.D., Clinical Assistant Professor of Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University; Staff Department of Hematology and Oncology, Director Multiple Myeloma Program, Taussig Cancer Institute, Co-Director Amyloidosis CenterCleveland Clinic

MB-106 Poster Presentation:

Title: Third Generation CD20 Targeted CAR T-Cell Therapy (MB-106) for Treatment of Patients with Relapsed/Refractory B-Cell Non-Hodgkin LymphomaSession: 704. Immunotherapies: Poster IAbstract: 1443Date and Time: Saturday, December 5, 2020, 10:00 a.m. - 6:30 p.m. ETPresenter: Mazyar Shadman, M.D., M.P.H., Associate Professor, Clinical Research Division, Fred Hutch, Seattle, WA

For more information, please visit the 62nd ASH Annual Meeting and Exposition website at https://www.hematology.org/meetings/annual-meeting/abstracts.

About CAEL-101 (Light Chain Fibril-reactive Monoclonal Antibody for AL Amyloidosis)CAEL-101 is a first-in-class monoclonal antibody (mAb) designed to improve organ function by reducing or eliminating amyloid deposits in the tissues and organs of patients with AL amyloidosis. The antibody is designed to bind to misfolded light chain protein and amyloid and shows binding to both kappa and lambda subtypes. In a Phase 1a/1b study, CAEL-101 demonstrated improved organ function, including cardiac and renal function, in 27 patients with relapsed and refractory AL amyloidosis who had previously not had an organ response to standard of care therapy. CAEL-101 has received Orphan Drug Designation from both the U.S. Food and Drug Administration and European Medicine Agency as a therapy for patients with AL amyloidosis.

About Caelum BiosciencesCaelum Biosciences, Inc. (Caelum) is a clinical-stage biotechnology company developing treatments for rare and life-threatening diseases. Caelums lead asset, CAEL-101, is a novel antibody for the treatment of patients with amyloid light chain (AL) amyloidosis. In 2019, Caelum entered a collaboration agreement with Alexion under which Alexion acquired a minority equity interest in Caelum and an exclusive option to acquire the remaining equity in the company based on Phase 3 CAEL-101 data. Caelum was founded by Fortress Biotech, Inc. (NASDAQ: FBIO). For more information, visitwww.caelumbio.com.

About MB-106 (CD20-targeted CAR T Cell Therapy)CD20 is a membrane-embedded surface molecule which plays a role in the differentiation of B-cells into plasma cells. The CAR T was developed by Mustangs research partner, Fred Hutchinson Cancer Research Center (Fred Hutch), in the laboratory of Oliver Press, M.D., Ph.D., and Brian Till, M.D., in the Clinical Research Division and exclusively licensed to Mustang Bio in 2017. MB-106 has been optimized as a third-generation CAR derived from a fully human antibody and is currently in a Phase 1/2 open-label, dose-escalation trial at Fred Hutch in B-cell non-Hodgkin lymphoma patients. Additional information on the trial can be found at http://www.clinicaltrials.gov using the identifier NCT03277729.

About Mustang BioMustang Bio, Inc. is a clinical-stage biopharmaceutical company focused on translating todays medical breakthroughs in cell and gene therapies into potential cures for hematologic cancers, solid tumors and rare genetic diseases. Mustang aims to acquire rights to these technologies by licensing or otherwise acquiring an ownership interest, to fund research and development, and to outlicense or bring the technologies to market. Mustang has partnered with top medical institutions to advance the development of CAR T therapies across multiple cancers, as well as a lentiviral gene therapy for X-linked severe combined immunodeficiency (XSCID), also known as bubble boy disease. Mustang is registered under the Securities Exchange Act of 1934, as amended, and files periodic reports with the U.S. Securities and Exchange Commission (SEC). Mustang was founded by Fortress Biotech, Inc. (NASDAQ: FBIO). For more information, visit http://www.mustangbio.com.

About Fortress Biotech Fortress Biotech, Inc. (Fortress) is an innovative biopharmaceutical company that was ranked number 10 in Deloittes 2019 Technology Fast 500, an annual ranking of the fastest-growing North American companies in the technology, media, telecommunications, life sciences and energy tech sectors, based on percentage of fiscal year revenue growth over a three-year period. Fortress is focused on acquiring, developing and commercializing high-potential marketed and development-stage drugs and drug candidates. The company has five marketed prescription pharmaceutical products and over 25 programs in development at Fortress, at its majority-owned and majority-controlled partners and at partners it founded and in which it holds significant minority ownership positions. Such product candidates span six large-market areas, including oncology, rare diseases and gene therapy, which allow it to create value for shareholders. Fortress advances its diversified pipeline through a streamlined operating structure that fosters efficient drug development. The Fortress model is driven by a world-class business development team that is focused on leveraging its significant biopharmaceutical industry expertise to further expand the companys portfolio of product opportunities. Fortress has established partnerships with some of the worlds leading academic research institutions and biopharmaceutical companies to maximize each opportunity to its full potential, including Alexion Pharmaceuticals, Inc., AstraZeneca, City of Hope, Fred Hutchinson Cancer Research Center, InvaGen Pharmaceuticals Inc. (a subsidiary of Cipla Limited), St. Jude Childrens Research Hospital and Nationwide Childrens Hospital. For more information, visit http://www.fortressbiotech.com.

Forward-Looking StatementsThis press release may contain forward-looking statements within the meaning of Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934, as amended. As used below and throughout this press release, the words we, us and our may refer to Fortress individually or together with one or more partner companies, as dictated by context. Such statements include, but are not limited to, any statements relating to our growth strategy and product development programs and any other statements that are not historical facts. Forward-looking statements are based on managements current expectations and are subject to risks and uncertainties that could negatively affect our business, operating results, financial condition and stock price. Factors that could cause actual results to differ materially from those currently anticipated include: risks relating to our growth strategy; our ability to obtain, perform under and maintain financing and strategic agreements and relationships; risks relating to the results of research and development activities; uncertainties relating to preclinical and clinical testing; risks relating to the timing of starting and completing clinical trials; our dependence on third-party suppliers; risks relating to the COVID-19 outbreak and its potential impact on our employees and consultants ability to complete work in a timely manner and on our ability to obtain additional financing on favorable terms or at all; our ability to attract, integrate and retain key personnel; the early stage of products under development; our need for substantial additional funds; government regulation; patent and intellectual property matters; competition; as well as other risks described in our SEC filings. We expressly disclaim any obligation or undertaking to release publicly any updates or revisions to any forward-looking statements contained herein to reflect any change in our expectations or any changes in events, conditions or circumstances on which any such statement is based, except as may be required by law, and we claim the protection of the safe harbor for forward-looking statements contained in the Private Securities Litigation Reform Act of 1995. The information contained herein is intended to be reviewed in its totality, and any stipulations, conditions or provisos that apply to a given piece of information in one part of this press release should be read as applying mutatis mutandis to every other instance of such information appearing herein.

Company Contacts:Jaclyn Jaffe and William BegienFortress Biotech, Inc.(781) 652-4500ir@fortressbiotech.com

Investor Relations Contact:Daniel FerryLifeSci Advisors, LLC(617) 430-7576daniel@lifesciadvisors.com

Media Relations Contact:Tony Plohoros6 Degrees(908) 591-2839tplohoros@6degreespr.com

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Fortress Biotech Announces Oral and Poster Data Presentations at the 62nd American Society of Hematology (ASH) Annual Meeting - GlobeNewswire

DetailsCategory: Small MoleculesPublished on Thursday, 05 November 2020 11:36Hits: 152

Patients treated with Lynparza and bevacizumab lived without disease progression for a median of 37.2 months vs. 17.7 months with bevacizumab alone

One in two women with advanced ovarian cancer has an HRD-positive tumour

LONDON, UK I November 5, 2020 I AstraZeneca and MSDs Lynparza (olaparib) has been approved in the European Union (EU) for the 1st-line maintenance treatment with bevacizumab of patients with homologous recombination deficient (HRD)-positive advanced ovarian cancer.

Ovarian cancer is the fifth most common cause of cancer death in the EU and the five-year survival rate is approximately 45%, due partly because women are often diagnosed with advanced disease (Stage III or IV).1-3

The approval by the European Commission was based on a biomarker subgroup analysis of the PAOLA-1 Phase III trial which showed Lynparza, in combination with bevacizumab maintenance treatment, demonstrated a substantial progression-free survival (PFS) improvement versus bevacizumab alone for patients with HRD-positive advanced ovarian cancer. It follows the recommendation for approval by the Committee for Medicinal Products for Human Use of the European Medicines Agency in September 2020.

Isabelle Ray-Coquard, principal investigator of the PAOLA-1 Phase III trial and medical oncologist, Centre Lon Brard and President of the GINECO group, Paris, France, said: For women with advanced ovarian cancer, the goal of 1st-line treatment is to delay disease progression for as long as possible with the intent of achieving long-term remission. Unfortunately, once a patients cancer recurs, it historically has been incurable. Lynparza together with bevacizumab has demonstrated an impressive median progression-free survival benefit of more than three years and is poised to become the standard of care for eligible patients with HRD-positive tumours in the EU.

Dave Fredrickson, Executive Vice President, Oncology Business Unit, said: Half of all newly diagnosed patients with advanced ovarian cancer have HRD-positive tumours. Women treated with Lynparza in combination with bevacizumab in the PAOLA-1 Phase III trial lived progression free for a median of more than three years, showing that HRD testing should be an essential component of clinical diagnosis. HRD status can help physicians select a personalised 1st-line treatment regimen for patients to substantially delay relapse in this devastating disease.

Roy Baynes, Senior Vice President and Head of Global Clinical Development, Chief Medical Officer, MSD Research Laboratories, said: Biomarker testing has rapidly enhanced our understanding of how PARP inhibition can help target this disease. The EU approval reinforces that HRD-positive tumours represent a distinct subset of advanced ovarian cancer and HRD testing is critical for women in this setting.

The PAOLA-1 Phase III trial showed thatLynparza,in combination with bevacizumab maintenance treatment, reduced the risk of disease progression or death by 67% (based on a hazard ratio of 0.33; 95% confidence interval 0.25-0.45). The addition ofLynparzaimproved PFS to a median of 37.2 months versus 17.7 with bevacizumab alone in patients with HRD-positive advanced ovarian cancer. The data from the PAOLA-1 trial was published inThe New England Journal of Medicinein 2019.

Further results recently presented at the European Society for Medical Oncology Virtual Congress 2020 showed a statistically significant improvement in the key secondary endpoint of the time to second disease progression (PFS2). Lynparza with bevacizumab provided benefit beyond first disease progression, improving PFS2 to a median of 50.3 months versus 35.3 with bevacizumab alone.

The full EU indication is for Lynparza in combination with bevacizumab for the maintenance treatment of adult patients with advanced (FIGO Stages III and IV) high-grade epithelial ovarian, fallopian tube or primary peritoneal cancer who are in response (complete or partial) following completion of 1st-line platinum-based chemotherapy in combination with bevacizumab and whose cancer is associated with HRD positive status defined by either a breast cancer susceptibility gene 1/2 (BRCA1/2) mutation and/or genomic instability.

Lynparzain combination with bevacizumab isapproved in the USand in several other countries as a 1st-line maintenance treatment for patients with HRD-positive advanced ovarian cancer and is currently under regulatory review in other countries around the world.

Financial considerations

Following this approval for Lynparza in the EU, AstraZeneca will receive a regulatory milestone payment from MSD of $25m, anticipated to be booked as collaboration revenue during the fourth quarter of 2020.

Ovarian cancer

In 2018, there were nearly 68,000 new cases of ovarian cancer diagnosed in the EU and around 45,000 deaths.3Approximately 50% of ovarian cancers are HRD-positive including BRCA1/2 mutation.4,5Approximately 15% of ovarian cancers have a BRCA1/2 mutation.6 The primary aim of 1st-line treatment is to delay disease progression for as long as possible with the intent to achieve long-term remission.7-9

Homologous recombination deficiency

HRD, which defines a subgroup of ovarian cancer, encompasses a wide range of genetic abnormalities, including BRCA mutations and beyond. As with BRCA gene mutations, HRD interferes with normal cell DNA repair mechanisms and confers sensitivity to PARP inhibitors including Lynparza.10

PAOLA-1

PAOLA-1 is a double-blinded Phase III trial testing the efficacy and safety ofLynparzaadded to standard-of-care bevacizumab versus bevacizumab alone, as a 1st-line maintenance treatment for newly diagnosed advanced FIGO Stage III-IV high-grade serous or endometroid ovarian, fallopian tube, or peritoneal cancer patients who had a complete or partial response to 1st-line treatment with platinum-based chemotherapy and bevacizumab.AstraZeneca and MSD announced in August 2019 that the trial met its primary endpoint of PFS in the overall trial population.

Lynparza

Lynparza (olaparib) is a first-in-class PARP inhibitor and the first targeted treatment to block DNA damage response (DDR) in cells/tumours harbouring a deficiency in homologous recombination repair (HRR), such as mutations in BRCA1 and/or BRCA2. Inhibition of PARP with Lynparza leads to the trapping of PARP bound to DNA single-strand breaks, stalling of replication forks, their collapse and the generation of DNA double-strand breaks and cancer cell death. Lynparza is being tested in a range of PARP-dependent tumour types with defects and dependencies in the DDR pathway.

Lynparza is currently approved in a number of countries, including those in the EU, for the maintenance treatment of platinum-sensitive relapsed ovarian cancer. It is approved in the US, the EU, Japan, China, and several other countries as 1st-line maintenance treatment of BRCA-mutated advanced ovarian cancer following response to platinum-based chemotherapy. It is also approved in the US as a 1st-line maintenance treatment with bevacizumab for patients with HRD-positive advanced ovarian cancer (BRCAm and/or genomic instability). Lynparza is approved in the US, Japan, and a number of other countries for germline BRCA-mutated, HER2-negative, metastatic breast cancer, previously treated with chemotherapy; in the EU, this includes locally advanced breast cancer. It is also approved in the US, the EU and several other countries for the treatment of germline BRCAm metastatic pancreatic cancer. Lynparza is approved in the US for homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (BRCAm and other HRR gene mutations). Regulatory reviews are underway in several countries for ovarian, breast, pancreatic and prostate cancers.

Lynparza, which is being jointly developed and commercialised by AstraZeneca and MSD, has been used to treat over 30,000 patients worldwide. Lynparza has the broadest and most advanced clinical trial development programme of any PARP inhibitor, and AstraZeneca and MSD are working together to understand how it may affect multiple PARP-dependent tumours as a monotherapy and in combination across multiple cancer types. Lynparza is the foundation of AstraZeneca's industry-leading portfolio of potential new medicines targeting DDR mechanisms in cancer cells.

The AstraZeneca and MSD strategic oncology collaboration

In July 2017, AstraZeneca and Merck & Co., Inc., Kenilworth, NJ, US, known as MSD outside the US and Canada, announced a global strategic oncology collaboration to co-develop and co-commercialise Lynparza, the worlds first PARP inhibitor, and Koselugo (selumetinib), a mitogen-activated protein kinase (MEK) inhibitor, for multiple cancer types. Working together, the companies will develop Lynparza and Koselugo in combination with other potential new medicines and as monotherapies. Independently, the companies will develop Lynparza and Koselugo in combination with their respective PD-L1 and PD-1 medicines.

AstraZeneca in oncology

AstraZeneca has a deep-rooted heritage in oncology and offers a quickly growing portfolio ofnew medicines that has the potential to transform patients lives and the Companys future. With seven new medicines launched between 2014 and 2020, and a broad pipelineof small molecules and biologics in development, the Company is committed to advance oncology as a key growth driver for AstraZeneca focused on lung, ovarian, breast and blood cancers.

By harnessing the power of four scientific platforms Immuno-Oncology, Tumour Drivers and Resistance, DNA Damage Response and Antibody Drug Conjugates and by championing the development of personalised combinations, AstraZeneca has the vision to redefine cancer treatment and, one day, eliminate cancer as a cause of death.

AstraZeneca

AstraZeneca (LSE/STO/Nasdaq: AZN) is a global, science-led biopharmaceutical company that focuses on the discovery, development and commercialisation of prescription medicines, primarily for the treatment of diseases in three therapy areas - Oncology, Cardiovascular, Renal & Metabolism, and Respiratory & Immunology. Based in Cambridge, UK, AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. Please visit astrazeneca.com and follow the Company on Twitter @AstraZeneca.

References

1. EuroHealth. (2018). Ovarian Cancer: The Silent Killer. Available at: https://eurohealth.ie/policy-brief-women-and-ovarian-cancer-in-the-eu-2018/ [Accessed October 2020].

2. ECIS. (2020).Estimates of cancer incidence and mortality in 2020, for all cancer sites. Available here [Accessed October 2020].

3. The World Health Organization. IARC. Globocan. (2018). Available at: http://gco.iarc.fr/ [Accessed October 2020].

4. Moschetta et al. (2016). BRCA somatic mutations and epigenetic BRCA modifications in serous ovarian cancer. Annals of Oncology, 27(8), pp.1449-1455.

5. Bonadio et al. (2018). Homologous recombination deficiency in ovarian cancer: a review of its epidemiology and management. Clinics, 73(Suppl 1): e450s.

6. Ramus. (2009). The Contribution of BRCA1 and BRCA2 to Ovarian Cancer. Molecular Oncology, 3(2), pp.138150.

7. Raja et al. (2012). Optimal first-line treatment in ovarian cancer. Annals on Oncology. 23 Suppl 10, x118-127.

8. NHS Choices, Ovarian Cancer Available at: https://www.nhs.uk/conditions/ovarian-cancer/treatment/ [Accessed October 2020].

9. Ledermann et al. (2013). Newly diagnosed and relapsed epithelial ovarian carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncology, 24, pp.vi24-vi32.

10. Moore, K. (2018). Maintenance Olaparib in Patients with Newly Diagnosed Advanced Ovarian Cancer. New England Journal of Medicine, 379(26), pp.2495-2505.

SOURCE: AstraZeneca

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Lynparza approved in the EU as 1st-line maintenance treatment with bevacizumab for HRD-positive advanced ovarian cancer | Small Molecules | News...

Nov. 2, 2020 13:00 UTC

Study shows significant cognitive improvement in domains related to language and caregivers reported improved language and daily functioning

Lead drug candidate continues to be safe and well-tolerated

GRAND RAPIDS, Mich.--(BUSINESS WIRE)-- Tetra Therapeutics, a wholly owned subsidiary of Shionogi & Co. Ltd., today announced positive topline results from its Phase 2 exploratory study in adult patients with Fragile X Syndrome (FXS). The study evaluated its lead candidate, BPN14770, a first-in-class phosphodiesterase4D (PDE4D) allosteric inhibitor. In this single-center, randomized, placebo-controlled, two-way crossover study, BPN14770 demonstrated excellent safety as well as benefits on cognitive function and behavior in 30 patients with FXS.

BPN14770 is a novel therapeutic agent that selectively inhibits phosphodiesterase4D (PDE4D). In preclinical studies, BPN14770 promoted the maturation of connections between neurons, which is impaired in patients with FXS, the most common genetic form of Autism.

We are very excited about the results of this study, said Mark Gurney PhD, Founder and Chief Executive Officer of Tetra. In addition to being safe and well tolerated, treatment with BPN14770 led to significant cognitive improvement, specifically in the language domains, and we also saw a clinically meaningful benefit in overall daily functioning. These findings validate our approach to treating this disease through a mechanism that addresses a core deficit in the disorder. On behalf of the entire Tetra team, I want to sincerely thank the patients, families and investigators who participated in this study as well as the FRAXA Research Foundation, for their assistance in this study.

The Phase 2 clinical trial was a randomized, placebo-controlled, two-way crossover study. Each period was 12 weeks in duration with no washout between periods. The study enrolled 30 adult male subjects age 18-41 years with FXS due to >200 CGG repeats in the FMR1 gene. Subjects received daily oral doses of 25 mg twice a day of BPN14770 or placebo. Parents/caregivers and physician raters were blinded to treatment. Study enrollment occurred between July 9, 2018 and July 31, 2020. All subjects completed both treatment periods, although carryover effects limited the primary statistical analysis to Period 1. The following results, therefore, describe the outcomes for patients who received BPN14770 during Period 1, compared to those who received placebo.

Cognitive assessments using the NIH-Toolbox revealed significant benefit in Oral Reading Recognition (LSMean Difference +2.80, p=0.0157), Picture Vocabulary (+5.79, p=0.0342), and Cognition Crystallized Composite Score (+5.29, p=0.0018). Parent/Caregiver ratings using 100 point Visual Analog Scales revealed benefit that was judged to be clinically significant in Language (LSMean Difference +14.04, p=0.0051) and Daily Functioning (+14.53, p=0.0017). The benefit of BPN14770 was maintained up to 12 weeks after the crossover from drug to placebo. BPN14770 was very well tolerated in the Phase 2 trial with few adverse events.

These results offer hope for Fragile X Syndrome patients and their parents said Dr. Elizabeth Berry-Kravis, pediatric neurologist, Rush University Medical Center, and principal investigator. The preponderance of clinical outcome measures were in favor of the drug. These included performance-based as well as parent and physician-rated scales which suggests a meaningful impact on the global FXS disease process. I find it exciting that we have a drug that potentially addresses a core deficit in FXS, a decrease in cAMP, that has been documented in patients as well as in the fly and mouse models of the disorder.

About the Phase 2 Trial

The Phase 2 clinical trial was a randomized, placebo-controlled, two-way crossover study in 30 adult male patients with FXS, ages 18-45, to assess the safety and efficacy of BPN14770. The study was conducted at Rush University Medical Center, Chicago, Illinois by principal investigator Elizabeth M. Berry-Kravis, M.D., Ph.D. with financial support from the FRAXA Research Foundation. Additional information is available through clinicaltrials.gov (Identifier: NCT03569631).

About BPN14770

BPN14770 is a novel therapeutic agent that selectively inhibits phosphodiesterase-4D (PDE4D) to increase the levels of cAMP, a key signaling molecule, in brain. In preclinical models, BPN14770 promotes the maturation of connections between neurons, which is impaired in patients with Fragile X Syndrome, an indication for which BPN14770 has received Orphan Drug Designation from the U.S. Food and Drug Administration (FDA). This unique mechanism of action has the potential to improve cognitive and memory function in devastating CNS disorders, including FXS, Alzheimer's disease and other dementias, learning/developmental disabilities and schizophrenia. BPN14770 currently is approved for investigational use only by the FDA.

About Tetra Therapeutics

Tetra Therapeutics, a wholly owned subsidiary of Shionogi & Co., Ltd., is a clinical stage biotechnology company developing a portfolio of therapeutic products that will bring clarity of thought to people suffering from Fragile X syndrome, Alzheimers disease, traumatic brain injury, and other brain disorders. Tetra uses structure-guided drug design to discover mechanistically novel, allosteric inhibitors of the phosphodiesterase 4 (PDE4) enzymes, a family of enzymes that play key roles in memory formation, learning, neuroinflammation, and traumatic brain injury. Tetra Therapeutics is headquartered in Grand Rapids, Michigan. For more information, please visit the companys website at http://www.tetratherapeutics.com.

About Shionogi

Shionogi & Co., Ltd. is a major Japanese research-driven pharmaceutical company dedicated to bringing benefits to patients based on its corporate philosophy of supplying the best possible medicine to protect the health and wellbeing of the patients we serve. The company currently markets products in several therapeutic areas including anti-infectives, pain, cardiovascular diseases, and gastroenterology. The Shionogi pipeline is focused on infectious disease, pain, CNS, and oncology. For more information on Shionogi & Co., Ltd., visit https://www.shionogi.com/global/en/.

Forward Looking Statement

This announcement contains forward-looking statements. These statements are based on expectations in light of the information currently available, assumptions that are subject to risks and uncertainties which could cause actual results to differ materially from these statements. Risks and uncertainties include general domestic and international economic conditions such as general industry and market conditions, and changes of interest rate and currency exchange rate. These risks and uncertainties particularly apply with respect to product-related forward-looking statements. Product risks and uncertainties include, but are not limited to, completion and discontinuation of clinical trials; obtaining regulatory approvals; claims and concerns about product safety and efficacy; technological advances; adverse outcome of important litigation; domestic and foreign healthcare reforms and changes of laws and regulations. Also, for existing products, there are manufacturing and marketing risks, which include, but are not limited to, inability to build production capacity to meet demand, unavailability of raw materials and entry of competitive products. The company disclaims any intention or obligation to update or revise any forward-looking statements whether as a result of new information, future events or otherwise.

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Tetra Therapeutics Announces Positive Topline Results from Phase 2 Study of BPN14770 in Patients with Fragile X Syndrome - BioSpace

(UroToday.com)Application of immune checkpoint inhibitor (ICI) therapy has seen significant progress in the last few years. Agents targeting programmed cell death protein 1 (PD-1) and its ligand PD-L1 have shown activity in locally advanced and metastatic urothelial carcinoma in the first- and second-line setting.1,2 However, a significant proportion of patients still perform poorly after receiving these therapies as their disease progresses rapidly.

In his keynote presentation at the 2020International Bladder Cancer Network (IBCN) Annual Meeting, Dr. Dan Theodorescu challenged the audience to seek alternative approaches to tackle this problem. He suggested that this may be addressed by either discovery of new therapies, or using novel modalities to enhance the effect of current ICI therapies. His research group has, more recently, focused on the latter approach.

While the idea of combination therapy has been successfully applied for chemotherapeutic regimens, an existing problem is that agnostic drug combinations could result in the need for far too many dual-drug clinical trials that would just not be feasible in the current environment. He, therefore, pointed out that an urgent need, therefore, is to rationally choose drugs that would be potentially optimal combinations with immune checkpoint inhibitors. The underlying goal of his groups current investigations is to identify molecular pathways that allow cancer growth while on ICI, and identify drugs that can target such pathways to enhance ICI response (Figure 1). His group has employed functional genomics to identify such lethal combinations.

Figure 1: Using functional genomics to identify rational combinations with ICI.

He elaborated on the technique for the construction of such functional genomic druggable libraries, wherein gene targets of drugs used in clinical trials for bladder cancer were identified, and five shRNAs per gene were constructed as part of a lentiviral library that were used to infect murine bladder cancer cells. The best performing shRNAs were selected as models for inhibiting the respective pathways and used to test in combination with ICI therapy. Using this approach, and in combination with anti PD-1 therapies, tumors that were resistant to the latter therapy were profiled using next-generation sequencing to identify pathways of ICI escape (Figure 2).

Figure 2: Identifying synthetic lethal combinations with anti PD-1

These investigations identified DDR2 and CCL2 alterations as key escape mechanisms. The DDR2 gene encodes for discoidin domain-containing receptor 2, a receptor tyrosine kinase that can be targeted by dasatinib.3 His group, therefore, proceeded to characterize DDR2 alterations in the context of ICI therapy in bladder cancer.4 Their analysis of published bladder cancer genomic profiling data indicated that patients with high DDR2 were associated with worse survival in four independent cohorts. When bladder cancer cells were transduced with DDR2 shRNAs in vitro, this resulted in appropriate reduction in protein levels (Figure 3). In the presence of anti PID-1, there was a significant reduction in subcutaneous tumor growth in syngeneic mice with bladder tumors that also stably expressed shDDR2, indicating a synergistic response. A similar response was also observed in melanoma and breast cancer in vivo models.

Figure 3: Effect of DDR2 depletion on anti PD-1 response.

RNA from mice bearing shControl and shDDR2-transduced bladder tumors treated with antiPD-1 were analyzed using RNAseq followed by gene set enrichment analysis. This revealed a strong immune response in the shDDR2 tumors treated with anti-PD-1 when compared with controls. Cytometry by time-of-flight analysis of these tumors revealed increased CD8+ T cell infiltration into shDDR2 tumors treated with anti-PD-1, which was not seen in the spleen. These observations suggested a strong T cell presence following the treatment of shDDR2-treated tumors with anti-PD-1.

To further evaluate the efficacy of targeting DDR2, the combination of dasatinib and anti-PD-1 was tested. Whereas therapeutic blockade of PD-1 or DDR2 alone had little or no effect on murine bladder tumors, treatment with the combination of dasatinib and anti-PD-1 showed a significant reduction in tumor burden (Figure 4). Similar results were seen within vivo colon cancer and sarcoma models.

Figure 4: Effect of dasatinib on PD-1 response.

Similar studies of synthetic lethal combinations of anti-PD-1 with CCL2 inhibitors are now underway in Dr. Theodorescus lab. Unpublished data from his group indicates that the combination of CCL2 depletion with anti-PD-1 has a significant effect in metastatic melanoma. The data indicate there may be potential benefits in considering triple-drug combinations that target DDR2, CCL2 and PD-1.

In closing, Dr. Theodorescu highlighted recent developing results from a Phase II trial of sitravatinib, a multi-receptor tyrosine kinase inhibitor in combination with nivolumab that is indicating encouraging clinical activity in checkpoint inhibitor nave, platinum-experienced patients with advanced or metastatic urothelial carcinoma.5 The combination with data generated from his lab and early trial results suggest that there is merit in the addition of targeted therapeutics with ICI for treatment of advanced bladder cancer.

Presented by: Dan Theodorescu, MD, Ph.D., Director of the Cedar-Sinai Cancer Center, Phase ONE Distinguished Endowed Chair in Cancer Research, Professor of the Departments of Surgery, Pathology and Laboratory Medicine, Cedars-Sinai Health System, Los Angeles, CA, USA.

References:1. Powles T, et al. Efficacy and safety of durvalumab in locally advanced or metastatic urothelial carcinoma: Updated results from a phase 1/2 open-label study. JAMA Oncol 2017;3(9):e172411.2. Sharma P, et al. Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial. Lancet Oncol 2017;18(3):312-322.3. Carafoli F, Hohenester E. Collagen recognition and transmembrane signalling by discoidin domain receptors. Biochim Biophys Acta 2013;183:2187-94.4. Tu MM, et al. Targeting DDR2 enhances tumor response to anti-PD-1 immunotherapy. Sci Adv 2019;5(2):eaav2437.5. Msaouel P, et al. 705MO Sitravatinib (sitra) in combination with nivolumab (nivo) demonstrates clinical activity in checkpoint inhibitor (CPI) nave, platinum-experienced patients (pts) with advanced or metastatic urothelial carcinoma (UC). Annals Oncol 2020;31(4):S556.

Written by:Anirban P. Mitra, MD, Ph.D., Urologic Oncology Fellow, The University of Texas MD Anderson Cancer Center, Houston, TX, USA, Twitter: @APMitra, with Ashish M. Kamat, MD, MBBS, President of IBCN and IBCG, Endowed Professor, The University of Texas MD Anderson Cancer Center, Houston, TX, USA, Twitter:@UroDocAsh,at the International Bladder Cancer Network (IBCN) Annual Meeting, #IBCN2020, October 17, 2020.

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IBCN 2020: Improving Immune Checkpoint Inhibitor Therapy In Cancer - UroToday

(UroToday.com) While cisplatin-based chemotherapy is a mainstay for neoadjuvant and adjuvant treatment of patients with muscle-invasive bladder cancer (MIBC), and none of the reported biomarkers for predicting response have been implemented in the clinic thus far.

Dr. Ann Taber presented data from researchers at the Aarhus University Hospital, Denmark, where they performed comprehensive genomic, transcriptomic, epigenomic, and proteomic analysis of 300 MIBC patients treated with cisplatin-based chemotherapy to identify molecular changes associated with treatment response. Based on mutational signatures, they identified two patient groups: those characterized by mutations in a tri-nucleotide signature 5 context (SBS5) that are related to ERCC2 mutations, and those related to APOBEC mutations.

Expression data identified the basal/squamous gene expression subtype to be associated with poor cisplatin-based treatment response. Immune cell infiltration and high PD-1 protein expression was also significantly associated with treatment response; they identified a unique subset that corresponds to an immune desert, which was associated with poor treatment response (Figure 1).

Figure 1: Association of immune cell infiltration and cisplatin-based treatment response.

The authors then assigned patients to high and low genomic instability groups based on SBS5 mutations, indels, allelic imbalance and BRCA2 mutation status. Patients with high genomic instability had a response rate of 71% versus 49% for patients with low genomic instability (p = 0.007). Through further integration, they identified a group of patients with a very high response rate (80%) characterized by high genomic instability and non-basal/squamous gene expression subtype and a group of patients with a very low response rate (25%) characterized by low genomic instability and basal/squamous gene expression subtype (p<0.001, Figure 2).

Figure 2: Patient subclassification based on genomic instability and basal/squamous gene expression subtype.

The results highlight several molecular correlates of chemotherapy response. These findings are now the basis of a new clinical trial for the treatment of metastatic bladder cancer following radical cystectomy.1

Presented by: Ann Taber, Ph.D., Department of Molecular Medicine (MOMA), Aarhus University Hospital, Denmark.

Written by:Anirban P. Mitra, MD, Ph.D., Urologic Oncology Fellow, The University of Texas MD Anderson Cancer Center, Houston, TX, USA, Twitter: @APMitra, with Ashish M. Kamat, MD, MBBS, President of IBCN and IBCG, Endowed Professor, The University of Texas MD Anderson Cancer Center, Houston, TX, USA, Twitter:@UroDocAsh,at the International Bladder Cancer Network (IBCN) Annual Meeting, #IBCN2020, October 17, 2020.

References:1. Treatment Of Metastatic Bladder Cancer at the Time Of Biochemical reLApse Following Radical Cystectomy (TOMBOLA). ClinicalTrials.gov identifier NCT04138628.

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IBCN 2020: IBCN 2020: Molecular Correlates of Cisplatin-Based Chemotherapy Response In Muscle-Invasive Blad... - UroToday

Dive Brief:

Biogen is at a crossroads, awaiting a regulatory decision on the Alzheimer's drug aducanumab by early March that will have wide-ranging implications for the biotech's future.

But while aducanumab's fate hangs in the balance, Biogen has been stocking up on other early-stage assets, aiming to diversify its portfolio beyond risky neuroscience bets. Company executives in 2019 said they were putting more emphasis on ophthalmology and immunology, for instance, and that same year, the company spent $800 million on an acquisition of the eye gene therapy company Nightstar Therapeutics.

ViGeneron offers a novel technology for harnessing adeno-associated virus vectors to treat eye disease. Its vgAAV vectors are designed to get around some of the limits of the standard gene therapy delivery tools and target a variety of different cell types. The two companies noted the technology's potential to more efficiently transduce retinal cells via eye injections, which in theory could lead to more potent treatments.

The company is still fairly new, however, having being spun off in 2017 by Ludwig-Maximilians University in Munich. Its investors include WuXi AppTec and Sequoia Capital China. None of its experimental treatments, led by a gene therapy for retinitis pigmentosa, are in human testing.

The deal is another bet by Biogen on genetic medicine. Earlier this year, the biotech formed a gene editing alliance with Sangamo Therapeutics that could be worth billions of dollars.

Still, investors at the moment are most focused on aducanumab. The roller coaster ride for the drug began in March 2019, when the drug appeared to have failed two clinical trials. Seven months later, however, the company said a further analysis showed significant benefits for a high dose in one clinical trial, and the Food and Drug Administration agreed to review the medicine.

In November 2020, the FDA convened a panel of outside experts, whose review was overwhelmingly negative. Panelists criticized the agency for being too optimistic about Biogen's data and voted near-unanimously against approving the drug.

The committee's vote isn't binding for the FDA, though the agency typically follows its advice. Regulators are due to make their final decision on aducanumab by March 7.

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Biogen pushes further into eye gene therapy with new deal - BioPharma Dive

Key Message

Chronic kidney disease (CKD) has a global prevalence of 816%, with serious morbidity and mortality.1 CKD is a direct risk factor for cardiovascular diseases, end-stage renal disease (ESRD)/CRF, and mortality.2 While replacement therapy with regular dialysis represents a temporary solution, renal transplantation is the permanent solution.3 Anaemia is one of the most important CRF complications, which develops early and worsens during the long-term progression of the disease.4 Coresh et al showed the association between lower Hb levels, the severity of anaemia and kidney function reduction.5 Erythropoietin (Epo), iron therapy, and continuous patient response monitoring provide a good tool for treating CKD-associated anaemia6 that helps to minimize transfusions and improve CKD patient survival.7 Although the response to rHuEpo is mostly good, resistance to Epo therapy among these cases ranges from 10% to 20%.8

Many factors may affect patients responses to replacement therapy with rHuEPO, including genetic factors, eg, ACE gene polymorphism that has an important impact on hematopoiesis. ACE gene is located at 17q23. It contains 26 exons and 25 introns.9 It has several single-nucleotide polymorphisms (SNPs). ACE G2350A (rs4343) SNP is located in exon 17 of the ACE gene and results in silent Thr 776 Thr (NP_000780.1) change. ACE gene SNPs may affect the patients response to Epo and could be useful genetic markers in assessing the required dose of Epo in such patients.10 ACE SNPs effect on CKD response to Epo therapy was evaluated with conflicting results. Varagunam et al reported a predictive role for it in determining Epo dosage in continuous ambulatory peritoneal dialysis English patients,11 while in another study in Korean HD patients, it was found to be associated with Epo resistance.10 ACE G2350A (RS4343) was selected for the present study based on a genome-wide-analysis study that reported the ACE G2350A (RS4343) is a good predictor of ACE activity12 due to the absence of wide genomic mapping in Arabian Countries, so our hypothesis that it may affect HD patients response to rHuEPO.

Although it was investigated concerning other clinical conditions, to the best of our knowledge, none of the international reports studied the effect of ACE G2350A (RS4343) gene polymorphisms on haematological markers of response to rHuEpo in CRF patients on HD. The current study aims to study the effect of ACE G2350A (RS4343) I/D gene polymorphisms on the response to rHuEpo, anaemia biomarkers, ACE content, inflammatory biomarkers, serum Epo and soluble Epo receptor (sEpoR) among CRF patients on HD.

Observational cross-sectional study.

Nephrology department and Biochemistry and molecular biology department, faculty of medicine, Cairo University.

Our cross-sectional study enrolled 256 CRF patients on HD for six months receiving rHuEpo therapy. They included 162 males and 103 females and aged 51.3 11.9 years. They were recruited from the nephrology unit, Internal Medicine Department, Cairo University, Cairo, Egypt, from April 2019 to June 2020. Matching 160 normal healthy control subjects were recruited from those accompanying outpatients and comprised 122 males and 38 females ageing 36.1 12.8 years (Table 1). Each participant had a five-minute interview to discuss the current studys objectives and aims before signing the informed consent and enrollment.

Table 1 General Characteristics and Laboratories of HD Patients versus Controls

Patients excluded from the study if age 18 years, acute renal failure, non-CKD-related anaemia, recent blood transfusion within the previous three months, a history of hepatitis B (HBV) or C (HCV) or HIV or other active acute or chronic infections, decompensated liver cirrhosis, pregnancy, and malignancy.

10 mL peripheral venous blood was collected on heparin. The recovered plasma by centrifugation (1000 x g for 10 min at 4 C) was aliquot stored at 40 C till used for assessment of ferritin, Transferrin (TF), soluble transferrin receptor (sTfR), EPO, sEpoR, ACE, and cytokines (IL-1, IL-6, and IL-10) content, iron workup (iron and total iron-binding capacity; TIBC). Iron (g/dL) and TIBC (g/dL) were assayed using colorimetric kits (Stanbio Laboratory, Boerne, TX, USA). Transferrin saturation (%) was calculated from iron and TIBC. Plasma proteins and cytokines were assayed using specific quantitative commercially available ELISA kits as instructed; ferritin in ng/mL and sTfR in nmol/L (Diagnostic Automation/Cortez Diagnostics Inc, CA, USA; cat#1601-16 and 3126-15), TF in mg/dL (Abcam, Cambridge, MA, USA, USA cat#ab187391), ACE in ng/mL and sEpoR in ng/mL (MyBioSource, Inc., San Diego, CA, USA; cat#MBS494753 and MBS702997), IL-1, IL-6, and IL-10 in pg/mL (RayBiotech, Inc., Peachtree Corners, GA, USA; cat# ELH-IL1b, ELH-IL6, and ELH-IL10), and Epo in mIU/mL (BioVision, Inc., Milpitas, CA, USA; cat# E4720-100). An aliquot of whole blood was also used to assess Hb, TLC count using a cell counter (Sysmex XT-4000i Automated Haematology Analyzer Lincolnshire, IL, USA). Hb level was measured in the 6th month three times, one week apart, the mean of these three readings was recorded. Half of the whole blood sample collected was used for genomic DNA extraction and real-time PCR analysis of ACE genes polymorphism.

Total DNA was isolated from whole blood mononuclear cells (MNC) using the extraction kit (Zymo Research, Irvine, CA, USA; cat# D302 Quick-DNA Microprep Kit) instructed. The DNA purity (A260/A280 ratio) and concentration were assessed spectrophotometrically (dual-wavelength Beckman, Spectrophotometer, USA). GAPDH house-keeping gene was assessed in all PCR reactions as an internal control and for DNA integrity. The extracted and purified DNA samples were stored at 80 C till used. ACE polymorphism genotyping and allelic discrimination was assessed using TaqMan Analysis. DNA was genotyped for ACE G/A at rs4343. PCRs were carried out in reaction volumes of 25 L containing 50 ng DNA, 10 L TaqMan Universal PCR Master Mix (Applied Biosystems, ThermoFisher Scientific Inc., Waltham, MA, USA) with the passive reference ROX (Perkin Elmer), 280 nmol/L of each primer and 200 nmol/L VIC-labeled probes for ACE G > A. Primers and minor groove binder probes were synthesized by Applied Biosystems. The primer sequence was forward: 5-GTGAGCTAAGGGCTGGA-3 and reverse: 5-CCAGCCCTCCCATGCCCATAA-3. PCR thermal cycler conditions included an initial incubation at 50 C for 2 minutes, 95 C for 10 minutes, followed by 35 cycles of 15 seconds at 92 C and 1 minute at 6062 C. Allele discrimination was accomplished by running endpoint detection using the StepOne and SDS 2.0 software. ACE AA = ACE Insertion/Insertion (I/I), ACE GA = ACE Insertion/Deletion (I/D) while ACE GG = ACE Deletion/Deletion (D/D).

Data were collected, tabulated, and analyzed using SPSS version 21 (IBM SPSS Statistics for Windows, Armonk, NY: IBM Corp). Deviation of genotype frequencies of the studied group of patients from Hardy-Weinberg equilibrium (HWE) was assessed by Chi-squared test with one degree of freedom (df) using the Michael H. Courts (20052008) calculator.13 If P 0.05, then the population is in HWE. For categorical data like gender was presented as frequency and percentage. Scale data like age, haematological parameters were presented as mean Standard Error of Mean (SEM). ShapiroWilk test was applied to determine the distribution of data. Chi-square test/ Fischer exact test was applied to measure the difference among categories. Independent samples t-test was used to measure the mean difference across two categories. Levenes test was applied to ascertain equal variance among the groups. One-way ANOVA with LSD posthoc analysis was applied to determine the difference in scale data among more than two categories. Correlations between ACE level and haematological parameters were using Pearsons correlation coefficient. The stepwise regression test was used to determine the independent parameters that may affect Hb or Hct values. A p-value < 0.05 was considered significant.

The current study protocol was approved by the Bioethics Committee, Medical College, Cairo University (Approval Number CU III F 40 20) and conducted following the Helsinki declaration.

Comparing HD patients vs healthy controls showed significant differences in plasma potassium, urea, creatinine, iron, TIBC, % TF Saturation, TF, sTfR, Hb, Hct, TLC, platelets count IL-6, IL-10 and IL-1, EPO, ACE and sEpoR (Table 1).

The prevalence of ACE G2350A (rs4343) I/D genotype among HD patients and healthy controls showed that the I/D genotype is the most prevalent while the I/I genotype is the least one. ACE G2350A (rs4343) I/D genotype distribution showed a significant difference in the gene allele distribution between HD patients compared to normal controls: I/D (n = 174 vs 85), I/I (n = 41 vs 6) and D/D (n = 50 vs 69) (p = 0.001). D allele is the most prevalent one either in HD patients (0.52) or among the control group (0.7) (Table 2).

Table 2 Patients and Control Group ACE Rs4343 Genotype and Allele Distributions

The mean Hb was highest in D/D genotype patients (11.120.19), followed by I/I (11.110.2) n I/D (10.470.1).

The effect of ACE G2350A (rs4343) genotypes on different parameters among CRF patients was evaluated using one-way ANOVA; a significant difference between the three categories was found, F= 5.9, P=0.003. Differences were significant between I/I and I/D genotype (mean difference=.63, P = 0.012), D/D and I/D genotype (mean difference =.65, P = 0.005). no significant difference was noted between I/I and D/D (P=0.956) Table 3.

Table 3 Comparison of Hb & Serum Iron in Different HD Patient Genotypes of ACE Gene Rs4343

The mean serum iron was highest in I/D genotype patients (44.53 .87), followed by I/I (40.951.3 n DD (40.61.05). A one-way ANOVA found a significant difference between three categories, F= 4.062, P=0.018. Differences were significant between I/D and II (mean difference=3.58. P =0.045), I/D and D/D (mean difference=3.93, P =0.018). I/I and D/D had not shown a significant difference (P= 0.871) Table 3.

There were insignificant differences among patients with I/I, D/D, or I/D genotypes regarding TLC (Figure 1A) or the inflammatory biomarkers (IL-6, IL-10, and IL-1) (Figure 1B).

Figure 1 Comparison of WBC (A), IL6 & IL10 & IL1 (B) regarding the ACE G2350A (rs4343) genotypes. Data presented as mean SEM. Evaluated by ANOVA test followed by LSD as a post hoc.

Figure 2 Comparison of Transferrin Saturation or sTfR (soluble transferrin receptor) (A), TIBC (Total Iron Binding Capacity), ferritin, and Transferrin (B) regarding the ACE G2350A (rs4343) genotypes. Data presented as mean SEM. Evaluated by ANOVA test followed by LSD as a post hoc.

There were insignificant differences among patients with I/I, D/D, or I/D genotypes regarding % TF Saturation and sTfR (Figure 2A), TIBC, Ferritin, or TF level (Figure 2B).

Figure 3 Comparison of Epo (erythropoietin), ACE (angiotensin-converting enzyme) and sEpoR (Soluble erythropoietin receptors) regarding the ACE G2350A (rs4343) genotypes. Data presented as mean SEM. Evaluated by ANOVA test followed by LSD as a post hoc.

The effect of ACE G2350A (rs4343) genotypes on levels of ACE, EPO, and sEpoR levels was evaluated among CRF patients. Our results showed insignificant differences between patients with different genotypes in that regard (Figure 3).

The D allele is the most prevalent allele among patients in the current study (Table 2). Analysis of the genotype correlation in a recessive mode of inheritance of the risk of D allele between Non-DD (II+ID) vs (DD) was done using an independent t-test. Our results showed a significant difference between the two groups regarding iron status (43.9.7, 40.61.1, respectively, F: 6.946, t: 2.529, CI: 0.7019:5.8004, P=0.013) and Hb level (10.6.1, 11.1.19, respectively, F: 0.261, t: 2.308, CI: 0.9797:0.0776, P=0.013) (Table 4).

Table 4 Comparison of Different Parameters Between Non-DD (ID+II) and DD Genotype Among HD Patients

Using Pearsons correlation coefficient, the correlation between the ACE level and haematological parameters among HD patients showed a significant positive correlation between the ACE level and Epo (r: 0.244, P=0.0001) and a significant negative correlation between the ACE level and HCT (r: 0.131, P=0.033) (Table 5).

Table 5 Correlations Between ACE Level and Haematological Parameters Using Pearsons Correlation Coefficient

Linear regression analysis revealed that among all parameters tested, ACE G2350A (rs4343) (R.194, P=0.001), TLC (R 0.282, P=0.001), and sEpoR (R 0.312, P=0.024) were independent predictors of Hb level (Table 6). While the ACE content (R. 0.292, P= 0.017), TLC (R. 0.255, P=0.015), and iron (R 0.209, P=0.001) were independent predictors of the Hct level (Table 7).

Table 6 Hb Stepwise Regression Test

Table 7 HCT Stepwise Regression Test

The current study is the first report that studied the effect of ACE G2350A (rs4343) gene polymorphism on the haematological indicators of response to rHuEpo therapy. It is well-established that genetic factors play an essential role in determining the efficacy and response to drug treatment.14 Pharmacogenomics analyses such relationships towards the personalization of medicine. Our lab showed the importance of such an approach in predicting the patients response to different drug therapy.15,16

The present study showed that HD patients with the ACE G2350A (rs4343) D/D and I/I genotype respond better to rHuEpo therapy than those with the I/D genotype as evidenced by the higher Hb level among the former group. This higher Hb level among D/D and I/I genotypes were not related to iron level. Our results showed that patients with the I/D allele had higher iron than patients with each of the D/D and I/I genotypes, despite the lower Hb level of the I/D allele holders. The better Hb response was recently partially reasoned to higher plasma angiotensin II (Ang II) levels in D/D and I/D genotypes compared to the II genotype.17

Ang II is the main effector member of the renin-angiotensin system acting through the AT1 receptor and is generated from Ang. I by an ACE-induced proteolytic cleavage.18 The Renin-angiotensin system plays a vital role in hematopoiesis and other diseases.19,20 However, the exact mechanism by which ACE may affect erythropoiesis and Hb level is still not well elucidated. Among the other plausible explanations is ACE inhibition of Ang IIinduced Epo release and prevention of the induction of pluripotent hematopoietic stem cells.21 ACE directs stem cell differentiation to erythroid progenitors synthesis.22 ACE may affect the Ang II level, directly increasing erythroid progenitors in vitro proliferation.23

Savin et al showed that the ACE D/D genotype is associated with higher Hb levels.24 Patients with the D/D genotype were shown to require less Epo dose than the I/I genotype.11

In a study that included 112 ambulatory peritoneal dialysis patients, Sharples et al25 showed that the ACE DD genotype requires less rHuEpo than other ACE genotypes, I/I or I/D. This result seems to be in line with our conclusion, albeit we could not identify the exact ACE SNPs that Sharples and his colleagues had examined. Similarly, Hatano et al26 showed that HD patients with D/D-allele require low rHuEPO.

The ACE rs4646994 D/D genotype was associated with a poor response to rHuEpo in HD Korean patients, suggesting that it could be a useful genetic tool in predicting Epo requirement and responsiveness in HD patients.10 Kiss et al,27 working on Hungarian and Al-Radeef et al,28 working on Iraqi HD patients, reported that ACE polymorphism had a non-significant effect on the Hb level. These variations may arise from the exact SNPs tested; we explored the ACE G2350A (rs4343) effect while they examined rs1799752 and rs4646994, respectively. Also, the small sample size of these studies compared to ours might have affected their conclusions.

Our results showed a higher iron store among the heterozygous ID genotype than II or DD genotype patients assuming a heterozygous advantage for the ACE G2350A (rs4343) ID genotype among HD patients included in the present study.

Heterozygote advantage or overdominant refers to better fitness of heterozygous genotype patients over both homozygous. It firstly appeared in 1922 to maintain polymorphism stability.29 Major histocompatibility complex (MHC) gene represent one of the prominent examples for the heterozygote advantage, in which MHC heterozygotes genetic diversity is abundant. Heterozygote genotype patients have better recognition of pathogen antigen and resist infections effectively than homozygous.30,31 Heterozygote advantage provides a protective effect against malaria for the sickle-cell anaemia allele carriers.32

Recently, A genome-wide association study revealed that heterozygous individuals were significantly healthy-aged compared to other individuals with other genotypes. Moreover, in the same age group population, a 10-year higher survival was associated with individuals with higher heterozygosity rates; the association is more likely to be explained by heterozygote advantage.33 Previous observations noted heterozygous advantages on ACE genotype patients among cardiovascular diseases; because of high linkage disequilibrium (LD) between the polymorphisms, ACE haplotypes needed to be determined in different populations with different evolutionary histories search for additional ancestral breakpoints. The phenotypes complexity also includes the possibility of multiple interactions between genes or genes and environmental factors. The high frequency of I/D, ie, 56.61%, could be because of heterozygote advantages against the two homozygotes D/D and I/I in cardiovascular diseases9 and kidney diseases; individuals with I/D genotype have the least levels of ACE. The DD genotype has the highest levels, followed by I/I34 or having lower plasma ACE levels,35 although these studies may differ from our study in its design, ethnicity, and allele distributions.

A 287-bp insertion/deletion (I/D) polymorphism in intron 16 of the ACE gene (17q22-q24, 26 exons, and 25 introns) in humans may control serum ACE levels. Many SNPs in linkage disequilibrium (LD) with the I/D polymorphism, including T5941C, A262T, T93C, T1237C, C4656T, and A11860G (rs 4343; exon 16),36,37 are known to influence serum ACE.38

Furthermore, rs1799752 is one of four SNPs that may be the most well-studied ACE SNP. It is an insertion/deletion of an Alu repetitive element in an ACE genes intron rather than a single nucleotide polymorphism.

ACE G2350A (rs4343) gene polymorphism is associated with increased ACE enzyme activity in physiological and pathological states.39 It increases ACE levels in subjects with a high-saturated-fat diet that enhances diet-dependent hypertension.40

Our data showed insignificant differences among the tested three ACE G2350A (rs4343) I/I, I/D, and D/D genotypes regarding the circulating ACE protein content. On the contrary, Mizuiri et al and Elshamaa et al demonstrated an opposite conclusion. ACE I/D genotype is associated with renal ACE gene expression in healthy Japanese subjects41 and plasma and tissue ACE levels.42 Nand et al showed D allele positively affects ACE serum level.43

Endogenous or rHuEpo binds to EPOr resulting in stimulation of erythropoiesis.44 sEpoR is generated from mRNA alternative splicing, and since it lacks the transmembrane domain, it is released into extracellular fluids. sEpoR buffers rHuEpo because of its high affinity to EPO; therefore, it acts as a potent antagonist to EPO, resulting in decreased response to rHuEpo treatment. sEpoR high level was correlated to a high need for rHuEpo dose.45,46

In the current work, there was an insignificant difference between ACE G2350A (rs4343) I/I, I/D, or D/D genotypes regarding plasma Epo and sEpoR content in the present study. This notion contradicts the finding of Al-Radeef et al, who showed that another rs1799752 I/D and D/D genotypes had a higher serum Epo level compared to the I/I genotype.28

Our patients were free of active infection, and the measured proinflammatory cytokine levels, IL-6, IL-1, and IL-10, were insignificant differences among the three ACE G2350A (rs4343) genotypes; I/I, I/D, or DD.

Increases in the inflammatory mediator, such as IL-6 and TNF-, lead to increases in the sEpoR level that would hinder erythropoiesis.46 sEpoR stabilizes proinflammatory cytokine ligand and modulates cytokine interaction to its membrane-bound receptor, leading to variation in its concentration.47 Inflammatory cytokines accompanying CRF and HD decrease rHuEpo efficacy. TNF-, IL-1, and IL-6 induce resistance against rHuEpo in erythroid progenitor cells reducing iron release from the reticuloendothelial system and decreasing Hb production.48,49 Betjes et al reported a lack of response to rHuEpo among CKD patients with cytomegalovirus infection mainly due to IFN- and TNF- production.50

Although our HD patients showed higher levels of % TF saturation and sTfR, TIBC, Ferritin, or TF, there were insignificant differences among patients with I/I, D/D, and I/D genotypes regarding these parameters.

Various tissues obtain their iron need via TF binding to its receptor, endocytosis of the complex, and iron download.51,52 The expression rate of the cell surface TF receptor is directly proportional to its iron need.53 The transmembrane glycoprotein TF receptor is formed of two disulfide-linked monomers; each polypeptide subunit comprises three major domains: a large C-terminal extracellular domain and a transmembrane and an N-terminal cytoplasmic domain. sTfR is the cleaved extracellular domain of the high-affinity iron-sensor TF receptor released soluble in extracellular fluids. Circulating levels of sTfR reflect the number of cells with receptors (erythropoietic activity) and the receptor density on cells (tissue iron status).54 Ferritin is used for diagnosing iron deficiency anaemia, but it could be falsely elevated in inflammation giving the erroneous impression of normal iron stores.55 sTfR is insensitive to inflammatory states and inflammatory biomarkers. It could detect anaemia even in subjects with the inflammatory condition; moreover, it could differentiate between anaemia due to iron deficiency or chronic diseases.56

Finally, we tested for independent factors that may affect the patients response to rHuEPO. Among all parameters tested, ACE protein level, TLC, and sEpoR were the independent predictors of Hb level. Simultaneously, ACE protein content, TLC, and iron are the independent predictors for the Hct level.

Previous works measured Hb level at the beginning, 3rd, and 6th months of treatment with rHuEpo [24, 28]. In the present study, we measured the Hb level after six months of the treatment with rHuEpo to allow more precision and avoid fluctuation of patient response to treatment. We took the mean of the three Hb levels in the 6th month. We could not retrieve accurate data considering the use of ACE inhibitors (ACEIs) or ARBs among our patients. We measured circulating ACE level as a protein rather than an activity that revealed insignificant differences among the three genotypes assessed to avoid any related confusion. We did not evaluate angiotensin II (Ang II) level in the current study and iron intake status, but we estimate Hct, iron, ferritin, TF, % TF saturation, sTfR, and TIBC. Many other ACE gene SNPs may affect the HD patients response to rHuEPOs as rs1799752, rs429, and rs4341 which may be in linkage disequilibrium with studied rs4343; however, the only studied here is the ACE G2350A (rs4343). These limitations of the current study are highly acknowledged and will be considered in our future studies.

Patients with either ACE G2350A (rs4343) I/I or D/D genotype showed better response to rHuEpo than those with I/D genotype. ACE protein content, TLC, and sEpoR may represent independent predictors for the HD patients response to rHuEPOs. Screening for ACE G2350A (rs4343) gene polymorphisms in the HD patients on HD before rHuEpo administration may predict patients response.

This project was funded by The Deanship for Scientific Research, Jouf University, Sakaka, Saudi Arabia (Grant # 40/345). The authors express their deepest thanks to Prof. Dr Dina Sabry (The Molecular Biology Lab, Faculty of Medicine, Cairo University, Cairo, Egypt) for facilitating the gene analysis and biochemical investigations.

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

The authors stated that they have no conflicts of interest for this work.

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Haematological Indicators of Response to Erythropoietin Therapy in Chr | PGPM - Dove Medical Press

PITTSBURGH, May 25, 2021 (GLOBE NEWSWIRE) -- NeuBase Therapeutics, Inc. (Nasdaq: NBSE) ("NeuBase" or the "Company"), a biotechnology company accelerating the genetic revolution using a new class of precision genetic medicines, today announced the appointment of Kia Motesharei, Ph.D., as Chief Business and Strategy Officer, effective May 24, 2021. Dr. Motesharei has more than 20 years of experience in business development, licensing and transactions, alliance management and strategy in the biotechnology and pharmaceutical industry.

Kia has successfully completed more than 100 deals, with particular expertise in scaling the output of platform biotechnology companies through partnerships to maximize shareholder value, with several drugs on market now as a direct result of his activities. Kia also has expertise in our programmatic areas including in neurology, oncology and rare diseases, said Dietrich A. Stephan, Ph.D., Founder, CEO and Chairman of NeuBase. We are excited to welcome Kia to the NeuBase team, as we evaluate potential partnership opportunities and expand our therapeutic pipeline, leveraging the broad capabilities of our PATrOLTM platform for precision genetic medicines.

Genetic mutations are the fundamental drivers of all diseases, rare and common, so NeuBases ability to specifically modulate mutated DNA and RNA can unlock a whole new class of medicines for diseases that currently have few treatment options, said Dr. Motesharei. I look forward to utilizing partnership strategies to expand the breadth of what we have the potential to accomplish with this technology to benefit patients around the world.

Most recently, Dr. Motesharei was Senior Vice President, Business Development & Corporate Strategy at Akcea Therapeutics, a late-stage development and commercial biopharmaceutical company focused on rare diseases, where he led and executed the regional partnership of Akceas marketed products Tegsedi and Waylivra with Sobi in Europe and the Middle East. Prior to Akcea, Dr. Motesharei headed Global Licensing & Business Development, Neurology & Immunology (N&I) at EMD Serono, the biopharmaceutical business of Merck KGaA. He was a core member of the N&I Franchise Leadership Team that executed the overall strategy of the $1.8 billion franchise, including product and pipeline development, partnering, regulatory and commercial and marketing decisions. He managed the global licensing team responsible for search and evaluation and transactions across the entire R&D spectrum for the immunology, neurology, allergy, fertility, medical device and global health franchises. Previously, Dr. Motesharei was a member of the management team and investor relations team at Dyax Corporation, a pharmaceutical company focused on development and commercialization of novel biotherapeutics for prevention of hereditary angioedema. He led the business development, alliance management and competitive intelligence functions covering Dyaxs phage display platform as well as pipeline products including Kalbitor and DX-2930 (now approved as Takhzyro) that contributed to its approximately $6.5 billion acquisition by Shire. Earlier in his career, he held a series of leadership positions at Genfit Corporation, ActivX Biosciences and Lion Bioscience. He currently serves on the board of Ariana Pharma. Dr. Motesharei received a Ph.D. in organic chemistry from the UCLA and a B.A. in chemistry from Colorado College. He completed his postdoctoral training as an NIH fellow at The Scripps Research Institute.

About NeuBase TherapeuticsNeuBase is accelerating the genetic revolution by developing a new class of precision genetic medicines which can be designed to increase, decrease, or change gene function, as appropriate, to resolve genetic defects that drive disease. NeuBases targeted PATrOL therapies are centered around its proprietary drug scaffold to address genetic diseases at the DNA or RNA level by combining the highly targeted approach of traditional genetic therapies with the broad organ distribution capabilities of small molecules. With an initial focus on silencing disease-causing mutations in debilitating neurological, neuromuscular and oncologic disorders, NeuBase is committed to redefining medicine for the millions of patients with both common and rare conditions. To learn more, visit http://www.neubasetherapeutics.com.

Use of Forward-Looking StatementsThis press release contains "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act. These forward-looking statements are distinguished by use of words such as "will," "would," "anticipate," "expect," "believe," "designed," "plan," or "intend," the negative of these terms, and similar references to future periods. These forward-looking statements include, among others, those related to Dr. Moteshareis leadership and development experience guiding the Company as it advances its preclinical portfolio and discovery and drug development platform and towards clinical trials and beliefs that Dr. Moteshareis ability will help the growth of the Company. These views involve risks and uncertainties that are difficult to predict and, accordingly, our actual results may differ materially from the results discussed in our forward-looking statements. Our forward-looking statements contained herein speak only as of the date of this press release. Factors or events that we cannot predict, including those risk factors contained in our filings with the U.S. Securities and Exchange Commission (the SEC), may cause our actual results to differ from those expressed in forward-looking statements. The Company may not actually achieve the plans, carry out the intentions or meet the expectations or projections disclosed in the forward-looking statements, and you should not place undue reliance on these forward-looking statements. Because such statements deal with future events and are based on the Company's current expectations, they are subject to various risks and uncertainties, and actual results, performance or achievements of the Company could differ materially from those described in or implied by the statements in this press release, including: the Company's plans to develop and commercialize its product candidates; the timing of initiation of the Company's planned clinical trials; the risks that prior data will not be replicated in future studies; the timing of any planned investigational new drug application or new drug application; the Company's plans to research, develop and commercialize its current and future product candidates; the clinical utility, potential benefits and market acceptance of the Company's product candidates; the Company's commercialization, marketing and manufacturing capabilities and strategy; global health conditions, including the impact of COVID-19; the Company's ability to protect its intellectual property position; and the requirement for additional capital to continue to advance these product candidates, which may not be available on favorable terms or at all, as well as those risk factors contained in our filings with the SEC. Except as otherwise required by law, the Company disclaims any intention or obligation to update or revise any forward-looking statements, which speak only as of the date hereof, whether as a result of new information, future events or circumstances or otherwise.

NeuBase Investor Contact:Dan FerryManaging DirectorLifeSci Advisors, LLCdaniel@lifesciadvisors.com OP: (617) 430-7576

NeuBase Media Contact:Jessica Yingling, Ph.D.Little Dog Communications Inc.(858) 344-8091jessica@litldog.com

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NeuBase Therapeutics Appoints Dr. Kia Motesharei Chief Business and Strategy Officer - GlobeNewswire

Streptococcus pneumoniae is an opportunistic pathogen that commonly infects young children and the elderly. This atlas will help researchers better understand how to treat these infections.

Streptococcus pneumoniae is an opportunistic pathogen that commonly infects young children and the elderly. This atlas will help researchers better understand how to treat these infections.The bacteria Streptococcus pneumoniae colonizes the nasopharynx and can cause pneumonia. Then, it can spread from the lungs to the bloodstream and cause organ damage. This opportunistic pathogen commonly infects young children, those who are immunocompromised and the elderly. In 2015, S. pneumoniae infections worldwide killed an estimated 192,000 to 366,000 children under age 5.

To understand how this pathogen adapts to different locations in the body, and also how the host responds to the invading microbe, researchers at the University of Alabama at Birmingham, the University of Maryland School of Medicine and Yale University School of Medicine measured bacterial and host gene expression at five different sites in a mouse model the nasopharynx, lungs, blood, heart and kidneys using three genetically different strains of S. pneumoniae.

Their resulting in vivo atlas of host-pathogen interactions at disease-relevant anatomical sites is now published in Proceeding of the National Academy of Sciences. The researchers identified shared and organ-specific transcriptomes of S. pneumoniae, and they showed that the bacterial and host gene expression profiles are highly distinct during asymptomatic colonization versus disease-causing infection.

This means the bacterium behaves differently, depending on which site it infects, and that the mouse organs, in turn, also respond differently to the presence of bacteria. Additionally, certain S. pneumoniae genes were found to always be highly expressed by all three strains of bacteria at all anatomical sites, which makes them ideal targets for new vaccines or therapies.

This was the first time that gene expression profiles during colonization and at multiple host infection sites were mapped from both the host and the pathogen perspectives.

We believe that the atlas of transcriptional responses during host-pathogen interactions presented here, the authors wrote, will constitute an essential resource for the pneumococcal and microbial pathogenesis research communities and serve as a foundation for identification and validation of key host and pneumococcal therapeutic targets in future studies.

Carlos J. Orihuela, Ph.D., professor in the UAB Department of Microbiology, and Herv Tettelin, Ph.D., professor in the University of Maryland School of Medicine Department of Microbiology and Immunology, are co-senior authors.

Carlos J. Orihuela, Ph.D.Besides a descriptive analysis of the transcriptomes, researchers confirmed their findings using bacterial mutants, in vivo challenge experiments and host treatments. In challenge experiments, the researchers found that an interferon beta anti-inflammatory treatment prevented the bacteria from invading vital organs and promoted host survival. This finding offers potentially new therapeutic avenues.

Symptoms of pneumococcal infection include fever, cough, shortness of breath, chest pain, stiff neck, confusion, increased sensitivity to light, joint pain, chills, ear pain, sleeplessness and irritability. While advances in antibiotics and the use of pneumococcal conjugate vaccines since 2000 have lowered deaths attributable to S. pneumoniae, the pathogen continues to show an increase in antibiotic resistance, and it also can switch to capsule types that are not covered by the current United States Food and Drug Administration-approved vaccines. Thus, pneumococcal infections continue to be a significant cause of illness and death.

Co-authors with Tettelin and Orihuela, in the study, An in vivo atlas of host-pathogen transcriptomes during Streptococcus pneumoniae colonization and disease, are Adonis DMello, Department of Microbiology and Immunology, University of Maryland School of Medicine; Ashleigh N. Riegler, Eriel Martnez, Sarah M. Beno and Tiffany Ricketts, UAB Department of Microbiology; and Ellen F. Foxman, Department of Laboratory Medicine, Yale University School of Medicine.

Support came from the Merck, Sharpe & Dohme Corp. Merck Investigator Studies Program award IISP ID#: 57329 and from National Institutes of Health grant AI114800.

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An atlas of S. pneumoniae and host gene expression during colonization and disease - The Mix

Durable and Clinically Meaningful Responses Reported from Phase 1/2 Studies of DTX401 for GSDIa and DTX301 for OTC

Phase 3 Studies for DTX401 and DTX301 to Begin in 2021

IND for UX701 for Wilson Disease Submitted; Expect to Enter Clinic in First Half 2021 using AAV Drug Product Made by HeLa PCL Platform

NOVATO, Calif. , Jan. 08, 2021 (GLOBE NEWSWIRE) -- Ultragenyx Pharmaceutical Inc. (NASDAQ: RARE), a biopharmaceutical company focused on the development and commercialization of novel products for rare and ultra-rare diseases, today announced positive longer-term safety and efficacy data from the first three cohorts of the ongoing Phase 1/2 studies of DTX401, an investigational adeno-associated virus (AAV) gene therapy for Glycogen Storage Disease Type Ia (GSDIa), and DTX301, an AAV gene therapy for ornithine transcarbamylase (OTC) deficiency. In addition, dosing is nearing completion for the prophylactic steroid cohorts in both studies. Discussions with regulatory agencies continue to progress for both programs, and Ultragenyx expects to initiate Phase 3 studies for DTX401 in the first half of 2021 and for DTX301 in the second half of 2021. The company also plans to start a seamless single-protocol Phase 1/2/3 study for UX701, an AAV gene therapy for Wilson disease.

We continue to see durable and clinically meaningful responses in patients in both the DTX401 and DTX301 programs. GSDIa patients treated with DTX401 demonstrate continually improved glucose metabolism with reduction or elimination of cornstarch dependence over time. OTC patients treated with DTX301 show good metabolic control after tapering or discontinuation of alternate pathway medications and protein restricted diet, saidEric Crombez, M.D., Chief Medical Officer of the Ultragenyx Gene Therapy development unit. With the initiation of the UX701 program in Wilson disease and progression of DTX401 and DTX301 to Phase 3 as well as progress in our preclinical stage programs, we are leveraging our proprietary platforms to advance one of the broadest portfolios of gene therapy programs in the industry.

DTX401 (GSDIa) Program

Phase 1/2 data update: All patients (n=9) responding and demonstrating continued improvement of glucose control while reducing or eliminating cornstarch therapy

All nine patients continue to demonstrate improved glucose control while tapering or discontinuing oral glucose replacement with cornstarch and improvements in energy metabolism pathways over the long term. Patients continue to taper the amount and frequency of cornstarch dosing with progress in eliminating overnight and daytime cornstarch doses. At the primary evaluation timepoint at Week 52, the overall mean reduction in cornstarch was 77% across all three cohorts, including two patients in Cohort 3 showing a reduction of greater than 75%. Longer term follow-up for more than two years for the three patients in Cohort 1 have shown sustained and continued cornstarch reductions with a mean reduction of 91% through weeks 104 and 120. Two patients (one each from Cohort 1 and 3) are completely off cornstarch therapy at weeks 127 and 60, respectively.

Data collected from continuous glucose monitoring (CGM) implemented in Cohort 3 indicate that glycemic control was maintained and even improved despite the reductions in cornstarch dependence. Through Week 48, these patients had decreased cornstarch use by between 30% and 92%. Even with these substantial cornstarch reductions, the patients had a mean 10% increase in the percent of time spent in euglycemia, defined by blood glucose levels in the normal range of 60 to 120 mg/dL.

Additionally, these reductions in cornstarch dosing have had an impact on energy metabolism and body weight. Seven of nine treated patients had decreases of 5% (5.6 kg) to 21% (10.5 kg) in bodyweight following DTX401 treatment, with a mean decrease of 12% from the mean baseline weight of 82.8 kg in these seven patients. The notable weight loss is attributed to improved glycemic control and potentially increased physical activity reported by patients.

Interviews with patients following their Week 24 and/or Week 52 visits provide support for the study results seen to date. Patients reported improvements in both their physical and mental health. This includes increased energy and strength, supporting normalization of daily activities and weight loss, as well as greater mental acuity and reduced stress, with the latter in part noted as related to diminished fears of missing a cornstarch dose. No negative patient feedback has been received to date on their experiences with DTX401.

The safety profile of DTX401 remains favorable; there have been no infusion-related adverse events and no treatment-related serious adverse events reported. All adverse events have been Grade 1 or 2.

All three GSDIa patients dosed in prophylactic steroid cohort doing well with no safety issues

All three patients in a fourth and final Phase 1/2 cohort, which utilizes prophylactic steroids, have been dosed at the same dose as Cohorts 2 and 3. There have been no safety issues through up to 11 weeks post-dosing, and all three patients are doing well and have demonstrated early reduction in daily cornstarch intake.

Phase 3 study of DTX401 in GSDIa expected to initiate in first half 2021

The company has completed Scientific Advice with the European Medicines Agency (EMA) and an End of Phase 2 (EOP2) meeting with the U.S. Food and Drug Administration (FDA) to discuss the Phase 2 data, the Phase 3 design, and endpoints. Based in part on this feedback, Ultragenyx plans to conduct a 48-week Phase 3 study in approximately 50 patients, randomized 1:1 to DTX401 or placebo. All patients in the study will cross over to the therapeutic arm and receive therapy at the end of the initial 48-week follow-up period.

Based on the regulatory discussion and pending finalization, Ultragenyx intends to study as primary endpoints glycemic control by assessing the maintenance of glucose control by CGM and the reduction in cornstarch requirements. These primary endpoints will be supported by key secondary endpoints of improvement in percent of time spent in normal glucose control (60-120 mg/dL), time to hypoglycemia in controlled fasting challenge, and the GSDIa functional assessment diary signs and symptom scale. The durability of the treatment will be supported by the longer-term Phase 1/2 data and early treated Phase 3 patients. Based on the results to date, the therapeutic benefit appears to increase over time during the second year after treatment. Ultragenyx expects to initiate the study in the first half of 2021.

DTX301 (OTC) Program

Phase 1/2 data update: All six previous responders demonstrate durable metabolic control, including greater than two-year sustained responses

As previously reported, six out of nine treated patients responded to DTX301 on a dose-dependent basis, including all three treated at the highest dose. The three complete responders have now been stable through 104, 130, and 156 weeks post-treatment with good ammonia control despite discontinuation of their alternative pathway medications and protein-restricted diets. The three other responders also remain stable through Weeks 52 and 130 and are either continuing to taper medications and diet or intend to continue tapering once COVID-19 restrictions are lifted and patients can be more closely followed in clinic. All responders remain in excellent clinical condition with no significant adverse events, hospitalizations, or other events related to OTC deficiency.

There have been no infusion-related adverse events and no treatment-related serious adverse events reported in the study. All treatment-related adverse events have been Grade 1 or 2.

Prophylactic steroid cohort: Two OTC patients dosed with no safety issues; third patient to be dosed this month

Two of three patients have been dosed in the prophylactic steroid cohort, the final cohort in the Phase 1/2 study, at the same dose as in Cohort 3. Through up to 18 weeks post-dosing, both patients are doing well clinically with good metabolic control and without any safety issues. The third patient in the cohort, who has not yet been dosed due to delays related to COVID-19, is expected to be dosed this month.

Phase 3 study of DTX301 in OTC expected to initiate in second half 2021

Ultragenyx completed the initial Scientific Advice process with the EMA regarding the Phase 3 development plan and continues to have discussions with the FDA regarding the Phase 3 study of DTX301. The EOP2 meeting with the FDA had been delayed and is now scheduled to occur late in the first quarter of 2021.

Based on regulatory feedback to date, the proposed Phase 3 study design will include approximately 50 patients, randomized 1:1 to DTX301 or placebo and followed for 48 weeks initially. The change in 24-hour ammonia levels is expected as the primary endpoint. The entry criteria will allow patients with higher baseline ammonia levels than in the Phase 1/2 study to allow sufficient power to assess the change in ammonia. The primary endpoint will be supported by the change in the rate of ureagenesis as a key secondary endpoint that evaluates the capacity to generate urea from ammonia. Additional secondary endpoints include reduction or discontinuation of scavenger medications and normalization of protein-restricted diet.

The Phase 3 study is expected to begin dosing in the second half of 2021. Placebo patients participating in the study will receive DTX301 at the end of the initial 48-week follow-up period. The company will continue to follow patients in the ongoing Phase 1/2 study during the Phase 3 in order to augment the overall long-term data package supporting the durability of DTX301.

Update on Dose Level Determination Method for DTX301 and DTX401

A new droplet digital PCR (ddPCR) test method has been implemented to determine the level of genome copy (GC) titers for Ultragenyxs gene therapy candidates. This new process improves the accuracy, precision, and specificity compared to the prior quantitative PCR (qPCR) approach. As a result, the actual highest Phase 1/2 dose and planned Phase 3 dose for DTX301 is 1.7 x 10^13 GC/kg (from 1.0 x 10^13 GC/kg) and for DTX401 is 1.0 x 10^13 GC/kg (from 6.0 x 10^12 GC/kg). This change in dose designation of the same product does not represent a change in dose but a more accurate estimate of the actual GC content of the product relative to qPCR, the prior method.

UX701 (Wilson Disease) Program using HeLa PCL Platform

Ultragenyx submitted an Investigational New Drug (IND) application in December as planned for UX701, an AAV9 gene therapy for the treatment of Wilson Disease. The company expects to initiate a seamless single-protocol Phase 1/2/3 study in the first half of 2021. Manufacture and testing of GMP grade drug product to supply the clinical study are complete using the companys proprietary HeLa 2.0 PCL process at the 2,000 liter scale.

Ultragenyx previously reported that UX701 has received orphan drug designation by the FDA. The European Commission has since also granted orphan drug designation for the gene therapy.

Advancing HeLa Producer Cell Line (PCL) Platform and Programs

Ultragenyx continues to advance the proprietary HeLa producer cell line (PCL) platform with recent HeLa 3.0 improvements. The platform enables large 2,000 liter commercial-scale manufacturing and yields high-quality product from a highly reproducible, highly scalable platform, and less expensive process.

Breaking Ground on Gene Therapy Manufacturing Plant

Ultragenyx recently broke ground on its new manufacturing facility to provide important internal capacity to develop and manufacture supply of the companys gene therapies for both clinical-stage and approved products. The initial 100,000 square foot facility will be able to support two independent manufacturing suites with an initial capacity of 30 runs per year and is expected to be complete in 2023.

DTX201 / BAY 2599023 (Hemophilia A) Program Partnered with Bayer AG and Currently Manufactured in HeLa PCL System

Updated Phase 1/2 data through three cohorts were presented at the American Society of Hematology Annual Meeting & Exposition in December 2020 for DTX201 / BAY 2599023, an AAVhu37 gene therapy in development by Bayer, using Ultragenyxs HeLa PCL platform. The data demonstrate dose-responsive and sustained FVIII levels with no evidence of loss of expression through follow-up between 40 and 80 weeks after treatment. Patients in Cohorts 2 and 3 were on FVIII prophylaxis prior to gene therapy, which they have discontinued since approximately 6 weeks after receiving treatment. No spontaneous bleeds have been reported after achieving protective FVIII levels of greater than 15 IU/dL.

No treatment-emergent serious adverse events have been reported. ALT elevations have been observed in three patients at higher doses, which were managed with corticosteroid treatment.

Preclinical HeLa PCL Programs Progress

Earlier-stage preclinical programs utilizing the HeLa PCL platform continue to advance, including:

About GSDIa and DTX401

GSDIa is the most severe genetically inherited glycogen storage disease. It is caused by a defective gene coding for the enzyme G6Pase-, resulting in the inability to regulate blood sugar (glucose). Hypoglycemia in patients with GSDIa can be life-threatening, while the accumulation of the complex sugar glycogen in certain organs and tissues can impair the ability of these tissues to function normally. If chronically untreated, patients can develop severe lactic acidosis, progress to renal failure, and potentially die in infancy or childhood. There are no approved pharmacologic therapies. An estimated 6,000 patients worldwide are affected by GSDIa.

DTX401 is an investigational AAV8 gene therapy designed to deliver stable expression and activity of G6Pase- under control of the native promoter. DTX401 is administered as a single intravenous infusion and has been shown in preclinical studies to improve G6Pase- activity and reduce hepatic glycogen levels, a well-described biomarker of disease progression. DTX401 has been granted Orphan Drug Designation in both the United States and Europe, and Regenerative Medicine Advanced Therapy (RMAT) designation and Fast Track designation in the United States.

About OTC Deficiency and DTX301

OTC deficiency, the most common urea cycle disorder, is caused by a genetic defect in a liver enzyme responsible for detoxification of ammonia. Individuals with OTC deficiency can build up excessive levels of ammonia in their blood, potentially resulting in acute and chronic neurological deficits and other toxicities. It is estimated that more than 10,000 people are affected by OTC deficiency worldwide, of whom approximately 80 percent are classified as late-onset and represent a clinical spectrum of disease severity. In the late-onset form of the disease, elevated ammonia can lead to significant medical issues for patients. Neonatal onset disease occurs only in males, presents as severe disease, and can be fatal at an early age. Approved therapies, which must be taken multiple times a day for the patient's entire life, do not eliminate the risk of future metabolic crises. Currently, the only curative approach is liver transplantation.

DTX301 is an investigational AAV type 8 gene therapy designed to deliver stable expression and activity of OTC following a single intravenous infusion. It has been shown in preclinical studies to normalize levels of urinary orotic acid, a marker of ammonia metabolism. DTX301 was granted Orphan Drug Designation in both the United States and Europe.

About Wilson Disease and UX701

Wilson disease is a rare inherited disorder caused by mutations in the ATP7B gene, which results in deficient production of ATP7B, a protein that transports copper. Loss of function of this copper-binding protein results in the accumulation of copper in the liver and other tissues, most notably the central nervous system. Patients with Wilson disease experience hepatic, neurologic and/or psychiatric problems. Those with liver disease can experience such symptoms as fatigue, lack of appetite, abdominal pain and jaundice, and can progress to fibrosis, cirrhosis, life-threatening liver failure and death. Wilson disease can be treated by reducing copper absorption or removing excess copper from the body using life-long chelation therapy, but unmet needs exist because some treated patients experience clinical deterioration and severe side effects. Wilson disease affects more than 50,000 individuals in the developed world.

UX701 is an investigational AAV type 9 gene therapy designed to deliver stable expression of a truncated version of the ATP7B copper transporter following a single intravenous infusion. It has been shown in preclinical studies to normalize copper trafficking and excretion from the body. UX701 was granted Orphan Drug Designation in the United States and European Union.

About Ultragenyx

Ultragenyx is a biopharmaceutical company committed to bringing novel products to patients for the treatment of serious rare and ultra-rare genetic diseases. The company has built a diverse portfolio of approved therapies and product candidates aimed at addressing diseases with high unmet medical need and clear biology for treatment, for which there are typically no approved therapies treating the underlying disease.

The company is led by a management team experienced in the development and commercialization of rare disease therapeutics. Ultragenyxs strategy is predicated upon time- and cost-efficient drug development, with the goal of delivering safe and effective therapies to patients with the utmost urgency and ensuring majority access to its therapies for patients who can benefit.

For more information on Ultragenyx, please visit the companys website at http://www.ultragenyx.com.

Ultragenyx Forward-Looking Statements

Except for the historical information contained herein, the matters set forth in this press release, including statements related to Ultragenyx's expectations and projections regarding its future operating results and financial performance, anticipated cost or expense reductions,the timing, progress and plans for its clinical programs and clinical studies, future regulatory interactions, and the components and timing of regulatory submissions are forward-looking statements within the meaning of the "safe harbor" provisions of the Private Securities Litigation Reform Act of 1995. Such forward-looking statements involve substantial risks and uncertainties that could cause our clinical development programs, collaboration with third parties, future results, performance or achievements to differ significantly from those expressed or implied by the forward-looking statements. Such risks and uncertainties include, among others, the effects from the COVID-19 pandemic on the companys clinical activities, business and operating results, risks related to reliance on third party partners to conduct certain activities on the companys behalf, uncertainty and potential delays related to clinical drug development, smaller than anticipated market opportunities for the companys products and product candidates, manufacturing risks, competition from other therapies or products, and other matters that could affect sufficiency of existing cash, cash equivalents and short-term investments to fund operations, the companys future operating results and financial performance, the timing of clinical trial activities and reporting results from same, and the availability or commercial potential of Ultragenyxs products and drug candidates. Ultragenyx undertakes no obligation to update or revise any forward-looking statements. For a further description of the risks and uncertainties that could cause actual results to differ from those expressed in these forward-looking statements, as well as risks relating to the business of Ultragenyx in general, see Ultragenyx's Quarterly Report on Form 10-Q filed with theSecurities and Exchange CommissiononOctober 27, 2020, and its subsequent periodic reports filed with theSecurities and Exchange Commission.

Contact Ultragenyx Investors & MediaJoshua Higa(415) 475-6370

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Ultragenyx Announces Progress Across Broad Gene Therapy Portfolio and Positive Longer-Term Data from Multiple Phase 1/2 Gene Therapy Studies -...

DUBLIN--(BUSINESS WIRE)--The "Regenerative Medicine in Pharma - Thematic Research" report has been added to ResearchAndMarkets.com's offering.

Regenerative medicine is a multidisciplinary field that seeks to develop the science and tools that can help repair, augment, replace, or regenerate damaged or diseased human cells, tissues, genes, organs, or metabolic processes, to restore normal function. It may involve the transplantation of stem cells, progenitor cells, or tissue, stimulation of the body's own repair mechanisms, or the use of cells as delivery vehicles for therapeutic agents such as genes and cytokines.

It is widely anticipated that Gene therapy is the most valuable regenerative medicine sector however, this market is also expected to be slowed down by high cost of therapies, which may limit its accessibility.

Existing programs will facilitate the approval and development of regenerative medicines, however, a reimbursement system especially for curative therapies is warranted.

The publisher's Regenerative Medicine in Pharma report combines primary research from a cross-specialty panel of experts with in-house analyst expertise to provide an assessment of the development landscape.

Scope

Reasons to Buy

Key Topics Covered:

For more information about this report visit https://www.researchandmarkets.com/r/dzfubj

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Thematic Research into the Global Regenerative Medicine in Pharma Market - Opportunities, Challenges, and Unmet Needs - ResearchAndMarkets.com -...

Twenty years ago, President Bill Clinton announced completion of what was arguably one of the greatest advances of the modern era: the first draft sequence of the human genome.

"Without a doubt, this is the most important, the most wondrous map ever produced by humankind," Clinton said on June 26, 2000 from the White House, predicting that genome science "will revolutionize the diagnosis, prevention and treatment of most, if not all, human diseases." In the future, he said, "doctors will increasingly be able to cure diseases like Alzheimer's, Parkinson's, diabetes, and cancer by attacking their genetic roots."

And indeed, the sequencing of the human genome achieved simultaneously by the Human Genome Project (HGP), an international consortium begun in 1990 and led by Francis Collins, MD, then director of the National Human Genome Research Institute, and by J. Craig Venter, PhD, with his team at the privately held Celera Genomics has revolutionized the approach to human health.

President Bill Clinton is flanked by Dr J. Craig Venter (left) and Dr Francis Collins announcing the first draft sequence of the human genome in June 2000.

Although the unbridled optimism of 20 years ago has not been matched with success in every quarter, much of the promise has begun to be realized. Scientists have so far identified 5000 rare diseases and 40 to 50 genes that confer cancer risk, developed simple prenatal blood tests to detect chromosomal abnormalities, and generated genetic profiles of tumors to facilitate better-targeted therapies, among other accomplishments. Even the current global fight against COVID-19 is relying on genomics.

"There hasn't been a pharmaceutical developed in last 20 years that hasn't utilized genome information," Venter told Medscape Medical News.

"Not a day goes by in science that we don't see some offshoot of benefit from what happened 20 years ago," said Eric Topol, MD, the chair of innovative medicine at Scripps Research in La Jolla, California, and Editor-in-Chief of Medscape.

Finding the genes was just the beginning though; describing function and using that information therapeutically is still just getting underway in many clinical areas. "We now know that genes are only a small fraction of the complexity of the human genome," says Eric Green, MD, PhD, the current director of the National Human Genome Research Institute (NHGRI).

When it started, the sequencing of the human genome did not seem like a value proposition nor was it expected to be. Congress authorized $3 billion for the HGP in 1990 and set a target completion date of 2005.

The final sequence, a database of some 3 billion DNA base pairs, came in under budget the NHGRI estimates the cost at $2.7 billion in 2003, two years ahead of schedule and exactly 50 years after James Watson and Francis Crick first described DNA.

It had been only 15 months since the international consortium of 1000 researchers across six nations began their sequencing effort in earnest, and a scant 9 months from when Venter's team starting sequencing its human genome. Celera Genomics spent just $100 million, Venter estimates.

What seemed like a massive investment at the time now looks like chicken scratch. "It was a bargain," Topol said.

The race to create the map of the human genome would generate goodwill, create strife, elevate egos, and make careers. Much has been written about the clash between Collins and Venter two polar opposites with different motivations and different approaches.

Collins, a dedicated public servant and man of deep Christian faith, believed in the power of the academic and governmental research enterprise.

Venter, on the other hand, ruffled feathers with his big ideas and generally more capitalistic approach. He began his career at the National Institutes of Health (NIH) in 1984 and created a gene discovery tool called expressed sequence tags (ESTs). That caught the eye of venture capitalists, who lured him out of the agency. They backed Venter's nonprofit, The Institute for Genomic Research (TIGR), to develop the technology.

At TIGR, Venter decoded the genome of Haemophilus influenzae using his whole genome "shotgun" technique. When he applied to the NIH for a grant to support the shotgun method, however, he was rejected. The maker of a DNA sequencing machine, PE Biosystems, then installed Venter as the CEO of the new, private Celera Genomics in 1998.

The NIH-led consortium did not see the value of the shotgun approach and instead relied on a more traditional sequencing method, which was more laborious and time-consuming, Topol recalls. After that NIH rejection, the competition was on, and the rivalry became bitter.

"There was no love lost between these two gentleman," Topol acknowledged. On that day in June 2000 when the announcement was made, "it required Clinton and whoever else to kind of get them to stand together and make nice," added Topol, who was present at the celebration.

A release from the NIH on the commemoration of the 20th anniversary in June of this year describes the situation this way: "The joint presence of these two scientific leaders signified the agreed-upon shared success of the public HGP and private Celera Genomics efforts in generating the first draft sequence of the human genome."

Still, the competition, in retrospect, was a good thing because it accelerated progress, Topol said.

The draft sequence unveiled in 2000 covered 90% of the genome at an error rate of one in 1000 base pairs, but there were more than 150,000 gaps, and only 28% of the genome had reached true completion. When the final version was made public in 2003, there were less than 400 gaps and 99% of the genome was finished with an accuracy rate of less than one error in every 10,000 base pairs.

Looking back, the technologies used then "now seem almost prehistoric," says NHGRI director Green. "Nothing in the way we sequence DNA is the same now. We can do it in a day or two and it costs less than a thousand dollars." He expects the cost of sequencing a human genome will eventually drop below $100.

The final, almost-complete sequence published in 2003 was "foundational," providing "the alphabet around which everything else has been constructed," said Mark McCarthy, MD, senior director and staff scientist in human genetics at the California-based biotechnology company, Genentech. "It's hard to think of a more concrete example in science other than maybe the periodic table," McCarthy told Medscape Medical News.

Doing genetic research before the full sequence was published, he says, was like being an "explorer in some novel land." Without a clear map of the terrain, researchers used analogue methods to try to determine locations of genes or recombination events, he said. It was frustrating and "a huge impediment to progress."

Now, scientists can "just click on a mouse and get almost immediately the worlds of data around any genomic regions," he said.

"Most scientists today never had to sequence a gene," Venter points out. "They don't have to, because they just look it up on the internet."

"Graduate students today can't imagine how we ever did any experiments or learned anything without having access to the human genome sequence with a click of a mouse," said Collins, in a video testimonial celebrating the 30th anniversary of the start of the project.

To Collins, one of the genome project's main goals was to give clinicians better tools to heal their patients. "Together we must develop the advances in medicine, that is the real reason for doing this work," he said in 2000.

If you would have told me that in my professional career I would have seen genomics actually change the practice of medicine in any way, shape, or form, I would have said, 'There's just no way, we're two generations away from that.' Dr Eric Green, director of the National Human Genome Research Institute

But it wasn't until a decade later that genomics was talked about in medicine, said Green. "Now, we have clear examples for genomics being used every day," he said.

"If you would have told me that in my professional career I would have seen genomics actually change the practice of medicine in any way, shape or form, I would have said, 'There's just no way, we're two generations away from that,'" Green said.

Perhaps the biggest impact of these advances in genomics to date has been in the practice of oncology.

"Cancer care has been one of the biggest beneficiaries of the genomic revolution," said Frederick M. Schnell, MD, chief medical officer of the Community Oncology Alliance (COA). Schnell points to the work of Brian Druker, MD, who helped discover the mutation that causes chronic myelogenous leukemia and also was instrumental in developing a precision treatment for CML, imatinib (Gleevec).

"That was probably the singular most important development for a particular, albeit not common, but not uncommon disease that had a disgraceful, horrible projected survival and mortality associated with it, and has changed it to a curable disease," Schnell told Medscape.

The HGP led to the Cancer Genome Atlas, a book of some 20,000 cancer genomes and matched normal samples spanning 33 cancer types.

"In order to understand what was going wrong in a cancer, you first had to understand what the genome was supposed to look like in somebody the cell that was not cancerous," said Richard Schilsky, MD, chief medical officer and executive vice president of the American Society of Clinical Oncology (ASCO).

The comparisons "help us identify mutations that are real drivers of cancer and have opened up the whole field of precision oncology," Schilsky, formerly chief of hematology/oncology and deputy director of the University of Chicago Comprehensive Cancer Center, told Medscape Medical News.

In addition to helping identify cancer susceptibility genes, the genome project also led to variations associated with how drugs are metabolized, Schilsky said.

For instance, it is now known that 10% of the population has a variant of the UGT1A1 gene that leads to poor metabolism of the chemotherapy drug irinotecan (Camptosar), causing worse side effects. The drug's label now notes the availability of a simple lab test to look for the variant.

Schilsky is lead investigator of an ASCO-sponsored trial called TAPUR that aims to match patients with certain tumor variants to therapies that might work, but are not FDA-approved for that particular cancer. Some 2000 individuals have enrolled and received free medications (provided by one of the eight drug companies participating) since the trial began in 2016, said Schilsky.

One goal is to collect evidence on off-label uses which might help therapies gain acceptance in clinical practice guidelines and, potentially, reimbursement. TAPUR also aims to help oncologists learn more about genomics.

Precision oncology is still not available to all cancer patients, however. Schnell said the COA is lobbying for better access and insurance coverage.

He believes that genomics could be used as a replacement for screening tests such as mammograms and colonoscopies. "This is going to be a big application point for the genomic revolution as it continues," he said.

Topol agrees that genomics could create a tailored approach to prevention. "Why does every woman need a mammogram when only 12% will ever develop breast cancer?" he says.

The progress made to date in understanding the human genome is also proving to be a key weapon as scientists fight the important current threat of the COVID-19 pandemic.

China made the first genetic sequence of the SARS-CoV-2 virus available on January 12, 2020, just weeks after the nation reported the initial cluster of cases.

Researchers have since uploaded 245,000 genomic sequences of the SARS-CoV-2 virus to the World Health Organization's Global Initiative on Sharing All Influenza Data (GISAID) portal. The speedy sequencing and widespread sharing of data led to quick development of molecular diagnostics and identification of potential targets for vaccines and therapeutics.

The NHGRI, among others, is supporting genomic studies around the world that aim to understand the differences between those who become severely ill and those "who barely seem to notice they have the disease," NHGRI director Green told Medscape Medical News. "There is no question there is going to be some genomic basis for the severity of the disease,"

He also expects genomics to be used in vaccine trials to separate responders from nonresponders.

While rare monogenic diseases were a relative cinch, common illnesses like hypertension, diabetes, and Alzheimer's disease have turned out to be more complicated.

It wasn't until the mid-2000s, when genome-wide association studies (which look for small variations that occur more frequently in people with disease) came into greater use, that scientists began to get a clearer picture, said Genentech's McCarthy.

It turns out that "hundreds, if not thousands of genetic variations and genetic regions" seem to predispose someone to a common disease, he said. He's applying genome-wide approaches in type 2 diabetes, but it requires datasets of a million or more people to get a robust result, McCarthy said.

Even then, "it just gives you a bunch of sign posts around the genome and then you have to work out what they do and how they influence predisposition in a given individual," he said. Researchers have begun to understand "the range of pathways and networks that are involved in the genetic predisposition to type 2 diabetes," which in turn is giving information on potential therapeutic targets.

The obstacle is not having enough genome-wide genetic data, which may change as more countries find ways to collect more genetic data, McCarthy said.

"We're not getting complete comprehensive views of all the genes involved and all the genomic variants that confer risk," for chronic diseases, agreed Green. "That's the big challenge for the next decade."

Another challenge that NHGRI has outlined in its strategic plan, released in October, is broadening human genome reference databases to include a wider representation of humanity. "Much like all other scientific disciplines, genomics is reckoning with systematic injustice and biases of the past," the agency said in a press release. The plan also addresses data control, privacy, genome editing, and barriers to a thriving genomics enterprise.

Venter believes that getting to the root of chronic diseases means combining the phenotype with the genotype. In 2013, he started Human Longevity, a company that offers sequencing, imaging, and a host of diagnostics to those who can afford the service, to give a complete picture.

"Without extensive phenotype information, the genome isn't highly useful on its own," said Venter, who feels the combination could be a true preventive medicine platform.

As much as the sequencing of the genome has brought to medicine, "I think the greatest promise of the genome remains to be realized," said Venter.

The initial focus was on genes. Humans, it turns out, have only 20,000 genes, not that many more than worms or fruit flies. But there's more to life outside of those genes, said Green.

The human genome "is a treasure chest, but we have only gotten a limited number of the keys so far," said Topol. "It is not nearly as informative as it could be."

And genomics still has the potential to do harm an issue that gets periodic scrutiny by commissions and the public. On that day in 2000 at the White House, Venter noted that a just-released poll had reported that 46% of Americans believed that "the impact of the Human Genome Project will be negative."

Privacy of genetic information is a perennial concern, and technologies such as gene editing, which allows scientists to alter DNA have brought up new ethical challenges.

On the other hand, the public has been mesmerized by genetic genealogy technologies that allow them to determine their own ancestry or disease risk, and that have more recently helped law enforcement solve crimes, some of them longstanding cold cases.

Twenty years ago, Venter predicted that the wonders would continue unabated. "The complexities and wonder of how the inanimate chemicals that are our genetic code give rise to the imponderables of the human spirit should keep poets and philosophers inspired for the millenniums," he said in 2000.

His view is more tempered today. "I'm optimistic about the future," says Venter now. "I'm pessimistic about how soon it will get here."

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The 'Wondrous Map': Charting of the Human Genome, 20 Years Later - Medscape