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Nearly 40 patients with a genetic disease that rapidly blinds young adults were successfully treated with gene therapy, according to a paper published today in Science Translational Medicine. The study was conducted by an international team coordinated by Dr. Jos-Alain Sahel from the University of Pittsburgh and Institut de la Vision, Paris, and Dr. Patrick Yu-Wai-Man from the University of Cambridge.

Dr. Jos-Alain Sahel

Surprisingly, scientists found that injecting a gene therapy vector into one eye of someone suffering from Leber hereditary optic neuropathy (LHON) the most common cause of blindness caused by dysfunctional mitochondria in cells of the retina significantly improved vision in both eyes.

LHON is a rapidly progressing genetic disease that causes optic nerve damage and develops in early adulthood. Within a few weeks of disease onset, the vision of most people affected deteriorates to the point where they are considered legally blind.

As someone who treats these young patients, I get very frustrated about the lack of effective therapies, said Sahel, senior investigator of the study and professor and chair of the Department of Ophthalmology at Pitt School of Medicine, as well as director of the UPMC Eye Center. These patients rapidly lose vision in the course of a few weeks to a couple of months. Our study provides a big hope for treating this blinding disease in young adults.

In their effort to correct a genetic error in the mitochondrial DNA a mutation in the gene called MT-ND4 researchers injected an artificial virus containing a template for the correct copy of the gene into the eyes of 37 patients.

We expected vision to improve only in the eyes treated with the gene therapy vector, said international coordinating investigator and neuro-ophthalmologist Yu-Wai-Man, from Cambridges Department of Clinical Neurosciences. Rather unexpectedly, both eyes improved for 78% of patients in the trial following the same trajectory over two years of follow-up.

On average, the best possible vision in treated and untreated eyes improved by three lines of vision 15 and 13 letters on the worldwide standard eye testing chart, respectively. In some patients, the effect was even larger, reaching 28.5 letters for the treated eyes and 24.5 letters for untreated eyes.

To better understand the mechanism by which the treatment of one eye could improve the other, the researchers conducted a study in long-tailed macaques. Macaques have a visual system similar to that of humans, which allows scientists to study the distribution and effects of the gene therapy vector in much greater detail.

The animal study suggested that the gene therapy can reach an untreated eye by passive diffusion traces of the viral vectors genetic material were detected in the back of the untreated eye, including retina and optic nerve.

Our approach isnt just limited to vision restoration, said Sahel. Other mitochondrial diseases could be treated using the same technology.

The technology, called mitochondrial targeting, was developed by the Institut de la Vision in Paris and licensed to GenSight Biologics, a biotech company co-founded by Sahel. The company is seeking marketing authorization from the European Medicines Agency to use its technology as treatment for patients with visual loss due to LHON caused by a confirmed mutation in the ND4 mitochondrial gene.

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Gene Therapy Injection in One Eye Surprises Scientists by Improving Vision in Both - UPMC

A little more than a decade ago, seven patients with hemophilia Ba disease caused by a mutation on the F9 gene that prevents patients from forming crucial clotting proteinsvolunteered to be the first humans to receive a gene therapy delivered using an adeno-associated virus as a vector. This particular treatment didnt move past the Phase 1/2 trial because, while it was deemed safe, the patients did not sustain expression of the gene. But two other gene therapies based on an adeno-associated virus (AAV), Luxturna for rare forms of blindness and Zolgensma for spinal muscular atrophy, have since been approved by the US Food and Drug Administration (FDA), and several pharmaceutical companies are now pursuing regulatory approval of AAV-carried gene therapies for hemophilia B.

Recently, scientists followed up with four of those original patients. In a study published in Molecular Therapy in September, they report that the men are still free of any worrisome toxicities related to the treatment. The study wasnt all good news, though. The team also found that after all these years, the men still had elevated levels of AAV-neutralizing antibodies. That means that if an AAV gene therapy is approved to treat their illness, they likely wont be able to benefit from itthe antibodies would chew up the vector before it could insert the corrective gene.

Administration of an AAV gene therapy is essentially a vaccine against AAV, says Lindsey George, a hematologist at the Childrens Hospital of Philadelphia who led the research. Hers was not the first study to identify antibodies as a problem for those receiving AAV gene therapies, but it is the first to show that elevated titers can last this long. This role of AAV neutralizing antibodies is huge, says George, as it stands to undermine the effectiveness of gene therapies.

Because AAVs are viruses, the human immune system creates antibodies upon exposure that recognize and neutralize them in subsequent encounters. Sometimes patients have neutralizing antibodies in their blood before ever having received a gene therapy because theyre exposed to AAVs in the environment.

The ability to effectively modulate the antibody-mediated immune response could make AAV gene therapies far more effective for far more patients than they are now.

Along with high levels of antibodies to the specific AAV vector that theyd receivedAAV2the patients Georges team evaluated also had neutralizing antibodies to several other commonly used AAV vectors, namely, AAV5 and AAV8, she tells The Scientist.

Andrew Davidoff, a pediatric surgeon at St. Jude Childrens Research Hospital who studies AAV gene therapies but was not involved in the study, says, This paper suggests that not only will they not be able to receive a second dose of vector of the same [type of AAV], but potentially even other [types].

If scientists can prevent antibodies from neutralizing the AAV, they would not only give patients like these another opportunity to receive a more effective dose of gene therapy, but it will expand the patients that we can treat with the therapy to include the 3050 percent of patients who have already been exposed to AAVs in the environment, says Giuseppe Ronzitti, who heads a lab focused on gene therapy research at Genethon.

But, Davidoff says, nobody has found a suitable solution yet that is likely to be accepted by patients. The body has evolved over millions of years, this immune system that helps fight off infections. So to overcome that, even temporarily, is not an easy task.

Some immunosuppressant drugs wont work if the body has already developed specific antibodies to a particular pathogen, such as AAV. Scientists are therefore testing combinations of different types of immunosuppressants they hope will prevent the body from attacking AAVs, but these are likely to come with major risks, chiefly, susceptibility to infection.

Another option is plasmapheresisa process in which a persons blood is removed from the body and the cells separated from the plasma so that they can be reinfused without the antibodies found in the plasmabut, like immunosuppressant drugs, the technique is nonspecific and comes with similar risks. Its a matter of risk-benefit with the continued immunosuppression, says Ronzitti.

So scientists have been looking for other ways to control the bodys response to these gene therapy vectors.

Ronzitti and his team recently proposed a solution in Nature Medicine. The scientists used the imlifidase (IdeS) protein, conditionally approved by the European Commission, to degrade immunoglobulin G (IgG) antibodies that are developed after the body encounters a specific antigen so that it can remember and target that antigen in the future, and thus might cause a patient to reject a transplanted kidney. IgG antibodies are responsible for the immune systems response to AAVs. Its a newer, less invasive alternative to plasmapheresis, Ronzitti tells The Scientist in an email.

The team injected monkeys with the IdeS protein before administering a dose of gene therapy targeting the liver. The treatment appeared safe, the monkeys levels of preexisting AAV antibodies went down, and the AAV vector successfully made its way to the liver. To model a scenario in which a patient would need more than one dose of gene therapy, the scientists administered an AAV gene therapy to another group of monkeys before giving them the IdeS protein to degrade the antibodies theyd developed in response, then readministered the gene therapy. Again, AAV antibodies diminished after the IdeS treatment and the second gene therapy dose was successfully delivered.

One drawback to the approach is that IgGs are the most prevalent type of antibody found in the blood, and destroying all of them may have undesirable side effects. In an attempt to develop a more targeted therapy, one group published a study in January demonstrating that a specialized version of plasmapheresis could reduce the levels of antibodies against human AAVs in mice to the point where a new gene therapy should be effective, without depleting all other immunoglobulins that formed in response to infections.

More recently, a team of researchers at the University of Pittsburgh Medical Center made use of CRISPR-Cas9 to increase the efficacy of AAV gene therapy in mice. Pathologist Samira Kiani and her team werent looking for ways to improve gene therapy, but instead were seeking to temporarily modulate immunity in hopes of changing the course of diseases such as septicemia, a precursor to sepsis that occurs when an infection makes its way to the blood. The researchers aimed to temporarily downregulate the Myeloid differentiation primary response 88(Myd88) gene, which would briefly dampen the immune response, and then remove the brakes.

The gene that we chose to target is known to a be a central gene for innate and adaptive immunity, says Kiani. It controls the production of IgG antibodies in response to AAV exposure, which provided a simple way to measure whether the strategy was effective. If the team administered an AAV to an animal shortly after it had received the CRISPR-Cas9 treatment, it should have a substantially lower antibody response to the virus.

First, they administered the CRISPR to tamp down Myd88 activity and measured a reduction in the expression of the Myd88 gene, as theyd expected. Then, the team used the technique to treat mice just before giving them a dose of AAV-based gene therapy that was designed to lower their cholesterol.

Weeks later, the researchers administered a second dose of the same AAV vector to determine if the temporary immunosuppression during the first dose had prevented the mice from making enough antibodies to thwart a second dose. The mice that were pretreated with the immune-modulating CRISPR showed lower levels of AAV-neutralizing antibodies and more dramatic responses to the cholesterol-lowering AAV treatment. The study was published in NatureCell Biologyin September.

If given prior to the administration of an AAV gene therapy, this approach would prevent the formation of new antibodies, so the patient could receive a second dose later, if needed, says Kiani. Given that the CRISPR treatment only prevents the development of antibodies temporarily, it shouldnt cause any long-term suppression of the rest of the immune system. On the flip side, because it doesnt clear existing antibodies, if the patients have already pre-existing antibodies [from natural exposure] this approach might not be the best approach.

All of the potential solutions have a long way to go, including still needing to be tested in human patients, but the ability to effectively modulate the antibody-mediated immune response could make AAV gene therapies far more effective for far more patients than they are now, says Ronzitti. The immune response to these vectors is quite a complex story, he says. But we are solving the issues one by one.

L. George et al., Long-term follow-up of the first in human intravascular delivery of AAV for gene transfer: AAV2-hFIX16 for severe hemophilia B,Molecular Therapy,doi:10.1016/j.ymthe.2020.06.001, 2020.

F. Moghadam et al., Synthetic immunomodulation with a CRISPR super-repressor in vivo,Nature Cell Biology,doi:10.1038/s41556-020-0563-3, 2020.

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Thwarting AAV-Neutralizing Antibodies Could Improve Gene Therapy - The Scientist

Having demonstrated the ability to offer improved treatment related outcomes and also enhance the quality of lives of patients suffering from a diverse range of clinical conditions, the demand for cell therapies is anticipated to increase in the near future

Roots Analysis has announced the addition of Cell Therapy Manufacturing Market (2nd Edition), 2018 2030 report to its list of offerings.

Given the commercial success of multiple cell therapies, such as RECELL (Avita Medical) and YESCARTA (Gilead Sciences), and an evolving clinical pipeline, the opportunity for contract development and manufacturing organizations (CDMOs) is anticipated to grow significantly. Over the years, many service providers have begun automating their operations, in order to eliminate chances of human error during manufacturing.

To order this 400+ page report, which features 125+ figures and 175+ tables, please visit this link.

Key Market Insights

Over 145 companies / organizations are actively involved in manufacturing cell-based therapiesThe market landscape is currently dominated by the presence of industry players, which represent more than 55% of the total number of players. Amongst these, over 45 are large or mid-sized firms (having more than 50 employees). It is also worth noting that this field has witnessed the entry of several start-ups.

50+ organizations claim to possess commercial manufacturing capabilities for cell therapiesAs most of the cell therapy products are under clinical evaluation, majority of the manufacturing facilities currently have the capacity to support clinical scale production requirements. At the same time, it is worth noting that several players (over 35%) have already developed / are developing commercial scale capacity for cell therapies.

Europe has emerged as a key region for the production of cell therapies with more than 40% of manufacturing facilitiesGlobally, 195 facilities have been established by various players for the manufacturing of the cell therapies; of these, 41% are located in Europe, followed by those based in North America (38%). Other emerging regions include Australia, China, Japan, Singapore, South Korea and Israel.

Close to 15 companies are presently offering automated solutions to cell therapy developersOver the years, automation has emerged as a key enabler of cell therapy manufacturing. Players that claim to offer consultancy services related to automation include (in alphabetical order) these include (in alphabetical order) Berkeley Lights, Cesca Therapeutics, Ferrologix, FluDesign Sonics, GE Healthcare and Terumo BCT. Further, we identified five players, namely (in alphabetical order) Fraunhofer Institute for Manufacturing Engineering and Automation IPA, Invetech, KMC Systems, Mayo Clinic Center for Regenerative Medicine and RoosterBio, that offer consultancy solutions related to automation.

150+ partnerships were inked between 2014 and 2018Of these, 32% were observed to be focused on the supply of cell-based therapy products for clinical trials. Other popular types of collaboration models implemented in this domain include additional services agreements (24%), joint ventures (9%) and acquisitions (3%).

North America anticipated to capture 50% of the cell therapy manufacturing market by 2030Owing to high venture capital funding and drug development activity, North America is anticipated to capture close to 50% of the total market share by 2030. It is also important to highlight that financial resources, technical expertise and established infrastructure is likely to drive cell therapy manufacturing market in Europe to grow at a CAGR of over 18%.

To request a sample copy / brochure of this report, please visit this link

Key Questions Answered

The USD 10+ billion (by 2030) financial opportunity within the cell therapy manufacturing market has been analyzed across the following segments:

The report features inputs from eminent industry stakeholders, according to whom manufacturing of cell therapies is largely being outsourced due to the exorbitant costs associated with setting-up in-house facilities. The report includes detailed transcripts of discussions held with the following experts:

The research covers profiles of key players (industry and non-industry) that offer contract manufacturing services for cell-based therapies, featuring an overview of the company, information on its manufacturing facilities, and recent collaborations.

For additional details, please visithttps://www.rootsanalysis.com/reports/view_document/cell-therapy-manufacturing-market-2nd-edition-2018-2030/209.html

or email [emailprotected]

Contact:Gaurav Chaudhary+1 (415) 800 3415+44 (122) 391 1091[emailprotected]

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cell therapy manufacturing market is projected to reach close to USD 11 Billion by 2030, growing at an annualized rate of 14.9% - The Daily Chronicle

The approval of KYMRIAH, YESCARTA, Alofisel and Zyntelgo has increased the interest of pharma stakeholders in cell therapies; further, owing to the technical challenges in this field, outsourcing manufacturing operations has become a necessity

Roots Analysis has announced the addition of Cell Therapy Manufacturing Market (3rd Edition), 2019 2030 report to its list of offerings.

Owing to various reasons, the demand for cell therapies is anticipated to increase over the coming years. Therefore, both therapy developers and contract service providers may need to strengthen their capabilities and expand available capacity. In this context, automation is expected to be a key enabler within the cell therapy manufacturing and contract services industry.

To order this 500+ page report, which features 160+ figures and 250+ tables, please visit this link

More than 160 organizations claim to be engaged in cell therapy manufacturingThe market landscape is dominated by industry players, representing more than 60% of the total number of stakeholders. Amongst these, over 55 are large or mid-sized firms (having more than 50 employees).

100+ players focused on T-cell and stem cell therapiesMost of these players are focused on manufacturing T-cell therapies, including CART, TCR or TILs. It is worth highlighting that more than 35 organizations claim to have necessary capabilities for the manufacturing of both types of therapies.

Presently, 70+ companies have commercial scale capacityAs majority of the cell therapy products are in clinical trials, the demand is high at this scale. However, it is worth noting that several players (~50%) have already developed commercial scale capacity for cell therapies.

Europe is currently considered a current hub for cell therapy productionMore than 220 manufacturing facilities have been established by various players, worldwide; of these, 35% are in Europe, followed by those based in North America. Other emerging regions include Australia, China, Japan, Singapore, South Korea and Israel.

50+ facility expansions reported between 2015-2019More than 85% of the expansions are related to setting up of new facilities across different regions. Maximum expansion activity was observed in the US and in certain countries within the Asia Pacific regions.

20+ companies offer automated solutions to cell therapy developersPlayers that claim to offer consultancy services related to automation include (in alphabetical order) Berkeley Lights, Cesca Therapeutics, Ferrologix, FluDesign Sonics, GE Healthcare and Terumo BCT. Further, we identified players, namely (in alphabetical order) Fraunhofer Institute for Manufacturing Engineering and Automation IPA, Invetech, KMC Systems, Mayo Clinic Center for Regenerative Medicine and RoosterBio, that offer consultancy solutions related to automation.

Partnership activity has grown at an annualized rate of 16%, between 2014 and 2018More than 200 agreements have been inked in the last 5 years; majority of these were focused on the supply of cell-based therapy products for clinical trials. Other popular types of collaboration models include manufacturing process development agreements (16%), services agreements (12%) and acquisitions (10%).

By 2030, developed geographies will capture over 60% of the market shareAsia Pacific is anticipated to capture the major share (~36%) of the market by 2030. It is also important to highlight that financial resources, technical expertise and established infrastructure is likely to drive cell therapy manufacturing market in Europe, which is estimated to grow at a CAGR of ~26%.

To request a sample copy / brochure of this report, please visit this link

The USD 10+ billion (by 2030) financial opportunity within the cell therapy manufacturing market has been analyzed across the following segments:

The report features inputs from eminent industry stakeholders, according to whom the manufacturing of cell therapies is largely being outsourced due to exorbitant costs associated with the setting-up of in-house expertise. The report includes detailed transcripts of discussions held with the following experts:

The research covers profiles of key players (industry and non-industry) that offer manufacturing services for cell-based therapies, featuring a company overview, information on manufacturing facilities, and recent collaborations.

For additional details, please visithttps://www.rootsanalysis.com/reports/view_document/cell-therapy-manufacturing/285.html or email [emailprotected]

You may also be interested in the following titles:

Contact:Gaurav Chaudhary+1 (415) 800 3415+44 (122) 391 1091[emailprotected]

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Detailed analysis of the competitive landscape in the Global Cell Therapy Manufacturing Market by 2030 - Eurowire

- Fetal Hemoglobin expression in human cellular models increased up to ~30% by FTX-6058 for the potential treatment of sickle-cell disease

- Company plans to initiate Phase 1 trial in healthy volunteers by year-end

- Non-provisional composition of matter patent application covering FTX-6058 published

CAMBRIDGE,Mass., Sept. 25, 2020 (GLOBE NEWSWIRE) -- Fulcrum Therapeutics, Inc.(Nasdaq: FULC), a clinical-stage biopharmaceutical company focused on improving the lives of patients with genetically defined rare diseases, today announced preclinical proof-of-concept data supporting the development of FTX-6058 to treat sickle cell disease and beta-thalassemia. FTX-6058, a small molecule designed to increase expression of fetal hemoglobin, demonstrated target engagement and good tolerability in multiple preclinical rodent models with once-a-day oral dosing. The Company presented these data today at the 14th Annual Sickle Cell Disease Research & Educational Symposium and 43rd National Sickle Cell Disease Scientific Meeting being held virtually. Slides from the presentation will be available on Fulcrums website at ir.fulcrumtx.com/events-and-presentations.

Despite newly approved therapies for sickle cell disease, a significant unmet need remains, saidMartin H. Steinberg, MD, Professor of Medicine at Boston University School of Medicine. An orally available small molecule therapeutic acting through a novel mechanism to induce increased pancellular HbF should be an important disease-modifying agent.

Fetal Hemoglobin (HbF) is a key modulator of sickle cell disease. Increasing HbF levels has the potential to prevent or reduce disease-related pathophysiology, resulting in reduction of recurring events such as vaso-occlusive crises (VOCs) and hemolysis. In some cases, sickle cell patients with high HbF levels have asymptomatic disease, underscoring the protective effect of HbF. Fulcrum has identified FTX-6058, a highly potent small molecule inhibitor of Embryonic Ectoderm Development (EED) capable of inducing robust HbF protein expression in cell and murine models. Additionally, Fulcrum believes that pharmacokinetics and human dose simulations support FTX-6058 may be given as a once daily oral compound.

The validation of EED as a target for sickle cell disease and the discovery of FTX-6058 as a novel HbF-inducing small molecule were conducted using Fulcrums Product Engine. Through inhibition of EED, Fulcrum has demonstrated the ability to modulate the activity of the Polycomb Repressive Complex 2 (PRC2), a key regulator of HbF expression, in preclinical studies. Fulcrum validated the role between EED binding/PRC2 modulation and HbF induction utilizing its proprietary CRISPR and chemical probe screening platform. Treatment of human CD34+-derived erythroid cells from healthy and sickle cell disease donors with FTX-6058 resulted in clinically desirable fetal hemoglobin levels (up to ~30% of total hemoglobin), demonstrating a superior globin profile relative to hydroxyurea and other small molecule compounds or mechanisms currently under development. In these preclinical studies, FTX-6058 also induced pancellular distribution of HbF similar to hereditary persistence of fetal hemoglobin.

In vivo preclinical studies showed elevation of HbF at the mRNA and protein levels at plasma concentrations predicted by Fulcrum to be achievable in patients. FTX-6058 treatment led to, elevation of the human HBG1 mRNA and HbF protein in the Townes SCD mouse model. In a head-to-head in-vivo preclinical study, FTX-6058 demonstrated superior HbF induction over hydroxyurea in the Townes SCD mouse model.

We continue to demonstrate important progress with our Product Engine, developing a robust pipeline focused on treatments for rare diseases and areas of significant unmet need, said Owen Wallace, Fulcrums chief scientific officer. We are very encouraged by these in vitro and in vivo findings, as the preclinical data support our novel approach to treating hemoglobinopathies, such as sickle cell disease and beta-thalassemia. In addition to achieving robust fetal hemoglobin levels in cell and murine models, an extensive nonclinical safety package and off-target profile has been established for FTX-6058. We believe FTX-6058 has the potential to offer a durable and transformative therapy for people living with sickle cell disease.

Fulcrum completed a comprehensive IND-enabling package, including preclinical safety studies and up to 28-day Good Laboratory Practices (GLP) toxicology studies, as well as Good Manufacturing Practices (GMP) material scale-up for its planned Phase 1 clinical trial. The Company remains on track to initiate a Phase 1 clinical trial by year-end. In addition, Fulcrums non-provisional composition of matter patent application covering FTX-6058 and related structures has published.

About Sickle Cell DiseaseSickle cell disease (SCD) is a genetic disorder of the red blood cells caused by a mutation in the HBB gene. This gene encodes a protein that is a key component of hemoglobin, a protein complex whose function is to transport oxygen in the body. The result of the mutation is less efficient oxygen transport and the formation of red blood cells that have a sickle shape. These sickle shaped cells are much less flexible than healthy cells and can block blood vessels or rupture cells. SCD patients typically suffer from serious clinical consequences, which may include anemia, pain, infections, stroke, heart disease, pulmonary hypertension, kidney failure, liver disease and reduced life expectancy.

About Fulcrum TherapeuticsFulcrum Therapeutics is a clinical-stage biopharmaceutical company focused on improving the lives of patients with genetically defined rare diseases in areas of high unmet medical need. Fulcrums proprietary product engine identifies drug targets which can modulate gene expression to treat the known root cause of gene mis-expression. The company has advanced losmapimod to Phase 2 clinical development for the treatment of facioscapulohumeral muscular dystrophy (FSHD) and has advanced losmapimod to Phase 3 for the treatment of COVID-19. Fulcrum also anticipates filing an IND in the third quarter with initiation of a clinical trial in the fourth quarter of 2020 with FTX-6058 for the treatment of sickle cell disease.

Please visit http://www.fulcrumtx.com.

Forward-Looking Statements This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that involve substantial risks and uncertainties, including statements regarding the development status of the Companys product candidates, including the timing of initiation of a Phase 1 clinical trial for FTX-6058, and the potential advantages and therapeutic potential of our product candidates. All statements, other than statements of historical facts, contained in this press release, including statements regarding the Companys strategy, future operations, future financial position, prospects, plans and objectives of management, are forward-looking statements. The words anticipate, believe, continue, could, estimate, expect, intend, may, plan, potential, predict, project, should, target, will, would and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Any forward-looking statements are based on managements 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, such forward-looking statements. These risks and uncertainties include, but are not limited to, risks associated with Fulcrums ability to obtain and maintain necessary approvals from the FDA and other regulatory authorities; continue to advance its product candidates in clinical trials; initiate and enroll clinical trials on the timeline expected or at all; correctly estimate the potential patient population and/or market for the Companys product candidates; replicate in clinical trials positive results found in preclinical studies and/or earlier-stage clinical trials of losmapimod and its other product candidates; advance the development of its product candidates under the timelines it anticipates in current and future clinical trials; obtain, maintain or protect intellectual property rights related to its product candidates; manage expenses; and raise the substantial additional capital needed to achieve its business objectives. For a discussion of other risks and uncertainties, and other important factors, any of which could cause the Companys actual results to differ from those contained in the forward-looking statements, see the Risk Factors section, as well as discussions of potential risks, uncertainties and other important factors, in the Companys most recent filings with the Securities and Exchange Commission. In addition, the forward-looking statements included in this press release represent the Companys views as of the date hereof and should not be relied upon as representing the Companys views as of any date subsequent to the date hereof. The Company anticipates that subsequent events and developments will cause the Companys views to change. However, while the Company may elect to update these forward-looking statements at some point in the future, the Company specifically disclaims any obligation to do so.

Contact:

Investors:Christi WaarichDirector, Investor Relations andCorporate Communicationscwaarich@fulcrumtx.com 617-651-8664

Stephanie AscherStern Investor Relations, Inc.stephanie.ascher@sternir.com 212-362-1200

Media:Kaitlin GallagherBerry & Company Public Relationskgallagher@berrypr.com212-253-8881

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Fulcrum Therapeutics Announces Preclinical Proof-of-Concept Data for FTX-6058 at the Virtual 14th Annual Sickle Cell Disease Research &...

There are no Food and Drug Administration (FDA)-approved treatments for COVID-19, the pandemic infection caused by a novel coronavirus. While several therapies are being tested in clinical trials, current standard of care involves providing patients with fluids and fever-reducing medications. To speed the search for new COVID-19 therapies, researchers are testing repurposed drugs medicines already known to be safe for human use because they are FDA-approved for other conditions for their abilities to mitigate the virus.

UC San Diego Health researchers recently reported that statins widely used cholesterol-lowering medications are associated with reduced risk of developing severe COVID-19 disease, as well as faster recovery times. A second research team at UC San Diego School of Medicine has uncovered evidence that helps explains why: In short, removing cholesterol from cell membranes prevents the coronavirus from getting in.

SARS-CoV-2 infection (green, left) is inhibited by 25HC treatment (right).

The clinical study, published September 15, 2020 in American Journal of Cardiology, was led by Lori Daniels, MD, professor and director of the Cardiovascular Intensive Care Unit at UC San Diego Health, and Karen Messer, PhD, professor and chief of the Division of Biostatics and Bioinformatics in the Department of Family Medicine and Public Health.

The mechanistic study, published September 18, 2020 in The EMBO Journal, was led by Tariq Rana, PhD, professor and chief of the Division of Genetics in the Department of Pediatrics at UC San Diego School of Medicine and Moores Cancer Center.

A molecule known as ACE2 sits like a doorknob on the outer surfaces of many human cells, where it helps regulate and lower blood pressure. ACE2 can be affected by prescription statins and other medications used for cardiovascular disease.

But, in January 2020, researchers discovered a new role for ACE2: SARS-CoV-2, the coronavirus that causes COVID-19, primarily uses the receptor to enter lung cells and establish respiratory infections.

When faced with this novel virus at the beginning of the pandemic, there was a lot of speculation surrounding certain medications that affect ACE2, including statins, and if they may influence COVID-19 risk, Daniels said. We needed to confirm whether or not the use of statins has an impact on a persons severity of SARS-CoV-2 infection and determine if it was safe for our patients to continue with their medications.

Lori Daniels, MD, professor and director of the Cardiovascular Intensive Care Unit at UC San Diego Health.

To do this, Daniels, Messer and team retrospectively analyzed the electronic medical records of 170 patients with COVID-19 and 5,281 COVID-negative control patients hospitalized at UC San Diego Health between February and June 2020. They collected anonymized data that included the patients disease severity, length of hospital stay, outcome, and use of statins, angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) within 30 days prior to hospital admission.

Among the patients with COVID-19, 27 percent were actively taking statins on admission, while 21 percent were on an ACE inhibitor and 12 percent on an ARB. The median length of hospital stay was 9.7 days for patients with COVID-19.

The researchers found that statin use prior to hospital admission for COVID-19 was associated with a more than 50 percent reduction in risk of developing severe COVID-19, compared to those with COVID-19 but not taking statins. Patients with COVID-19 who were taking statins prior to hospitalization also recovered faster than those not taking the cholesterol-lowering medication.

We found that statins are not only safe but potentially protective against a severe COVID-19 infection, said Daniels. Statins specifically may inhibit SARS-CoV-2 infection through its known anti-inflammatory effects and binding capabilities as that could potentially stop progression of the virus.

This initial study was relatively small and focused on a single health system. Moving forward, Daniels is partnering with the American Heart Association to analyze thousands of patients all over the country to corroborate the data shes developed locally.

I tell my patients who are on statins, ACE inhibitors or other ARBs to keep taking them, she said. Fears of COVID-19 should not be a reason to stop, if anything our research findings should be incentive to continue with their medication.

Statins werent yet on Ranas radar when they began their EMBO Journal study approximately six months ago. At first, his team was simply curious to see which genes are switched on in human lung cells in response to SARS-CoV-2 infection.

A gene called CH25H was blazing hot, Rana said. CH25H encodes an enzyme that modifies cholesterol. I got excited because with HIV, Zika, and a few others, we know that CH25H blocks the virus ability to enter human cells.

Heres whats happening inside our cells: CH25Hs enzymatic activity produces a modified form of cholesterol called 25-hydroxycholesterol (25HC). In turn, 25HC activates another enzyme called ACAT, found inside cells in the endoplasmic reticulum. ACAT then depletes accessible cholesterol on the cells membrane. Its a normally occurring process that gets kicked into high gear during some viral infections.

The team quickly got to work examining 25HC in the context of SARS-CoV-2 from several angles. They explored what happens to human lung cells in the lab with and without 25HC treatment when they are exposed to first a noninfectious virus that carries the SARS-CoV-2 spike protein (its key to cell entry) or to live SARS-CoV-2 virus itself.

No matter which way they came at it, added 25HC inhibited the ability of the virus to enter cells blocking infection almost completely.

The difference between untreated cells and those treated with 25HC was like day and night, Rana said.

While SARS-CoV-2 uses the ACE2 receptor to initially dock on a cell, Ranas study suggests that the virus also needs cholesterol (normally found in cell membranes) in order to fuse with and enter the cell. 25HC takes away a lot of that membrane cholesterol, preventing viral entry.

In a similar way, statins are likely beneficial in preventing or reducing the severity of SARS-CoV-2 infection because, while intended to remove cholesterol from blood vessels, they are also removing cholesterol from cell membranes. As a result, the coronavirus cant get in.

This is already happening in our bodies on a regular basis, so perhaps we just need to give it a boost, with statins or by other means, to better resist some viruses, Rana said. Its not unlike cancer immunotherapy the idea that sometimes instead of attacking a tumor directly, its better to arm a patients immune system to do a better job of clearing away tumors on its own.

If it can be developed into a therapeutic, 25HC might work even better as an antiviral than statins, Rana said. Thats because it works specifically on cholesterol in cell membranes, rather than cholesterol throughout the body. Like all medications, statins can cause negative side effects, including digestive problems and muscle pains, and may not be an option for many people with COVID-19. Whats more, while some previous studies suggested statins may also elevate ACE2 levels, which could allow more viral entry, Ranas team did not see an increase in the receptor in response to 25HC.

Statins are FDA-approved for human use, but 25HC is a natural product currently available only for laboratory work. Rana and team plan to continue optimizing 25HC as a potential antiviral agent. Many steps remain before it might be tested in human clinical trials.

Co-authors of the American Journal of Cardiology study also include: Christopher Longhurst, Amy Sitapati, Jing Zhang, Jingjing Zou, Quan Bui, Junting Ren, Michael Criqui, all at UC San Diego.

Funding for this research came, in part, from the University of California Office of the President (grant R00RG24990).

Co-authors of The EMBO Journal study also include: Shaobo Wang, Wanyu Li, Hui Hui, Shashi Kant Tiwari, Qiong Zhang, Ben A. Croker, Stephen Rawlings, Davey Smith and Aaron F. Carlin, all at UC San Diego.

Funding for this research came, in part, from National Institutes of Health (grants CA177322, DA039562, DA049524 and AI125103), Burroughs Wellcome Fund and John and Mary Tu Foundation.

Disclosure: Tariq Rana is a founder of ViRx Pharmaceuticals and has an equity interest in the company. The terms of this arrangement have been reviewed and approved by the University of California San Diego in accordance with its conflict of interest policies.

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Statins Reduce COVID-19 Severity, Likely by Removing Cholesterol That Virus Uses to Infect - UC San Diego Health

DURHAM, N.C., Sept. 25, 2020 /PRNewswire/ -- Predigen Inc., a privately held diagnostic company and emerging leader in precision medicine, spun-out from Duke University, announced today a study published in The Lancet Infectious Diseases identifying biomarkers that detect viral infections before clinical disease develops. These findings, stemming from work performed by Duke Health scientists, could form the basis of novel approaches for early diagnosis, treatment and management of emerging viral outbreaks and pandemics.

"The study is exciting because, currently, there is no reliable way to identify pre-symptomatic patients," said Ephraim Tsalik, M.D., Ph.D., Predigen's chief science officer and co-founder, and a clinical investigator of this study. "Early diagnosis can lead to earlier, more effective therapy as well as quarantine before someone can spread the infection to others. Predigen's team of physician-scientists at Duke University used machine learning to discover these molecular signatures, representing a more rapid and accurate means to predict, diagnose and manage disease. Especially in light of the challenges posed by COVID-19, these results offer hope for new solutions."

According to the authors of this five-year study involving 1465 participants, these findings arethe first to validate, in a real-world setting, that a blood-based, host gene expression test can accurately predict respiratory viral infection before typical symptoms are present.

For years, Tsalik and colleagues in the Duke Center for Applied Genomics and Precision Medicine have focused on developing innovative tests to diagnose infectious diseases such as sepsis, fungal infection, and most notably, to distinguish between viral and bacterial infections. The ability to discriminate these various causes of illness can help reduce the unnecessary use of antibiotics, a major cause of antibiotic resistance. Predigen has licensed the intellectual property for the company's viral signature, referred to as HR-PreV (Host Response PreViral).

With testing solutions that assess the immune response to stress and disease, Predigen is collaborating with Biomeme, Inc. to deliver host response tests to the point-of-need. Applying Predigen's tests to Biomeme's "PCR anywhere" platform will deliver a better diagnostic methodology (host response signatures) for use in a wide variety of settings that are more accessible to patients.

About the SciencePredigen's scientists from Duke University focused on gene expression, which is a measure of how active or inactive a gene may be in a given situation. By looking at the expression of tens of thousands of genes, the team used machine learning to discover patterns (or signatures) in that data. They found a gene expression signature indicating the presence of a bacterial infection and another signature for viral infection. However, there were no readily available technologies that could measure these biomarkers in a simple and rapid format. To address this need, Predigen formed a partnership with Biomeme, tapping into their 27-target, multiplex, quantitative, RT-PCR assay, which delivers results in about 60 minutes. The signatures and interpretive algorithms have been combined into a point-of-need prototype utilizing Biomeme's Franklin thermocycler and its companion mobile app.

"Predigen's tests focus on the host response, which is itself a molecular measurement of health and disease," said Tsalik. "As such, our tests have been shown to be very accurate and have potential to provide valuable information to inform healthcare providers' management of patients. It has long been clear that tests to reliably distinguish bacterial and viral infections simply don't exist on the market. Moving forward, Predigen will focus on translating its successful research to real-world utilization of its tests by physicians, delivering innovative testing solutions to the point of need."

About PredigenPredigen, Inc. is a global leader in the development of host gene expression signatures for use as prognostic, diagnostic, and therapeutic monitoring tools. Predigen is devoted to advancing the diagnostics field in areas of high unmet need, including infectious disease, cardiovascular disease, autoimmune and inflammatory disease, cancer and drug response. For more information on Predigen, please visit the company's website atwww.predigen.com.

Media Contact:Betsy Levy | Phone: (415) 377-3112 | Email: [emailprotected] | http://predigen.com

SOURCE Predigen

http://www.predigen.com

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Study Reveals Blood-Based Host Response Test Can Accurately Predict Respiratory Viral Infection in Pre-Symptomatic Patients - PRNewswire

Newswise DALLAS Sept. 24, 2020 Two studies led by UT Southwestern researchers shed light on the biology and potential vulnerabilities of schistosomes parasitic flatworms that cause the little-known tropical disease schistosomiasis. The findings, published online today in Science, could change the course of this disease that kills up to 250,000 people a year.

About 240 million people around the world have schistosomiasis mostly children in Africa, Asia, and South America in populations that represent the poorest of the poor, says study leader James J. Collins III, Ph.D., associate professor in UTSWs department of pharmacology.

Most of those infected survive, but those who die often suffer organ failure or parasite-induced cancer. Symptoms can be serious enough to keep people from living productive lives, Collins says.

The parasite that causes this disease has a complicated life cycle that involves stages in both freshwater snails and mammals. Dwelling in mammalian hosts circulatory systems, schistosomes feed on blood and lay copious numbers of eggs, all while causing an array of symptoms including abdominal pain, diarrhea, bloody stool, or blood in the urine. Larval worms are released from snails into water, where the flatworms then may infect humans by penetrating the skin. Schistosomiasis may become a chronic disease that affects the person for years.

Only one drug, praziquantel, is available to treat this condition. However, Collins explains, it is of limited use it doesnt kill all intramammalian stages of the schistosome life cycle, and it has a variable cure rate in some endemic settings. Theres been little interest by pharmaceutical companies in developing new drugs for this disease, he adds, because there is no monetary incentive to do so. Consequently, relatively few studies have been devoted to understanding schistosomes basic biology, which might reveal inherent weaknesses that could serve as targets for new drugs.

To that end, Collins and his colleagues embarked upon two separate studies one at the cellular level and another at the molecular level to better understand these organisms.

In the first study, the researchers delved into the cell types that make up these flatworms. Although the worms are multicellular organisms composed of a variety of unique tissue types, researchers knew little about the different cell populations in these parasites.

With a goal to create an atlas of cell types in Schistosoma mansoni one of the schistosome species that commonly causes schistosomiasis Collins and his team used a technique called single-cell RNA sequencing that distinguishes individual cell types based on their unique gene expression patterns. With this method, they identified 68 molecularly unique clusters of cells, including a population of stem cells that form the gut. When the researchers used a targeted approach called RNA interference (RNAi) to shut down the activation of a key gene in these cells, the resulting worms couldnt digest red blood cells a key to their growth and a pivotal part of the pathology they cause.

In the second study, the researchers used RNAi to sort out the function of about 20 percent of S. mansonis protein coding genes 2,216 in total. Previously, only a handful of genes in these organisms had been assessed.

By deactivating the genes one by one, Collins and his colleagues identified more than 250 genes crucial for survival. Using a database of pharmacological compounds, the researchers then searched for drugs that had the potential to act on proteins produced by these genes, identifying several compounds with activity on worms. The team also uncovered two protein kinases a group of proteins renowned for their ability to be targeted by drugs that are essential for muscle function. When these kinases were inhibited, the worms became paralyzed and eventually died, suggesting that drugs targeting these proteins could eventually treat people with schistosomiasis. A next step in the research will be to search for inhibitors of these proteins.

Collins notes that these strides in understanding the basic biology of schistosomes could eventually lead to new treatments to save untold lives in places where schistosomiasis is endemic.

This is a very important disease that most people have never heard of, he says. We need to invest and invigorate research on these parasites.

UTSW researchers who contributed to the first study include George Wendt, Lu Zhao, Rui Chen, and Michael L. Reese. UTSW researchers who contributed to the second study include Jipeng Wang, Carlos Paz, Irina Gradinaru, and Julie N. R. Collins.

The first study was supported by grants from the National Institutes of Health (R01 R01AI121037, R01 R01AI150715, R21 R21AI133393, and F30 1F30AI131509-01A1, the Welch Foundation (I-1948-20180324 and I-1936-20170325), the National Science Foundation (MCB1553334), the Burroughs Wellcome Fund, the Wellcome Trust (107475/Z/15/Z), and the Bill and Melinda Gates Foundation (OPP1171488).

The second study was supported by grants from the National Institutes of Health (R01AI121037), the Welch Foundation (I-1948-20180324), the Burroughs Wellcome Fund, and the Wellcome Trust (107475/Z/15/Z and 206194).

James Collins is Rita C. and William P. Clements, Jr. Scholar in Biomedical Research.

About UTSouthwestern Medical Center

UTSouthwestern, one of the premier academic medical centers in the nation, integrates pioneering biomedical research with exceptional clinical care and education. The institutions faculty has received six Nobel Prizes, and includes 23 members of the National Academy of Sciences, 16 members of the National Academy of Medicine, and 13 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 2,500 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UTSouthwestern physicians provide care in about 80 specialties to more than 105,000 hospitalized patients, nearly 370,000 emergency room cases, and oversee approximately 3 million outpatient visits a year.

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Finding The Achilles Heel of A Killer Parasite - Newswise

(UroToday.com) In this study, the authors present a retrospective analysis of the co-occurrence between actionable gene mutations and microsatellite instability-high status from next-generation sequencing of 20,296 tumors collected by 3D Medicines, a precision medicine company in China.

The cohort is shown below. Fusions that were considered actionable include those involving ALK, RET, ROS1, FGFR1-4 and NTRK1-3 genes.

The incidence of MSI-H status was highest in the uterine cancer subcohort (11%). No information was provided regarding how MSI status was ascertained.

The incidence of actionable fusions is shown below, with lung cancers harboring the highest incidence of these genomic events (6.4%). ALK mutations were the most common fusion detected across all samples.

The greatest differences in fusion status with microsatellite status was observed in intestinal cancers. Only 0.2% (9/4507) of microsatellite stable intestinal cancers had actionable fusions, but 4.2% of MSI-H (16/384)patients harbored actionable fusions, predominantly in NTRK.

Cases with both MSI-H and actionable fusions were profiled for mRNA expression of immune-related genes, with a suggestion of higher expression levels of TMEM173 as well as multiple MHC II genes.

These results provide additional information regarding the incidence of high levels of microsatellite instability and certain genomic fusions across a variety of cancer subtypes, and identify specific rates of co-occurrence between fusions and MSI-H. These cases show up-regulation of certain immune-related genes even relative to MSI-H tumors lacking the fusions, with potential consequences for response to immunotherapy.

Presented by: Tao Fu, Peking University Cancer Hospital, Beijing, China

Written by: Alok Tewari, MD, PhD, Medical Oncologist at the Dana-Farber Cancer Institute, at the 2020 European Society for Medical Oncology Virtual Congress (#ESMO20), September 19th-September 21st, 2020.

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ESMO VIrtual Congress 2020: Co-Occurrence of Actionable Gene Fusions and Microsatellite Instability-High in... - UroToday

BOSTON--(BUSINESS WIRE)--Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX) today announced that data from the companys portfolio of cystic fibrosis (CF) medicines will be presented at the 43rd European Cystic Fibrosis Digital Conference (ECFS) held September 24-25, 2020 and the 2020 North American Cystic Fibrosis Virtual Conference (NACFC) taking place October 7-23, 2020. An oral presentation at the ECFS Digital Conference will highlight, for the first time, interim results from the TRIKAFTA open-label extension study, which showed safety and efficacy consistent with the results of the Phase 3 pivotal studies in patients with CF ages 12 and older with F508del/Minimal Function (F/MF) or F508del/F508del (F/F) genotypes. Four additional scientific abstracts for ORKAMBI and TRIKAFTA were published in the Journal of Cystic Fibrosis as part of the ECFS conference. In addition, six scientific presentations will occur at NACFC regarding KALYDECO, ORKAMBI and TRIKAFTA, including new data from KALYDECO in infants ages 4 to less than 6 months old.

As we continue to reach additional people with CF with our medicines, gaining a better understanding of their long-term and real-world impact becomes even more important, said Carmen Bozic, M.D., Executive Vice President, Global Medicines Development and Medical Affairs, and Chief Medical Officer at Vertex. We are pleased to report the first longer-term data for TRIKAFTA which show the significant benefits seen early are maintained through one year of treatment.

Data highlighting interim results from the ongoing TRIKAFTA open-label extension (OLE) study to evaluate long-term safety and efficacy in people with CF ages 12 and older with F508del/Minimal Function (F/MF) or F508del/F508del (F/F) genotypes who completed pivotal studies will be presented at the ECFS Digital Conference. In the interim analysis, TRIKAFTA was generally well-tolerated, with no new safety concerns. The data show that the marked improvements observed in the prior pivotal studies across multiple efficacy endpoints, including, percent predicted forced expiratory volume in 1 second (ppFEV1), sweat chloride (SwCl), Cystic Fibrosis Questionnaire Revised (CFQ-R) respiratory domain score, and body mass index (BMI), were sustained with continued treatment with TRIKAFTA.

A full listing of Vertex scientific presentations at ECFS and NACFC are below:

Abstract Title

PresentationType

PresentingAuthor

Date/ Time

ELX/TEZ/IVA

A phase 3, open-label extension study of elexacaftor/tezacaftor/ivacaftor: interim analysis of safety and efficacy in people with cystic fibrosis and F508del/minimal function or F508del/F508del genotypes

ECFS Oral Presentation

Professor Griese

September 24, 2020

11:21-11:45 a.m. CET

Impact of elexacaftor/tezacaftor/ivacaftor triple combination therapy on health-related quality of life in people with cystic fibrosis heterozygous for F508del and a minimal function mutation: results from a phase 3 clinical study

ECFS published abstract: Journal of Cystic Fibrosis 19S2 (2020) S55S168, P221

NACFC Poster Presentation #447

Professor Fajac

Oct 7 Oct 23, 2020

Impact of elexacaftor/tezacaftor/ivacaftor triple combination therapy on health-related quality of life in people with cystic fibrosis homozygous for F508del: results from a phase 3 clinical study

ECFS published abstract: Journal of Cystic Fibrosis 19S2 (2020) S1S36, WS19.6

NACFC Poster Presentation #478

Professor Majoor

Oct 7 Oct 23, 2020

IVA

An observational study of ivacaftor in people with cystic fibrosis and selected non-G551D gating mutations: outcomes from the third interim analysis of the VOCAL study

NACFC Poster Presentation

#466

Professor Kors van der Ent

Oct 7 Oct 23, 2020

Ivacaftor in 4 to < 6-month-old infants with a gating mutation: results of a 2-part, single-arm, phase 3 study

NACFC Poster Presentation

#415

Dr. Rosenfeld

Oct 7 Oct 23, 2020

Real-world outcomes in children aged 2-5 with CF treated with ivacaftor

NACFC Poster Presentation

#141

Dr. Volkova

Oct 7 Oct 23, 2020

LUM/IVA

Long-term safety of lumacaftor/ivacaftor in persons with cystic fibrosis aged 2-5 years homozygous for the F508del-CFTR mutation (F/F)

ECFS Published abstract:

Journal of Cystic Fibrosis 19S2 (2020) S1S36, WS19.2

Disease progression in F508del homozygous (F/F) persons with cystic fibrosis treated with lumacaftor/ivacaftor (LUM/IVA): interim results of a long-term safety study using data from the US Cystic Fibrosis Foundation Patient Registry (CFFPR)

ECFS Published abstract:

Journal of Cystic Fibrosis 19S2 (2020) S1S36, WS13.1

NACFC Poster Presentation

#190

Dr. Bower

Oct 7 Oct 23, 2020

About Cystic Fibrosis

Cystic Fibrosis (CF) is a rare, life-shortening genetic disease affecting approximately 75,000 people worldwide. CF is a progressive, multi-system disease that affects the lungs, liver, GI tract, sinuses, sweat glands, pancreas and reproductive tract. CF is caused by a defective and/or missing CFTR protein resulting from certain mutations in the CFTR gene. Children must inherit two defective CFTR genes one from each parent to have CF. While there are many different types of CFTR mutations that can cause the disease, the vast majority of all people with CF have at least one F508del mutation. These mutations, which can be determined by a genetic test, or genotyping test, lead to CF by creating non-working and/or too few CFTR proteins at the cell surface. The defective function and/or absence of CFTR protein results in poor flow of salt and water into and out of the cells in a number of organs. In the lungs, this leads to the buildup of abnormally thick, sticky mucus that can cause chronic lung infections and progressive lung damage in many patients that eventually leads to death. The median age of death is in the early 30s.

INDICATION AND IMPORTANT SAFETY INFORMATION FOR KALYDECO (ivacaftor), TRIKAFTA (elexacaftor/tezacaftor/ivacaftor and ivacaftor), and ORKAMBI (lumacaftor/ivacaftor)

What is KALYDECO?KALYDECO is a prescription medicine used for the treatment of cystic fibrosis (CF) in patients age 6 months and older who have at least one mutation in their CF gene that is responsive to KALYDECO. Patients should talk to their doctor to learn if they have an indicated CF gene mutation. It is not known if KALYDECO is safe and effective in children under 6 months of age.

What is TRIKAFTA?TRIKAFTA is a prescription medicine used for the treatment of CF in patients aged 12 years and older who have at least one copy of the F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Patients should talk to their doctor to learn if they have an indicated CF gene mutation. It is not known if TRIKAFTA is safe and effective in children under 12 years of age.

What is ORKAMBI?ORKAMBI is a prescription medicine used for the treatment of CF in patients age 2 years and older who have two copies of the F508del mutation (F508del/F508del) in their CFTR gene. ORKAMBI should only be used in these patients. It is not known if ORKAMBI is safe and effective in patients under 2 years of age.

Patients should not take KALYDECO or TRIKAFTA if they take certain medicines or herbal supplements, such as: the antibiotics rifampin or rifabutin; seizure medicines such as phenobarbital, carbamazepine, or phenytoin; or St. Johns wort.

Patients should not take ORKAMBI if they take certain medicines or herbal supplements, such as: the antibiotics rifampin or rifabutin; the seizure medicines phenobarbital, carbamazepine, or phenytoin; the sedatives and anti-anxiety medicines triazolam or midazolam; the immunosuppressant medicines cyclosporine, everolimus, sirolimus, or tacrolimus; or St. Johns wort.

Before taking KALYDECO, TRIKAFTA, or ORKAMBI, patients should tell their doctor about all of their medical conditions, including if they: have or have had liver problems; have kidney problems; have had an organ transplant; are pregnant or plan to become pregnant because it is not known if KALYDECO, TRIKAFTA, or ORKAMBI will harm an unborn baby; or are breastfeeding or planning to breastfeed because it is not known if KALYDECO, TRIKAFTA, or ORKAMBI passes into breast milk. Before taking ORKAMBI, patients should tell their doctor if they are using birth control as hormonal contraceptives, including oral, injectable, transdermal, or implantable forms should not be used as a method of birth control when taking ORKAMBI.

KALYDECO, TRIKAFTA, or ORKAMBI may affect the way other medicines work, and other medicines may affect how KALYDECO, TRIKAFTA, or ORKAMBI work. Therefore, the dose of KALYDECO, TRIKAFTA, or ORKAMBI may need to be adjusted when taken with certain medications. Patients should especially tell their doctor if they take antifungal medications such as ketoconazole, itraconazole, posaconazole, voriconazole, or fluconazole; or antibiotics such as telithromycin, clarithromycin, or erythromycin.

KALYDECO or TRIKAFTA can cause dizziness in some people who take it. Patients should not drive a car, use machinery, or do anything that needs them to be alert until they know how KALYDECO or TRIKAFTA affects them.

When taking ORKAMBI, patients should tell their doctor if they stop taking ORKAMBI for more than 1 week as their doctor may need to change the dose of ORKAMBI or other medicines the patient is taking.

Patients should avoid food or drink containing grapefruit or Seville oranges while taking KALYDECO. Patients should avoid food or drink containing grapefruit while taking TRIKAFTA.

KALYDECO, TRIKAFTA, and ORKAMBI can cause serious side effects, such as:

High liver enzymes in the blood have been reported in patients receiving KALYDECO, TRIKAFTA, or ORKAMBI. The patient's doctor will do blood tests to check their liver before starting treatment with KALYDECO, TRIKAFTA, or ORKAMBI; every 3 months during the first year of treatment; and every year while on treatment. For patients who have had high liver enzymes in the past, the doctor may do blood tests to check the liver more often. Patients should call their doctor right away if they have any of the following symptoms of liver problems: pain or discomfort in the upper right stomach (abdominal) area; yellowing of their skin or the white part of their eyes; loss of appetite; nausea or vomiting; or dark, amber-colored urine.

Breathing problems such as shortness of breath or chest tightness in patients when starting ORKAMBI, especially in patients who have poor lung function. If a patient has poor lung function, their doctor may monitor them more closely when starting ORKAMBI.

An increase in blood pressure in some people receiving ORKAMBI. The patients doctor should monitor their blood pressure during treatment with ORKAMBI.

Abnormality of the eye lens (cataract) in some children and adolescents treated with KALYDECO, TRIKAFTA, or ORKAMBI. If the patient is a child or adolescent, their doctor should perform eye examinations before and during treatment with KALYDECO, TRIKAFTA, or ORKAMBI to look for cataracts.

The most common side effects of KALYDECO include headache; upper respiratory tract infection (common cold), which includes sore throat, nasal or sinus congestion, and runny nose; stomach (abdominal) pain; diarrhea; rash; nausea; and dizziness.

The most common side effects of TRIKAFTA include headache, diarrhea, upper respiratory tract infection (common cold) including stuffy and runny nose, stomach (abdominal) pain, inflamed sinuses, increase in liver enzymes, increase in a certain blood enzyme called creatine phosphokinase, rash, flu (influenza), and increase in blood bilirubin.

The most common side effects of ORKAMBI include breathing problems, such as shortness of breath and chest tightness; nausea; diarrhea; fatigue; increase in a certain blood enzyme called creatinine phosphokinase; rash; gas; common cold, including sore throat, stuffy or runny nose; flu or flu-like symptoms; and irregular, missed, or abnormal periods (menses) and increase in the amount of menstrual bleeding. Additional side effects seen in children include: cough with sputum, stuffy nose, headache, stomach pain, and increase in sputum.

These are not all the possible side effects of KALYDECO, TRIKAFTA, or ORKAMBI. Please click product link to see the full Prescribing Information for KALYDECO, TRIKAFTA, or ORKAMBI.

About Vertex

Vertex 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, UK. 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 10 consecutive years on Science magazine's Top Employers list and top five on the 2019 Best Employers for Diversity list by Forbes. 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.

Special Note Regarding Forward-looking Statements

This press release contains forward-looking statements as defined in the Private Securities Litigation Reform Act of 1995, including, without limitation, statements made by Dr. Carmen Bozic in this press release, statements regarding the potential benefits, safety and efficacy of TRIKAFTA, KALYDECO and ORKAMBI, and our plans to present data at the ECFS and the NACFC, including data from our TRIKAFA open-label extension study, scientific abstracts for ORKAMBI and TRIKAFTA, and scientific presentations regarding KALYDECO, ORKAMBI and TRIKAFTA. 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 may not support registration, approval or further development of its compounds due to safety, efficacy or other reasons, risks related to approval and commercialization of our medicines, 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)

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Vertex to Present New Data at European and North American Virtual Cystic Fibrosis Conferences Highlighting Long-Term Use of CFTR Modulators - Business...

getty

In the excitement of todays biotech IPO market, and the bullish period since 2013, its almost hard to remember how painful the equity capital markets were back in the day.

When I began my career in venture capital in 2004, the IPO markets were just opening up after the fallout from the bursting of the tech and genomics twin bubbles in 2001. Great companies like Atlas-backed Alnylam and Momenta were going public. Sixteen years later those two are a $15B commercial-stage biotech and a recent $6.5B acquisition by J&J, respectively very successful biotechs by any measure. But most folks forget that their IPOs were really painful: both priced their offerings ~50% below the mid-point of the expected price range (here, here). This wasnt an uncommon occurrence.

The IPO markets for most of the 2000s never warmed up much. Jazz Pharma, now a high flying $8B company, took it on the chin when it went public in 2007, nearly 30% below its target range. And in 2010, as things emerged from the Global Financial Crisis, the markets continued to be painful: for example, Anacor, acquired later for $5B by Pfizer, came in with an IPO that priced 70% below its target range; Pacira, now $2.5B, was 50% below its IPO mid-point; and Horizon, now $17B, priced its 2011 offering 20% below the range. And those are some of the winners.

Very much related to these challenging pricing discussions, valuations were also extremely constrained back then. Continuing a few of the examples above, Alnylam was preclinical and raised $35M at a $90M pre-money valuation, Momenta was in Phase 3 and raised $40M at $130M, Horizon was also in Phase 3 and raised $50M at $145M. Pre-money valuations during this period was often at or below the private investor cost basis in many IPOs.

In light of that rather bleak market context, in August 2009 I wrote a Nature Biotech article titled Beyond the biotech IPO: a brave new world which reflected on the chronic deterioration in the viability of the public capital markets for the past decade. It was indeed a challenging period.

During most of that decade, terms like over-subscribed, upsized and above-the-range were almost never used to describe biotech IPOs. Yet today, and to a large extent over the past 7 years, they are almost commonplace descriptors of new offerings.And valuations have also changed remarkably, particularly for early stage preclinical and Phase 1 stories.

Before digging into the reasons why, heres a snapshot of some aggregate longitudinal data, courtesy of BMO Capital Markets, relating to how IPOs priced back then versus more recently:

LifeSciVC

The obvious observation from the two left hand panels is that there was pervasive and significant mispricing, or mis-setting, of the expected valuation range in the IPO process of the 2004-2012 period versus the more recent periods. The setting of a price range is often more art than science, and requires gauging likely but not certain IPO-buying behaviors before deciding on the optimal valuation guardrails. But it appears that eager bankers and aspiring biotechs got it wrong way more than they got it right in the 2000s.

And the clear takeaway from the right hand panel is that theres significantly more demand for biotech IPOs today, and hence valuation appreciation.

So what changed in the IPO markets before/after 2012?

Two of the more well-appreciated responses involve (a) greater innovation and (b) the depth of the capital markets.

Biopharma has certainly been innovating and making new medicines that matter, and the markets have paid attention. As a sector weve taken the promises of the prior decades, like those around the Human Genome Project, and begun translating them into real medicines with impact. Think about the advances in precision genetic medicine, engineered cell therapies, gene therapies, oligos, and many others.Further, COVID and our response to it have highlighted the role of science and biopharma in leading us out of this crisis. These innovations are real and will continue to deliver, and the markets have taken notice.

Further, the equity capital markets for biotech are indeed much deeper: there is a lot more capital in the healthcare equity markets across biotech specialists at mutual funds, hedge funds, and even sovereign wealth funds.In particular, early in the period (2011-2015) several of the Big Biotechs drove significant outperformance of the NASDAQ Biotech Index, drawing more investors into the sector. Even though Big Biotech stock appreciation may have waned in the recent few years, many small and mid-cap biotech stocks have outperformed. All of this has deepened the pool of capital churning in the sector in search of the next big one. The feast or famine nature to risk-on/risk-off capital flows, characteristic of the biotech sectors first 30 years, seems to have abated.

The greater capital market interest in biopharma has created a virtuous cycle for the sectors IPOs. In the past, companies often raised less ($30-50M) at challenging valuations, could barely fund their R&D aspirations, and had to come back to the markets frequently. Given the small size of the raise, many large institutional investors couldnt participate: their allocations would be far too small, and the illiquidity too constraining. Today, a much more positive cycle exists: companies are raising more capital, which gives larger funds opportunities to deploy meaningful amounts, which increases demand and raises valuations. These higher valuations enable raising more capital without taking on dilution beyond the typical 20-25% IPO range. More capital means more robust R&D programs and broader pipelines. A positive cycle, for sure, and one that has enabled larger generalist pools of capital to participate in the sector.

These two dynamics innovation and the deeper capital markets - are certainly valid, and explain a lot of the increase in valuations and interest in the space.

But they dont explain the more efficient IPO pricing process in the recent period relative to the 2000s with regard to the expected valuation range.

Two major structural changes to the way IPOs get launched explain that change: the JOBS Act and the rise of the crossover round have unleashed a much more efficient price discovery mechanism in the post-2012 era.

Jumpstarting IPO efficiency

The Jumpstart Our Business Startups (JOBS) Act is the unsung hero of the biotech IPO boom since its passage in 2Q 2012. While largely discounted by the tech sector, the impact of the JOBS Act on biotech IPOs cant be over-estimated in my opinion.

Candidly, I dont think any of the financial reporting or cost reduction elements of the law, widely touted as really important at the time for Emerging Growth Companies,have actually had any meaningful impact, as supported by other research (here).

However, the two primary de-risking elements of the JOBS Act were profoundly important in biotech:

Several factors contributed to the uncertainty in pricing before the JOBS Act. Given the complexity of the science behind most biotechs, especially early stage stories, and the lack of insight financial modeling provides in many of these, jumping into a biotech IPO as a public investor is difficult to do after one short initial meeting during the traditional road show. This is in part why crossover investing has appeal: the ability to do deep due diligence in a private round to establish conviction about an upcoming IPO.

Furthermore, bankers competing for underwriting business are often picked for telling a management team and Board that their company is worth a lot. Perhaps a lot more than it really is worth.And without the TTW process of price discovery, the initial price ranges for many IPOs of the pre- JOBS Act era were inflated as a consequence.

The JOBS Act helped resolve those inefficiencies in price-setting.

Crossover rounds: the quest for alpha.

Crossover rounds are name given to venture financings that are meant as the last private round before a public offering and involve investors that are typically public market players.These have become commonplace today as biotechs chart their path to an IPO.

While nowhere near as frequent as in todays market, crossover rounds did happen before.And they didnt protect a company from mispricing their IPO ranges.Merrimack Pharma, priced just before the JOBS Act, had a marquee list of public investors in their last private rounds; unfortunately, MACK still priced below the range, 22% below the midpoint, in March 2012.Other 2010-2011 IPOs with public crossovers involved included Ironwood and Tengion, both of which came in below their targeted range. Much of the insider participation in many of these IPOs came from crossover investors, a characteristic that remains true today.

The crossover phenom in biotech really caught momentum in the 2012-2014 period immediately following the JOBS Act. This was in large part driven by the quest for alpha.Just playing the market indices wasnt enough. To outperform, there was a belief you needed the alpha of picking the beset new IPOs and catching the pop.Generally speaking, biotech IPOs were performing well in that period (see here for 2011-2012, 2013, 2014), but in order to get a meaningful allocation and a good cost basis, many public investors would seek out these private rounds to secure positions. And, as noted in a blog here in 2014, the involvement of the best blue-chip crossover investors appeared to be a good biomarker for an IPOs quality: better valuations, bigger raises, and stronger aftermarket performance in the 2012-2014 period.

The positive dynamic of meaningful crossover involvement has continued since that period. Crossover rounds have multiple benefits. As noted above, they allow public investors a chance to thoroughly evaluate a biotech before the TTW process. By doing so, they enable a biotech to build deeper relationships with important public buysiders.They also strengthen the balance sheet.

And they help guide the price of the IPO. Bankers love to use the step-up analysis to put guardrails on the IPO price: if the median step-up of the last 25 offerings is 1.4-1.5x, then thats where they will typically start. Take a 40-50% premium to the price of the crossover round, and thats often the mid-point of the valuation range. And with the crossovers providing significant insider participation in the IPO, they help to stabilize pricing around that expected range or at least not below that range.

This crossover phenom has definitely contributed to the dramatic reduction in the frequency of below the range mispricings in the past few years.

New structural change: virtual IPO roadshow?

While crossover participation and the two major derisking elements of the JOBS Act are both continuing to support a vibrant IPO market, the reality is the traditional IPO process still creates a challenging tension on valuation for companies.

Crossover investors often just have a toehold position pre-IPO, and want to put a lot more capital to work in the IPO and beyond so they arent necessarily incentivized for higher prices.The friendly cabal of thought-leader buyside accounts wield significant influence on how an IPO comes together.

Ultimately, its the sense of scarcity and demand that drives a truly successful IPO, and this sentiment is often borne out of how the early book-building process happens in an IPO.Do you have just 1x of the expected raise covered with demand by the end of the first day, or is it 4-5x? The faster that book builds, and with what quality, sends a very strong message to the market.

Traditionally, an IPO roadshow would take 7-9 days, interacting with 100+ investors and traveling all over the country. The IPO order book would build slowly at first, with many investors waiting to get a read of the sentiment from the underwriters. Further, the buyside would call each other and talk about the deal. There was always a weekend in between, when investors could further watch and wait to see how things were coming together. I wont suggest theres been collusion on constraining pricing, though there might be, but the orderly and rather prolonged process of the roadshow put most of the leverage on the side of the buyers, not the sellers (biotech).

This is where COVID comes in and the launch of the virtual IPO roadshow. I think this is a structural change that flips that balance, helping biotechs regain some of the leverage and create a more efficient market for their offering.

The virtual IPO roadshow is typically only 4 days, and some stronger IPOs close their books on the night of the 3rd. Management teams meet the same number of investors, but they do it via videoconferencing without the travel friction and distractions. The book-building happens quickly, and exposes the company to less market volatility. If buysiders like the story, they cant wait to see how the book builds over the first 5-6 days of a traditional roadshow. They need to put their orders in quickly or will miss out. The virtual roadshow helps inject some FOMO into the biotech IPO process, and thats a good thing for companies.

The data appear to support this conclusion: since the first virtual roadshow in April 2020, nearly every IPO has priced at or above the range (as shown in the charts above). Demand has been strong, and upsizing above the range has been a common occurrence.

Of course, overall sentiment towards biotech has been strong since hitting the bottom in March and has obviously been a positive force for driving IPO demand. If (when) that sentiment cools, there will certainly be some less successful IPOs, especially if the quality of the stories declines in frothier moments. That said, weve had strong periods for the biotech equity markets since 2012, with robust numbers of IPOs, and yet never saw pricing at or above the range with this frequency. I think, at least in part, the strength of the recent IPO market is the result of a structural change associated with the virtual 3-4 day roadshow process.

Critics might also say if so many biotechs are pricing above the range it means the underwriters are underpricing them. If valuations were low, I might share this view. But with IPO valuations moving upwards, as shown in the prior chart, its hard to see merit in that critique in aggregate - though there is certainly mispricing (up and down) on specific stories.

Todays IPOs are some of the most highly-valued offerings weve ever seen, and the price setting mechanisms in the S1/IPO process are much more efficient than before. There are still challenges with how the IPO process enables companies to access the capital markets, which in large part explains the rise of SPACs (Special Purpose Acquisition Companies) as an alternative path to IPO (and likely the subject of a future blog).

As we all know, a biotech IPO is really just a financing to help fuel an R&D pipeline and today theres much more capital being allocated to fund those pipelines. Of course, positive post-IPO performance is far more important than the IPO pricing event itself, and often reflects the generation of exciting data or deal-making that further advances the companys prospects (or not).

But a healthy, efficient IPO process that unlocks strong demand in the equity markets is a critical step in the biotech lifecycle and its evident there are many structural and market forces contributing to that positive dynamic today.

So whats the next decade of IPO financings going to look like?Lots of reasons for optimism, but its anyones guess given how much has changed durably from a decade ago, and market cycles will always play a role.

Continue reading here:
Evolution Of The Biotech IPO Markets From Busted To Booming - Forbes

Summary

In a study of people with lung cancer whose tumors contained the mutation targeted by sotorasib, 52 of 59 patients experienced disease control, which means that their tumors stopped growing.

Targeted therapies aim to block the activity of genes that cause cancer, providing a direct attack on tumors while sparing healthy cells. Identifying genes that trigger tumor growth is only the first hurdle to developing targeted drugs just because investigators know a gene may cause cancer doesnt mean they can prevent it from wreaking havoc.

The cancer gene KRAS (pronounced kay-rass) is a case in point. Its been studied for about 40 years and is known to be responsible for many of the most common cancers. This includes about one-quarter of lung cancers and between one-third and one-half of colon and rectal cancers. Until recently, however, the KRAS protein was considered an undruggable target.

On September 20, 2020, in the New England Journal of Medicine (NEJM), investigators reported results from CodeBreak 100, the first-ever clinical study of a drug that directly targets KRAS. In this international phase 1 trial, researchers found that a drug called sotorasib (AMG 510) slowed or stopped cancer growth in many people with advanced cancer that had a KRAS mutation. The investigators say much more research is needed to determine how to best use this drug, but this trial is a significant first step.

KRAS was one of the first cancer genes discovered and is the most common cancer-causing gene.

Sotorasib is not a cure, but this study is the first to crack KRAS in a clinically meaningful way, says Memorial Sloan Kettering medical oncologist Bob Li, a senior investigator and corresponding author of the study. Its an important step forward, but its not yet a home run.

The challenge in targeting the KRAS gene comes from the uncommon shape of the KRAS protein. Most proteins have a lumpy, irregular shape, with many clefts and pockets where a drug can wedge in. When this happens, a drug can act as a key, locking up a protein and shutting down its activity. By contrast, the KRAS protein is quite round and smooth, Dr. Li explains. Theres no lock-and-key approach.

In 2013, researchers at the University of California, San Francisco, reported there may be a way in: They found a small pocket in a version of the mutant KRAS protein, called KRAS-G12C, and designed a drug to fit into this pocket when it was open.

In 2016, MSK physician-scientists Piro Lito and Neal Rosen published a study that built on this work. They described the trapping mechanism that enables the new class of drugs to shut down the growth of cancer cells driven by the KRAS-G12C mutation.

When one of these drugs goes in the proteins pocket, it traps KRAS-G12C in its off state, says Dr. Lito, who is also a senior author on the new NEJM paper. The protein cant wake up, and the tumor cell cannot grow.

Sotorasib, which was developed by investigators at the biopharmaceutical company Amgen, is an improved and more potent KRAS-G12C inhibitor. Combining their respective strengths in phase 1 clinical trial development and translational science, Drs. Li and Lito partnered with Amgen to bring the first-in-class KRAS-G12C inhibitor sotorasib to patients.

In the trial for sotorasib, 129 people whose tumors had KRAS-G12C received the drug, which is taken as a pill. Fifty-nine of them had non-small cell lung cancer, 42 had colorectal cancer, and 28 had other types of tumors. All of the study participants had disease that spread to other parts of the body; they already had received an average of three previous treatments. The trial included people treated at more than two dozen hospitals around the world.

Among those 59 people with lung cancer, seven patients did not respond and 52 experienced disease control (which means that their tumors either stopped growing or shrank). In that group of 52, 19 patients had their tumors shrink substantially. The average time until the disease got worse was about six months. That level of response is significant for this population of patientsbecause most of them have exhausted other treatment options. Dr. Li explains.

We're already thinking one step ahead about how to use this drug for the greatest benefit of people who need it.

A little more than half of the people in the trial (73 patients) had some side effects, but only 15 of them had significant side effects. All but one patient were able to safely continue the drug when the side effects resolved, and no one died from side effects. Because the drug is selective for this specific KRAS mutation, it was well tolerated by patients, Dr. Lito says. It only binds to and inhibits the mutated form of the protein in cancer cells. This is important because it enables high doses of the drug to be safely administered.

Responses for other types of cancer including colorectal cancer, as well as pancreatic, endometrial (uterine), and appendiceal cancers and melanoma were not as good as they were for lung cancer. But some patients with those other cancers did benefit with substantial tumor shrinkage. The investigators plan to study why sotorasib appears to work better in some types of cancer than it does in others, even when the cancers have the same mutated protein. Additional trials are already underway to continue studying sotorasib, both alone and in combination with other drugs.

Research on how to block KRAS is continuing in the laboratory as well. In January 2020, Dr. Litos lab published a study that looked at new approaches for combining KRAS inhibitors with other drugs. Were taking what weve learned in patients back to the bench to continue developing new treatments, Dr. Lito says. Were already thinking one step ahead about how to use this drug for the greatest benefit of people who need it.

The results from this clinical trial are also being presented at the European Society for Medical Oncology 2020 Virtual Congress.

The rest is here:
Promising Results from the First-Ever Trial of a Drug that Blocks Cancer Gene KRAS - On Cancer - Memorial Sloan Kettering

Genetic Testing to Establish Strong Foothold in Current and Future Healthcare System

The notable rise in the demand for hereditary genetic testing over the past few years is one of the major factors that is expected to fuel the growth of the global genetic analysis services market in the upcoming decade. Technological advancements coupled with the drive to discover new and innovative genetic analysis techniques are set to shape the overall growth trajectory of the global genetic analysis services market during the forecast period. Over the past decade, the genome testing sector has witnessed consistent developments due to which, the global genetic analysis services market is anticipated to expand at an impressive rate during the assessment period.

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Hereditary genetic testing has emerged as ideal, and a rapidly evolving technology within the genetic analysis services market. This is likely to continue, owing to advancements in technology and findings of research activities. The increasing demand for improved and cutting-edge prediction and diagnostic tools and services coupled with surge in demand for disease monitoring is anticipated to play a key role in the overall growth of the global genetic analysis services market during the assessment period.

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Healthcare experts and credible researchers around the world are of the opinion that genetic testing is expected to be the future of the healthcare ecosystem. Advancements in the biomedical field coupled with the notable rise in the number of companies that are developing new genetic-testing kits are expected to augment the global genetic analysis services market during the forecast period. Moreover, as interest levels for precision medicine continues to witness sizeable growth around the world, as a result of which the demand for genetic analysis services is projected to grow at an impressive pace.

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Uptake of Next-generation Sequencing and Multi-gene Tests to Drive Market

Advancements in the genetic technology are likely to play an instrumental role in shaping the growth trajectory of the global genetic analysis services market during the forecast period. Furthermore, due to advancements in technology, the scope of genetic testing has widened by a considerable margin due to which, the demand for genetic analysis services is increasing. While genetic analysis services in the past were largely time-consuming and cumbersome, at present, increasing speed and availability of genomic testing are anticipated to present a plethora of opportunities to the players involved in the current market landscape for genetic analysis services.

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In addition, the gradual shift in the point of access to testing is evolving, as more number of consumers can avail genetic analysis services outside the healthcare setting. Advancements in genetic medicine at the back of advancements in technology are likely to bolster the growth of the global genetic analysis services market during the assessment period.

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Research and Development Activities in Full Swing amid COVID-19 Pandemic

Research and development activities are expected to continue in full swing amid the ongoing COVID-19 pandemic. The significant rise in the demand for genetic counseling services during the ongoing COVID-19 crisis is anticipated to generate consistent revenue for the players involved in the genetic analysis services market. Furthermore, researchers and scientists are increasingly focusing on discovering genetic mechanisms that are required to prevent the spread and transmission of the novel coronavirus disease. Genetic research is estimated to unlock various intricate details of the novel coronavirus, thereby opening up new opportunities for mitigation. The ongoing research pertaining to genetics and its correlation with the ongoing pandemic is expected to provide a detailed and microscopic understanding of the overall cellular mechanisms of the virus.

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Genetic Analysis Services Market: Uptake of Next-generation Sequencing and Multi-gene Tests to Drive Market - BioSpace

(UroToday.com)The KEYNOTE-052 trial showed that pembrolizumab monotherapy has durable antitumor activity as first-line therapy in cisplatin-ineligible patients with locally advanced unresectable or metastatic urothelial carcinoma (UC)1. Moreover, pembrolizumab has also shown durable activity as 2nd line therapy in patients with platinum-refractory advanced UC in the KEYNOTE-045 trial2.

Immune gene expression profiling in UC has the potential to identify patients whose tumors are more likely to respond to antiPD-1/PD-L1 treatment3,4. Several factors have been shown to be associated with resistance to antiPD-1/PD-L1 treatment in advanced UC5. These include stromal tumor microenvironment, epithelial to mesenchymal transition (EMT), and transforming growth factor-beta (TGF-) gene expression signatures.

In an exploratory biomarker analysis of KEYNOTE-052, response to pembrolizumab was positively associated with the 18-gene T-cellinflamed gene expression profile (GEP) and negatively associated with a stromal signature (stroma/EMT/TGF-)6,7.

The objective of the presented study was to determine the association of T-cellinflamed GEP and stromal signatures with outcomes in patients treated with pembrolizumab monotherapy in an exploratory analysis of advanced UC patients from the KEYNOTE-045 trial (NCT02256436).

The KEYNOTE-045 trial was an open-label, international, phase 3 trial (N = 542)2 (Figure 1). Patients were randomly assigned 1:1 to receive either pembrolizumab 200 mg every three weeks or the investigator's choice of chemotherapy (paclitaxel, docetaxel, or vinflunine). Association of the signatures as continuous variables with the outcomes was assessed in each treatment arm separately, using univariate analysis, performed using logistic regression (objective response rate [ORR]), and Cox proportional hazards (progression-free survival [PFS], overall survival [OS]) modeling, adjusted for Eastern Cooperative Oncology Group (ECOG) performance status.

Figure 1 KEYNOTE 045 trial:

The results demonstrated that 147 of 266 pembrolizumab-treated patients (55%) and 127 of 255 chemotherapy-treated patients (50%) had available RNA-sequencing data. Key baseline characteristics were similar between the overall study population and the population with available RNA-sequencing data.

The results show that T-cellinflamed GEP, as a continuous variable, was positively associated with ORR to pembrolizumab but not to chemotherapy (Table 1). There was no association with PFS or OS in either the pembrolizumab or chemotherapy group (table 1). Pembrolizumab improved PFS and OS vs. chemotherapy in the T-cellinflamed GEP non-low group (Figure 1). The stromal signature, assessed as a continuous variable, was not associated with favorable outcomes with pembrolizumab (Figures 3 and 4).

Table 1 - Association Between T-CellInflamed GEP/Stromal Signature and Clinical Outcomes in Each Treatment Group:

Figure 1- Clinical Utility of the Prespecified T-CellInflamed GEP Cutoff for objective response rate:

Figure 2 Clinical Utility of the Prespecified T-CellInflamed GEP Cutoff for PFS and OS:

Figure 3 Clinical Utility of the Prespecified Stromal Signature Median for objective response rate:

Figure 4 - Clinical Utility of the Prespecified Stromal Signature Median for PFS for stromal >= median, PFS for stromal < median, OS for stromal >=median, OS for stromal

In conclusion, this exploratory biomarker analysis of patients with advanced UC, T-cellinflamed GEP, as a continuous variable, was positively associated with ORR to pembrolizumab but not chemotherapy. No association with PFS or OS was observed in either the pembrolizumab or chemotherapy group. HR estimates using a prespecified T-cellinflamed GEP cutoff suggested that pembrolizumab improved PFS and OS vs.

Chemotherapy in the T-cellinflamed GEP non-low group.

T-cellinflamed GEP should continue to serve as a useful exploratory gene signature to support the mechanism of action of pembrolizumab in highly inflamed tumors. The stromal signature assessed as a continuous variable was not associated with favorable outcomes with pembrolizumab. HR estimates, using a prespecified stromal median, did not support the hypothesized negative association between increased stromal signature median and response to pembrolizumab previously observed in KEYNOTE-0527.

More analyses are currently exploring differences in the association of the stromal signature with pembrolizumab between KEYNOTE-052 and KEYNOTE-045. It is worth mentioning that patients in KEYNOTE-045 received therapy before enrollment, potentially affecting the tumor microenvironment and limiting the ability of the stromal signature to predict response to pembrolizumab.

Presented by: Dr. Petros Grivas, Associate Professor and the Clinical Director of the Genitourinary Cancers Program at the University of Washington, and an Associate Member of the Clinical Research Division at the Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America

Written by: Hanan Goldberg, MD, MSc., Assistant Professor of Urology, SUNY Upstate Medical University, Syracuse, NY, USA @GoldbergHananat the European Society for Medical Oncology Virtual Congress, ESMO Virtual Congress 2020 #ESMO20, 18 Sept - 21 Sept 2020

References:

1.Balar AV, Castellano D, O'Donnell PH, et al. First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2 study. The Lancet Oncology 2017; 18(11): 1483-92.2.Bellmunt J, de Wit R, Vaughn DJ, et al. Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma. New England Journal of Medicine 2017; 376(11): 1015-26.3. Ayers M, Lunceford J, Nebozhyn M, et al. IFN--related mRNA profile predicts clinical response to PD-1 blockade. The Journal of clinical investigation 2017; 127(8): 2930-40.4. Cristescu R, Mogg R, Ayers M, et al. Pan-tumor genomic biomarkers for PD-1 checkpoint blockade-based immunotherapy. Science (New York, NY) 2018; 362(6411).5. Wang L, Saci A, Szabo PM, et al. EMT- and stroma-related gene expression and resistance to PD-1 blockade in urothelial cancer. Nature Communications 2018; 9(1): 3503.6. O'Donnell PH, Plimack ER, Bellmunt J, et al. Pembrolizumab (Pembro; MK-3475) for advanced urothelial cancer: Results of a phase IB study. Journal of Clinical Oncology 2015; 33(7_suppl): 296-.7. Grivas P, Castellano DE, O'Donnell PH, et al. Association between stromal/TGF-/EMT gene expression signature and response to pembrolizumab monotherapy in cisplatin-ineligible patients with locally advanced (unresectable) or metastatic urothelial carcinoma. Journal of Clinical Oncology 2019; 37(7_suppl): 433-.

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ESMO Virtual Congress 2020: Association Between Gene Expression Signatures and Pembrolizumab Efficacy in Pa... - UroToday

DBMR has added a new report titled Global Precision Medicine Market with analysis provides the insights which bring marketplace clearly into the focus and thus help organizations make better decisions. This Global Precision Medicine Market research report understands the current and future of the market in both developed and emerging markets. The report assists in realigning the business strategies by highlighting the business priorities. It throws light on the segment expected to dominate the industry and market. It forecast the regions expected to witness the fastest growth. This report is a collection of pragmatic information, quantitative and qualitative estimation by industry experts, the contribution from industry across the value chain. Furthermore, the report also provides the qualitative results of diverse market factors on its geographies and Segments.

Global Precision Medicine Market to grow with a substantial CAGR in the forecast period of 2019-2026. Growing prevalence of cancer worldwide and accelerating demand of novel therapies to prevent of cancer related disorders are the key factors for lucrative growth of market

Global Precision Medicine Market By Application (Diagnostics, Therapeutics and Others), Technologies (Pharmacogenomics, Point-of-Care Testing, Stem Cell Therapy, Pharmacoproteomics and Others), Indication (Oncology, Central Nervous System (CNS) Disorders, Immunology Disorders, Respiratory Disorders, Others), Drugs (Alectinib, Osimertinib, Mepolizumab,Aripiprazole lauroxil and Others), Route of Administration (Oral,Injectable), End- Users (Hospitals, Homecare, Specialty Clinics, Others), Geography (North America, South America, Europe, Asia-Pacific, Middle East and Africa) Industry Trends and Forecast to 2026

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Competitive Analysis:

The precision medicine market is highly fragmented and is based on new product launches and clinical results of products. Hence the major players have used various strategies such as new product launches, clinical trials, market initiatives, high expense on research and development, agreements, joint ventures, partnerships, acquisitions, and others to increase their footprints in this market. The report includes market shares of mass spectrometry market for global, Europe, North America, Asia Pacific and South America.

Market Definition:

Precision medicines is also known as personalized medicines is an innovative approach to the patient care for disease treatment, diagnosis and prevention base on the persons individual genes. It allows doctors or physicians to select treatment option based on the patients genetic understanding of their disease.

According to the data published in PerMedCoalition, it was estimated that the USFDA has approved 25 novels personalized medicines in the year of 2018. These growing approvals annually by the regulatory authorities and rise in oncology and CNS disorders worldwide are the key factors for market growth.

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Market Drivers

Market Restraints

Key Developments in the Market:

Competitive Analysis:

Global precision medicine market is highly fragmented and the major players have used various strategies such as new product launches, expansions, agreements, joint ventures, partnerships, acquisitions, and others to increase their footprints in this market. The report includes market shares of global precision medicine market for Global, Europe, North America, Asia-Pacific, South America and Middle East & Africa.

Key Market Players:

Few of the major competitors currently working in the global precision medicine market are Neon Therapeutics, Moderna, Inc, Merck & Co., Inc, Bayer AG, PERSONALIS INC, GENOCEA BIOSCIENCES, INC., F. Hoffmann-La Roche Ltd, CureVac AG, CELLDEX THERAPEUTICS, BIONTECH SE, Advaxis, Inc, GlaxoSmithKline plc, Bioven International Sdn Bhd, Agenus Inc., Immatics Biotechnologies GmbH, Immunovative Therapies, Bristol-Myers Squibb Company, Gritstone Oncology, NantKwest, Inc among others.

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Market Segmentation:

By technology:- big data analytics, bioinformatics, gene sequencing, drug discovery, companion diagnostics, and others.

By application:- oncology, hematology, infectious diseases, cardiology, neurology, endocrinology, pulmonary diseases, ophthalmology, metabolic diseases, pharmagenomics, and others.

On the basis of end-users:- pharmaceuticals, biotechnology, diagnostic companies, laboratories, and healthcare it specialist.

On the basis of geography:- North America & South America, Europe, Asia-Pacific, and Middle East & Africa. U.S., Canada, Germany, France, U.K., Netherlands, Switzerland, Turkey, Russia, China, India, South Korea, Japan, Australia, Singapore, Saudi Arabia, South Africa, and Brazil among others.

In 2017, North America is expected to dominate the market.

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Global Precision Medicine Market 2020 Overview By Size, Share, Trends, Growth Factors and Leading Players With Detailed Analysis of Industry Structure...

DUBLIN--(BUSINESS WIRE)--The "Gene Expression Market By Product And Services, By Capacity, By Application, And Segment Forecasts To 2027" report has been added to ResearchAndMarkets.com's offering.

Increasing demands for cancer medicines, falling cost of sequencing procedures, and a rise in demand for personalized medicines are key factors contributing to the high CAGR of the gene expression market during the forecast period.

The Global Gene Expression Market is expected to reach USD 6.78 billion by the year 2027, in terms of value at a CAGR of 8.1% over the forecast period. Gene expression promises to tap into a previously unexplored segment in the vast and burgeoning genetic engineering industry.

An increase in investments towards technological advancements and a rise in healthcare expenditure are estimated to shape the growth of the gene expression market. Drug discovery & development and increased demand for personalized medicine in chronic diseases, such as cancer, would be the most lucrative applications for gene expression analysis in the forecast period. Application of gene expression in clinical diagnostics, on the other hand, will reflect a moderate growth throughout the analysis period. Moreover, the falling costs of sequencing have facilitated the integration of genomic sequencing into medicine. With the increased availability and lowering costs of DNA technologies, gene expression has become a more readily used tool indispensable in drug discovery and development. Many companies and educational institutions are collaborating to make gene expression publicly accessible through databases, such as the Connectivity Map (CMap), Library of Integrated Network-based Cellular Signatures (LINCS), and the Tox 21 project.

Further key findings from the report suggest:

Key Topics Covered:

Chapter 1. Market Synopsis

Chapter 2. Executive Summary

Chapter 3. Indicative Metrics

Chapter 4. Gene Expression Market Segmentation & Impact Analysis

Chapter 5. Gene Expression Market By Product and Services Insights & Trends

Chapter 6. Gene Expression Market By Capacity Insights & Trends

Chapter 7. Gene Expression Market By Application Insights & Trends

Chapter 8. Gene Expression Market Regional Outlook

Chapter 9. Competitive Landscape

Chapter 10. Company Profiles

For more information about this report visit https://www.researchandmarkets.com/r/h0rxkm.

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Global Gene Expression Market By Product And Services, By Capacity, By Application, And Segment Forecasts To 2027 - ResearchAndMarkets.com - Business...

As the precision medicine field evolves and the science behind personalized therapies for complex conditions surges ahead, reimbursement models are racing to catch up. Precision medicine treatments, like cell and gene therapies, tend to have high price tags and novel delivery mechanisms. This makes creating effective payment models for these therapies a challenge, but drug developers and payers are working together to create out-of-the-box solutions.

Determining prices for breakthrough cell and gene therapies is a complicated process, said Laura Okpala, director of reimbursement policy at Gilead Sciences, at the MedCity INVEST Precision Medicine conference. Though there is a strong belief that the pricing process needs to be driven by value value means different things to different people. Biopharmaceutical companies, like Gilead Sciences, must consult with various stakeholders, including patients, caregivers and payers, who all have different perspectives on value.

Part of why the pricing is so difficult is because of the inherent complexities in the healthcare system, Okpala said. When we think of traditionally how drugs are paid for, were thinking about chronic treatment, were thinking about treatment over a long, extended period, treatment over and over again, reimbursement every single time, and that adds up.

But when you think about cell and gene therapies, all those costs and all of that treatment happens upfront, she added. And then you get that durable response, up to four years at this point. And that is really a paradigm shift when you think about [a] healthcare system that really isnt set up to deal with that upfront cost and that value delivered over time.

But the upfront payment is just one of many challenges. Mark Trusheim, strategic director of the NEWDIGS initiative at the MIT Center for Biomedical Innovation, said at the virtual conference that there are two more key challenges that arise: the performance uncertainty regarding these therapies, particularly around their durability, and the actuarial uncertainty it causes for payers. Most of these therapies are for rare conditions, so a single high-cost therapy in any given month can have a negative impact on payers income statements.

To combat these challenges, several innovative reimbursement models have been developed.

One is a model based on treatment milestones. Per this model, a certain amount of money is paid upfront, and if the therapy doesnt show the intended effects in certain predetermined timeframes, the drug developer pays back a portion of the initial payment.

[The model allows] some risk sharing between the developer and the payer, so they dont have to argue quite so much up front, Trusheim said. And the actual product performance [resolves] how much [is] finally the net reimbursement or the net price for that therapy.

This model helps manage the different expectations and fears of both parties, he added.

Another is a subscription-based model, which includes a fixed fee for unlimited access to certain therapies, Trusheim explained. Cigna has an insurance product that offers this reimbursement model, where plan members contribute a certain amount each month that is used to pay for therapies as needed. Cigna takes on the risk, guaranteeing that they will provide as much therapy as the members require.

This model is a great example of how payers can manage the actuarial fluctuation that occurs when funding cell and gene therapies, Trusheim said. But it comes with its challenges, because in some cases, its difficult to ascertain the eligible population for a particular therapy especially if there are alternate therapies already available.

But Trusheim is confident that innovation in reimbursement will catch up to clinical innovation in the precision medicine arena.

Were now in an era where innovation in payment structures and approaches are beginning to match the kind of innovation we have in the transformative science for patients, he said. Successfully providing patient access and benefit requires both kinds of innovation, not just scientific innovation. The creativity is there we are going to succeed. Just as the science has succeeded, the payment innovation is also moving forward and having success.

Photo credit: Devrimb, Getty Images

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Innovative payment models to support cell and gene therapies on the rise - MedCity News

SwanBio has been making tremendous progress in the advancement of our AAV-based pipeline of therapeutics for the treatment of neurological diseases, and we are thrilled to expand our Board of Directors with these key appointments, said Tom Anderson, Chief Executive Officer of SwanBio. Patty, Danny and Alex each bring a wealth of knowledge and expertise within their individual focus-areas, and their insights will be invaluable as we advance toward becoming a clinical company. We look forward to benefiting from their experience and collaborating on the important work ahead to deliver new medicines to patients with devastating diseases.

Im pleased to join the SwanBio Board of Directors, along with Danny and Alex, at this pivotal moment in the companys evolution, said Ms. Allen. SwanBio is driven by an exceptional team and founded based on innovative science, with a gene therapy approach that could make a significant difference for a number of people who suffer from genetic neurological diseases. I am excited for the future of this company and the opportunity to help guide them forward.

Ms. Allen is a business finance and operations leader with more than 25 years of experience leading private and public companies through initial public offerings, equity and debt financings, SEC reporting, investor relations, sell-side and buy-side, strategic and long-range planning, FP&A, treasury, risk management and business development. Most recently, she served as Chief Financial Officer of Zafgen, Inc. (now Larimar Therapeutics) from 2013-2020. Prior to Zafgen, Ms. Allen was an independent financial consultant from 2011-2012; served as Vice President of Finance, Treasurer and Principal Financial Officer of Alnylam Pharmaceuticals, Inc from 2004-2011; and as Director of Finance at Alkermes from 1992-2004. Ms. Allen also serves as a Director on the Board of Directors of several biotechnology companies and serves as the Chair of their Audit Committees. Ms. Allen graduated summa cum laude from Bryant College with a B.S. in business administration.

Dr. Bar-Zohar is a certified physician with proven expertise in drug development and a personal commitment to change peoples lives by developing sustainable, transformative healthcare solutions using both traditional and emerging technologies. He was recently appointed Global Head of Development at Merck KGaA in Darmstadt, Germany. Prior to Merck KGaA, Dr. Bar-Zohar was a Partner at Syncona and held various roles at Novartis Pharma AG from 2013-2020, most recently serving as Global Head, Clinical Development and Analytics. Before Novartis, Dr. Bar-Zohar held various clinical and medical affairs roles at Teva Pharmaceuticals Industries from 2006-2012. He obtained his medical doctor degree at the Sackler Faculty of Medicine, Tel-Aviv University and was trained in general surgery at the Tel-Aviv Medical Center.

Dr. Hamilton is an experienced financial leader within the biotech and pharmaceutical industries. Since SwanBios founding, Dr. Hamilton has played a key role in helping shape the companys strategy as a Board Observer. Before joining Syncona, he was a member of the Healthcare Investment Banking team at Jefferies International, where he worked on a range of financings and mergers and acquisitions across the biotechnology, pharmaceutical and healthcare sectors. Dr. Hamilton received his Ph.D. in immunology from the University of Cambridge.

About SwanBio Therapeutics

SwanBio Therapeutics is a gene therapy company that aims to bring life-changing treatments to people with devastating, genetically defined neurological conditions. SwanBio is advancing a pipeline of AAV-based gene therapies, designed to be delivered intrathecally, that can address targets within both the central and peripheral nervous systems. This approach has the potential to be applied broadly across three disease classifications spastic paraplegias, monogenic neuropathies and polygenic neuropathies. SwanBios lead program is being advanced toward clinical development for the treatment of adrenomyeloneuropathy (AMN). For more information, visit SwanBioTherapeutics.com.

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SwanBio Therapeutics Expands Board of Directors with Appointments of Proven Industry Leaders - BioSpace

PLYMOUTH MEETING, Pa., Dec. 3, 2020 /PRNewswire/ -- INOVIO (NASDAQ:INO), a biotechnology company focused on bringing to market precisely designed DNA medicines to treat and protect people from infectious diseases and cancer, today announced the execution of an agreement with Kaneka Eurogentec S.A., an affiliate of Kaneka Corporation, for Eurogentec to manufacture INOVIO's COVID-19 vaccine candidate INO-4800 at their industry-leading GMP plasmid production scales. Terms of the agreement were not disclosed.

Kaneka Eurogentec joins existing partners Thermo Fisher Scientific, Richter-Helm BioLogics and Ology Biosciences in INOVIO's global manufacturing consortium. Each contract development and manufacturing organization that has been selected to join the consortium is compliant with commercial GMP standards and capable of supporting INOVIO's future large-scale global manufacturing needs across its portfolioof DNA medicines and vaccines.

INOVIO's President & CEO, Dr. J. Joseph Kim, said, "Our partnership with Kaneka Eurogentec, one of the world's largest and most experienced plasmid manufacturers, provides additional scale to our growing global manufacturing coalition. Kaneka Eurogentec will be a crucial member of INOVIO's global manufacturing consortium, supporting our plans to produce, manufacture and scale our COVID-19 vaccine candidate, INO-4800."

Dr. Lieven Janssens, Kaneka Eurogentec's President and CEO, said, "We are excited to join INOVIO's growing global manufacturing consortium and look forward to supporting the manufacturing needs of DNA medicines and vaccines across INOVIO's platform. We are pleased that our large-scale manufacturing technologies are well-recognized by INOVIO, a leading player in the DNA plasmid field."

INOVIO's Senior Vice President of Biological Manufacturing and Clinical Supply Management, Robert J. Juba Jr., said, "Kaneka Eurogentec brings a wealth of DNA plasmid manufacturing expertise and innovation to INOVIO's global consortium to manufacture INO-4800. We look forward to working with them to utilize their state-of-the-art, large-scale manufacturing capabilities towards our goal of producing hundreds of millions of doses of INO-4800 for worldwide distribution."

INOVIO recognizes the importance of having a robust coalition to support its broader development platform for DNA medicines as well as its COVID-19 vaccine candidate, INO-4800. As a result, the company continues to build the coalition to ensure timely, cost-effective and scalable production of DNA medicines and vaccines. INOVIO's third-party manufacturers will produce the patent-protected formulation for INO-4800, developed to enhance stability of the vaccine with a favorable tolerability profile. Importantly, INO-4800 has shown an excellent thermo-stability profile. INOVIO's other platform DNA vaccine candidates have also demonstrated a shelf life of greater than 5 years when refrigerated and stability for more than 30 days at 37 degrees Celsius, and more than one year at room temperature. INOVIO's candidates also do not need to be frozen during transport or storage, a vital factor when implementing immunizations on a global scale. INO-4800 is administered via INOVIO's proprietary CELLECTRA smart delivery device, which delivers the vaccine locally into the patient's skin, a process that takes only a few seconds.

INOVIO is conducting a Phase 2 segment of its planned Phase 2/3 clinical trial for INO-4800, its COVID-19 vaccine candidate. The planned Phase 2/3 clinical trial, called INNOVATE (INovio INO-4800 Vaccine Trial for Efficacy), is a randomized, blinded, placebo-controlled safety and efficacy trial of INO-4800 to be conducted in adults in the U.S. The INNOVATE trial will be funded by the U.S. Department of Defense (DoD) Joint Program Executive Office for Chemical, Biological, Radiological and Nuclear Defense (JPEO-CBRND) in coordination with the Office of the Assistant Secretary of Defense for Health Affairs (OASD (HA)) and the Defense Health Agency (DHA).

The DoD has agreed to provide funding for both the Phase 2 and Phase 3 segments of the INNOVATE clinical trial, in addition to the $71 million of funding previously announced in June for the large-scale manufacture of the company's proprietary smart device CELLECTRA 3PSP and the procurement of CELLECTRA 2000 devices.

About the INO-4800 "INNOVATE" Phase 2/3 Clinical Trial

The lead Principal Investigator for the INNOVATE trial is Dr. Pablo Tebas, Professor of Medicine at the Hospital of the University of Pennsylvania. The Phase 2 segment of the trial is designed to evaluate safety, tolerability and immunogenicity of INO-4800 in a 2-dose regimen (1.0 mg or 2.0 mg), in a three-to-one randomization to receive either INO-4800 or placebo for each dose, to confirm the more appropriate dose(s) for each of three age groups (18-50 years, 51-64 years and 65 years and older) for the subsequent Phase 3 efficacy evaluation. The company intends to work diligently to ensure diversity in enrollment, targeting specific populations that are working or residing in environments with high infection rates and/or areas where there is greater risk of exposure to SARS-CoV-2, for whom exposure may be relatively prolonged or for whom personal protective equipment (PPE) may be inconsistently used, especially in confined settings.

In the Phase 3 segment of the trial, INOVIO intends to enroll healthy men and non-pregnant women 18 years and older, to evaluate the efficacy of the proposed dose(s) based on the data from the Phase 2 evaluation.Participants will be enrolled in a one-to-one randomization to receive either INO-4800 or a placebo. The Phase 3 segment will be case-driven with the final number of enrollees to be determined by the incidence of COVID-19 during the Phase 3 segment. The primary endpoint of the Phase 3 segment will be virologically-confirmed COVID-19 disease.

About INOVIO's Global Coalition Advancing INO-4800

INOVIO has assembled a global coalition of collaborators, partners and funders to rapidly advance the development of INO-4800. R&D collaborators to date include the Wistar Institute, the University of Pennsylvania, the University of Texas, Fudan University and Laval University. INOVIO has partnered with Advaccine and the International Vaccine Institute to conduct clinical trials of INO-4800 in China and South Korea, respectively. INOVIO is also assessing nonclinical efficacy of INO-4800 in several animal challenge models with Public Health England (PHE) and Commonwealth Scientific and Industrial Research Organization (CSIRO) in Australia. INOVIO is working with a team of contract manufacturers including Kaneka Eurogentec, Thermo Fisher Scientific, Richter-Helm BioLogics, and Ology Bioservices to manufacture INO-4800 on a commercial scale and is seeking additional external funding and partnerships to further scale up manufacturing capacities to satisfy the urgent global demand for safe and effective vaccines. To date, the Coalition for Epidemic Preparedness Innovations (CEPI), the Bill & Melinda Gates Foundation, and the U.S. Department of Defense have contributed significant funding to the advancement and manufacturing of INO-4800.

About INO-4800

INO-4800 is INOVIO's DNA vaccine candidate intended to protect against SARS-CoV-2, the novel coronavirus that causes COVID-19. INOVIO has extensive experience working with coronaviruses and was the first company to initiate a Phase 2a trial for INO-4700, a vaccine for Middle East Respiratory Syndrome (MERS), another coronavirus related to SARS-CoV-2.

INO-4800 is the only nucleic-acid based vaccine that is stable at room temperature for more than a year and does not need to be frozen in transport of storage, which are important factors when implementing mass immunizations.

About INOVIO's DNA Medicines Platform

INOVIO has 15 DNA medicine clinical programs currently in development focused on HPV-associated diseases, cancer, and infectious diseases, including coronaviruses associated with MERS and COVID-19 diseases being developed under grants from the Coalition for Epidemic Preparedness Innovations (CEPI) and the U.S. Department of Defense. DNA medicines are composed of optimized DNA plasmids, which are small circles of double-stranded DNA that are synthesized or reorganized by a computer sequencing technology and designed to produce a specific immune response in the body.

INOVIO's DNA medicines deliver optimized plasmids directly into cells intramuscularly or intradermally using INOVIO's proprietary hand-held smart device called CELLECTRA. The CELLECTRA device uses a brief electrical pulse to reversibly open small pores in the cell to allow the plasmids to enter, overcoming a key limitation of other DNA and other nucleic acid approaches, such as mRNA. Once inside the cell, the DNA plasmids enable the cell to produce the targeted antigen. The antigen is processed naturally in the cell and triggers the desired T cell and antibody-mediated immune responses. Administration with the CELLECTRA device ensures that the DNA medicine is efficiently delivered directly into the body's cells, where it can go to work to drive an immune response. INOVIO's DNA medicines do not interfere with or change in any way an individual's own DNA. The advantages of INOVIO's DNA medicine platform are how fast DNA medicines can be designed and manufactured; the stability of the products, which do not require freezing in storage and transport; and the robust immune response, safety profile, and tolerability that have been observed in clinical trials.

With more than 2,000 patients receiving INOVIO investigational DNA medicines in more than 7,000 applications across a range of clinical trials, INOVIO has a strong track record of rapidly generating DNA medicine candidates with potential to meet urgent global health needs.

About Kaneka Eurogentec

Eurogentec was founded in 1985 as a spin-off of the University of Lige (Belgium). Kaneka Eurogentec contributes to improving health and fighting diseases by supplying products and services to scientists involved in life science research, molecular diagnostics, and therapeutic developments. The Lige-based company is recognized as one of the major suppliers in the field of genomics and proteomics as well as a trusted US FDA inspected Contract Development and Manufacturing Organization (CDMO) for the bio-production of pharmaceuticals vaccines and medicines. Kaneka Eurogentec is a leading company in large scale production of GMP DNA Plasmid for DNA vaccines and starting materials for vector-based gene medicines. In parallel, Kaneka Eurogentec offers CDMO services for GMP mRNA, the active molecule of RNA vaccines and RNA based gene therapy. In 2010, Eurogentec, renamed Kaneka Eurogentec in April 2017, became part of Kaneka Corporation, a large Japanese chemical company focusing on technology and innovation. For more information, visit https://www.eurogentec.com/

About INOVIO

INOVIO is a biotechnology company focused on rapidly bringing to market precisely designed DNA medicines to treat and protect people from infectious diseases, cancer, and diseases associated with HPV. INOVIO is the first and only company to have clinically demonstrated that a DNA medicine can be delivered directly into cells in the body via a proprietary smart device to produce a robust and tolerable immune response. Specifically, INOVIO's lead candidate VGX-3100, currently in Phase 3 trials for precancerous cervical dysplasia, destroyed and cleared high-risk HPV 16 and 18 in a Phase 2b clinical trial. High-risk HPV is responsible for 70% of cervical cancer, 91% of anal cancer, and 69% of vulvar cancer. Also in development are programs targeting HPV-related cancers and a rare HPV-related disease, recurrent respiratory papillomatosis (RRP); non-HPV-related cancers glioblastoma multiforme (GBM) and prostate cancer; as well as externally funded infectious disease DNA vaccine development programs in Zika, Lassa fever, Ebola, HIV, and coronaviruses associated with MERS and COVID-19 diseases. Partners and collaborators include Advaccine, ApolloBio Corporation, AstraZeneca, The Bill & Melinda Gates Foundation, Coalition for Epidemic Preparedness Innovations (CEPI), Defense Advanced Research Projects Agency (DARPA)/Joint Program Executive Office for Chemical, Biological, Radiological and Nuclear Defense (JPEO-CBRND)/Department of Defense (DOD), HIV Vaccines Trial Network, International Vaccine Institute (IVI), Kaneka Eurogentec, Medical CBRN Defense Consortium (MCDC), National Cancer Institute, National Institutes of Health, National Institute of Allergy and Infectious Diseases, Ology Bioservices, the Parker Institute for Cancer Immunotherapy, Plumbline Life Sciences, Regeneron, Richter-Helm BioLogics, Thermo Fisher Scientific, University of Pennsylvania, Walter Reed Army Institute of Research, and The Wistar Institute. INOVIO also is a proud recipient of 2020 Women on Boards "W" designation recognizing companies with more than 20% women on their board of directors. For more information, visit http://www.inovio.com.

CONTACTS:

Media: Jeff Richardson, 267-440-4211, [emailprotected] Investors: Ben Matone, 484-362-0076, [emailprotected]

This press release contains certain forward-looking statements relating to our business, including our plans to develop and manufacture DNA medicines, our expectations regarding our research and development programs, including the planned initiation and conduct of the Phase 2/3 clinical trial of INO-4800, and our ability to successfully manufacture and produce large quantities of our product candidates if they receive regulatory approval. Actual events or results may differ from the expectations set forth herein as a result of a number of factors, including uncertainties inherent in preclinical studies, clinical trials, product development programs and commercialization activities and outcomes, our ability to secure sufficient manufacturing capacity to mass produce our product candidates, the availability of funding to support continuing research and studies in an effort to prove safety and efficacy of electroporation technology as a delivery mechanism or develop viable DNA medicines, our ability to support our pipeline of DNA medicine products, the ability of our collaborators to attain development and commercial milestones for products we license and product sales that will enable us to receive future payments and royalties, the adequacy of our capital resources, the availability or potential availability of alternative therapies or treatments for the conditions targeted by us or our collaborators, including alternatives that may be more efficacious or cost effective than any therapy or treatment that we and our collaborators hope to develop, issues involving product liability, issues involving patents and whether they or licenses to them will provide us with meaningful protection from others using the covered technologies, whether such proprietary rights are enforceable or defensible or infringe or allegedly infringe on rights of others or can withstand claims of invalidity and whether we can finance or devote other significant resources that may be necessary to prosecute, protect or defend them, the level of corporate expenditures, assessments of our technology by potential corporate or other partners or collaborators, capital market conditions, the impact of government healthcare proposals and other factors set forth in our Annual Report on Form 10-K for the year ended December 31, 2019, our Quarterly Report on Form 10-Q for the quarter ended September 30, 2020 and other filings we make from time to time with the Securities and Exchange Commission. There can be no assurance that any product candidate in our pipeline will be successfully developed, manufactured or commercialized, that final results of clinical trials will be supportive of regulatory approvals required to market products, or that any of the forward-looking information provided herein will be proven accurate. Forward-looking statements speak only as of the date of this release, and we undertake no obligation to update or revise these statements, except as may be required by law.

SOURCE INOVIO Pharmaceuticals, Inc.

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INOVIO Expands Global Manufacturing Consortium For Its COVID-19 Vaccine Candidate INO-4800 With Addition of Kaneka Eurogentec SA - PRNewswire

CAMBRIDGE, Mass.--(BUSINESS WIRE)--Nov 5, 2020--

bluebird bio, Inc. (Nasdaq: BLUE) announced today that data from its gene and cell therapy programs for sickle cell disease (SCD), transfusion-dependent beta-thalassemia (TDT) and multiple myeloma (MM) will be presented, including seven oral presentations, at the 62 nd American Society of Hematology (ASH) Annual Meeting and Exposition, taking place virtually from December 5-8, 2020.

Updated results from patients in Group C of the companys Phase 1/2 HGB-206 study of LentiGlobin for SCD gene therapy (bb1111) will be presented.

bluebird bio will also present updated long-term efficacy and safety results from the LTF-303 follow-up study; outcomes across genotypes; and outcomes in pediatric patients from Phase 3 studies HGB-207 and HGB-212 of betibeglogene autotemcel (beti-cel; formerly LentiGlobin for -thalassemia) in TDT.

Data from across the companys multiple myeloma program will be presented. Presentations will include updated safety and efficacy results from the Phase 1 CRB-401 clinical study of idecabtagene vicleucel (ide-cel, bb2121) and preliminary data from the ongoing Phase 1 CRB-402 clinical study of bb21217, as well as subgroup analyses of the pivotal Phase 2 KarMMa study of ide-cel. Ide-cel and bb21217 are investigational B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T cell immune therapies being studied, in partnership with Bristol-Myers Squibb, for the treatment of adult patients with MM.

Sickle Cell Disease Data at ASH

Improvements in Health-Related Quality of Life for Patients Treated with LentiGlobin for Sickle Cell Disease (bb1111) Gene Therapy

Presenting Author: Julie Kanter, MD, University of Alabama at Birmingham, Birmingham, AL

Date/Time: Oral #365, Sunday, December 6, 2020, 9:45 am PST

Resolution of Serious Vaso-occlusive Pain Crises and Reduction in Patient-Reported Pain Intensity: Results from the Ongoing Phase 1/2 HGB-206 Group C Study of LentiGlobin for Sickle Cell Disease (bb1111) Gene Therapy

Presenting Author: Alexis A. Thompson, MD, Hematology Section Head, Ann & Robert H. Lurie Childrens Hospital, Chicago, IL

Date/Time: Oral #677, Monday, December 7, 2020, 1:30 pm PST

The GRNDaD Registry: Contemporary Natural History data and an analysis of real-world patterns of use and limitations of Disease Modifying Therapy in adults with SCD

Presenting Author: Alexandra Boye-Doe, MD, University of North Carolina School of Medicine, Chapel Hill, NC

Date/Time: Poster #1730, Sunday, December 6, 2020, 7:00 am 3:30 pm PST

Transfusion-Dependent -Thalassemia Data at ASH

Long-Term Efficacy and Safety of Betibeglogene Autotemcel Gene Therapy for the Treatment of Transfusion-Dependent -Thalassemia: Results in Patients with up to 6 Years of Follow-up

Presenting Author: Janet L. Kwiatkowski, MD, MSCE, Director, Thalassemia Center at Children's Hospital of Philadelphia, Philadelphia, PA

Date/Time: Oral #153, Saturday, December 5, 2020, 12:00 pm PST

Favorable Outcomes in Pediatric Patients in the Phase 3 HGB-207 (Northstar-2) and HGB-212 (Northstar-3) Studies of betibeglogene autotemcel Gene Therapy for the Treatment of Transfusion-dependent -thalassemia

Presenting Author: Alexis A. Thompson, MD, MPH, Hematology Section Head, Ann & Robert H. Lurie Childrens Hospital of Chicago, Chicago, IL

Date/Time: Oral #154, Saturday, December 5, 2020, 12:15 pm PST

Improvement in Erythropoiesis Following Treatment with Betibeglogene Autotemcel Gene Therapy in Patients with Transfusion-Dependent -Thalassemia in the Phase 3 HGB-207 Study

Presenting Author: John B. Porter, MA, MD, FRCP, FRCPath, Head of Red Cell Unit, University College London Hospital, London, UK

Date/Time: Poster #776, Saturday, December 5, 2020, 7:00 am 3:30 pm PST

Response of patients with transfusion-dependent -thalassemia (TDT) to betibeglogene autotemcel (beti-cel; LentiGlobin for -thalassemia) gene therapy based on HBB genotype and disease genetic modifiers

Presenting Author: Mark C. Walters MD, Medical Director, Jordan Family Center for BMT & Cellular Therapies Research, UCSF Benioff Childrens Hospital Oakland, Oakland, CA

Date/Time: Poster #1699, Sunday, December 6, 2020, 7:00 am 3:30 pm PST

Multiple Myeloma Data at ASH

Updated results from the Phase I CRB-402 study of anti-BCMA CAR-T cell therapy bb21217 in patients with relapsed and refractory myeloma: correlation of expansion and duration of response with T cell phenotypes

Presenting Author: Melissa Alsina, MD, Department of Blood and Marrow Transplantation and Cellular Immunotherapy, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL

Date/Time: Oral #130, Saturday, December 5, 2020, 9:45 am PST

Idecabtagene Vicleucel (ide-cel, bb2121), a BCMA-directed CAR T cell therapy, in patients with relapsed and refractory multiple myeloma: updated results from phase 1 CRB-401 study

Presenting Author: Yi Lin, MD, PhD, Division of Hematology, Mayo Clinic, Rochester, MN

Date/Time: Oral #131, Saturday, December 5, 2020, 10:00 am PST

Secondary Quality-of-Life Domains in Patients With Relapsed and Refractory Multiple Myeloma Treated With the BCMA-Directed CAR T Cell Therapy Idecabtagene Vicleucel (ide-cel; bb2121): Results from the KarMMa Clinical Trial

Author: Nina Shah, MD, University of California San Francisco, San Francisco, CA

Date/Time: Oral #437, Sunday, December 6, 2020, 12:15 pm PST

Efficacy and Safety of Idecabtagene Vicleucel (ide-cel, bb2121) in Elderly Patients with Relapsed/Refractory Multiple Myeloma: KarMMa Subgroup Analysis

Presenting Author: Jess Berdeja, MD, Sarah Cannon Research Institute and Tennessee Oncology, Nashville, TN

Date/Time: Poster #1367, Saturday, December 5, 2020, 7:00 am 3:30 pm PST

Characterization of Cytokine Release Syndrome in the KarMMa Study of Idecabtagene Vicleucel (ide-cel, bb2121) For Relapsed and Refractory Multiple Myeloma

Presenting Author: Ankit Kansagra, MD, Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX

Date/Time: Poster #1378, Saturday, December 5, 2020, 7:00 am 3:30 pm PST

Molecular and Phenotypic Profiling of Drug Product and Post-infusion Samples from CRB-402, an Ongoing: Phase I Clinical Study of bb21217 a BCMA-directed CAR T Cell Therapy

Presenting Author: Olivia Finney, PhD, Associate Director, Immunotherapy, bluebird bio

Date/Time: Poster #1401, Saturday, December 5, 2020, 7:00 am 3:30 pm PST

Effects of Prior Alkylating Therapies on Preinfusion Patient Characteristics and Starting Material for CAR T Cell Product Manufacturing in Late-Line Multiple Myeloma

Presenting Author: Julie Rytlewski, PhD, Bristol Myers Squibb, Princeton, NJ

Date/Time: Poster #1405, Saturday, December 5, 2020, 7:00 am 3:30 pm PST

KarMMa-4: Idecabtagene Vicleucel (ide-cel, bb2121), a BCMA-Targeted CAR T Cell Therapy, in High-Risk Newly Diagnosed Multiple Myeloma

Presenting Author: Saad Z. Usmani, MD, Director, Clinical Research in Hematologic Malignancies, Levine Cancer Institute/Atrium Health, Charlotte, NC

Date/Time: Poster #1418, Saturday, December 5, 2020, 7:00 am 3:30 pm PST

Healthcare Resource Utilization and Cost of Cytokine Release Syndrome and Neurologic Events in Patients with Relapsed and Refractory Multiple Myeloma Receiving the BCMA-directed CAR T Cell Therapy Idecabtagene Vicleucel (ide-cel, bb2121) in the KarMMa Trial

Presenting Author: Parmeswaran Hari, MD, Medical College of Wisconsin, Milwaukee, WI

Date/Time: Poster #1598, Saturday, December 5, 2020, 7:00 am 3:30 pm PST

A Matching-Adjusted Indirect Comparison of Efficacy Outcomes for Idecabtagene Vicleucel (ide-cel, bb2121), a BCMA-directed CAR T Cell Therapy Versus Conventional Care in Triple-Class Exposed Relapsed and Refractory Multiple Myeloma

Presenting Author: Nina Shah, MD, University of California San Francisco, San Francisco, CA

Date/Time: Poster #1653, Saturday, December 5, 2020, 7:00 am 3:30 pm PST

Idecabtagene Vicleucel (ide-cel, bb2121) Responses Are Characterized by Early and Temporally Consistent Activation and Expansion of CAR T Cells With a T Effector Phenotype

Presenting Author: Nathan Martin, PhD, Bristol Myers Squibb, Princeton, NJ

Date/Time: Poster #2315, Sunday, December 6, 2020, 7:00 am 3:30 pm PST

KarMMa-3: A Phase 3 Study of Idecabtagene Vicleucel (ide-cel,bb2121), a BCMA-Targeted CAR T Cell Therapy Versus Standard Regimens in Relapsed and Refractory Multiple Myeloma

Presenting Author: Michel Delforge, MD, PhD, University Hospital Leuven, Leuven, Belgium

Date/Time: Poster #2323, Sunday, December 6, 2020, 7:00 am 3:30 pm PST

Idecabtagene Vicleucel (ide-cel, bb2121) in Relapsed and Refractory Multiple Myeloma: Analyses of High-Risk Subgroups in the KarMMa Study

Presenting Author: Noopur S. Raje, MD, Massachusetts General Hospital, Boston, MA

Date/Time: Poster #3234, Monday, December 7, 2020, 7:00 am 3:00 pm PST

Health State Utility Valuation in Patients with Triple-Class Exposed Relapsed and Refractory Multiple Myeloma Treated with the BCMAdirected CAR T Cell Therapy, Idecabtagene Vicleucel (idecel, bb2121): Results from the KarMMa Trial

Presenting Author: Michel Delforge, MD, PhD, University Hospital Leuven, Leuven, Belgium

Date/Time: Poster #3465, Monday, December 7, 2020, 7:00 am 3:00pm PST

Abstracts outlining bluebird bios accepted data at ASH are available on the ASH conference website.

About LentiGlobin for SCD (bb1111)

SCD is a serious, progressive and debilitating genetic disease caused by a mutation in the -globin gene that leads to the production of abnormal sickle hemoglobin (HbS), causing red blood cells (RBCs) to become sickled and fragile, resulting in chronic hemolytic anemia, vasculopathy and painful vaso-occlusive events (VOEs). For adults and children living with SCD, this means unpredictable episodes of excruciating pain due to vaso-occlusion as well as other acute complicationssuch as acute chest syndrome (ACS), stroke, and infections, which can contribute to early mortality in these patients.

LentiGlobin for SCD (bb1111) is an investigational gene therapy being studied as a potential treatment for SCD. bluebird bios clinical development program for LentiGlobin for SCD includes the ongoing Phase 1/2 HGB-206 study and the ongoing Phase 3 HGB-210 study.

LentiGlobin for SCD was designed to add functional copies of a modified form of the -globin gene ( A-T87Q -globin gene) into a patients own hematopoietic (blood) stem cells (HSCs). Once patients have the A-T87Q -globin gene, their red blood cells can produce anti-sickling hemoglobin (Hb A-T87Q ) that decreases the proportion of HbS, with the goal of reducing sickled red blood cells, hemolysis and other complications.

As of March 3, 2020, a total of 37 patients have been treated with LentiGlobin for SCD to-date in the HGB-205 (n=3) and HGB-206 (n=34) clinical studies. The HGB-206 total includes: Group A (n=7), B (n=2) and C (n=25).

LentiGlobin for SCD received orphan medicinal product designation from the European Commission for the treatment of SCD, and Priority Medicines (PRIME) eligibility by the European Medicines Agency (EMA) in September 2020.

The U.S. Food and Drug Administration (FDA) granted orphan drug designation, fast track designation, regenerative medicine advanced therapy (RMAT) designation and rare pediatric disease designation for LentiGlobin for SCD. LentiGlobin for SCD continues to be evaluated in the ongoing Phase 1/2 HGB-206 and Phase 3 HGB-210 studies.

bluebird bio is conducting a long-term safety and efficacy follow-up study (LTF-303) for people who have participated in bluebird bio-sponsored clinical studies of LentiGlobin for SCD. For more information visit: https://www.bluebirdbio.com/our-science/clinical-trials or clinicaltrials.gov and use identifier NCT02633943 for LTF-303.

LentiGlobin for SCD is investigational and has not been approved in any geography.

About betibeglogene autotemcel

Transfusion dependent beta-thalassemia (TDT) is a severe genetic disease caused by mutations in the -globin gene that result in reduced or significantly reduced hemoglobin (Hb). In order to survive, people with TDT require chronic blood transfusions to maintain adequate Hb levels. These transfusions carry the risk of progressive multi-organ damage due to unavoidable iron overload.

Betibeglogene autotemcel (beti-cel) adds functional copies of a modified form of the -globin gene ( A-T87Q -globin gene) into a patients own hematopoietic (blood) stem cells (HSCs). Once a patient has the A-T87Q -globin gene, they have the potential to produce HbA -T87Q, which is gene therapy-derived adult hemoglobin, at levels that may eliminate or significantly reduce the need for transfusions.

The European Commission granted conditional marketing authorization (CMA) for beti-cel, marketed as ZYNTEGLO gene therapy, for patients 12 years and older with transfusion-dependent -thalassemia (TDT) who do not have a 0 / 0 genotype, for whom hematopoietic stem cell (HSC) transplantation is appropriate, but a human leukocyte antigen (HLA)-matched related HSC donor is not available.

As of March 3, 2020, a total of 60 pediatric, adolescent and adult patients, including 11 patients with at least 5 years of follow-up, across genotypes of TDT have been treated with beti-cel in the Phase 1/2 Northstar (HGB-204) and HGB-205 studies, and the Phase 3 Northstar-2 (HGB-207) and Northstar-3 (HGB-212) studies. In studies of beti-cel, patients were assessed for transfusion independence, defined as no longer needing red blood cell transfusions for at least 12 months while maintaining a weighted average Hb of at least 9 g/dL.

Non-serious adverse events (AEs) observed during clinical studies that were attributed to beti-cel included abdominal pain, thrombocytopenia, leukopenia, neutropenia, hot flush, dyspnoea, pain in extremity, tachycardia and non-cardiac chest pain. One serious adverse event (SAE) of thrombocytopenia was considered possibly related to beti-cel.

Additional AEs observed in clinical studies were consistent with the known side effects of HSC collection and bone marrow ablation with busulfan, including SAEs of veno-occlusive disease. On April 28, 2020, the European Medicines Agency (EMA) renewed the CMA for beti-cel. The CMA for beti-cel is valid in the 27 member states of the EU as well as UK, Iceland, Liechtenstein and Norway. For details, please see the Summary of Product Characteristics (SmPC).

The U.S. FDA granted beti-cel orphan drug designation and Breakthrough Therapy designation for the treatment of TDT. Beti-cel is not approved in the United States. Beti-cel continues to be evaluated in the ongoing Phase 3 Northstar-2 (HGB-207) and Northstar-3 (HGB-212) studies.

bluebird bio is conducting a long-term safety and efficacy follow-up study (LTF-303) for people who have participated in bluebird bio-sponsored clinical studies of beti-cel.

About idecabtagene vicleucel (ide-cel, bb2121)

Ide-cel is a B-cell maturation antigen (BCMA)-directed genetically modified autologous chimeric antigen receptor (CAR) T cell immunotherapy. The ide-cel CAR is comprised of a murine extracellular single-chain variable fragment (scFv) specific for recognizing BCMA, attached to a human CD8 hinge and transmembrane domain fused to the T cell cytoplasmic signaling domains of CD137 4-1BB and CD3- chain, in tandem. Ide-cel recognizes and binds to BCMA on the surface of multiple myeloma cells leading to CAR T cell proliferation, cytokine secretion, and subsequent cytolytic killing of BCMA-expressing cells.

Ide-cel is being developed as part of a Co-Development, Co-Promotion and Profit Share Agreement between Bristol Myers Squibb and bluebird bio. Ide-cel was granted accelerated assessment by the European Medicines Agency (EMA) on March 26, 2020, and the Marketing Authorization Application (MAA) was validated by the EMA on May 20, 2020. The FDA accepted the ide-cel Biologics License Application (BLA) for priority review on September 22, 2020.

KarMMa (NCT03361748) is a pivotal, open-label, single-arm, multicenter, multinational, Phase 2 study evaluating the efficacy and safety of ide-cel in adults with RRMM in North America and Europe. The primary endpoint of the study is overall response rate as assessed by an independent review committee (IRC) according to the International Myeloma Working Group (IMWG) criteria. Complete response rate is a key secondary endpoint. Other secondary endpoints include time to response, duration of response, progression-free survival, overall survival, minimal residual disease evaluated by Next-Generation Sequencing (NGS) assay and safety. The study enrolled 140 patients, of whom 128 received ide-cel across the target dose levels of 150-450 x 10 6 CAR+ T cells after receiving lymphodepleting chemotherapy. All enrolled patients had received at least three prior treatment regimens, including an immunomodulatory agent, a proteasome inhibitor and an anti-CD38 antibody, and were refractory to their last regimen, defined as progression during or within 60 days of their last therapy.

CRB-401 (NCT02658929) is an open-label Phase 1 study evaluating the preliminary safety and efficacy of ide-cel in patients with relapsed and refractory multiple myeloma (RRMM). The primary endpoint of the study is safety. CRB-401 was designed as a two-part (dose escalation and dose expansion) study to determine the maximum tolerated dose and further evaluate the safety, tolerability and clinical activity at the recommended Phase 2 dose; these findings established the recommended dose of the Phase 2 KarMMa trial. All patients have been treated in the study and follow-up is ongoing.

In addition to the pivotal KarMMa and CRB-401 trials, bluebird bio and Bristol Myers Squibbs broad clinical development program for ide-cel includes clinical studies (KarMMa-2, KarMMa-3, KarMMa-4) exploring ide-cel combinations and activity in earlier lines of treatment for patients with multiple myeloma, including newly diagnosed multiple myeloma. For more information visit clinicaltrials.gov.

Ide-cel is not approved for any indication in any geography.

About bb21217

bb21217 is an investigational BCMA-targeted CAR T cell therapy that uses the ide-cel CAR molecule and is cultured with the PI3 kinase inhibitor (bb007) to enrich for T cells displaying a memory-like phenotype with the intention to increase the in vivo persistence of CAR T cells. bb21217 is being studied for patients with multiple myeloma in partnership with Bristol Myers Squibb.

bluebird bios clinical development program for bb21217 includes the ongoing Phase 1 CRB-402 study. CRB-402 is the first-in-human study of bb21217 in patients with relapsed and refractory multiple myeloma (RRMM), designed to assess safety, pharmacokinetics, efficacy and duration of effect. CRB-402 is a two-part (dose escalation and dose expansion), open-label, multi-site Phase 1 study of bb21217 in adults with RRMM. For more information visit: clinicaltrials.gov using identifier NCT03274219.

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bluebird bio to Present Data from Gene and Cell Therapy Programs During the 62nd American Society of Hematology (ASH) Annual Meeting and Exposition -...