Category Archives: Gene Medicine

BEDFORD, Mass.--(BUSINESS WIRE)--Stoke Therapeutics, Inc. (Nasdaq: STOK), a biotechnology company pioneering a new way to treat the underlying cause of genetic diseases by precisely upregulating protein expression, today announced that four abstracts related to the Companys work in Dravet syndrome have been selected for presentation at the upcoming American Epilepsy Society (AES) 2020 Virtual Annual Meeting, taking place December 4 8, 2020. Dravet syndrome is a severe and progressive genetic epilepsy characterized by frequent, prolonged and refractory seizures that usually begin within the first year of life. The disease is classified as a developmental and epileptic encephalopathy due to the developmental delays and cognitive impairment associated with the disease.

Highlights from the Companys presentations include:

Our understanding of the diagnosis, progression and effects of Dravet syndrome continues to expand and everything we are learning reinforces the urgent need for a medicine that treats the underlying cause of the disease, said Barry Ticho, M.D., Ph.D., Chief Medical Officer of Stoke Therapeutics. The data from our BUTTERFLY study give us a strong foundational understanding of the course of the disease and validate the applicability of several measures of cognition and other non-seizure comorbidities that will be helpful in evaluating potential disease-modifying medicines like STK-001.

Details for the AES presentations are as follows:

Title: Observational Study to Investigate Cognition and Other Non-seizure Comorbidities in Children and Adolescents with Dravet Syndrome: Patient Analysis of the BUTTERFLY StudySession Date & Time: Available on-demand December 4Presenter: Joseph Sullivan, M.D., Professor of Neurology at the University of California San Francisco and Director of the Benioff Childrens Hospital Pediatric Epilepsy Center of ExcellenceAbstract Number: 81

Title: Reducing the Time to Diagnosis and Increasing the Detection of Individuals with SCN1A-Related Disease Through a No-cost, Sponsored Epilepsy Genetic Testing ProgramSession Date & Time: Available on-demand December 4Presenter: Dianalee McKnight,Ph.D., Director, Medical Affairs, InvitaeAbstract Number: 392

Title: Safety and Pharmacokinetics of Antisense Oligonucleotide STK-001 in Children and Adolescents with Dravet Syndrome: Single Ascending Dose Design for the Open-Label Phase 1/2a MONARCH StudySession Date & Time: Available on-demand December 4Presenter: Linda Laux, M.D, Associate Professor of Pediatrics (Neurology and Epilepsy) at Northwestern University Feinberg School of Medicine and Attending Physician, Neurology and Epilepsy Center, Ann & Robert H. Lurie Children's Hospital of ChicagoAbstract Number: 344

Title: Targeted Augmentation of Nuclear Gene Output (TANGO) of SCN1A Reduces Seizures and Rescues Parvalbumin Positive Interneuron Firing Frequency in a Mouse Model of Dravet SyndromeSession Date & Time: Available on-demand December 4Presenter: Eric Wengert, Researcher, Department of Anesthesiology, University of VirginiaAbstract Number: 236

About STK-001

STK-001 is an investigational new medicine for the treatment of Dravet syndrome currently being evaluated in a Phase 1/2a clinical trial. Stoke believes that STK-001, a proprietary antisense oligonucleotide (ASO), has the potential to be the first disease-modifying therapy to address the genetic cause of Dravet syndrome. STK-001 is designed to upregulate NaV1.1 protein expression by leveraging the non-mutant (wild-type) copy of the SCN1A gene to restore physiological NaV1.1 levels, thereby reducing both occurrence of seizures and significant non-seizure comorbidities. Stoke has generated preclinical data demonstrating proof-of-mechanism and proof-of-concept for STK-001. STK-001 has been granted orphan drug designation by the FDA as a potential new treatment for Dravet syndrome.

About Phase 1/2a Clinical Study (MONARCH)

The MONARCH study is a Phase 1/2a open-label study of children and adolescents ages 2 to 18 who have an established diagnosis of Dravet syndrome and have evidence of a pathogenic genetic mutation in the SCN1A gene. The primary objectives for the study will be to assess the safety and tolerability of STK-001, as well as to characterize human pharmacokinetics. A secondary objective will be to assess the efficacy as an adjunctive antiepileptic treatment with respect to the percentage change from baseline in convulsive seizure frequency over a 12-week treatment period. Stoke also intends to measure non-seizure aspects of the disease, such as quality of life, as secondary endpoints. Enrollment and dosing are ongoing in MONARCH and Stoke plans to enroll approximately 48 patients in the study across 20 sites in the United States.

Additional information about the MONARCH study can be found at https://www.monarchstudy.com/.

About Dravet Syndrome

Dravet syndrome is a severe and progressive genetic epilepsy characterized by frequent, prolonged and refractory seizures, beginning within the first year of life. Dravet syndrome is difficult to treat and has a poor long-term prognosis. Complications of the disease often contribute to a poor quality of life for patients and their caregivers. The effects of the disease go beyond seizures and often include severe intellectual disabilities, severe developmental disabilities, motor impairment, speech impairment, autism, behavioral difficulties and sleep abnormalities. Compared with the general epilepsy population, people living with Dravet syndrome have a higher risk of sudden unexpected death in epilepsy, or SUDEP. Dravet syndrome affects approximately 35,000 people in the United States, Canada, Japan, Germany, France and the United Kingdom, and it is not concentrated in a particular geographic area or ethnic group.

About Stoke Therapeutics

Stoke Therapeutics (Nasdaq: STOK) is a clinical-stage biotechnology company pioneering a new way to treat the underlying causes of severe genetic diseases by precisely upregulating protein expression to restore target proteins to near normal levels. Stoke aims to develop the first precision medicine platform to target the underlying cause of a broad spectrum of genetic diseases in which the patient has one healthy copy of a gene and one mutated copy that fails to produce a protein essential to health. These diseases, in which loss of approximately 50% of normal protein expression causes disease, are called autosomal dominant haploinsufficiencies. Stoke is headquartered in Bedford, Massachusetts with offices in Cambridge, Massachusetts. For more information, visit https://www.stoketherapeutics.com/ or follow the company on Twitter at @StokeTx.

Cautionary Note Regarding Forward-Looking Statements

This press release contains forward-looking statements within the meaning of the safe harbor provisions of the Private Securities Litigation Reform Act of 1995, including, but not limited to: preclinical data and study results regarding OPA1, future operating results, financial position and liquidity, the direct and indirect impact of COVID-19 on our business, financial condition and operations, including on our expenses, supply chain, strategic partners, research and development costs, clinical trials and employees; our expectation about timing and execution of anticipated milestones, responses to regulatory authorities, expected nomination of future product candidates and timing thereof, our ability to complete lead optimization of ASOs for ADOA, the timing and results of ADOA preclinical studies, our ability to develop ASOs treat the underlying causes of ADOA, our ability to advance OPA1 as our next preclinical target, and our ability to use study data to advance the development of STK-001; the ability of STK-001 to treat the underlying causes of Dravet syndrome; and the ability of TANGO to design medicines to increase protein production and the expected benefits thereof. These forward-looking statements may be accompanied by such words as aim, anticipate, believe, could, estimate, expect, forecast, goal, intend, may, might, plan, potential, possible, will, would, and other words and terms of similar meaning. These forward-looking statements involve risks and uncertainties, as well as assumptions, which, if they do not fully materialize or prove incorrect, could cause our results to differ materially from those expressed or implied by such forward-looking statements. These statements involve risks and uncertainties that could cause actual results to differ materially from those reflected in such statements, including: our ability to develop, obtain regulatory approval for and commercialize STK-001, OPA1 and future product candidates; the timing and results of preclinical studies and clinical trials; the risk that positive results in a clinical trial may not be replicated in subsequent trials or success in early stage clinical trials may not be predictive of results in later stage clinical trials; risks associated with clinical trials, including our ability to adequately manage clinical activities, unexpected concerns that may arise from additional data or analysis obtained during clinical trials, regulatory authorities may require additional information or further studies, or may fail to approve or may delay approval of our drug candidates; the occurrence of adverse safety events; failure to protect and enforce our intellectual property, and other proprietary rights; failure to successfully execute or realize the anticipated benefits of our strategic and growth initiatives; risks relating to technology failures or breaches; our dependence on collaborators and other third parties for the development, regulatory approval, and commercialization of products and other aspects of our business, which are outside of our full control; risks associated with current and potential delays, work stoppages, or supply chain disruptions caused by the coronavirus pandemic; risks associated with current and potential future healthcare reforms; risks relating to attracting and retaining key personnel; failure to comply with legal and regulatory requirements; risks relating to access to capital and credit markets; environmental risks; risks relating to the use of social media for our business; and the other risks and uncertainties that are described in the Risk Factors section of our most recent annual or quarterly report and in other reports we have filed with the U.S. Securities and Exchange Commission. These statements are based on our current beliefs and expectations and speak only as of the date of this press release. We do not undertake any obligation to publicly update any forward-looking statements.

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Stoke Therapeutics Announces Presentations Related to the Company's Work in Dravet Syndrome at the American Epilepsy Society 2020 Virtual Annual...

Newswise Princess Margaret scientists have revealed how stem cells are able to generate new blood cells throughout our life by looking at vast, uncharted regions of our genetic material that hold important clues to subtle biological changes in these cells.

The finding, obtained from studying normal blood, can be used to enhance methods for stem cell transplantation, and may also shed light into processes that occur in cancer cells that allow them to survive chemotherapy and relapse into cancer growth many years after treatment.

Using state-of-the art sequencing technology to perform genome-wide profiling of the epigenetic landscape of human stem cells, the research revealed important information about how genes are regulated through the three-dimensional folding of chromatin.

Chromatin is composed of DNA and proteins, the latter which package DNA into compact structures, and is found in the nucleus of cells. Changes in chromatin structure are linked to DNA replication, repair and gene expression (turning genes on or off).

The research by Princess Margaret Cancer Centre Senior Scientists Drs. Mathieu Lupien and John Dick is published in Cell Stem Cell, Wednesday, November 25, 2020.

We dont have a comprehensive view of what makes a stem cell function in a specific way or what makes it tick, says Dr. Dick, who is also a Professor in the Department of Molecular Genetics, University of Toronto.

Stem cells are normally dormant but they need to occasionally become activated to keep the blood system going. Understanding this transition into activation is key to be able to harness the power of stem cells for therapy, but also to understand how malignant cells change this balance.

Stem cells are powerful, potent and rare. But its a knifes edge as to whether they get activated to replenish new blood cells on demand, or go rogue to divide rapidly and develop mutations, or lie dormant quietly, in a pristine state.

Understanding what turns that knifes edge into these various stem cell states has perplexed scientists for decades. Now, with this research, we have a better understanding of what defines a stem cell and makes it function in a particular way.

We are exploring uncharted territory, says Dr. Mathieu Lupien, who is also an Associate Professor in the Department of Medical Biophysics, University of Toronto. We had to look into the origami of the genome of cells to understand why some can self-renew throughout our life while others lose that ability. We had to look beyond what genetics alone can tell us.

In this research, scientists focused on the often overlooked noncoding regions of the genome: vast stretches of DNA that are free of genes (i.e. that do not code for proteins), but nonetheless harbour important regulatory elements that determine if genes are turned on or off.

Hidden amongst this noncoding DNA which comprise about 98% of the genome - are crucial elements that not only control the activity of thousands of genes, but also play a role in many diseases.

The researchers examined two distinct human hematopoietic stem cells or immature cells that go through several steps in order to develop into different types of blood cells, such as white or red blood cells, or platelets.

They looked at long-term hematopoietic stem cells (HSCs) and short-term HSCs found in the bone marrow of humans. The researchers wanted to map out the cellular machinery involved in the dormancy state of long-term cells, with their continuous self-renewing ability, as compared to the more primed, activated and ready-to-go short-term cells which can transition quickly into various blood cells.

The researchers found differences in the three-dimensional chromatin structures between the two stem cell types, which is significant since the ways in which chromatin is arranged or folded and looped impacts how genes and other parts of our genome are expressed and regulated.

Using state-of-the-art 3D mapping techniques, the scientists were able to analyze and link the long-term stem cell types with the activity of the chromatin folding protein CTCF and its ability to regulate the expression of 300 genes to control long-term, self-renewal.

Until now, we have not had a comprehensive view of what makes a stem cell function in a particular way, says Dr. Dick, adding that the 300 genes represent what scientists now think is the essence of a long-term stem cell.

He adds that long-term dormant cells are a protection against malignancy, because they can survive for long periods and evade treatment, potentially causing relapse many years later.

However, a short-term stem cell that is poised to become active, dividing and reproducing more quickly than a long-term one, can gather up many more mutations, and sometimes these can progress to blood cancers, he adds.

This research gives us insight into aspects of how cancer starts and how some cancer cells can retain stem-cell like properties that allow them to survive long-term, says Dr. Dick.

He adds that a deeper understanding of stem cells can also help with stem cells transplants for the treatment of blood cancers in the future, by potentially stimulating and growing these cells ex vivo (out of the body) for improved transplantation.

The research was supported by The Princess Margaret Cancer Foundation, Ontario Institute for Cancer Research, Canadian Institutes for Health Research (CIHR), Medicine by Design, University of Toronto, Canadian Cancer Society Research Institute, and the Terry Fox Research Institute.

Competing Interests

Dr. John Dick served on the SAB at Trillium Therapeutics, and has ownership interest (including patents) in Trillium Therapeutics. He also reports receiving a commercial research grant from Celgene.

About Princess Margaret Cancer Centre

Princess Margaret Cancer Centre has achieved an international reputation as a global leader in the fight against cancer and delivering personalized cancer medicine. The Princess Margaret, one of the top five international cancer research centres, is a member of the University Health Network, which also includes Toronto General Hospital, Toronto Western Hospital, Toronto Rehabilitation Institute and the Michener Institute for Education at UHN. All are research hospitals affiliated with the University of Toronto. For more information: http://www.theprincessmargaret.ca

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Mapping out the mystery of blood stem cells - Newswise

The global spread of the COVID-19 pandemic and the resulting economic impact and public health burden has highlighted the urgent need for a vaccine to prevent the disease. The challenges associated with rapidly developing and producing a vaccine at a large scale are, however, enormous.

Verdict has conducted a poll to assess the time that could be taken for the approval of a COVID-19 vaccine and its availability to the public.

Analysis of the results shows a high chance for an approved COVID-19 vaccine to be available over the next six months, as opined by a majority 36% of the poll respondents, whereas 28% of the respondents feel it could take six to 12 months for the same.

Less than one-fourth (22%) of the poll respondents opined that the approval and availability of a COVID-19 vaccine could take between 12 and 18 months, while 14% felt that it could take more than 18 months.

The analysis is based on 875 responses received from readers of Verdicts Pharmaceutical Technology site between 18 June and 01 July.

The poll findings are in line with those of another poll conducted by Verdict earlier in April, which found high confidence about the possible development of a COVID-19 vaccine within 12 months.

Research organisations and pharmaceutical companies have joined hands in developing a vaccine against the COVID-19 virus that has affected millions of people.

Existing drugs such as remdesivir have been granted emergency use authorisation (EUA) to treat the disease, meanwhile.

Antimalarial drugs including chloroquine and hydroxychloroquine were also awarded EUA, but later revoked after studies showed that they were ineffective in treating the disease.

In another poll conducted on Pharmaceutical Technology site, Verdict tried to assess readers opinion about who should be given priority access to a COVID-19 vaccine upon licensure.

The poll options included three groups namely those with high-risk such as the elderly and patients with co-morbidities, everyone, and those in high-risk geographies from infection.

A majority 46% of the respondents opined that elderly and people with co-morbidities should be given priority access, followed by 33% who opined that everyone should have the same access to the vaccine.

Prioritising the vaccines accessibility to high-risk geographies is of high importance for just 21% of the respondents.

The analysis is based on 354 responses received between 18 June and 08 July.

Eight vaccines are in phase three/two clinical trials currently, while another 120 are in pre-clinical evaluation, according to the World Health Organization (WHO).

The vaccines that have reached advanced clinical trials include ChAdOx1-S by University of Oxford and AstraZeneca, an adenovirus type 5 vector vaccine by CanSino Biological and Beijing Institute of Biotechnology, mRNA-1273 vaccine by Moderna, and National Institute of Allergy and Infectious Diseases.

Sinopharm is collaborating with the Wuhan Institute of Biological Products and Beijing Institute of Biological Products to develop an inactivated vaccine.

Sinovac is developing an inactivated vaccine with alum and Novavax is developing a full-length recombinant SARS CoV-2 glycoprotein nanoparticle vaccine, while BioNTech, Fosun Pharma, and Pfizer are developing a vaccine based on 3 LNP-mRNAs.

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Gene therapy innovations: Sarepta and Codiak partner on exosomes - Pharmaceutical Technology

Cindy Black has spent more than four years out of the past decade in hospital being treated for depression.

There have been several suicide attempts in that time, including one that left her in a coma for over a month.

"You just wish you had not got to that point where you felt like there is no other option," Ms Black said.

"It's not a life when you're at that point. It is just existence."

She tried countless medications over the years, but none of them worked.

That changed in 2018, when her doctor recommended that she take a multi-gene test so that a treatment plan could be guided by her genetic makeup.

As a result, Ms Black was prescribed an antidepressant medication she said had changed her life.

"It has just absolutely changed everything," she said.

"It has brought my overall mood up by 80 to 90 per cent, to a point where I was able to say I am actually really happy.

"I don't think I have ever said that or felt that."

The medication she was prescribed was an old drug which required a strict dietary regime, but Ms Black said it was worth it.

"The benefits of having something that works as opposed to spending another 15 years shuffling around to find something else, is a complete no-brainer," she said.

"If I'd had this knowledge a lot earlier on, things could have been a lot different."

While Ms Black continued to live with depression, her outlook had improved dramatically.

After meeting her partner 18 months ago, the pair got engaged on Valentine's Day and have a baby on the way.

"That has been my ultimate dream, having a family," she said.

"It is unthinkable that, for so long, I did not think that this was going to happen."

The testing Ms Black took to narrow down her search for the right medication which involved a brain scan and a cheek swab is not widely used in mainstream healthcare.

The collected cells are used in a multi-gene test, otherwise known as a pharmacogenomic (PG) test, which surveys around one dozen genes that are known to play a role in metabolism.

The same test will be applied to hundreds of newly-diagnosed patients in WA, NSW and Victoria as part of a study to determine whether first-line medications have a better chance of succeeding if their prescription is guided by the patient's individual genetic make-up.

WA North Metropolitan Health Service psychiatrist Sean Hood said finding the right medication for depressed patients often involved trial and error.

"Most patients, when they get treated [for] depressive disorders, don't get full remission on the first medication they are put on," he said.

"Trialling and looking at different medication therapies can take a lifetime for many patients; it can take many years.

"In the past, it has just been clinical wisdom and therapeutic guessing to find the medicine that is going to be best for that person.

"But this sort of testing hopefully will give us the ability to better target the medications that are going to be suitable for that patient early on.

"I hope this can be a game-changer for the treatment of mainstream depression."

A personalised treatment plan will also be prepared for each of the study's participants, but only half of the plans will be guided by patients' results the rest will be developed following current standard-of-care guidelines.

The treatment plans will be reviewed by a national panel of experts to assess whether patients had significant earlier benefit over those receiving standard care.

Office of Population Health Genomics Director Kristen Nowak said although PG testing had been available for many years and there was growing recognition of its value, it had not been adopted widely for guiding medication choice and dosing.

She said if the study proved successful, it could become standard practice in the treatment of depression and be covered by Medicare.

"Given the time, cost and patient impacts of potentially having to try several medications and the fact PG testing has now come right down in cost and turnaround times we think there is real value in assessing the potential benefits of more personalised care," she said.

"We're hoping that if the evidence in this clinical trial shows us that doing this test early in a person's health journey can be effective for them then we would strongly consider making that more standard practice here in Western Australia and across Australia."

The trial, which was funded by the Commonwealth Government's Medical Research Future Fund, will enrol 550 patients, including 275 from WA.

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DNA research aims to take 'trial and error' out of depression medication treatment - ABC News

A confirmed diagnosis may take time.

Diagnosis represents the first step on this rare disease journey. Sometimes doctors will notice something off about the child during a newborn screening, and a genetic test will identify a known mutation in the DNA. But not all conditions are so quickly detected, and it can take several years for parents to get a confirmed diagnosis.

About half of all children never get that far, according to Marshall Summar, M.D., the director of the Rare Disease Institute at Childrens National Hospital in Washington, D.C. When you sequence someones DNA, you are going to find a lot of changes, Dr. Summar said. Figuring out which change might be the one that is causing it is a tremendous challenge.

Genetic counselors warn parents beforehand that they may not get a definitive answer as to what condition their child could have. They may have to check back each year. Dr. Summar estimates that between five and 10 new rare diseases are described in the scientific literature every week, making it challenging for the medical field to keep up.

Meanwhile, the realization that a child may have a debilitating, lifelong condition weighs heavily. Some parents, particularly mothers, blame themselves, said Lemuel Pelentsov, Ph.D., a nurse who studies the needs of rare disease families at the University of South Australia, in Adelaide. In a 2016 study by Dr. Pelentsov and his colleagues, about 40 percent of the 300 rare parents surveyed reported being treated for depression and an equal number for anxiety. One of the things they do to combat that, he said, is get very invested in the childs disease.

When parents reach out to other parents, they are not simply looking for emotional support or advice. They are rebuilding a social life, one that will revolve around their childs disease. Many rare diseases have their own support groups. Global Genes is an umbrella group that supports 600 disease-specific foundations, as well as parents of children whose diseases are so rare they have no foundation.

We encourage folks to work together, said Kimberly Haugstad, the organizations executive director whose son has a rare form of hemophilia, a condition in which the blood doesnt clot normally. The parent is going to come from such different places in their own walk of life.

Each year, Global Genes hosts a Rare Boot Camp to mentor and teach parents how to set up a nonprofit, create patient registries and fund research. After attending the boot camp, the Van Wyks and other parents founded GACI Global, an organization that connects families affected by GACI, along with medical professionals.

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The Wilderness of Rare Genetic Diseases and the Parents Navigating It - The New York Times

Because of the role genetic testing now plays in the management of cancer, and in the identification of risk for the disease, physicians should make sure that patients know the limits of a key federal privacy law, Leonard Gomella, MD, said during a panel session at the virtual American Urological Association 2020 Annual Meeting.

A new set of recommendations on the use of genetic testing published in June by the International Philadelphia Prostate Cancer Consensus Conference, which Gomella cochairs strongly endorses the testing of all men with metastatic prostate cancer to aid with treatment decisions and to assess eligibility for clinical trials.

But it is important to understand that there are limits to the Genetic Information Nondiscrimination Act (GINA) of 2008, which was written to protect against discrimination in employment and medical insurance for people with known genetic risk factors for disease, said Gomella, who is chair of the Department of Urology at Thomas Jefferson University in Philadelphia.

"It may not necessarily protect the patient if they are looking for disability or long-term care insurance, a subtle but an important point," he said.

To some degree, GINA builds on protections offered by the Americans With Disabilities Act (ADA) of 1990. But there are important distinctions, said Elizabeth Pendo, JD, a specialist in disability law, bioethics and the law, and health law and policy at St.Louis University in Missouri.

This is, in part, because GINA has a legislative history distinct from other disability laws. The ADA and other laws, such as the Rehabilitation Act of 1973, were built on histories that showed patterns and practices of discrimination.

The enactment of GINA, in contrast, stemmed largely from concerns that people would be reluctant to undergo genetic testing or to participate in research projects that involved the collection of DNA, Pendo said.

A person who appears, on genetic testing, to have a predisposition to a disease but does not show signs of it would have protection under GINA but not under the ADA, she told Medscape Medical News.

"They don't have a disability as defined under that statute," she explained. "To be protected under the Americans With Disabilities Act, you need to have a physical or mental impairment that substantially limits a major life activity or a history of an impairment or be regarded as having an impairment."

Many states had laws on their books before GINA that addressed the potential for misuse of genetic information. New York law prohibits discrimination on the basis of "predisposing genetic characteristics" in the narrow context of hiring, retaining, and discharging interns, according to a recent report.

And a "handful" of states, including California, have laws that prohibit genetic discrimination in housing, lending, land use, and other contexts, the authors explain.

"In sum, the patchwork of state laws addressing [genetic discrimination] in various contexts spans the domains of life insurance, long-term care insurance, disability insurance, health insurance, employment, and housing, to name a few," the team writes. "Unfortunately, there is a wide variation in coverage among states, and many of the laws lack adequate coverage, protections, or remedies."

Congress could amend GINA to include protection against discrimination in the sale of life insurance or long-term care insurance, for example, although the issues around long-term care are more complex because of the financial demands, said Pendo. "Whether there is enough of a movement to motivate Congress to do that is a different question."

Two new diagnostic tests were approved earlier this year: FoundationOneCDx (Foundation Medicine) for the identification of patients with metastatic castration-resistant prostate cancer (mCRPC) who carry HRR gene alterations; and BRACAnalysisCDx (Myriad Genetic Laboratories) for the identification of patients with mCRPC who carry germline BRCA1/2 alterations.

Urologists should become familiar with the common commercial genetic test panels for prostate cancer, such as those from Ambry Genetics, Fulgent Genetics, GeneDx, Invitae, Neo Genomics, and Strand Diagnostics products, said Gomella.

The makers of these tests can help urologists and their patients process and understand test findings. Some of these firms provide sheets for gathering family histories, which can be handy tools for busy practices, he said. And many of the companies help with various levels of telehealth genetic counseling for patients.

It's not just about ordering the test. It's about the implications of what it means.

"There is a lot to understand about genetic counseling," he explained, noting that some genetic alterations can have implications for relatives of a patient. "It's not just about ordering the test. It's about the implications of what it means."

During his presentation, Gomella highlighted recent advances in the management of prostate cancer that stem from an understanding of genetic triggers.

"In 2020, precision medicine took a big leap ahead in prostate cancer and genetic testing with the approval of the two new" Poly (ADP-ribose) polymerase (PARP) enzyme inhibitors, he reported.

On May15, the US Food and Drug Administration (FDA) announced the accelerated approval of rucaparib (Rubraca, Clovis Oncology) for patients with deleterious BRCA mutation-associated mCRPC who have been treated with androgen-receptor-directed therapy and a taxane-based chemotherapy. The drug had previously been approved for ovarian cancer.

Then, on May19, approval was announced for olaparib (Lynparza, AstraZeneca) for adults with deleterious or suspected deleterious germline or somatic HRR gene-mutated mCRPC who progressed after treatment with enzalutamide (Xtandi, Pfizer/Astellas) or abiraterone (Zytiga, Janssen). The drug had previously been approved for breast, ovarian, and pancreatic cancers.

Gomella has participated in advisory boards for Clovis, AstraZeneca, and Strand Diagnostics.

American Urological Association (AUA) 2020 Annual Meeting. Presented June27, 2020.

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Physicians, Patients Need to Know Limits of DNA Privacy Law - Medscape

A large prostate cancer genomics study suggests African-American men, who are disproportionately affected by the cancer, should also benefit from current therapies that target specific genetic mutations causing the disease.

However, the researchersbased at Boston University School of Medicine, University of California San Francisco, and Northwestern Universitydid discover some genetic differences between the cancers from European Americans and African Americans, which they believe warrants further investigation.

African-American men have a 15% chance of developing prostate cancer compared with a 10% chance for European-American men. They are more likely to develop aggressive disease and are twice as likely to die from the cancer than White men. It is possible that this inequality may be due to socio-economic status and healthcare disparities, but genetic differences in cancer mutational status could also be responsible.

In what they claim is the largest such study to date, the researchers studied mutations linked to prostate cancer in 250 African American and 611 European American men from four publicly available datasets. They then compared these to prostate cancer mutations found in 436 African American and 3018 European American men with both localized and metastatic prostate cancer who contributed samples to the Foundation Medicine commercial cohort.

As reported in the journal Clinical Cancer Research, the team found no notable differences in genetic variation that would impact the efficacy of current therapies for prostate cancer, such as treatment with PARP inhibitors targeting DNA repair genes, between the two groups of men.

However, they did find some genetic differences between the two groups. For example, two genes linked to prostate cancer suppression, ETV3 and ZFHX3, were more often mutated in African-American men with prostate cancer than in European Americans. The MYC gene, which is often overexpressed in cancers, was also more often amplified in African-American men with metastatic prostate cancer.

These results reinforce the idea that there can be biological differences in prostate cancers between different ancestral groups and that samples from Black Americans need to be included in future molecular studies to fully understand these differences, said Joshua Campbell, PhD, an assistant professor at Boston University School of Medicine who is one of the study authors.

The differences in rates of onset and outcome of prostate cancer has been recognized before and in 2018 the RESPOND study was set up by the US National Institute of Health to investigate this issue further. It aims to enroll 10,000 African-American men with prostate cancer and will investigate whether environmental issues, genetic differences, or both are responsible for the higher rates and more aggressive disease seen in these men.

Previous studies have looked in isolation at different biological, social and environmental drivers of well-known racial disparities in prostate cancer, said Franklin Huang, MD, PhD, an assistant professor at UCSF and corresponding author on the current study. RESPOND is a nationwide effort to integrate all these components and ultimately identify specific steps that can be taken to eliminate prostate cancers unequal burden in Black communities.

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African American, European Ancestry Men Benefit from Same Targeted Prostate Cancer Therapies - Clinical OMICs News

Putting your employees and company culture first keeps the focus on inclusion and innovation, giving the company an incredible competitive advantage. At least thats the mantra at the heart of MyoKardia, a California-based biotech company that is developing precision medicine for cardiovascular diseases (CVDs).

We want to change the world for people with cardiovascular disease by taking a patient-focused, scientifically driven approach, Tassos Gianakakos, MyoKardias CEO, told BioSpace. When youre addressing hard problems, you need different opinions, approaches, and expertise at the table. That is the only way to effectively deliver on the mission.

Companies are at risk of getting it wrong when they dont focus on culture early on you need to launch out of the gate with a culture mindset, Gianakakos added. You get back what you put out there, so being a mission-driven, culture-valuing company will help draw in likeminded employees. That group genius is what enables remarkable improvements to health outcomes for society.

CVD, also called heart disease, is a blanket term used to describe many diseases that affect the heart or blood vessels. Globally, heart diseases are by far the number one killer in the world, with CVDs responsible for 17.9 million deaths worldwide. These conditions are highly prevalent throughout the population 30.3 million US adults have been diagnosed with CVDs.

Credit: WHO

We lose more people in the U.S. and around the world to cardiovascular conditions than any other disease, Gianakakos. MyoKardias entire purpose is to change that. We want to be the leading company developing precision medicine for CVDs. Our approach is different; were subtyping patient populations within these large, heterogeneous conditions so that we can identify effective, targeted therapeutics. The idea is to discover and develop medicines that have transformative potential for people.

MyoKardias late-stage pipeline focuses on two CVDs: hypertrophic cardiomyopathy (HCM), where the heart muscle becomes abnormally thick (hypertrophied), making it harder for the heart to pump blood; and dilated cardiomyopathy (DCM), where the hearts main pumping chamber (called the left ventricle) stretches and thins (dilates), making it harder for the heart to pump blood.

HCM is frequently caused by gene mutations in heart muscle proteins that cause the heart muscle to squeeze with more force than needed, leading to abnormal thickening over time. It is the most common inherited heart disease, occurring in about 1 in 500 people (over 650,000 people in the US). HCM is the most common cause of cardiac arrest (where the heart suddenly stops beating), in younger people. Although certain medications, like beta blockers and blood thinners, are used to treat some HCM symptoms, there arent any drugs that specifically address the underlying problem in HCM the genetic mutation-induced thickened heart muscle.

Positive results from a Phase III clinical trial of mavacamten, MyoKardias lead drug candidate for HCM, were announced in May. MyoKardia aims to submit a New Drug Application (NDA) submission with the FDA in the first quarter of 2021 and is planning for its first product launch.

DCMs causes may be varied in addition to genetics, a number of diseases are linked to left ventricle dilation, including diabetes, obesity, high blood pressure, infections, and drug and alcohol abuse. It is a common cause of systolic heart failure (where the heart isnt pumping blood as well as it should be). Medications such as angiotensin-converting enzyme (ACE) inhibitors, beta blockers, and blood thinners can successfully treat heart failure, but none of them are specific to the heart and have systemic side effects.

MyoKardias investigational drug danicamtiv is intended to increase heart contractions without interfering with the hearts ability to fill. The company recently reported encouraging data from their Phase IIa study of danicamtiv in chronic heart failure patients. They plan to advance into two new Phase II studies in specific patient populations: genetic DCM patients and systolic heart failure patients with paroxysmal or persistent atrial fibrillation (AFib).

BioSpace spoke to Gianakakos and Ingrid Boyes, MyoKardias Senior Vice President of Human Resources, about the companys pipeline, culture, and why building a culture of diversity and inclusion is foundational to a company.

(Boyes previously spoke to BioSpace in 2015 about what MyoKardia is looking for when theyre hiring.)

COMPANY CULTURE, DIVERSITY & INCLUSION

BioSpace: Why is company culture and diversity so important to a successful company? How do you promote diversity and inclusion at MyoKardia?

Gianakakos: The diseases we are tackling know no ethnic, gender or socioeconomic boundaries. So our company culture needs to reflect this. Our teams need to reflect this and the patients we are working to help. Its hard for us to see doing good science and achieving our mission any other way. And it goes beyond the science. To have a successful and meaningful company, we need to innovate more broadly in growth strategies, commercial models, and new ways to more effectively get our therapies to patients who need it around the world.

Im proud of how we embrace each others differences gender, ethnicity and race, orientation, socioeconomic status and beliefs -- and highlight the importance of company culture. Everyone at MyoKardia shares the same mission, the same values, but we embrace and value each persons differences. We want our employees to feel safe sharing their own voice and know that different points of view are valued and respected.

Boyes: Tassos passion for company culture is a large part of why I joined the company five years ago. As a Hispanic woman, its really important to me to create an environment where people can thrive and grow. We have fun while creating a valuable community. As employee number 50, I was able to focus on how to help build a company culture with Tassos that values diversity by building on employees experiences. We were very intentional about company culture and how we evolve it. Every voice at MyoKardia counts and every person plays an important role in improving CVD patients lives.

We actively seek input from our employees and encourage them to challenge the status quo. We also invite employees to lead activities and bring their unique perspectives to work.

Gianakakos: We want to bring great people who are passionate to the company and play to their strengths. Focusing on increasing their engagement and creating an energizing work environment allows employees to do their most creative and best work. Having people build the skills they want and need by cross-training and encouraging lifelong learning improves the connectivity and the innovation within the company.

We believe this is one of the key competitive advantages at MyoKardia connecting and supporting people to engage and excite them and ensuring they have a voice that is valued. Having diverse perspectives and a commitment to listening leads us to much better decisions and results.

What kind of diversity and engagement activities do you do both within MyoKardia and externally with the general public?

Boyes: We always strive to improve the culture by actively soliciting feedback from our employees though a number of channels, including engagement surveys. Implementing employee-led initiatives has brought great features into the companys culture, such as a womens forum that brings in external women speakers and identifies female role models, a green team focused on being more sustainable, and a community volunteer team that actively supports our community. All of these activities also help to develop valuable leadership skills regardless of title within our organization.

Gianakakos: Based on employee feedback, weve also implemented several policy changes, such as increasing the companys 401k match and giving each employee a six-week sabbatical once they have been with the company for six years.

Boyes: We want to be connected with diverse organizations and participate as much as possible externally connecting with others in the community with culture-focused passion. We are always looking to connect with driven people who share our company values.

Switching gears to the science, what does CVD drug development look like right now?

Gianakakos: In many ways, CVD is where oncology was 20 years ago there were no precision medicines and non-specific treatments such as chemotherapy and radiation were used regardless of cancer type. The number of drugs in development for CVDs is woefully low relative to its global burden. There are over 1,100 oncology drugs in development, but only 200 for cardiovascular diseases, despite CVDs killing more people annually than all cancers combined. In oncology today, precision medicine approaches have given us countless targeted therapies that have completely transformed patient care. We are making this happen today in CVD, where we feel may even have advantages over oncology given the many tools now available to monitor the heart, such as wearables and patches that measure the heart rate and rhythm.

What made you focus on precision cardiac medicine? Why now?

Gianakakos: Momentum around precision medicine in other disease areas was clearly growing and resulting in important advances when MyoKardia started eight years ago. The first cystic fibrosis drug that treated the underlying cause rather than the symptoms (ivacaftor) was just launched by Vertex and a few years prior to MyoKardia our founding investors were involved in launching several exciting new companies like Foundation Medicine, Agios and bluebird bio who were developing potentially game-changing targeted therapies.

Traditionally, CVD clinical trials are massive, expensive, and often fail. When there is a lack of understanding of the underlying disease biology and its unclear exactly what the drug is doing, that can result in a large signal-to-noise ratio. This in turn, requires larger studies which are more expensive, and the therapies have to benefit large numbers of patients for the investment to make sense. This is a recipe that doesnt lead to innovative or efficient drug discovery. Identifying smaller, more homogenous subgroups of patients who all share the same disease pathology, and targeting them with drugs designed specifically to address the underlying disease biology is so powerful. Were matching the tailored treatment to address each persons underlying condition understanding how to identify the right drugs for the right patients.

CARDIOVASCULAR DISEASE DRUG DEVELOPMENT & MYOKARDIAS PIPELINE

What are the major knowledge gaps that need to be addressed to make precision cardiac medicine achievable for many patients? What does the landscape look like right now for precision cardiac medicine?

Gianakakos: There needs to be a cultural shift in the CVD field to move away from grouping broad heterogenous patients together, to focusing on smaller, well defined patient groups treated with targeted therapies and learning as much as we can from those that respond very well and, as importantly, those that do not.

Matching patient profiles to drugs that specifically address their underlying disease is key. Leaning on existing technology, such as wearables, genetic sequencing, imaging, and biomarker profiles to subtype CVD patients and deeply understand the biological drivers of disease will lead to critically important targeted therapies and much more effective clinical trials.

In terms of other precision cardiac medicine approaches in development, gene therapies are being explored. While that technology is maturing, most gene therapies for CVDs are still in early-stage research, but eventually could be helpful for certain sub-groups of patients with CVD.

Relative to other disease areas, like oncology, it has been challenging for companies to invest in new approaches to drug discovery and development in areas like CVD and neurology. However, given the staggering medical need, and with progress being made by companies like ours, I expect interest in CVD precision medicine to increase over the next 3-5 years.

What does MyoKardias pipeline look like?

Gianakakos: Our Phase III drug, called mavacamten (MYK-461), is for HCM. HCM is a genetic disease where the heart thickens due to excessive force of contraction cause by mutations in the heart muscle proteins. There are two common subtypes of HCM: obstructive, where the thickening also occurs near the base of the aorta and prevents (obstructs) blood from flowing well out of the heart; and non-obstructive, where the thick muscle makes it challenging for the heart to relax and fill, reducing the amount of blood flow out of the heart without physically obstructing blood flow. About one-third of HCM patients have the non-obstructive type.

Mavacamten is a small molecule that targets the heart muscle protein myosin reducing the excessive force of contraction, directly addressing the underlying cause of HCM. We announced positive data from our Phase III trial (EXPLORER-HCM) of mavacemten in about 250 symptomatic obstructive HCM patients and we are now able to move full steam ahead on our first regulatory submission for approval. Encouraging results from a Phase II trial (MAVERICK-HCM) of mavacamten in about 60 participants with symptomatic non-obstructive HCM were recently presented and we are going to be moving mavacamten forward in non-obstructive patients. We are also conducting a long-term extension study is also ongoing for patients who participated in either EXPLORER-HCM or MAVERICK-HCM.

We started hyper focused in a disease with a defined genetic background and will expand in a deliberate way into adjacent diseases with similar problems, such as heart failure with preserved ejection fraction. About 3 million people in the U.S. have problems filling and relaxing their hearts and we estimate that approximately 10% of them share similar pathology to HCM. Are these disease subtypes related? Do they have similar genetic mutations? We plan to start a Phase II trial in the next few months to explore if mavacamten can help that specific heart failure population and learn much more about this devastating form of heart failure.

We also have a Phase II molecule, called danicamtiv (MYK-491), for DCM that is designed to increase the force of contraction in the heart - the opposite of what mavacamten has been created to do. Danicamtiv is a small molecule that selectively increases the number of myosin-actin cross bridges, supporting heart muscle contractions to help the heart pump more efficiently. It has recently completed a Phase Ib/IIa trial in DCM or stable heart failure patients and has shown very promising early results. We are now moving into a separate Phase II study in DCM patients with certain genetic mutations. Among the most interesting new findings from our clinical study of danicamtiv is that it appears to have a direct effect on the performance of the left atrium. We were able to confirm and learn more about these findings in nonclinical studies, which is leading us to explore danicamtiv in patients with systolic dysfunction and atrial fibrillation.

MyoKardia has gone from startup to successfully completing our first Phase III trial in eight years. In the coming months, we will be submitting our first drug to the FDA this year, which if approved will bring the first every therapy designed specifically for HCM to people with this debilitating condition.

We design our therapies with the aim of targeting the underlying disease mechanism to treat and, in some cases, reverse the problem, actually slowing down or reversing disease progression. That allows patients to live full lives, free from fear and complications. We are very excited and remain super ambitious. The magic and special sauce is really our employees and our culture.

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MyoKardia: The Precision Cardiac Medicine Company with Diversity and Inclusion at its Heart - BioSpace

CAMBRIDGE, Mass.--(BUSINESS WIRE)-- Alnylam Pharmaceuticals Inc. (Nasdaq: ALNY), the leading RNAi therapeutics company, announced today that the UKs Medicines and Healthcare Products Regulatory Agency (MHRA) has granted lumasiran, an investigational RNAi therapeutic in development for the treatment of primary hyperoxaluria type 1 (PH1), a positive scientific opinion through the Early Access to Medicines Scheme (EAMS). With this decision, eligible PH1 patients in the UK, many of whom are children, can gain access to lumasiran before the drug is granted marketing authorization by the European Commission (EC).

The aim of EAMS is to provide early availability of innovative, unlicensed medicines to UK patients who have a high degree of unmet clinical need. The medicines included in the scheme are those that are intended to treat, diagnose or prevent seriously debilitating or life-threatening conditions where there are no adequate treatment options.

PH1 is an ultra-rare orphan disease characterized by excessive oxalate production, which can lead to end-stage kidney disease (ESKD) and other systemic complications. PH1 affects 1-3 individuals per million in Europe and the United States; in the United Kingdom, it is estimated that there are 100 patients diagnosed with PH1. Current treatment approaches do not prevent oxalate overproduction and aim to lessen damage to the kidneys and delay progression to ESKD. PH1 patients with advanced kidney disease require dialysis to help filter waste products from their blood, until they are able and eligible to receive a dual or sequential liver/kidney transplant. However, long-term dialysis and post-transplant complications can severely impact patients quality of life.

This positive scientific opinion to make lumasiran available through the EAMS is wonderful news for PH1 patients and their families, who currently have limited treatment options, said Brendan Martin, Country Manager, UK & Ireland at Alnylam. New medicines that address the underlying cause of this ultra-rare condition, and have the potential for a favorable impact on disease manifestations, are urgently needed. This decision will allow eligible PH1 patients in the UK to have access to lumasiran at the earliest opportunity.

The MHRAs decision is based on the evaluation of the effects of lumasiran in PH1 patients and its safety profile, including data from the ILLUMINATE-A Phase 3 study. The results of the ILLUMINATE-A study were presented at the European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) International Congress, held June 6-9, 2020 as a virtual event.

A marketing authorization application (MAA) for lumasiran has been submitted to the European Medicines Agency (EMA) in April 2020 and was granted Accelerated Assessment. Lumasiran previously received Priority Medicines (PRIME) designation. The EC decision, which will apply to the UK, is expected in late 2020. In addition, Alnylam filed a New Drug Application (NDA) with the U.S. Food and Drug Administration (FDA). The FDA has granted a Priority Review for the NDA and has set an action date of December 3, 2020 under the Prescription Drug User Fee Act (PDUFA).

About Lumasiran

Lumasiran is an investigational, subcutaneously administered RNAi therapeutic targeting hydroxyacid oxidase 1 (HAO1) in development for the treatment of primary hyperoxaluria type 1 (PH1). HAO1 encodes glycolate oxidase (GO). Thus, by silencing HAO1 and depleting the GO enzyme, lumasiran inhibits production of oxalate the metabolite that directly contributes to the pathophysiology of PH1. Lumasiran utilizes Alnylam's Enhanced Stabilization Chemistry (ESC)-GalNAc-conjugate technology, which enables subcutaneous dosing with increased potency and durability and a wide therapeutic index. Lumasiran has received both EU and U.S. Orphan Drug Designations, Priority Medicines (PRIME) designation from the European Medicines Agency (EMA) and Breakthrough Therapy Designation from the U.S. Food and Drug Administration (FDA). The safety and efficacy of lumasiran are under evaluation by the FDA and EMA.

About ILLUMINATE-A Phase 3 Study

ILLUMINATE-A (NCT03681184) is a six-month randomized, double-blind, placebo-controlled, global, multicenter Phase 3 study (with a 54-month extension period) to evaluate the efficacy and safety of lumasiran in 39 patients with a documented diagnosis of PH1. Patients were randomized 2:1 to receive three monthly doses of lumasiran or placebo followed by quarterly maintenance doses at 3 mg/kg. The primary endpoint was the percent change in 24-hour urinary oxalate excretion from baseline to the average of months 3 to 6 in the patients treated with lumasiran as compared to placebo. Treatment arms were stratified at randomization based upon mean 24-hour urinary oxalate during screening ( 1.7 or > 1.7 mmol/24hr/1.73m2). Key secondary and exploratory endpoints were designed to evaluate additional measures of urinary oxalate, plasma oxalate, estimated glomerular filtration rate (eGFR), nephrocalcinosis, renal stone events, safety and tolerability.

About Primary Hyperoxaluria Type 1 (PH1)

PH1 is an ultra-rare disease in which excessive oxalate production results in the deposition of calcium oxalate crystals in the kidneys and urinary tract and can lead to the formation of painful and recurrent kidney stones and nephrocalcinosis. Renal damage is caused by a combination of tubular toxicity from oxalate, calcium oxalate deposition in the kidneys, and urinary obstruction by calcium oxalate stones. Compromised kidney function exacerbates the disease as the excess oxalate can no longer be effectively excreted, resulting in subsequent accumulation and crystallization in bones, eyes, skin, and heart, leading to severe illness and death. Current treatment options are very limited and include frequent renal dialysis or combined organ transplantation of liver and kidney, a procedure with high morbidity that is limited due to organ availability. Although a small minority of patients respond to vitamin B6 therapy, there are no approved pharmaceutical therapies for PH1.

About RNAi

RNAi (RNA interference) is a natural cellular process of gene silencing that represents one of the most promising and rapidly advancing frontiers in biology and drug development today. Its discovery has been heralded as "a major scientific breakthrough that happens once every decade or so," and was recognized with the award of the 2006 Nobel Prize for Physiology or Medicine. By harnessing the natural biological process of RNAi occurring in our cells, a new class of medicines, known as RNAi therapeutics, is now a reality. Small interfering RNA (siRNA), the molecules that mediate RNAi and comprise Alnylam's RNAi therapeutic platform, function upstream of todays medicines by potently silencing messenger RNA (mRNA) the genetic precursors that encode for disease-causing or disease pathway proteins, thus preventing them from being made. This is a revolutionary approach with the potential to transform the care of patients with genetic and other diseases.

About Alnylam Pharmaceuticals

Alnylam (Nasdaq: ALNY) is leading the translation of RNA interference (RNAi) into a whole new class of innovative medicines with the potential to transform the lives of people afflicted with rare genetic, cardio-metabolic, hepatic infectious, and central nervous system (CNS)/ocular diseases. Based on Nobel Prize-winning science, RNAi therapeutics represent a powerful, clinically validated approach for the treatment of a wide range of severe and debilitating diseases. Founded in 2002, Alnylam is delivering on a bold vision to turn scientific possibility into reality, with a robust RNAi therapeutics platform. Alnylams commercial RNAi therapeutic products are ONPATTRO (patisiran), approved in the U.S., EU, Canada, Japan, Brazil, and Switzerland, and GIVLAARI (givosiran), approved in the U.S and the EU. Alnylam has a deep pipeline of investigational medicines, including six product candidates that are in late-stage development. Alnylam is executing on its "Alnylam 2020" strategy of building a multi-product, commercial-stage biopharmaceutical company with a sustainable pipeline of RNAi-based medicines to address the needs of patients who have limited or inadequate treatment options. Alnylam is headquartered in Cambridge, MA.

Alnylam Forward Looking Statements

Various statements in this release concerning Alnylam's future expectations, plans and prospects, including, without limitation, Alnylams views with respect to the safety and efficacy of lumasiran as demonstrated in the ILLUMINATE-A Phase 3 study and the potential for lumasiran to have a favorable impact on PH1 disease manifestations, Alnylams expectations regarding the implications of the positive scientific opinion through the EAMS for eligible PH1 patients in the UK, many of whom are children, Alnylam's expectations with respect to the review timelines for the lumasiran NDA and MAA by the FDA and EMA, respectively, Alnylams plans, assuming favorable regulatory reviews, to bring lumasiran to patients with PH1 around the world, and expectations regarding the continued execution on its Alnylam 2020 guidance for the advancement and commercialization of RNAi therapeutics, constitute forward-looking statements for the purposes of the safe harbor provisions under The Private Securities Litigation Reform Act of 1995. Actual results and future plans may differ materially from those indicated by these forward-looking statements as a result of various important risks, uncertainties and other factors, including, without limitation: the direct or indirect impact of the COVID-19 global pandemic or a future pandemic, such as the scope and duration of the outbreak, government actions and restrictive measures implemented in response, material delays in diagnoses of rare diseases, initiation or continuation of treatment for diseases addressed by Alnylam products, or in patient enrollment in clinical trials, potential supply chain disruptions, and other potential impacts to Alnylams business, the effectiveness or timeliness of steps taken by Alnylam to mitigate the impact of the pandemic, and Alnylams ability to execute business continuity plans to address disruptions caused by the COVID-19 or a future pandemic; Alnylam's ability to discover and develop novel drug candidates and delivery approaches and successfully demonstrate the efficacy and safety of its product candidates; the pre-clinical and clinical results for its product candidates, which may not be replicated or continue to occur in other subjects or in additional studies or otherwise support further development of product candidates for a specified indication or at all; actions or advice of regulatory agencies, which may affect the design, initiation, timing, continuation and/or progress of clinical trials or result in the need for additional pre-clinical and/or clinical testing; delays, interruptions or failures in the manufacture and supply of its product candidates, including lumasiran, or its marketed products; obtaining, maintaining and protecting intellectual property; intellectual property matters including potential patent litigation relating to its platform, products or product candidates; obtaining regulatory approval for its product candidates, including lumasiran, and maintaining regulatory approval and obtaining pricing and reimbursement for its products, including ONPATTRO and GIVLAARI; progress in continuing to establish a commercial and ex-United States infrastructure; successfully launching, marketing and selling its approved products globally, including ONPATTRO and GIVLAARI, and achieving net product revenues for ONPATTRO within its revised expected range during 2020; Alnylams ability to successfully expand the indication for ONPATTRO in the future; competition from others using technology similar to Alnylam's and others developing products for similar uses; Alnylam's ability to manage its growth and operating expenses within the ranges of guidance provided by Alnylam through the implementation of further discipline in operations to moderate spend and its ability to achieve a self-sustainable financial profile in the future without the need for future equity financing; Alnylams ability to establish and maintain strategic business alliances and new business initiatives, including completing an agreement for funding by Blackstone of certain R&D activities for vutrisiran and ALN-AGT; Alnylam's dependence on third parties, including Regeneron, for development, manufacture and distribution of certain products, including eye and CNS products, Ironwood, for assistance with the education about and promotion of GIVLAARI, and Vir for the development of ALN-COV and other potential RNAi therapeutics targeting SARS-CoV-2 and host factors for SARS-CoV-2; the outcome of litigation; the risk of government investigations; and unexpected expenditures; as well as those risks more fully discussed in the "Risk Factors" filed with Alnylam's most recent Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission (SEC) and in other filings that Alnylam makes with the SEC. In addition, any forward-looking statements represent Alnylam's views only as of today and should not be relied upon as representing its views as of any subsequent date. Alnylam explicitly disclaims any obligation, except to the extent required by law, to update any forward-looking statements.

View source version on businesswire.com: https://www.businesswire.com/news/home/20200713005319/en/

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Alnylam Announces that the United Kingdom's MHRA Grants Early Access to Lumasiran - BioSpace

Black men in the United States are known to suffer disproportionately from prostate cancer, but few studies have investigated whether genetic differences in prostate tumors could have anything to do with these health disparities.

Now, in the largest study of its kind to date, researchers from Boston University School of Medicine (BUSM), UC San Francisco (UCSF), and Northwestern University have identified genes that are more frequently altered in prostate tumors from men of African ancestry compared to other racial groups, though the reasons for these differences is not known, the authors say. None of the individual tumor genetic differences that were identified are likely to explain significant differences in health outcomes or to prevent Black Americans from benefiting from a new generation of precision prostate cancer therapies, the authors say, as long as the therapies are applied equitably.

The newly identified gene variants could potentially lead to precision prostate cancer therapies specifically focused on men of African ancestry, and will inform broader efforts by the National Cancer Institutes RESPOND study to link gene variants to health outcomes in an even larger cohort of Black patients nationwide.

Despite declines in mortality related to cancer in the U.S., disparities by race have persisted. One in every six Black Americans will be diagnosed with prostate cancer in their lifetime, and these men are twice as likely to die from the disease as men of other races. But it is not yet clear to researchers whether differences in prostate cancer genetics contribute to these health disparities in addition to the social and environmental inequities known to drive poorer health outcomes across the board.

To date, studies trying to figure out what genes are commonly mutated in prostate cancers often have had very few samples from racial/ethnic minority groups despite the greater burden of prostate cancer in these populations. In May, the FDA approved a class of drugs known as PARP inhibitors as a therapy for men with prostate cancers driven by specific genetic mutations, but it is not known how prevalent these mutations are in people of African descent. As more genetic health studies are performed in minority populations, it has become clear that other genetically targeted therapies that have been developed based on studies of patients of European descent are at times much less effective, and in some cases cause dangerous side-effects, in other racial and ethnic groups.

In the new study, published July 10, 2020 in Clinical Cancer Research, a journal of the American Association for Cancer Research, the research team set out to better understand differences in the mutations driving prostate cancer tumors in men with African versus European ancestry, and whether any such differences could influence disease outcomes or the effectiveness of PARP inhibitors or other targeted therapies.

The researchers collected and analyzed DNA sequencing data from previously published studies and from a commercial molecular diagnostics company. In total, they examined mutational patterns in prostate cancers from more than 600 Black men, representing the largest such study of this population to date.

The team found that the frequency of mutations in DNA repair genes and other genes that are targets of current therapeutics are similar between the two groups, suggesting that at least these classes of current precision prostate cancer therapies should be beneficial in people of both African and European ancestry, according to corresponding author Franklin Huang, MD, PhD, an assistant professor in UCSFs Division of Hematology/Oncology and member of the UCSF Helen Diller Family Comprehensive Cancer Center, UCSF Institute for Human Genetics, and UCSF Bakar Computational Health Sciences Institute.

While the researchers found no significant differences in frequencies of mutations in genes important for current prostate cancer therapies, they did identify other genes, such as ZFXH3, MYC, and ETV3, that were more frequently mutated in prostate cancers from Black men.

"These results reinforce the idea that there can be biological differences in prostate cancers between different ancestral groups and that samples from Black Americans need to be included in future molecular studies to fully understand these differences," said co-corresponding author Joshua Campbell, PhD, assistant professor of medicine at BUSM.

The poorer health outcomes we see in Black men with prostate cancer are not easily explained by any of the distinct gene mutations we identified in prostate tumors from men of African ancestry. This highlights the need to examine the environmental and social inequities that are well known to influence health outcomes across the board, Huang added. On the other hand, our tumor genomic analysis also showed that current precision medicine approaches ought to be as effective in Black Americans as they have been for other groups if we can ensure that these drugs are applied equitably going forward."

Developing a comprehensive understanding of how tumor genomics and other biological factors interact with social and environmental inequities to drive poorer clinical outcomes for Black prostate cancer patients should be an important priority for the efforts to improve precision medicine for these patients, the researchers say.

These types of studies will remain important to understand when certain therapies may preferentially benefit Black patients, who continue to remain underrepresented in clinical trials, Campbell said.

In particular, the results will inform the efforts of the NCI-funded RESPOND Study. RESPOND provided funding for the new UCSF-BUSM-Northwestern study to guide its efforts to perform targeted gene sequencing in tumors from an even larger cohort of Black prostate cancer patients, said Huang, who leads RESPONDs tumor genetics studies based at UCSF. Through partnerships with Black communities across the country, RESPOND aims to recruit 10,000 Black prostate cancer patients in an effort to better understand the drivers of the diseases outsize burden among Black Americans.

"Previous studies have looked in isolation at different biological, social and environmental drivers ofwell-knownracial disparities in prostate cancer,Huangsaid. RESPOND is a nationwide effort to integrate all these components and ultimately identify specific steps that can be taken toeliminateprostate cancers unequal burden in Black communities.

Authors: The studys lead authors are Yusuke Koga of BUSM, Hanbing Song of UCSF, and Zachary Chalmers of Northwestern University. Additional authors are Elad Ziv of UCSF; Justin Newberg and Garrett M. Frampton of Foundation Medicine, in Cambridge; Eejung Kim and Daphnee Piou of the Broad Institute of MIT and Harvard; Jian Carrot-Zhang and Matthew Meyerson of the Broad Institute and Dana-Farber Cancer Institute; Paz Polak of Mt. Sinai School of Medicine in New York; and Sarki Abdulkadir of Northwestern University.

Funding: The study was supported by the U.S. Department of Defense (W81XWH-17-PCRP-HD); the U.S. National Institutes of Health (NIH) National Cancer Institute (NCI) (P20 CA233255-01, U19 CA214253); and the Prostate Cancer Foundation.

Disclosures: The authors declare no relevant conflicting financial interests.

About UCSF:The University of California, San Francisco (UCSF) is exclusively focused on the health sciences and is dedicated to promoting health worldwidethrough advanced biomedical research, graduate-level education in the life sciences and healthprofessions, and excellence in patient care. It includes UCSF Health, which comprises three top-ranked hospitals, as well as affiliations throughout the Bay Area.

About BUSM: Originally established in 1848 as the New England Female Medical College, and incorporated into Boston University in 1873, Boston University School of Medicine (BUSM) today is a leading academic medical center with an enrollment of more than 700 medical students and 950 students pursuing degrees in graduate medical sciences.BUSM faculty contribute to more than 950 active grants and contracts, with total anticipated awards valued at more than $693 million in amyloidosis, arthritis, cardiovascular disease, cancer, infectious diseases, pulmonary disease and dermatology, among other areas. The Schools teaching affiliates include Boston Medical Center, its primary teaching hospital, the Boston VA Healthcare System, Kaiser Permanente in northern California, as well as Boston HealthNet, a network of 15 community health centers. For more information, please visithttp://www.BUSM.bu.edu/busm/.

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Largest-Ever Study of Prostate Cancer Genomics in Black Men IDs Potential Targets for Precision Therapies - UCSF News Services