Category Archives: Genetic medicine

Advice for healthcare professionals:

Aminoglycosides are broad-spectrum bactericidal antibiotics. The group includes gentamicin, amikacin, tobramycin, and neomycin.

There is a narrow therapeutic window for aminoglycosides and their use can result in toxicity, including nephrotoxicity and ototoxicity, which can result in permanent hearing loss. This effect is related to the dose and duration of treatment and is exacerbated by renal or hepatic impairment or both and is more likely in elderly people and newborn babies.

To minimise the risk of ototoxicity with systemic aminoglycosides, regular serum concentration monitoring is recommended to maintain aminoglycoside levels below the toxic threshold for the cochleo-vestibular system. The product information for each medicine provides dosing considerations and recommendations for toxicity thresholds.

Assessment of auditory, vestibular, and renal function is particularly necessary in patients with additional risk factors.

In 2020, we conducted a safety review following concerns received about the impact of mitochondrial mutations on the risk of ototoxicity with aminoglycosides. We identified several published epidemiological studies showing an increased risk of deafness in patients with the m.1555A>G mutation who were given aminoglycosides. There have also been reported cases of deafness in m.1555A>G patients with aminoglycoside use within the recommended serum levels. Some cases were associated with a maternal history of deafness or mitochondrial mutations or both.

Although no cases were identified with neomycin or topical preparations of gentamicin, amikacin, or tobramycin, based on a shared mechanism of action there is the potential for a similar effect with neomycin and other aminoglycosides that are administered at the site of toxicity (the ear).

The m.1555A>G mutation is the most common mitochondrial DNA (mtDNA) mutation, with an estimated prevalence of 0.2% in the general population. The mutation is associated with sensorineural deafness and occurs in families with maternally transmitted deafness.

Clinicians should follow local guidelines on mitochondrial mutation screening in patients with a maternal history of deafness or mitochondrial mutations or both and who require aminoglycoside therapy. Genetic screening may be especially appropriate in patients requiring recurrent or long-term aminoglycoside therapy where the risk of ototoxicity is increased.

Our review focused on four key epidemiological studies that reported an association between having mitochondrial mutations and an increased risk of deafness with aminoglycoside use. In addition, 10 case reports were identified from the medical literature indicating this toxicity. This evidence is further supported by a plausible biological mechanism where mutated mitochondrial ribosome more closely resembles the bacterial ribosome and may provide a binding site for aminoglycosides; this effect has been shown in biochemical tests.

While many of the epidemiological studies had weak statistical power due to the rarity of the mitochondrial mutations, the evidence is considered sufficient to update the product information for aminoglycoside products with systemic absorption or that are administered at the site of toxicity (the ear).

The product information will be updated to include warnings of a potentially increased risk of ototoxicity in patients with known mitochondrial mutations. The patient information leaflet will ask patients to talk to their doctor or pharmacist before taking this medicine if they know (or think they have) a mitochondrial disease.

These mitochondrial mutations are rare, and the penetrance of the observed increased ototoxic effect is unknown. For patients known to have susceptible mutations, it is important to consider the need for aminoglycoside treatment and the alternative treatment options available when making prescribing decisions.

Any suspected adverse drug reactions to aminoglycosides should be reported to us on a Yellow Card.

Healthcare professionals, patients, and caregivers are asked to submit reports using the Yellow Card scheme electronically using:

When reporting please provide as much information as possible, including information about batch numbers, medical history, any concomitant medication, onset, treatment dates, and product brand name.

Report suspected side effects to medicines, vaccines or medical device and diagnostic adverse incidents used in coronavirus (COVID-19) using the dedicated Coronavirus Yellow Card reporting site or the Yellow Card app. See the MHRA website for the latest information on medicines and vaccines for COVID-19.

Article citation: Drug Safety Update volume 14, issue 6: January 2021: 6.

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Aminoglycosides (gentamicin, amikacin, tobramycin, and neomycin): increased risk of deafness in patients with mitochondrial mutations - GOV.UK

Rare disease and gene therapy industry veterans Steven Altschuler, M.D., R. Nolan Townsend and Jay Barth, M.D., team up with gene therapy pioneer Ronald Crystal, M.D., to launch fully integrated gene therapy company

Financing led, structured and syndicated by Longitude Capital and Omega Funds

Comprehensive pipeline includes three clinical-stage gene therapy programs in monogenic diseases and up to 15 potential additional AAV gene therapy programs in monogenic and acquired diseases primarily developed at Weill Cornell Medicine

NEW YORK, Jan. 07, 2021 (GLOBE NEWSWIRE) -- LEXEO Therapeutics, a clinical-stage gene therapy company, debuted today with an oversubscribed $85 million Series A financing, led by Longitude Capital and Omega Funds, and joined by Lundbeckfonden Ventures, PBM Capital, Janus Henderson Investors, Invus, Woodline Partners LP, the Alzheimers Drug Discovery Foundationiand Alexandria Venture Investments. Proceeds from the financing will help advance the companys three lead investigational programs, including: LX2006, an IV-administered therapy for cardiomyopathy associated with Friedreichs ataxia (Phase 1 start planned for 2021); LX1004, a CNS-administered therapy for CLN2 Batten disease (Phase 1/2 completed); and LX1001, a CNS-administered therapy for APOE4-associated Alzheimers disease (Phase 1 ongoing).

We are thrilled to launch today with a mission to advance LEXEOs promising clinical-stage pipeline of gene therapy treatments for patients diagnosed with some of societys most challenging diseases, said R. Nolan Townsend, Chief Executive Officer of LEXEO Therapeutics. We have the pleasure of collaborating with Dr. Ronald Crystal one of the industrys most accomplished pioneers in the gene therapy space and, drawing on my years of rare disease leadership experience at Pfizer, will together build a world-class gene therapy organization driven by premier science that has the potential to address a range of therapeutic indications.

Founder and Chief Scientific Advisor Dr. Ronald Crystal is Professor and Chairman of Weill Cornells Department of Genetic Medicine and Director of the Belfer Gene Therapy Core Facility. Dr. Crystal has more than 30 years of experience with adenovirus and adeno-associated virus vectors, from basic vector design through clinical development. Dr. Crystal has 14 approved gene therapy investigational new drug applications and has published more than 300 papers on gene therapy, with experience in CNS, cardiac, pulmonary and liver-mediated diseases.

I am excited to work with LEXEO Therapeutics to move our extensive academic portfolio into clinical development and ultimately bring it to patients, said Dr. Crystal. LEXEOs AAV-mediated gene therapy programs have the potential for broad applicability across a range of therapeutic indications, and in a single company pipeline present an opportunity for the natural evolution of gene therapy from rare genetic conditions to more common diseases.

LEXEO Therapeutics Chairman, Dr. Steven Altschuler, is currently Managing Director at Ziff Capital Investments and was formerly Chairman of gene therapy biotech pioneer Spark Therapeutics, which was responsible for the first FDA-approved gene therapy, Luxturna, and was acquired by Roche in 2019 for $4.3 billion.

LEXEOs impressive management team, with Nolans years of rare disease leadership experience at Pfizer, as well as its pioneering scientific founder and high-quality investor syndicate, will propel the development of the companys pipeline of promising and innovative programs, said Dr. Altschuler. I am honored to have the opportunity to partner with Nolan and his team to build a leading gene therapy company.

LEXEO Therapeutics has also appointed Dr. Jay Barth as Executive Vice President and Chief Medical Officer to oversee Medical Affairs, Regulatory Affairs and Clinical Development. Dr. Barth was formerly the Chief Medical Officer at Amicus Therapeutics and Senior Vice President, Clinical Development, at PTC Therapeutics, where he oversaw all clinical development programs and the approval of Galafold for Fabry disease at Amicus, as well as Translarna, the first approved treatment for Duchenne muscular dystrophy at PTC Therapeutics.

Other members of LEXEO Therapeutics Board of Directors include CEO R. Nolan Townsend, Sandip Agarwala of Longitude Capital, Bernard Davitian of Omega Funds and Mette Kirstine Agger of Lundbeckfonden Ventures.

Initial Indications

Friedreichs ataxia (FA) is a rare, degenerative multi-system disorder affecting approximately 1 in 50,000 people in the United States. FA is caused by a gene mutation that disrupts the normal production of the protein frataxin, critical to the function of mitochondria (the energy producing factories) in a cell. FA is inherited in an autosomal recessive manner, usually begins in childhood, and leads to impaired muscle coordination (ataxia) that worsens over time, typically progressing to serious heart conditions, includinghypertrophic cardiomyopathy and arrythmias.FA is also associated with vision impairment, hearing loss, scoliosis, diabetes and slurred speech. Friedreichs ataxia can shorten life expectancy, with heart failure the most common cause of death. Supported by de novo, soon to be published pre-clinical research, LX2006 is an IV-administered AAV-mediated frataxin gene therapy treatment focused on the cardiac pathology of FA. The company is completing IND-enabling pre-clinical studies and expects to initiate a Phase 1 trial in 2021.

CLN2 disease (late infantile Batten disease) is an autosomal recessive lysosomal storage disease with fewer than 1,000 cases worldwide, with typical onset in children between 2 and 4 years of age. The disease is caused by mutations in the CLN2 gene, resulting in progressive cognitive impairment, visual failure, seizures and deteriorating motor development. LX1004 is an AAV-meditated gene therapy treatment delivering CLN2 to the central nervous system. In December 2020, clinical data published in Science Translational Medicine found a single administration of AAV-mediated CLN2 gene therapy (LX1004) slowed the progression of CLN2 disease in children. Treatment with LX1004 was well tolerated, with minimal serious adverse events in the acute/post-operative period (0-14 days) and over the 18-month study period (14 days 18 months). With this Phase 1/2 study complete, the company plans to advance the program into a pivotal study in 2022.

Alzheimer's disease is the leading cause of late-onset dementia, characterized by progressive memory loss and cognitive decline in humans. APOE is a major cholesterol transporter and is in part linked to the pathogenesis of Alzheimer's disease due to development of amyloid plaques and tau-tangles in the brain. People who inherit APOE4 alleles are at significantly higher risk for developing Alzheimers disease and at an earlier age of onset than people who inherit APOE3 or APOE2 alleles, which have normal and reduced risk of disease onset, respectively.iiLX1001 is an AAV-mediated gene therapy treatment delivering APOE2 to the central nervous system of people with two APOE4 alleles (homozygotes), via a CNS route of administration. A Phase 1 clinical study is ongoing.

About LEXEO Therapeutics, Inc. LEXEO Therapeutics is a New York City-based, fully integrated biotechnology company currently headquartered at the Alexandria Center for Life Science that aims to apply the transformational science of gene therapy to address some of the worlds most devastating genetic and acquired diseases. LEXEO Therapeutics pipeline consists of adeno-associated virus (AAV)-mediated therapies primarily developed at Weill Cornell Medicines Department of Genetic Medicine. Beyond LEXEO Therapeutics lead programs which are focused on both rare and non-rare monogenic (single gene mutation) diseases the companys preclinical pipeline spans monogenic diseases, as well as hereditary and acquired diseases across a spectrum of patient population sizes and a range of unmet medical needs. Importantly, LEXEO Therapeutics will focus on advancing clinical programs through to commercialization, with the goal of maintaining an ongoing research collaboration with Weill Cornell Medicines Department of Genetic Medicine to help advance the companys pre-clinical pipeline. For more information, please visit http://www.lexeotx.com or LinkedIn.

Investor ContactLEXEO Therapeutics, Inc.investors@lexeotx.com

Media Contact Sheryl Seapy, W2O Group(949) 903-4750sseapy@w2ogroup.com

ihttps://www.alzdiscovery.org/ iihttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC1350934/

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LEXEO Therapeutics Launches with $85 Million Series A Financing to Develop Gene Therapies for Rare and Non-Rare Monogenic Diseases - GlobeNewswire

Dive Brief:

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

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

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

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

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

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

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

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

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

For Immediate Release: January 04, 2021 Statement From:

Statement Author

Leadership Role

Acting Director - Center for Drug Evaluation and Research

Deputy Center Director for Operations - Center for Drug Evaluation and Research | CDER

Advances in scientific knowledge and drug development technology have provided an opportunity for new approaches to drug development, including the development of drugs for the treatment of rare diseases. These advances have contributed to an increase in development and approval of drugs for the treatment of rare diseases in recent years. In fact, in the past eight years, the U.S. Food and Drug Administration has approved more than twice as many drugs for rare diseases, often referred to as orphan drugs, as in the previous eight years.

For genetic diseases, recent approaches to testing and molecular diagnosis have allowed us to pinpoint, in some cases, the exact cause of a patients disease. For a patient with a very rare genetic disease, development of a drug product that is tailored to that patients specific genetic variant may be possible. This is an important advance in treatment for those with very rare genetic diseases, especially those for which there are no adequate therapies available to treat the disease. Often, these very rare diseases are rapidly progressing, debilitating, and in many cases, can lead to premature death if left untreated.

Developing these products also referred to as n of 1 therapies by some because they are designed for a patient population of one person brings a set of challenges and considerations not seen with the typical drug development process. First, as noted above, the disease is often rapidly progressing, requiring prompt medical intervention. Therefore, development needs to proceed very quickly to have a chance at helping the individual. Second, drug discovery and development for these drug products may be carried out by academic investigators, rather than by biopharmaceutical or pharmaceutical companies. These investigators may be less familiar with FDAs regulations, policies and practices, and less experienced in interacting with the FDA.

At this time, development of individualized genetic drug products is most advanced for antisense oligonucleotide (ASO) products. Therefore, we are taking the first steps in bringing clarity to this emerging area of individualized drug development by releasing a new draft guidance on investigational new drug (IND) submissions for individualized ASO drug products.

The guidance was developed to advise those developing ASO products on an approach to interacting with, and making regulatory submissions to, the FDA. The guidance addresses the following points:

As also discussed in a New England Journal of Medicine editorial in October 2019, we are fully aware that this new drug-discovery paradigm raises many ethical and societal issues that will need to be addressed throughout the process. For example, in these situations, the individuals and their families often function more like drug development collaborators than traditional trial participants. Therefore, it is important to discuss with the individual and family members how effectiveness will be measured. It is also important to ensure that the individual and family members understand the parameters for continuing administration of the investigational drug product before emotions influence decisions, and to recognize that some investigational drug products may fail, or worse, lead to unforeseen side effects.

The FDA understands that well need to work together with the developers of these drug products to bring them safely to patients, and we are willing to engage as needed to address the challenges. For example, for those developing these drug products, it will be important to further understand the required data and information that must be submitted to the FDA so that clinical testing can begin. The FDA is continuing to consider and further develop policy to address some of these issues.

We also are optimistic that development of these individualized drug products may spur gene sequencing that leads to the development of additional individualized drug products for the same disease (though perhaps caused by a different mutation). For this approach to drug development, we need to determine collectively how to effectively bring these drug products to all who need them. If we have the scientific ability to develop drug products for these rare diseases, we need to find a way to bring them to patients while ensuring there is the right balance of risk to benefit. This guidance, which provides clarity on the early development and IND submission process, is the FDAs first step in working with those who are developing these individualized drug products.

The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nations food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

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FDA Takes Steps to Provide Clarity on Developing New Drug Products in the Age of Individualized Medicine - FDA.gov

By now, everyone has seen countless images of people receiving the COVID-19 vaccine. But once its injected into the upper arm, how does it actually interact with the body?

Dr. M. Fahad Khalid, chief of the Division of Hospital Medicine at Penn State Health Milton S. Hershey Medical Center, and Dr. Mohammad Ali, an infectious diseases physician at Penn State Health Holy Spirit Medical Center, say while the vaccine doesnt contain any live COVID-19 virus, it teaches the human immune system to protect against it.

Both vaccines that received Emergency Use Authorization from the U.S. Food and Drug Administration (FDA) the Pfizer-BioNTech and Moderna vaccines are mRNA (messenger RNA) vaccines. They are not live viruses. Instead, they work by giving your body a blueprint to create a piece of the virus that causes COVID-19, called a spike protein.

Once you receive the vaccine, your cells machinery uses the mRNA instructions to make the spike protein. This protein is then displayed on the cell surface, and the immune system sees it and responds to it. While mRNA is a type of genetic code, it never enters the center (nucleus) of your cells. That means it never converts into DNA, Khalid said. The mRNA itself is destroyed by the cells after they produce the spike protein.

The spike protein the vaccines create is the same one found on the surface of the virus that causes COVID-19. However, the vaccines do not contain any live virus. The spike protein itself cannot cause an infection, Ali said.

Khalid and Ali also addressed many common questions people have about both vaccines:

The vaccines were approved quickly. Are they safe? Advances in vaccinology and vaccine production allowed pharmaceutical companies to create vaccines in months. However, both vaccines followed rigorous FDA guidelines, including the normal regimen of clinical trials and Phase 1, 2 and 3 trials. Their effectiveness is tremendous, Ali said. The flu vaccine is typically 40% to 60% effective, and the COVID-19 vaccines are 94% to 95% effective.

Do people get severe allergic reactions to the vaccine? The Centers for Disease Control and Prevention (CDC) reports a limited number of incidents where people experienced a severe allergic reaction (anaphylaxis) or reaction such as hives, swelling or wheezing. The CDC recommends against people taking the vaccine who had a prior severe allergic reaction to any ingredient in the COVID-19 vaccine. People who have had allergic reactions to other vaccines should ask their doctor about taking the COVID-19 vaccine. People with nonvaccine-related allergies food allergies, pet allergies, seasonal allergies are safe to get vaccinated, says the CDC.

Will the vaccine side effects be worse than getting COVID-19? Possible side effects, such as swelling or pain at the injection site, fever, headache or muscle pain, are temporary. Those side effects arent nearly as bad as severe cases of COVID-19, which can be fatal, Khalid said.

Do I need a vaccine if I already had COVID-19? Yes. Currently, the CDC recommends vaccination even in people who have had COVID-19 in the past. This is because we do not know how long immunity to the virus lasts after someone is infected.

Do I need to wear a mask after getting the COVID-19 vaccine? Yes, you must continue to wear a mask, practice social distancing and continue to wash your hands. The vaccine protects you from getting sick with COVID-19, but researchers still dont know if individuals can still get infected and transmit the virus to others.

Is there any kind of microchip tracking in the vaccines? No. The vaccine also will not cause infertility. Theres a lot of misinformation out there, Ali said. The most trustworthy resource for accurate information is the CDC website.

Alison Enimpah, a registered nurse who provided direct care for COVID-19 patients at the Milton S. Hershey Medical Center, was among the earliest group of health care workers to get vaccinated. Shell receive her second dose later this month. The vaccine adds a layer of reassurance that were making forward progress in keeping ourselves and our community safe during the pandemic, she said.

TheMedical Minuteis a weekly health news feature produced by Penn State Health. Articles feature the expertise of faculty, physicians and staff, and are designed to offer timely, relevant health information of interest to a broad audience.

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The Medical Minute: How the body responds to the COVID-19 vaccine - Penn State News

News Release

Wednesday, January 6, 2021

Using a recently developed DNA base-editing technique, researchers correct accelerating aging disorder.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

The National Human Genome Research Institute (NHGRI) is one of the 27 institutes and centers at the NIH, an agency of the Department of Health and Human Services. The NHGRI Division of Intramural Research develops and implements technology to understand, diagnose and treat genomic and genetic diseases. Additional information about NHGRI can be found at: https://www.genome.gov.

About the National Institutes of Health (NIH):NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.

NIHTurning Discovery Into Health

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DNA-editing method shows promise to treat mouse model of progeria - National Institutes of Health

Every drug, from morphine to ibuprofen, has a standard dose -- a sort of one-size-fits all recommendation. But a new study suggests that when it comes to drug doses, "one size fits all" rarely applies.

Stanford Medicine professor Russ Altman, MD, PhD, and a team of scientists found that almost everyone (99.5% of individuals) is likely to have an abnormal or "atypical" response to at least one therapeutic drug. This, at least, is the case for people in the United Kingdom, as the study's data came from the UK Biobank, a project that collects, studies and shares data.

The research found that nearly a quarter of the study's participants had been prescribed a drug for which they were predicted to have an atypical response, based on their genetic makeup. On average, participants were predicted to have an atypical response to 10 drugs.

"Ultimately, the hope is that we can show how pervasive drug response variability is and encourage more doctors to rethink the standard prescription protocols that are largely used today and use genetic testing to predict and adjust forthis variability," said Altman, who is an expert in pharmacogenetics, a field that studies the intersection of drugs and genetics.

An "atypical" drug response encompasses a lot of things; but generally speaking, it means a certain drug might not affect one person the way it does another.

For instance, someone who has an atypical metabolic response might process that drug more efficiently, strengthening its initial effects but decreasing its efficacy over time. On the flip side, it could mean that that person is unable to metabolize the drug at all, leaving them without therapeutic aid, or even with dangerous side effects.

These differences in response to a drug are partially due to our genetics. Specific proteins -- workhorse molecules in the body -- break down drugs in order for the body to benefit from the therapeutic. Those proteins are regulated by a specific group of genes. Natural variation in those genes leads to differences in how an individual's body reacts to a given drug molecule.

Altman and his team, including graduate students and first authors of the study Greg McInnes and Adam Lavertu, analyzed data from nearly 500,000 participants.

For 230,000 participants in the study, the team had primary care data going back about 30 years. That includes which drugs had been prescribed, the dose, and all of the patient's different diagnoses. The researchers also had access to detailed genetic information about each patient. They paid special attention to genetic variations in a group of genes that are known to influence the human drug response.

By comparing an individual's genetics against the variations known to exist in the group of drug-response-associated genes, the researchers could predict how any given patient might respond to a drug.

"Pharmacogenetics as a field has been around for a long time, but it hasn't really been adopted into clinical use," McInnes told me. "It's been growing in the last few years as more people realize the impact that it could have on personalized health. For a long time, it's been this overlooked aspect of genetics that I think is actually one of the most clinically actionable advances that has come out of human genetics."

What's more, he said, the wide variability in the human drug response applies to common therapeutics most everyone has encountered or is familiar with -- ibuprofen, codeine, statins and beta blockers among others.

Moving forward, Lavertu says that the goal is to expand drug-gene variant interaction analyses into more diverse populations. The data from the UK Biobank provided critical insight, but it was largely only representative of a British population, where the majority shares European ancestry. A next step for the researchers is to investigate the same genes in the Million Veteran Program, a government research program with a more diverse study population, that is examining how genes, lifestyle and military exposures affect health and illness.

"Our hope is that doing more of these studies will help us find new relationships between genetic variants and drug response, so that pharmacogenetics can benefit more people," Lavertu said.

Photo byMicha Parzuchowski

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Based on genes, nearly everyone is likely to have an atypical response to at least one drug - Scope

Kathryn Anderson, a developmental biologist at the Memorial Sloan Kettering Cancer Center known for her work detailing the genetics of early embryogenesis, died November 30 at age 68.

Throughout her scientific career, Anderson used rigorous genetic screening assays to identify mutations suspected of disrupting cell division and differentiation in model systems. Having identified a gene of interest, she would then turn to a technique known as forward genetics, creating model organisms such as fruit flies and mice with a particular phenotype to better understand its molecular underpinnings. Using these tools, Anderson made important contributions to scientists understanding of several genetic pathwaysmost notably the Toll and Hedgehog pathwaysrequired for proper development of these animals.

Kathryn was fearless and very open-minded, Tatiana Omelchenko, a senior research scientist in Andersons lab who uses confocal microscopy to do live imaging of mouse embryos, tells The Scientist. Every lab has its own environment and its own mood, and when you stepped into Kathryns lab, you immediately felt very focused.

Born in La Jolla, California, in 1952, Anderson became interested in science at a young age, stemming back to an article in LIFEthat included a detailed image of a human fetus, according to an interview released shortly after her death. She attended the University of California, Berkeley, where she earned her undergraduate degree in biochemistry before heading to a graduate program in neurodevelopment at Stanford University in 1973.

Anderson left that program after only two years, earning a masters degree in neuroscience, and spent the next several years looking for her scientific niche. She enrolled briefly in medical school at the University of California, San Diego, an experience that led her to realize her love of basic research. The clinical work wasnt my cup of tea, Anderson shared in a 2005 biography. The lab was where I felt most at home.

Ultimately, Anderson landed at the University of California, Los Angeles, studying the developmental genetics of Drosophilaunder the guidance of biologist Judith Lengyel. For her PhD work, Anderson showed that in the first two hours after fertilization, the development of Drosophilaembryos remains under maternal control, with maternal RNA and proteins directing cell division and differentiation within the egg.

Looking to further her study of fruit flies, Anderson next traveled to the Max Planck Institute for Developmental Biology in Germany as a postdoc to work with Drosophilageneticist Christiane Nsslein-Volhard. In 1995, Nsslein-Volhard would share a Nobel Prize for her work using mass screenings to identify mutations that disrupt embryonic development, and Anderson would continue studying a handful of the genes identified in these early screens throughout her career.

One such gene, known as Toll, turned out to play an important role in dorsal-ventral (D-V) differentiationdictating, as Anderson said in her biography, how a fly embryo knows its back from its belly. In addition to probing the function of Toll,Anderson continued building out the wider Toll pathway after returning to the University of California, Berkeley, as an assistant professor in 1985, and later in her own lab at the Sloan Kettering Institute, which she launched in 1996 at Memorial Sloan Kettering. During this time, Anderson and her team identified roughly a dozen genes involved in cell differentiation along the D-V axis, and she used similar screening methods to better understand Tolls role in innate immunity of Drosophila. Her findings were noted by geneticists Jules Hoffmann and Bruce Beutler, whose study of Toll-like receptors in both fruit fly and mammalian immunity would later earn them a Nobel Prize.

Kathryn Anderson

Memorial Sloan Kettering Cancer Center

After her successes in fruit flies, Anderson began thinking about applying her same methods to the study of mice. She spent a year on sabbatical in the lab of Rosa Beddington at the National Institute for Medical Research in the UK, where she showed that Toll had no analogous role in the D-V differentiation of mammals. It demonstrated, she said in a 2016 interview with Development, that there are things about early mammalian development that you cant figure out by extrapolating from flies.

Back at the Sloan Kettering Institute, Anderson began once again using mass genetic screenings, this time to identify mutations of interest in mice, and then studying them in fine detail. These were lengthy experiments that often took years to yield results. I think her major contribution is discovering the functions and roles of genes through this mutagenesis screen, Omelchenko says. This is amazing because . . . the mouse embryo model is quite complex, but she did the work.

Anderson and her team screened more than 12,000 mutations, selecting roughly 40 that produce obvious phenotypic disruptions midway through gestation. Working diligently over many years, Anderson identified previously unknown pathways that have since prompted new research directions in the field of developmental biology.

Through her screening, for example, Anderson identified a previously unknown relationship between ciliamicroscopic, hairlike structures on the outside of some cellsand proper signaling of the Hedgehog pathway that dictates cell differentiation in mammalian embryos. Further research showed that components of this pathway are enriched in cilia, while mice with certain mutations in genes involved in Hedgehog signaling lacked cilia altogether in a structure called the node that directs gastrulation in vertebrate embryos. That turned out to be pretty amazing, actually: theres this whole organelle required for Hedgehog signaling in vertebrates, but not in flies, Anderson said in her Developmentinterview. Its a geneticists dream, but raises the question of why organize the genome like this: there are so many weak points in Hedgehog signalingand Hedgehog is so vital.

For her contributions to the field of developmental biology, Anderson was inducted into the National Academy of Sciences in 2002 and elected as a member of the Institute of Medicine of the National Academies in 2008. In addition, she was awarded the Thomas Hunt Morgan Medal for lifetime contributions to the science of genetics in 2012, the Federation of American Societies for Experimental Biologys Excellence in Science Award in 2014, and the Society for Developmental Biologys Edwin G. Conklin Medal for distinguished and sustained research in 2016, among other honors.

Prior to her death, Anderson had spoken about the possible extension of her research into human genetics, as disruptions in hedgehog signaling have since been linked both to birth defects and to a series of diseases referred to as ciliopathies. It was, however, a line of questioning she planned to leave to other scientists, content to continue her methodical work exploring mutations in mice.

Many scientists are very quiet people, but contemporary society requires you to be very loud [so] that people will listen to you, Omelchenko says. Kathryn is such a great example of being quiet, being a very deep thinker, and at the same time becoming a very successful and bright scientist. I think I will keep learning from her even though she has passed away.

Anderson is survived by her husband, Timothy Bestor, a geneticist at Columbia University.

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Developmental Biologist Kathryn Anderson Dies at 68 - The Scientist

DALLAS--(BUSINESS WIRE)--ProPath, the largest fully physician-owned pathology practice in the United States, today announced that Julia A. Bridge, M.D., a board-certified pathologist and geneticist with an extensive medical career and expertise in solid tumor molecular testing, has joined the ProPath team.

Dr. Bridge, who recently directed the Molecular Pathology Research Division at the Translational Genomics Research Institute in Phoenix, AZ, will be directing ProPaths fluorescence in situ hybridization (FISH) and cytogenetics team. She will also be incorporating her testing expertise in bone/soft tissue tumors for ProPaths molecular pathology team.

We are thrilled to have Dr. Bridge join our team, said Cory A. Roberts, M.D., President, Chairman and CEO of ProPath. She has a rare combination of expertise in both anatomic pathology and cytogenetics that make her an expert with an international consultative practice. Her ability to interpret microscopic morphology in concert with her unsurpassed knowledge of the molecular and genetic signature of tumors is unsurpassed and will carry ProPaths abilities in these areas to the forefront of all practices.

Dr. Bridge received her medical degree from the University of Nebraska Medical Center and completed her pathology residency at the University of Kansas Medical Center followed by clinical cytogenetic and molecular fellowships at the University of Nebraska Medical Center and the Southwest Biomedical Research Institute in Scottsdale Arizona.

Dr. Bridge serves or has served on editorial boards for pathology, orthopedic, and genetics journals, in consulting or advisory board positions for cancer networks and industry (including as key investigator for landmark FDA approvals for two novel gene-based tests), the national Childrens Oncology Group Soft Tissue Sarcoma and Ewing sarcoma committees, College of American Pathology (CAP) Glioma Expert Panel, and Secretarial Appointee to the national Department of Veterans Affairs Genomic Medicine Program Advisory Committee. She has authored greater than 300 scientific articles, chapters, review papers, digital and web-based materials, and is co-author or co-editor of several books (e.g. AFIP Atlas of Tumor Pathology; 4th Series, Fascicle 2: Tumors of the Bones and Joints and editions of the WHO Classification of Tumours of Soft Tissue and Bone). Dr. Bridge is the current President of the United States and Canadian Academy of Pathology.

About ProPath:

ProPath is the largest, nationwide, fully physician-owned pathology practice in the United States. Led by a team of world-class physicians and scientists, ProPath routinely diagnoses cases from 45 states and several foreign countries. Its over 500 employees reside in 10 states and staff labs and facilities in three states. For 55 years, ProPaths mission has been to provide patient-centered, high quality and effective medical diagnostics, prognostics and research that creates better patient outcomes.

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ProPath Appoints Soft Tissue Tumor Expert, Julia A. Bridge, M.D., as Director of Cytogenetics and FISH - Business Wire

CAMBRIDGE, Mass.--(BUSINESS WIRE)--Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi therapeutics company, announced today that the HELIOS-A Phase 3 study of vutrisiran, an investigational RNAi therapeutic in development for the treatment of transthyretin-mediated (ATTR) amyloidosis, met its primary and both secondary endpoints at nine months in patients with hATTR amyloidosis with polyneuropathy. The primary endpoint was the change from baseline in the modified Neuropathy Impairment Score (mNIS+7) at 9 months as compared to historical placebo data from the APOLLO Phase 3 study of patisiran. The two secondary endpoints were changes in quality of life assessed by the Norfolk Quality of Life Questionnaire-Diabetic Neuropathy (Norfolk QoL-DN) and gait speed assessed by the timed 10-meter walk test (10-MWT) compared to historical placebo. Vutrisiran met the primary endpoint (p less than 0.001) and achieved statistically significant results (p less than 0.001) for each of the Norfolk QoL-DN and 10-MWT secondary endpoints. In addition, vutrisiran treatment showed improvement compared to placebo on the exploratory cardiac biomarker endpoint, NT-proBNP (nominal p less than 0.05). Vutrisiran also demonstrated an encouraging safety and tolerability profile.

Based on these positive results, the Company plans to submit a New Drug Application (NDA) for vutrisiran with the U.S. Food and Drug Administration (FDA) in early 2021, and to follow with regulatory filings in additional countries, such as Brazil and Japan. The Company plans to submit a Marketing Authorisation Application (MAA) in the EU upon obtaining the results of the 18-month analysis expected in late 2021 as previously aligned with the European Medicines Agency (EMA).

We are excited to report positive topline results from the HELIOS-A study, which show that vutrisiran reduces neurologic impairment and improves quality of life in patients with hATTR amyloidosis with polyneuropathy as soon as 9 months, with an encouraging safety and tolerability profile. In addition, were very pleased to see evidence for reversal of polyneuropathy manifestations of disease and also favorable effects on the exploratory cardiac endpoint, NT-proBNP. We believe that vutrisiran, as a low-dose, once-quarterly, subcutaneously administered therapy, has the potential to be a highly attractive therapeutic option for patients living with this progressive, life-threatening, multi-system disease. We look forward to presenting the full 9-month results from HELIOS-A at a medical meeting in early 2021 and to announcing additional 18-month results, including additional exploratory cardiac endpoint data, in late 2021, said Akshay Vaishnaw, M.D., Ph.D., President of R&D at Alnylam. We would like to recognize and extend our profound gratitude to the patients, caregivers, investigators, and study staff who are participating in HELIOS-A and who, through their commitment during an especially difficult year, have helped make possible another potential advancement in the treatment of hATTR amyloidosis with polyneuropathy. We look forward to initiating our regulatory filings in early 2021 as we work to bring this investigational treatment one step closer to patients with this rare disease.

HELIOS-A (NCT03759379) is a Phase 3 global, randomized, open-label study to evaluate the efficacy and safety of vutrisiran. The study enrolled 164 patients with hATTR amyloidosis with polyneuropathy at 57 sites in 22 countries. Patients were randomized 3:1 to receive either 25mg of vutrisiran (N=122) via subcutaneous injection once every three months or 0.3 mg/kg of patisiran (N=42) via intravenous infusion once every three weeks (as a reference comparator) for 18 months. The primary endpoint is the change from baseline in mNIS+7 score at 9 months1, relative to historical placebo. Secondary endpoints at 9 months are the change from baseline in the Norfolk QoL-DN score and the timed 10-MWT, relative to historical placebo. Changes from baseline in NT-proBNP were evaluated as an exploratory endpoint at 9 months. The efficacy results of vutrisiran in HELIOS-A are compared to historical placebo control data from the landmark APOLLO Phase 3 study, which evaluated the efficacy and safety of patisiran in a patient population similar to that studied in HELIOS-A. Additional secondary endpoints at 18 months will be evaluated in the HELIOS-A study, including change from baseline in mNIS+7, Norfolk QoL-DN, 10-MWT, modified body mass index (mBMI), Rasch-built Overall Disability Scale (R-ODS), and serum transthyretin (TTR) levels. Additional exploratory cardiac endpoint data at the 18-month time point will be evaluated, including NT-proBNP, echocardiographic measures and cardiac amyloid assessments with technetium scintigraphy imaging. Following the 18-month study period, all patients are eligible to receive vutrisiran for an additional 18 months as part of an open-label extension study. Full 9-month results will be presented at a medical conference in early 2021 and topline 18-month results, including further exploratory cardiac endpoint data, are expected to be announced in late 2021.

Vutrisiran demonstrated an encouraging safety profile. There were two study discontinuations (1.6 percent) due to adverse events in the vutrisiran arm by Month 9, both due to deaths, neither of which was considered related to study drug. There were two serious adverse events (SAEs) deemed related to vutrisiran by the study investigator, consisting of dyslipidemia and urinary tract infection. Treatment emergent adverse events (AEs) occurring in 10 percent or more patients included diarrhea, pain in extremity, fall and urinary tract infections, with each of these events occurring at a similar or lower rate as compared with historical placebo. Injection site reactions (ISRs) were reported in five patients (4.1 percent) and were all mild and transient. There were no clinically significant changes in liver function tests (LFTs).

The HELIOS-A results reinforce our commitment to building an industry-leading franchise of medicines for the treatment of ATTR amyloidosis which began with the development and approval of ONPATTRO as a treatment for patients with hATTR amyloidosis with polyneuropathy. Indeed, the vutrisiran results from HELIOS-A now serve as a second example of the potential for RNAi therapeutics to have a meaningful impact for patients, showing the ability to halt and potentially even reverse polyneuropathy manifestations of the disease. Furthermore, our robust development program, including the APOLLO-B and HELIOS-B studies, investigates the potential of patisiran and vutrisiran, respectively, to treat the cardiac manifestations of disease across a broad spectrum of patients with ATTR amyloidosis, said John Maraganore, Ph.D., Chief Executive Officer of Alnylam. We believe that our ATTR amyloidosis franchise will be a significant driver of Alnylams growth in the years to come, with the potential to position Alnylam as a top tier biopharma company.

Vutrisiran has been granted Orphan Drug Designation in the United States and the European Union for the treatment of ATTR amyloidosis. Vutrisiran has also been granted a Fast Track designation in the United States for the treatment of the polyneuropathy of hATTR amyloidosis in adults. The safety and efficacy of vutrisiran are being evaluated in the comprehensive HELIOS clinical development program and have not yet been evaluated by any health authority. The ongoing HELIOS-B Phase 3 clinical trial in patients with ATTR amyloidosis with cardiomyopathy was initiated in late 2019 and is currently enrolling at sites around the world. Together, the HELIOS-A and -B studies are intended to demonstrate the broad impact of vutrisiran across the multisystem manifestations of disease and the full spectrum of patients with ATTR amyloidosis.

Conference Call InformationAlnylam management will discuss the HELIOS-A results via conference call on Thursday, January 7, 2021, at 8:00 am ET. A webcast presentation will also be available on the Investors page of the Companys website, http://www.alnylam.com. To access the call, please dial 877-312-7507 (domestic) or +1-631-813-4828 (international) five minutes prior to the start time and refer to conference ID 4398564. A replay of the call will be available beginning at 11:00 am ET on the day of the call. To access the replay, please dial 855-859-2056 (domestic) or +1-404-537-3406 (international) and refer to conference ID 4398564.

About hATTR AmyloidosisHereditary transthyretin (TTR)-mediated amyloidosis (hATTR) is an inherited, progressively debilitating, and often fatal disease caused by mutations in the TTR gene. TTR protein is primarily produced in the liver and is normally a carrier of vitamin A. Mutations in the TTR gene cause abnormal amyloid proteins to accumulate and damage body organs and tissue, such as the peripheral nerves and heart, resulting in intractable peripheral sensory-motor neuropathy, autonomic neuropathy, and/or cardiomyopathy, as well as other disease manifestations. hATTR amyloidosis, represents a major unmet medical need with significant morbidity and mortality affecting approximately 50,000 people worldwide. The median survival is 4.7 years following diagnosis, with a reduced survival (3.4 years) for patients presenting with cardiomyopathy.

About VutrisiranVutrisiran is an investigational, subcutaneously administered RNAi therapeutic in development for the treatment of ATTR amyloidosis, which encompasses both hereditary (hATTR) and wild-type (wtATTR) amyloidosis. It is designed to target and silence specific messenger RNA, blocking the production of wild-type and variant transthyretin (TTR) protein before it is made. Quarterly administration of vutrisiran may help to reduce deposition and facilitate the clearance of TTR amyloid deposits in tissues and potentially restore function to these tissues. Vutrisiran utilizes Alnylams Enhanced Stabilization Chemistry (ESC)-GalNAc-conjugate delivery platform, designed for increased potency and high metabolic stability that allows for infrequent subcutaneous injections. The safety and efficacy of vutrisiran have not been evaluated by the U.S. Food and Drug Administration, European Medicines Agency or any other health authority.

About RNAiRNAi (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 Alnylams RNAi therapeutic platform, function upstream of todays medicines by potently silencing messenger RNA (mRNA) the genetic precursors that encode for disease-causing 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 PharmaceuticalsAlnylam (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), GIVLAARI (givosiran), OXLUMO (lumasiran), and, in Europe, Leqvio (inclisiran). Alnylam has a deep pipeline of investigational medicines, including six product candidates that are in late-stage development. Alnylam exceeded the goals first established in 2015 under 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. For more information about our people, science and pipeline, please visit http://www.alnylam.com and engage with us on Twitter at @Alnylam or on LinkedIn.

Alnylam Forward Looking StatementsVarious statements in this release concerning Alnylam's future expectations, plans and prospects, including, without limitation, expectations regarding the direct or indirect effects on Alnylams business, activities and prospects as a result of the COVID-19 pandemic, or delays or interruptions resulting therefrom and the success of Alnylams mitigation efforts, Alnylam's views and plans with respect to the potential for RNAi therapeutics, including vutrisiran and patisiran, expectations regarding the safety and efficacy of vutrisiran as a treatment for hATTR amyloidosis with polyneuropathy, and its potential to have a meaningful impact on the course of this disease, expectations regarding the potential of vutrisiran and patisiran to treat the cardiac manifestations of ATTR amyloidosis across a broad spectrum of patients, Alnylams prospects for building an industry-leading ATTR amyloidosis franchise and to become a top-tier biopharma company, the expected timing for the filing of regulatory submissions for vutrisiran the presentation of full 9-month results and the announcement of 18-month topline results, including exploratory cardiac endpoint data, 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 any future pandemic, such as the scope and duration of the outbreak, government actions and restrictive measures implemented in response, the availability of safe and effective vaccine(s), 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 any 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, including vutrisiran; 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 or its or its partner Novartis marketed products, including ONPATTRO, GIVLAARI, OXLUMO and Leqvio (in Europe); 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 vutrisiran, and the success of its partner Novartis, in obtaining regulatory approval for inclisiran in the U.S. and elsewhere, and maintaining regulatory approval and obtaining pricing and reimbursement for its products, including ONPATTRO, GIVLAARI, and OXLUMO, as well as its partner Novartis success obtaining pricing and reimbursement for Leqvio; progress in continuing to establish an ex-United States infrastructure; successfully launching, marketing and selling its approved products globally, including ONPATTRO, GIVLAARI, and OXLUMO, 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; Alnylam's dependence on third parties, including Novartis for the continued development and commercialization of Leqvio, Regeneron for development, manufacture and distribution of certain products, including eye and CNS products, 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.

1 In alignment with the EMA, the primary endpoint of change from baseline in mNIS+7 will be evaluated at 18 months to support an MAA.

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Alnylam Reports Positive Topline Results from HELIOS-A Phase 3 Study of Vutrisiran in Patients with hATTR Amyloidosis with Polyneuropathy - Business...