Category Archives: Gene Medicine

In early April, about four months after a new, highly infectious coronavirus was first identified in China, an international group of scientists reported encouraging results from a study of an experimental drug for treating the viral disease known as COVID-19.

It was a small study, reported in the New England Journal of Medicine, but showed that remdesivir, an unapproved drug that was originally developed to fight Ebola, helped 68% of patients with severe breathing problems due to COVID-19 to improve; 60% of those who relied on a ventilator to breathe and took the drug were able to wean themselves off the machines after 18 days.

Repurposing drugs designed to treat other diseases to now treat COVID-19 is one of the quickest ways to find a new therapy to control the current pandemic. Also in April, researchers at Vanderbilt University enrolled the first patients in a much-anticipated study of hydroxychloroquine. Its already approved to treat malaria and certain autoimmune disorders like rheumatoid arthritis and lupus but hasnt been studied, until now, against coronavirus. Yet the medication has become a sought-after COVID-19 treatment after first Chinese doctors, and then President Trump touted its potential in treating COVID-19. The data from China is promising but not conclusive, and infectious disease experts, including Trumps coronavirus task force scientific advisor Dr. Anthony Fauci, arent convinced its ready for prime time yet in Americas emergency rooms and intensive care units.

But doctors facing an increasing flood of patients say they dont have time to wait for definitive data. In a survey of 5,000 physicians in 30 countries conducted by health care data company Sermo, 44% prescribed hydroxychloroquine for their COVID-19 patients, and 38% believed it was helping. Such off-label use in using a drug approved to treat one disease to treat another is allowed, especially during a pandemic when no other therapies are available. A similar percentage said remdesivir was very or extremely effective in treating COVID-19. (Although remdesivir is not approved for treating any disease, the Food and Drug Administration granted special authorization for doctors to use it to treat the sickest COVID-19 patients.)

That explains the unprecedented speed with which the hydroxychloroquine studyand others like itare popping up around the world. There are no treatments proven to disable SARS-CoV-2, the virus that causes the disease, which means all the options scientists are exploring are still very much in the trial-and-error stage. Still, they are desperate for anything that might provide even a slim chance of helping their patients survive, which is why studies are now putting dozens of different therapies and a handful of vaccines to the test. The normal road to developing new drugs is often a long oneand one that frequently meanders into dead ends and costly mistakes with no guarantees of success. But given the speed at which SARS-CoV-2 is infecting new hosts on every continent across the globe, those trials are being ushered along at a breakneck pace, telescoping the normal development and testing time by as much as half.

The newly launched Vanderbilt study, led by the National Heart, Lung, and Blood Institute of the U.S. National Institutes of Health, will enroll more than 500 people who have been hospitalized with COVID-19 and randomly assign them to receive hydroxychloroquine or placebo. It would be the first definitive trial to test whether hydroxychloroquine should be part of standard therapy for treating COVID-19, and its lead scientist expects results in a few months.

The sense of urgency is pushing other researchers at academic institutes as well as pharmaceutical companies to turn to their libraries of thousands of approved drugs or compounds that are in early testing and screening to see if any can disable SARS-CoV-2. Because these are either already approved and deemed safe for people, if any emerge as possible anti-COVID-19 therapies, companies could begin testing them in people infected with the virus within weeks. Other teams are mining recovered patients blood for precious COVID-19-fighting immune cells, and because the virus seems to attack the respiratory system, scientists are also finding clever ways to stop it from compromising lung tissue.

These are all stop-gap measures, however, since ultimately, a vaccine against COVID-19 is the only way to arm the worlds population against new waves of infection. Established pharmaceutical powers like Johnson & Johnson, Sanofi and Glaxo SmithKline are racing shoulder-to-shoulder to with startups using new technology to develop dozens of potential new vaccines, with the hope of inoculating the first people next yearnone too soon before what public health officials anticipate might be another season of either the same, or potentially new, coronavirus.

We know these viruses reside in animal species, and surely another one will emerge, says Dr. David Ho, director of the Aaron Diamond AIDS Research Center and professor of medicine at Columbia University, who is heading an effort to screen antiviral drug compounds for new COVID-19 treatments. We need to find permanent solutions to treating them, and should not repeat the mistake that once an epidemic wanes, interest and political will and funding also wanes.

Its an old-school approach that dates back to the late 19th century, but the intuitive logic behind using plasma from recovered patientstechnically called convalescent plasmaas a treatment might still apply today. Plasma treatments have been used with some success to treat measles, mumps and influenza. The idea is to use immune cells extracted from the blood of people who have recovered from COVID-19 and infuse them into those who are infected, giving them passive immunity to the disease, which could at least minimize some of its more severe symptoms.

Its part of a broader range of tactics that utilize the bodys own immune response as a molecular North Star for charting the course toward new treatments. And by far, antibodies against the virus are the most abundant and efficient targets, so a number of pharmaceutical and biotechnology companies are concentrating on isolating the ones with the strongest chance of neutralizing SARS-CoV-2.

In late March, New York Blood Center became the first U.S. facility to start collecting blood from recovered COVID-19 patients specifically to treat other people with the disease. Doctors at New Yorks Mount Sinai Health System are now referring recovered (and willing) patients to the Blood Center, which collects and processes the plasma and provides the antibody-rich therapy back to hospitals to treat other COVID-19 patients.. Its not clear yet whether the practice will work to treat COVID-19, but the Food and Drug Administration (FDA) is allowing doctors to try the passive immunity treatment in the sickest patients on a case by case basis, as long as they apply for permission to use or study the plasma an investigational new drug. If we can passively transfuse antibodies into someone who is actively sick, they might temporarily help that person fight infection more effectively, so they can get well a little bit quicker, says Dr. Bruce Sachais, chief medical officer at New York Blood Center Enterprises.

The biggest drawback to this approach, however, is the limited supply of antibodies. Each recovered donor has different levels of antibodies that target SARS-CoV-2, so collecting enough can be a problem, especially if the need continues to surge during an ongoing pandemic. At the Maryland-based pharmaceutical company Emergent BioSolutions, scientists are trying to overcome this challenge by turning to a unique source of plasma donors: horses. Their size makes them ideal donors, says Laura Saward, head of the companys therapeutic business unit. Scientists already use plasma from horses to produce treatments for botulism (a bacterial infection), and have found that the volume of plasma the animals can donate means each unit can treat more than one patient (with human donors, at this point, one unit of plasma from a donor can treat one patient). Horses plasma may also have higher concentrations of antibody, so the thought is that a smaller dose of equine plasma would be effective in people because there would be higher levels of antibody in smaller doses, says Saward. By the end of the summer, the company expects its equine plasma to be ready for testing in people.

Scientists are also looking for other ways to generate the virus-fighting antibodies produced by COVID-19 patients. At Regeneron, a biotechnology firm based in New York, researchers are turning to mice bred with human-like immune systems and infected with SARS-CoV-2. Theyre searching hundreds of antibodies these animals produce for the ones that can most effectively neutralize the virus. By mid-April, the company plans to start manufacturing the most powerful candidates and prepare them (either solo or in combination) for human testingboth in those who are already infected, as well as in healthy people, to protect from getting infected in the first place, like a vaccine.

Its not just people and animals that can produce antibodies. Scientists now have the technology to build what are essentially molecular copying machines that can theoretically churn out large volumes of the antibodies found in recovered patients. At GigaGen, a San Francisco-based biotech startup founded by Stanford University professor Dr. Everett Meyer, scientists are identifying the right antibodies from recovered COVID-19 patients and hoping to use them as a template for synthesizing new ones, in a more consistent and efficient way so a handful of donors could potentially produce enough antibodies to treat millions of patients. What GigaGens technology does is almost Xerox copy a big swath of the human repertoire of antibodies, and then takes those copies and grows it in cells [in the lab] to manufacture more antibodies outside of the human body, says Meyer. So we can essentially keep up with the virus. If all goes well and the FDA gives its green light, the company intends to start testing their antibody concoctions in COVID-19 patients early next year.

Researchers at Rockefeller University are following another clue from the human bodys virus-fighting defenses. They discovered in 2017 that human cells make a protein called LY6E that can block a viruss ability to make copies of itself. Working with scientists at the University of Bern in Switzerland and the University of Texas Southwestern Medical Center, they found that mice genetically engineered to not produce the protein became sicker, and were more likely to die after infection with other coronaviruses, including SARS and MERS, compared to mice that were able to make the protein. If the mice have the protein they pretty much survive, says John Schoggins, associate professor of microbiology at the University of Texas. If they dont have it, they dont survivebecause their immune system cant control the virus. While these studies havent yet been done on SARS-CoV-2, given its similarity to the original SARS virus, theres hope a therapy based on LY6E might be useful.

Ideally, Schoggins is hoping to start testing LY6Es potential in infected human lung cells, which SARS-CoV-2 appears to target for disease. The closest mouse model for coronavirus, created to study the original SARS virus, has been retired since research on that virus dwindled after cases wanted following the 2003 outbreak. There wasnt the need to keep the mouse around, and that tells us a lot about the state of our research, says Schoggins. We dont really work on thing unless everyones hair is on fire.

Its not just immune cells that make good targets for new drugs. Other companies are looking at broader immune-system changes triggered by stressduring cancer, for example, or infection with a new virus like SARS-CoV-2that end up making it easier for a virus to infect cells. Drugs that inhibit these stress-related changes would act like molecular gates slamming shut on the cells that viruses are trying to infect.

Because SARS-CoV-2 preferentially attacks lung tissue and causes cells in the respiratory tract to launch a hyperactive immune response, researchers are exploring ways to tame that aggressive response by dousing those cells with a familiar gas: nitric oxide, often used to relax blood vessels and open up blood flow in hospital patients on ventilators who have trouble breathing. While working on a new, portable system for delivering nitric oxide developed by Bellerophon Therapeutics to treat a breathing disorder in newborns, Dr. Roger Alvarez, an assistant professor of medicine at University of Miami, got the idea that the gas might be helpful for COVID-19 patients as well. One symptom of the viral infection is low oxygen levels in the lungs, and nitric oxide is ideally designed to grab more oxygen molecules from the air with each breath and feed it to the lungs. With this system, patients dont need to be in the ICU [Intensive Care Unit] at all, he says. The patient can be in a regular hospital bed, or even at home. So you save the cost of the ICU and from a resource standpoint, you save on needing nursing care, respiratory therapists and other ICU monitoring.

In theory, if this system could be used for COVID-19 patients with moderate symptoms, it could keep those patients from needing a ventilatora huge benefit in the current context where ventilator shortages are one of the biggest threats to the U.S. health care system. So far, Alvarez has received emergency use authorization from the FDA to test a version of his system on one COVID-19 patient at the University of Miami Health System. That patient improved and is ready to go home. Its great news and gives me the information to say that this appears at least safe to study further, he says, which is what he plans to do with the first small trial of nitric oxide for COVID-19 at his hospital.

When it comes to developing a new antiviral treatment, it doesnt always pay to start from scratch. There are dozens of drugs that have become life-saving therapies for one disease after their developers accidentally discovered that the medications had other, equally useful effects. Viagra, for example, was originally explored as a heart disease drug before its unintended effect in treating erectile dysfunction was discovered, and gabapentin was developed as an epilepsy drug, but is now also prescribed to control nerve pain.

Within weeks of COVID-19 cases spiking to alarming levels in China, researchers at Gilead in Foster City, Cal., saw an opportunity. A drug the company had developed against Ebola, remdesivir, had shown glimmers of hope in controlling that virus in the laband also showed promise as a tool to treat coronaviruses like those that caused SARS and MERS. In fact, says Merdad Parsey, chief medical officer of Gilead, We knew in the test tube that remdesivir had more activity against coronaviruses like SARS and MERS than against Ebola. So it wasnt entirely surprising that when the company began testing it in people during last years Ebola outbreak in the Democratic Republic of Congo, the results were disappointing. The early studies against Ebola werent as encouraging in people as they were in animals. So we were basically on hold with the drug, waiting to see if there would be another [Ebola] outbreak to see if we could test it earlier in the infection, says Parsey.

Then COVID-19 happened. As the infection roared through Wuhan, Chinathe original epicenter of the diseaseresearchers there reached out to Gilead, knowing that the company had released data suggesting that remdeisivir had strong antiviral effects in lab studies against coronaviruses. They launched two studies of the drug in the sickest patients.

In mid-January, a man in Everett, Wash., who had recently visited Wuhan, checked into a clinic after a few days of feeling sick. He quickly went from having a fever and cough to having difficulty breathing because of pneumonia. Concerned that the man was worsening by the day, his doctor contacted the U.S. Centers for Disease Control; suspecting this might be a case of COVID-19and knowing there was no proven treatment for the infectionexperts at the agency suggested he try an experimental therapy, remdesivir.

The CDC team felt relatively confident about the drugs safety, if not its effectiveness, since Gilead had studied it extensively in animal models and, in the early trials in people, it didnt lead to any serious side effects and appeared safe. They were also aware of the companys promising data with human cells against the original SARS.

For the Washington patient, the experimental drug might be a lifesaver. A day after receiving remdesivir intravenously, his fever dropped, and he no longer needed supplemental oxygen to breathe. About two weeks after entering the hospital, he was discharged to self-isolate for several more days at home.

That set off a rush for remdesivir as cases in the U.S. went from a trickle to a flood, and doctors grasped for anything to treat quickly declining patients. Gilead initially offered the drug on a compassionate use basis, a process that allows companies, with the FDAs permission, to provide unapproved drugs currently being studied to patients who need them as a last resort. These programs are designed for one-off uses, and companies usually receive two to three requests a month from doctors . But in this case, Gilead was flooded with requests for remdesivir at the beginning of March. And because each one is evaluated on a case-by-case basis to ensure that each patient is eligible and that the potential risks of trying an untested drug dont outweigh the benefits, a backlog developed and the company couldnt respond to the requests in a timely way, says Parsey. So on March 30, Gilead announced it would no longer provide remdesivir through that program but through an expanded access program instead. Doctors can get access to the drug for their COVID-19 patients via dozens of clinical trials of remdesivir, two of which Gilead initiated. One is focused on patients with mild symptoms and one involves those with severe symptoms. The National Institutes of Health is currently heading another large study of the drug, at multiple centers around the country.

Finding a new purpose for existing drugs is ideal; they are likely already proven safe and their developers have a substantial dossier of information on how the drugs work. Thats what happened with hydroxychloroquine, a malaria drug developed after the parasite that causes the illness became resistant to the chloroquine, a drug discovered during World War II and since used widely to fight the disease. As researchers studied hydroxychloroquine in the lab in recent decades , they learned it can block viruses, including coronaviruses, from infecting cells. In lab studies, when researchers infected human cells with different viruses and then bathed them in hydroxychloroquine, those cells could generally stop viruses like influenza, SARS-CoV-2, and the original SARS virus, another type of coronavirus, from infecting the cells. The problem is that what happens in the lab often doesnt predict what happens in a patient, says Dr. Otto Yang, from the department of microbiology, immunology and molecular genetics at the David Geffen School of Medicine at the University of California Los Angeles. In fact, in the case of influenza, the drug wasnt as successful in stopping infection in animals or in people. Similarly, when scientists brought hydroxychloroquine out of the lab and tested it in people, the drug failed to block infection with HIV and dengue as well.

Thats why doctors are approaching hydroxychloroquine with healthy skepticism when it comes to COVID-19 and are only using it on the sickest patients with no other options. Doctors at a number of hospitals, including Johns Hopkins, the University of California Los Angeles, and Brigham and Womens, for example, are starting to use hydroxychloroquine to treat patients with severe COVID-19 symptoms when they dont improve on current supportive treatments. Its not ideal, but If someone is sick in the ICU you try everything possible you can for that person, says Dr. David Boulware, a professor of medicine at the University of Minnesota, who is conducting a study of hydroxychloroquine effectiveness both in treating those with severe disease and in protecting health people from infection.

Other researchers are attempting to trace the same path with other repurposed drugs, including a flu treatment from Toyama Chemical, a pharmaceutical division of the Japanese conglomerate Fujifilm, called favipiravir, which Chinese researchers used to treat patients with COVID-19. More rigorous studies of both remdesivir and favipirivir against SARS-CoV-2 are ongoing; all researchers can say at this point is that they are worth studying further, and that they appear to be safe.

Even cancer drugs are showing promise as COVID-19 treatments, not by neutralizing the virus but by healing the damage infection does to the immune system. The Swiss pharmaceutical giant Novartis, for example, has ruxolitinib (sold under the trade name Jakavi), which was approved by the FDA in 2011 to treat a number of different cancers, and is designed to tamp down an exaggerated immune responsewhich can be caused by both tumor cells and a virus. In the case of SARS-CoV-2, a hyperactive immune response can trigger breathing problems, called a cytokine storm, that require extra oxygen therapy or mechanical ventilation. In theory, ruxolitinib could suppress this virus-caused cytokine storm. Novartis is making its drug available on an emergency use basis for doctors willing to try it on their sickest patients.

Eli Lilly is also testing one of its anti-inflammatory drugs, baricitinib, in severe COVID-19 patients. Like ruxolitinib, baricitinib interferes with the revved up signalling among immume cells that can trigger the inflammatory cytokine storm. According to president of Lilly Bio-Medicines Patrik Jonsson, there are even early hints from case studies of doctors treating COVID-19 patients that the drug may target the virus too, which could mean that it helps to lower the viral load in infected patients. The company is working with NIAID to confirm whether this is the case in a more rigorous study of severe COVID-19 patients, and expects to see results by summer.

It wasnt immediately obvious that baricitinib could potentially treat COVID-19; it took an artificial intelligence effort by UK-based BenevolentAI to scour existing medical literature and descriptions of drug structures to identify baricitinib as a possible therapy.

Such machine learning-based techniques are making the search for new therapies far more efficient than ever before. Chloroquine, hydroxychloroquines parent, came out of a massive war-time drug discovery effort in the 1940s, when governments and pharmaceutical companies combed through existing drug libraries for promising new ways to treat malaria. With computing power that is orders of magnitude greater now, its now possible to single out not just existing drugs with antiviral potential, but entirely new ones that may have gone unnoticed.

When Sumit Chanda first heard of the mysterious pneumonia-like illnesses spiking in Wuhan, China, he had an eerie feeling that the world was about to face a formidable viral foe. He had spent his entire career studying all the clever and devilish ways that bacteria, viruses and pathogens find hospitable hosts and then take up residence, oblivious to how much illness, disease and devastation they may cause. And as director of the immunity and pathogenesis program at Sanford Burnham Prebys Medical Discovery Institute in San Diego, Chanda knew that if the mystery illness striking in China was indeed caused by a new virus or bacteria, then doctors would need new ways to treat itand quickly.

So, he and his team started canvassing a 13,000 drug library, which is funded by the Bill and Melinda Gates Foundation and created by Scripps Research. Our strategy is to take existing drugs and see if they might have any efficacy as an antiviral to fight COVID-19, he says. The advantage of this approach is that you can shave years upon years off the development process and the studies on safety. We want to move things quickly into [testing] in people. In a matter of weeks, he has narrowed down the list of potential coronavirus drug candidates, and because these are already existing drugs and approved for treating other diseases, they are relatively safe, and can quickly be tested in people infected with SARS-CoV-2.

Chandas team isnt the only one taking advantage of this approach. Researchers at numerous pharmaceutical companies, biotech outfits and academic centers are screening their libraries of drugsboth approved and in developmentfor any anti-COVID-19 potential.

At Columbia University, Dr. David Ho, who pioneered ways of creating cocktails of drugs to make them more potent against HIV, is scouring a different library of virus-targeting drugs to pluck out ones that could be effective against SARS-CoV-2. Altogether, he has some 4,700 drugs (approved and in development) to look through, and he believes there is a strong chance of finding something that might be effective against not just SARS-CoV-2 but any other coronavirus that might pop up in coming years. The key, says Ho, is to be prepared for the next outbreak so the work on finding antiviral drugs doesnt have to start from scratch. We know these viruses reside in animal species, he says. We predict in the coming decade there will be more [outbreaks]. And we need to find permanent solutions. We should not repeat the mistake we made after SARS and after MERS, that once the epidemic wanes, the interest and the political will and the funding also wanes. If we had followed through with the work that had begun with SARS, we would be so much better off today.

But today, we are in the midst of a pandemic, and scientists are eager to leave no potentially promising technology untried. Banking on the growing body of science looking at how newborn babies are able to avoid life-threatening infections in their first days in the world, researchers at New Jersey-based Celularity are investigating how placental cells, rich with immune cells that protect the baby in utero, might also become a source of immune defense therapy against COVID-19. Its part of a broader strategy of cell-based treatments that scientists are beginning to explore for treating cancer as well as infectious disease.

On April 1, the company received FDA clearance for its placental cell treatment, based on a group of immune cells called natural killer cells that circulate in the placenta, and are designed to protect the developing fetus from infection. They are programmed to recognize red flags typically sent up by cells infected with viruses like SARS-CoV-2, and destroy them. After the 2002-2003 SARS epidemic, researchers in China found that people who had more severe symptoms of that disease also had deficient populations of natural killer cells.

The FDA green light means the company can launch a small human study using placental natural killer cells against COVID-19. Dr. Robert Hariri, Celularitys founder and CEO, wants to test them first in people who are infected, to see if they can stop the infection from getting worse. Our approach is to flatten the immunologic curve, he says. Our hope is to decrease the size of the viral load and keep it below the threshold of serious symptomatic disease until the patients own immune system can be revved up and respond. If those studies are encouraging, then the company will look at how natural killer cells might be used to pre-charge the immune system to prevent infection with SARS-CoV-2 in the first place.

As effective and critical as these therapies might be, they are a safety net for the best weapon against an infectious disease: a vaccine.

The main reason that a new virus like SARS-CoV-2 has such free license to infect hundreds of thousands of people around the world is because its an entirely new enemy for the human immune system making the planets population an open target for infection. But a vaccine that can prime the body to build an army of antibodies and immune cells trained to recognize and destroy the coronavirus would act as an impenetrable molecular fortress blocking invasion and preventing disease.

Unfortunately, vaccines take time to developyears, if not decades. Scientists at Johnson & Johnson are currently working on a vaccine using fragments of the SARS-CoV-2 spike protein, an easy protein target that sprinkles the surface of the virus like a crown (hence the name coronavirus, from the Latin for crown). The company loads the viral gene for the spike protein into a disabled common-cold virus vector that delivers the genetic material to human cells. The immune system then recognizes the viral fragments as foreign and deploys defensive cells to destroy it. In the process, the immune system learns to recognize the genetic material of the virus, so when the body is confronted by the actual virus, its ready to attack.

Given the manufacturing requirements to build the vaccine, and the studies in animals needed to get a hint of whether the vaccine will work, however, J&Js project is unlikely to come to fruition until mid-2021. We plan to have the first data on the vaccine before the end of the year, says Paul Stoffels, chief science officer at J&J. I would hope that in the first half of next year, we should be able to get vaccines ready for people in high risk groups like health care workers on the front lines.

That timeline is already accelerated quite a bit compared to vaccine research in non-pandemic contexts. But new technology that doesnt require a live transport system could shrink the time to human tests even further. Working with the National Institute of Allergy and Infectious Diseases, Moderna Therapeutics, a biotech based in Cambridge, Mass., developed its mRNA vaccine in a record 42 days after the genetic sequence of the new coronavirus was released in mid January. Its system turns the human body into a living lab to churn out the viral proteins that activate the immune system.

Researchers at Moderna hot wired the traditional vaccine-making process by packing their shot with mRNA, the genetic material that comes from DNA and makes proteins. The viral mRNA is encased in a lipid vessel that is injected into the body. Once inside, immune cells in the lymphatic system process the mRNA and use it like a genetic beacon to attract immune cells that can mount toxic responses against the virus. Our vaccine is like the software program for the body, says Dr. Stephen Hoge, president of Moderna. So which then goes and makes the [viral] proteins that can generate an immune response.

Because this method doesnt involve live or dead virusesall it requires is a lab that can synthesize the correct genetic viral sequencesit can be scaled up quickly since researchers dont have to wait for viruses to grow. Almost exactly two months after the genetic sequence of SARS-CoV-2 was first published by Chinese researchers, the first volunteer received an injection of the Moderna vaccine. The companys first study of the vaccine, which will include 45 healthy participants, will monitor its safety. Hoge is already gearing up to produce hundreds and thousands of more doses to prepare for the next stage of testing, which will enroll hundreds of people, most likely those at high risk of getting infected, like health care workers.

If those results arent as promising as health experts hope, there are other innovative options in the works. At the University of Pittsburgh, scientists who had been developing a vaccine against the original SARS virus have switched to making a shot against the new one. Their technology involves hundreds of microneedles in a band-aid like patch that deliver parts of the coronavirus protein directly into the skin. From there, the foreign viral proteins are swept into the blood and into the lymph system, where immune cells recognize them as invaders and develop antibodies against them. After seeing animals inoculated with their vaccine develop strong antibodies against SARS-CoV-2, the team is ready to submit an application to the FDA to begin testing in people.

Whats different about these new coronavirus efforts is the fact that they arent all designed to control SARS-CoV-2 alone. Recognizing that this coronavirus is the third in recent decades to cause pandemic disease, scientists are focusing on building therapies, including vaccines, that can quickly be adapted to target different coronaviruses that might emerge in coming years. We hope these new technologies become the kinds of things we build in our tool kits that as humans will allow us to respond in a much more accelerated way to the next pandemic, says Modernas Hoge. Because we expect continuing threats from viruses in the future.

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Excerpt from:
Vaccines, Antibodies and Drug Libraries. The Possible COVID-19 Treatments Researchers Are Excited About - TIME

Gene therapy is a technique that involves the delivery of nucleic acid polymers into a patients cells as a drug to treat diseases. It fixes a genetic problem at its source. The process involves modifying the protein either to change the genetic expression or to correct a mutation. The emergence of this technology meets the rise in needs for better diagnostics and targeted therapy tools. For instance, genetic engineering can be used to modify physical appearance, metabolism, physical capabilities, and mental abilities such as memory and intelligence. In addition, it is also used for infertility treatment. Gene therapy offers a ray of hope for patients, who either have no treatment options or show no benefits with drugs currently available. The ongoing success has strongly supported upcoming researches and has carved ways for enhancement of gene therapy.

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Leading Gene Therapy Market Players:

The Gene Therapy Market report give a 360-degree holistic view of the market and highlights the key developments, drivers, restraints and future trends with impact analysis of these trends on the market for short-term, mid-term and long-term during the forecast period. In addition, the report also provides profiles of major companies along with detailed SWOT analysis, financial facts and key developments of products/service from the past three years.

The global gene therapy market is segmented based on vector type, gene type, application, and geography. Based on vector type, it is categorized into viral vector and non-viral vector. Viral vector is further segmented into retroviruses, lentiviruses, adenoviruses, adeno associated virus, herpes simplex virus, poxvirus, vaccinia virus, and others. Non-viral vector is further categorized into naked/plasmid vectors, gene gun, electroporation, lipofection, and others. Based on gene type, the market is classified into antigen, cytokine, tumor suppressor, suicide, deficiency, growth factors, receptors, and others. Based on application, the market is divided into oncological disorders, rare diseases, cardiovascular diseases, neurological disorders, infectious disease, and other diseases. Based on region, it is analyzed across North America, Europe, Asia-Pacific, and LAMEA.

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Table of Contents

Chapter 1: Introduction

Chapter 2: Executive Summary

Chapter 3: Market Overview

Chapter 4: Gene Therapy Market, By Component

Chapter 5: Gene Therapy Market, By Deployment

Chapter 6: Gene Therapy Market, By Organization Size

Chapter 7: Gene Therapy Market, By Application

Chapter 8: Gene Therapy Market, By Region

Chapter 9: Competitive Landscape

To Continue

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Gene Therapy Market 2020 Increasing Demand with Leading Key Players Bluebird Bio, Editas Medicine, GlaxoSmithKline Plc., Intellia Therapeutics -...

In a recent study, University of California San Diego researchers moved one step closer to the ability to make heparin in cultured cells. Heparin is a potent anti-coagulant and the most prescribed drug in hospitals, yet cell-culture-based production of heparin is currently not possible.In particular, the researchers found a critical gene in heparin biosynthesis: ZNF263 (zinc-finger protein 263). The researchers believe this gene regulator is a key discovery on the way to industrial heparin production. The idea would be to control this regulator in industrial cell lines using genetic engineering, paving the way for safe industrial production of heparin in well-controlled cell culture.

Heparin is currently produced by extracting the drug from pig intestines, which is a concern for safety, sustainability, and security reasons. Millions of pigs are needed each year to meet our needs, and most manufacturing is done outside the USA. Furthermore, ten years ago, contaminants from the pig preparations led to dozens of deaths. Thus, there is a need to develop sustainable recombinant production. The work provides new insights on exactly how cells control synthesis of heparin.

Since regulators for heparin were not known, a research team led by UC San Diego professors Jeffrey Esko and Nathan Lewis used bioinformatic software to scan the genes encoding enzymes involved in heparin production and specifically look for sequence elements that could represent binding sites for transcription factors. The existence of such a binding site could indicate that the respective gene is regulated by a corresponding gene regulator protein, i.e. a transcription factor.

One DNA sequence that stood out the most is preferred by a transcription factor called ZNF263 (zinc-finger protein 263), explains UC San Diego professor Nathan E. Lewis, who holds appointments in the UC San Diego School of Medicines Department of Pediatrics and in the UC San Diego Jacobs School of Engineerings Department of Bioengineering. While some research has been done on this gene regulator, this is the first major regulator involved in heparin synthesis, said Lewis. He is also Co-Director of the CHO Systems Biology Center at the UC San Diego Jacobs School of Engineering.

Using the gene-editing technology, CRISPR/Cas9, the UC San Diego researchers mutated ZNF263 in a human cell line that normally does not produce heparin. They found that the heparan sulfate that this cell line would normally produce was now chemically altered and showed a reactivity that was closer to heparin.

Experiments further showed that ZNF263 represses key genes involved in heparin production. Interestingly, analysis of gene expression data from human white blood cells showed suppression of ZNF263 in mast cells (which produce heparin in vivo) and basophils, which are related to mast cells. The researchers report that ZNF263 appears to be an active repressor of heparin biosynthesis throughout most cell types, and mast cells are enabled to produce heparin because ZNF263 is suppressed in these cells.

This finding could have important relevance in biotechnology. Cell lines used in industry (such as CHO cells that normally are unable to produce heparin) could be genetically modified to inactivate ZNF263 which could enable them to produce heparin, like mast cells do.

Philipp Spahn, a project scientist in Nathan Lewis lab in the Departments of Pediatrics and Bioengineering at UC San Diego, described further directions the team is pursuing: Our bioinformatic analysis revealed several additional potential gene regulators which can also contribute to heparin production and are now exciting objects of further study.ReferenceWeiss et al. (2020) ZNF263 is a transcriptional regulator of heparin and heparan sulfate biosynthesis. PNAS. DOI: https://doi.org/10.1073/pnas.1920880117

This article has been republished from the following materials. Note: material may have been edited for length and content. For further information, please contact the cited source.

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Moving Closer to Producing Heparin In the Lab - Technology Networks

Clinical Plan Includes Healthy Volunteers in New Zealand andOTC-Deficient Patients Across Several Sites in United States

Investor Conference Call at 4:00 pm ET Today

SAN DIEGO, April 13, 2020 (GLOBE NEWSWIRE) -- Arcturus Therapeutics (the Company, NASDAQ: ARCT), a leading clinical-stage messenger RNA medicines company focused on the discovery, development and commercialization of therapeutics for rare diseases and vaccines, today announced the acceptance of two clinical trials for its flagship asset ARCT-810, also known as LUNAR-OTC, a first-in-class mRNA therapeutic being developed to treat ornithine transcarbamylase (OTC) deficiency. The Companys Investigational New Drug (IND) application for a Phase 1b study in patients with OTC deficiency was allowed to proceed by the U.S. Food and Drug Administration (FDA), and an additional Clinical Trial Application(CTA) for a Phase 1 study in healthy volunteers was approved by the New Zealand Medicines and Medical Devices Safety Authority (Medsafe). OTC deficiency is a life-threatening genetic disease that results in high blood ammonia levels and can cause seizures, coma, and death in untreated patients. Present standard of care, which comprises low protein diet and drugs to remove toxic ammonia from the body, does not effectively prevent life-threatening spikes of ammonia in many patients. There are no disease modifying therapies approved for OTC deficiency.

Allowance to proceed into human trials represents a significant milestone for Arcturus as we become a clinical-stage company with a candidate that may provide new hope to patients suffering from ornithine transcarbamylase deficiency, saidJoseph Payne, President & CEO ofArcturus Therapeutics.

Dr. Steve Hughes, Chief Development Officer of Arcturus, stated, Arcturus continues to establish itself as a world leader in the field of intravenously-dosed messenger RNA therapeutics. Our team looks forward to ushering ARCT-810 efficiently through the clinic and to providing OTC-deficient patients access to this potentially disease-modifying messenger RNA therapy.

The primary endpoint for both studies includes evaluation of safety and tolerability. Multiple biomarkers, including ureagenesis assay, plasma OTC activity, plasma ammonia and orotic acid in the urine, are being evaluated as exploratory endpoints. The program plans to enroll up to 30 healthy volunteers in the Auckland Clinical Studies (ACS) site in New Zealand, and up to 12 OTC-deficient patients recruited across several sites in the U.S. The first healthy subjects are expected to be enrolled in New Zealand soon, with the first patients enrolled under the IND in Q3 or Q4, depending on the status of SARS-CoV-2 infections in the U.S.

ARCT-810, is a low-dose, systemically administered, investigational mRNA medicine that utilizes Arcturus' novel messenger RNA construct and proprietary LUNAR delivery system to deliver OTC messenger RNA to liver cells. In 2019, the FDA granted Orphan Drug Designation to the drug substance of ARCT-810 for the treatment of the rare disease OTC deficiency supported by the promising results of preclinical studies. Expression of OTC enzyme in the liver can potentially restore urea cycle activity to detoxify ammonia, thereby potentially preventing neurological damage and removing the need for liver transplantation.

The GMP manufacturing campaign for ARCT-810 is complete, with drug product amounts sufficient to support early clinical trials. ARCT-810 batches were manufactured utilizing Arcturus proprietary processes for both mRNA drug substance and LUNAR formulated drug product.

Investor Conference Call: Monday April 13th @ 4:00 PM ETToday's call will provide additional detail pertaining to the ARCT-810 clinical plan, along with additional information regarding the Companys COVID-19 vaccine program.

About ARCT-810ARCT-810, Arcturus first development candidate, represents a novel approach to treat ornithine transcarbamylase deficiency.ARCT-810 is based on Arcturus mRNA design construct and proprietary manufacturing process. ARCT-810 also utilizes Arcturus extensive and propriety lipid library and employs the Company's LUNAR delivery platform to deliver OTC mRNA to hepatocytes. ARCT-810 is an investigational mRNA medicine designed to enable OTC-deficient patients to naturally produce healthy functional OTC enzyme in their own liver cells. Replacing the deficient OTC protein has the potential to restore activity of the urea cycle pathway, resulting in reduced plasma ammonia and urinary orotate concentrations.

About Ornithine Transcarbamylase Deficiency Ornithine transcarbamylase (OTC) deficiency is the most common urea cycle disorder. Urea cycle disorders are a group of inherited metabolic disorders that make it difficult for affected patients to remove toxic waste products as proteins are digested. OTC deficiency is caused by mutations in the OTC gene which leads to a non-functional or deficient OTC enzyme. OTC is a critical enzyme in the urea cycle, which takes place in liver cells, and together with the other enzymes in the urea cycle converts ammonia to urea. This conversion does not occur properly in patients with OTC deficiency and ammonia accumulates in their blood, acting as a neurotoxin and liver toxin. A lack of the OTC enzyme in liver cells results in high blood ammonia levels and can cause seizures, coma, and death in untreated patients. OTC deficiency is an inherited disease that can cause developmental problems, seizures and death in newborn babies. It is an X-linked disorder, so is more common in males. Patients with less severe symptoms may present later in life, as adults. There is currently no cure for OTC deficiency, apart from liver transplant. However, this treatment comes with significant risk of complications such as organ rejection, and transplant recipients must take immunosuppressant drugs for the rest of their lives. Current standard of care for OTC patients is a low-protein diet and ammonia scavengers to try and prevent patients from accumulating ammonia. These treatments do not address the underlying cause of disease.

About Arcturus TherapeuticsFounded in 2013 and based in San Diego, California, Arcturus Therapeutics Holdings Inc. (Nasdaq: ARCT) is a clinical-stage mRNA medicines and vaccines company with enabling technologies (i) LUNAR lipid-mediated delivery, (ii) STARR mRNA Technology and (iii) mRNA drug substance along with drug product manufacturing expertise. Arcturus diverse pipeline of RNA therapeutic candidates includes programs to potentially treat Ornithine Transcarbamylase (OTC) Deficiency, Cystic Fibrosis, Glycogen Storage Disease Type 3, Hepatitis B, non-alcoholic steatohepatitis (NASH) and a self-replicating mRNA vaccine for SARS-CoV-2. Arcturus versatile RNA therapeutics platforms can be applied toward multiple types of nucleic acid medicines including messenger RNA, small interfering RNA, replicon RNA, antisense RNA, microRNA, DNA, and gene editing therapeutics. Arcturus technologies are covered by its extensive patent portfolio (187 patents and patent applications, issued in the U.S., Europe, Japan, China and other countries). Arcturus commitment to the development of novel RNA therapeutics has led to collaborations with Janssen Pharmaceuticals, Inc., part of the Janssen Pharmaceutical Companies of Johnson & Johnson, Ultragenyx Pharmaceutical, Inc., Takeda Pharmaceutical Company Limited, CureVac AG, Synthetic Genomics Inc., Duke-NUS, and the Cystic Fibrosis Foundation. For more information visit http://www.Arcturusrx.com

Forward Looking StatementsThis press release contains forward-looking statements that involve substantial risks and uncertainties for purposes of the safe harbor provided by the Private Securities Litigation Reform Act of 1995. Any statements, other than statements of historical fact included in this press release, including those regarding strategy, future operations, collaborations, the likelihood of success efficacy or safety of ARCT-810, the ability to initiate or complete preclinical and clinical development programs, including as a result of the COVID-19 pandemic, the supply and delivery of any product or substance, the likelihood that preclinical data will be predictive of clinical data, and the ability to enroll subjects therein are forward-looking statements. Arcturus may not actually achieve the plans, carry out the intentions or meet the expectations or projections disclosed in any forward-looking statements such as the foregoing and you should not place undue reliance on such forward-looking statements. Such statements are based on managements current expectations and involve risks and uncertainties, including those discussed under the heading "Risk Factors" in Arcturus Annual Report on Form 10-K for the fiscal year ended December 31, 2019, filed with the SEC on March 16, 2020 and in subsequent filings with, or submissions to, the SEC. Except as otherwise required by law, Arcturus disclaims any intention or obligation to update or revise any forward-looking statements, which speak only as of the date they were made, whether as a result of new information, future events or circumstances or otherwise.

ContactArcturus TherapeuticsNeda Safarzadeh(858) 900-2682IR@ArcturusRx.com

LifeSci Advisors LLCMichael Wood(646) 597-6983mwood@lifesciadvisors.com

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Arcturus Therapeutics Announces Allowance of IND & Approval of Clinical Trial Application (CTA) for ARCT-810, a First-in-Class Investigational...

Theres a profound disconnect between what the latest gene-editing methods can do to increase yields and enhance crop disease and stress resistance and the trickle of such improved crops actually getting out into farmers fields.

The first generation of genetically modified (GM) crops has been remarkably successful. The whole world eats food containing ingredients derived from GM crops and feeds them to its myriad agricultural animals and pets. Despite many dire predictions of long-term negative health effects, a quarter century has passed and none have materialized.1 This remarkably clean track record should have assuaged public fears and assured the rapid development and adoption of GM crops of all kinds.

But it hasnt.

Decades after four major commodity biotech crops corn, soybeans, cotton and canola were introduced and rapidly soared to near market saturation in the countries that permitted their cultivation, the number of new GM crops being released to farmers remains tiny.

[Editors note: This article is part one of a four-part series on the progress of agricultural biotechnology.]

Yet the need for higher yielding, disease-resistant and stress-tolerant crops grows with each passing year. The pressures of population growth and climate warming are already outpacing the speed with which conventional breeding practices are expanding the global food supply.2 Land and water availability are rapidly becoming limiting, hence the focus is sharply on the intensification of agriculture.3 But the breeding methods that fueled the spectacular advances in agricultural productivity over the 20th century are near exhaustion.

Over the same period, knowledge of plant physiology and genetics has grown at an explosive pace, as has the technology for identifying and modifying genes of agronomic interest. We know vastly more about what genes do and how plant genomes change both naturally and under human intervention than we did even when the first GM crops were introduced in 1996.4

The recent invention and rapid development of gene- or genome-editing technology (aka SSN or sequence-specific nuclease technology) has facilitated a quantum leap in the ease and precision of genetic intervention, positioning researchers to accelerate the increase in crop yields and to make crop plants more resilient to the biotic and abiotic stresses exacerbated by climate warming.5

Yet just a few of the crops that need to be improved are being improved using the latest techniques and of those, only a few reach farmers each year. To understand this deep disconnect between what can be done to improve crops using modern molecular techniques and what is being done requires a look at the tangle of issues around GM technology at the interface between science, business and society.

In this four-part series, I first examine the factors that led to the disconnect between what can be done and what is being done. I then review both the successes and failures of the first generation of GM crops modified using recombinant DNA (rDNA) technology. I next introduce the new gene-editing technologies and what they promise. And finally, I take a look at the regulatory, political and business decisions that actually determine what gets out of research laboratories and into farmers fields. The entire essay will be available as a single publication following the completion of this series.

Part 1: The origins of the disconnect between the science and the farmer

Public resistance to innovation is not unusual, but hardly universal. People line up for the newest Apple iPhone, but have to be persuaded to try a GM apple that doesnt turn brown. Resistance generally subsides as a technology is widely adopted and proves harmless. GM technology in medicine, for example, is now broadly accepted, be it human insulin or any of the many new protein-based therapeutics. But the controversies around GM crops have persisted, and indeed intensified through the deliberate vilification efforts of both individuals and organizations.6,7

According to polls, the public remains largely ignorant of what GM organisms (GMOs) are and of how modern molecular methods fit into the long history of crop improvement.8 Because fear-based disinformation strategies are so effective, what has grown instead is the widespread conviction that GMOs are bad, meaning variously that they are harmful to health, unnatural, or produced by big biotech companies that unfairly exploit farmers.7,9

Part of the problem is that public awareness of genetic modification in agriculture is recent, arguably dating back only to the late 1980s when controversies erupted over field testing of the so-called ice-minus bacterium modified to eliminate a protein that promotes ice formation on the leaves of strawberries.10 Yet in a strictly scientific context, genetic modification denotes the entire spectrum of human interventions in the genetics of other organisms over more than 10 millenia.11

For crop plants, these encompass domestication, breeding, mutation breeding and, most recently, genetic improvement by molecular techniques. All involve genetic changes, aka mutations. Domestication and conventional plant breeding rely on organisms inherent genetic variation.

Direct genetic manipulation of crop plants using chemical and radiation mutagenesis (mutation breeding) dates back to the 1930s.12 But even now, few people other than plant breeders are aware that crops have long been improved through deliberate efforts to induce new mutations using both chemicals and irradiation. So today, it is the general understanding that genetically modified organisms (GMOs) are only those that have been modified by molecular methods. That is, most people think genetic modification is quite new.

And then theres what the regulators built

As if this were not sufficiently problematic, the way in which the regulatory environment evolved reinforced suspicions about GM safety. Early efforts to regulate the commercial introduction of GM crops emphasized the need to regulate new crop traits rather than the particular method by which they were introduced. But thats not what happened.

Starting from the beginning of the regulatory activities in the late 1980s, the U.S. agencies that oversee GM organisms have regulated only organisms modified by molecular methods and theyve regulated all of them, without regard to either nature of the organism or the trait that was added.13 This has been true of the US Department of Agriculture (USDA) and the Environmental Protection Agency (EPA), although the Food and Drug Administration has generally followed its practice of post-market oversight. None of the agencies subjected new crop varieties produced by the older methods of chemical and radiation mutagenesis to regulatory oversight.

Complying with the regulatory requirements proved not only time consuming and prohibitively expensive to developers,14 but also reinforced the altogether unfounded popular conviction that molecular methodology is dangerous. Both negative popular views of GM foods and the high regulatory costs associated with their introduction have shaped the present availability of GMOs in agriculture. Indeed, it is virtually impossible to understand the contemporary paucity of GM crop varieties without considering both regulatory and acceptance issues.

The recent development of gene-editing methods has led to a new round of public and bureaucratic controversy worldwide over what should be classified as a GMO and subject to regulatory oversight. Because gene-editing techniques15 introduce the same kinds of mutations as the older mutagenesis methods, crops modified by gene editing can be indistinguishable at the molecular level from those improved by mutation breeding.

Mutation breeding has been in safe use for a century, hence there is no scientifically defensible rationale for imposing regulations on crops with the same kinds of genetic changes produced by the new, far more precise methods. This is being recognized in some countries by decreasing the regulatory burden on certain types of crop modifications produced by gene-editing techniques.

However, in 2018 the European Court of Justice ruled that gene-edited crops should undergo the same level of regulatory scrutiny as crops modified by older molecular methods.16 As they have over the past 4 decades, the outcome of such regulatory decisions will profoundly influence the kinds of genetic improvements that will be undertaken and actually become available to farmers and consumers.

Thus both public opinion and regulatory practices have made major contributions to the disconnect between the modern science of crop improvement and the farmer.

1EC (2010). A decade of EUfunded GMO research (20012010). European Commission https://ec.europa.eu/research/biosociety/pdf/a_decade_of_eu-funded_gmo_research.pdf; NASEM (2016). Genetically Engineered Crops: Experiences and Prospects. National Academies of Sciences, Engineering, and Medicine 978-0-309-43735-6 http://www.nap.edu/catalog/23395/genetically-engineered-crops-experiences-and-prospects

2Ray DK et al. (2013). Yield trends are insufficient to double global crop production by 2050. PloS One 8:e66428.

3Tilman D et al. (2011). Global food demand and the sustainable intensification of agriculture. Proc Natl Acad Sci USA 108:20260-4.

4Richroch AE (2013). Assessment of GE food safety using -omics techniques and long-term animal feeding studies. New Biotechnol 30:351-54; Fedoroff NV (2013). Plant transposons and genome dynamics in evolution. (Wiley-Blackwell, Oxford, UK), p.212; Anderson JE et al. (2016). Genomic variation and DNA repair associated with soybean transgenesis: a comparison to cultivars and mutagenized plants. BMC Biotechnol 16:41.

5Podevin N et al. (2013). Site-directed nucleases: a paradigm shift in predictable, knowledge-based plant breeding. Trends Biotechnol 31:375-83; Zhang D et al. (2016). Targeted gene manipulation in plants using the CRISPR/Cas technology. J Genet Genomics 43:251-62; Zhang Y et al. (2019). The emerging and uncultivated potential of CRISPR technology in plant science. Nature Plants 5:778-94.

6Apel A (2010). The costly benefits of opposing agricultural biotechnology. New Biotechnol 27:635-40.

7Ryan CD et al. (2019). Monetizing disinformation in the attention economy: The case of genetically modified organisms (GMOs). European Management J 38:7-18.

8Funk C et al. (2015). Public and scientists views on science and society. Pew Research Center http://www.pewinternet.org/2015/01/29/public-and-scientists-views-on-science-and-society/

9Funk C and Kennedy B (2016). Public opinion about genetically modified foods and trust in scientists connected with these foods. Pew Research Center http://www.pewinternet.org/2016/12/01/public-opinion-about-genetically-modified-foods-and-trust-in-scientists-connected-with-these-foods/

10Palca J (1986). Ice-minus bacteria: Further snag and further delay. Nature 320:2.

11Fedoroff NV (2015). Food in a future of 10 billion. Agricult Food Security 4:11.

12Ahloowalia B et al. (2004). Global impact of mutation-derived varieties. Euphytica 135:187-204.

13Fedoroff NV (2013). Will common sense prevail? Trends Genet 29:188-9; Wolt JD et al. (2016). The regulatory status of genomeedited crops. Plant Biotechnol J 14:510-8; Van Eenennaam A and Fedoroff N. How the federal government can get biotech regulation right. Des Moines Register, 1 March 2018

14McDougall P (2011). The cost and time involved in the discovery, development and authorisation of a new plant biotechnology derived trait. Crop Life International https://croplife.org/plant-biotechnology/regulatory-2/cost-of-bringing-a-biotech-crop-to-market/

15Kleter GA et al. (2019). Gene-edited crops: towards a harmonized safety assessment. Trends Biotechnol 37:443-7.

16Kupferschmidt K (2018). EU verdict on CRISPR crops dismays scientists. Science 361:435.

Nina V. Fedoroff is an Emeritus Evan Pugh Professor atPenn State University

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Viewpoint: How consumer fear and misguided regulation limit the progress of crop biotechnology - Genetic Literacy Project

CAMBRIDGE, Mass.--(BUSINESS WIRE)-- Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi therapeutics company, announced today that the U.S. Food and Drug Administration (FDA) has granted Fast Track designation to vutrisiran, an investigational therapeutic for the treatment of the polyneuropathy of hereditary transthyretin-mediated (hATTR) amyloidosis in adults. According to the FDA, Fast Track designation is designed to facilitate the development and expedite the review of drugs that treat serious conditions and fill an unmet medical need. With this designation, Alnylam will be eligible to submit a rolling New Drug Application for vutrisiran.

Vutrisiran has demonstrated an encouraging safety profile in the Phase 1 study, with infrequent quarterly dosing with low-volume, subcutaneous administration which potentially reduces the burden of care for this progressive, life-threatening and multisystem disease. We are therefore pleased that the FDA has granted vutrisiran Fast Track designation, said Rena Denoncourt, Vutrisiran Program Leader at Alnylam. After completing enrollment earlier this year, we look forward to sharing topline results of the HELIOS-A Phase 3 study of vutrisiran in early 2021. More broadly, we remain committed to developing additional therapeutic options for the treatment of ATTR amyloidosis to augment the market-leading position of ONPATTRO (patisiran), approved for the treatment of the polyneuropathy of hATTR amyloidosis in adults.

In addition to Fast Track designation, vutrisiran has been granted Orphan Drug designation in the United States and the European Union for the treatment of ATTR amyloidosis. The safety and efficacy of vutrisiran are being evaluated in the ongoing HELIOS-A and HELIOS-B Phase 3 clinical trials. Together, these studies comprise a comprehensive clinical development program intended to demonstrate the broad impact of vutrisiran across the multisystem manifestations of disease and the full spectrum of patients with ATTR amyloidosis.

About Vutrisiran Vutrisiran 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 mutant 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 next-generation delivery platform known as the Enhanced Stabilization Chemistry (ESC)-GalNAc-conjugate delivery platform. 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 HELIOS-A Phase 3 Study HELIOS-A is a Phase 3 global, randomized, open-label study to evaluate the efficacy and safety of vutrisiran in patients with hATTR amyloidosis with polyneuropathy. The trial randomized patients 3:1 to receive either 25mg of vutrisiran subcutaneously once every 12 weeks or 0.3 mg/kg of patisiran intravenously once every three weeks. For most endpoints, results from the vutrisiran arm will be compared to results from the placebo arm of the landmark APOLLO Phase 3 study, which evaluated the efficacy and safety of patisiran in people with hATTR amyloidosis with polyneuropathy. The co-primary endpoints of HELIOS-A are the change from baseline in the modified Neurologic Impairment Score +7 (mNIS+7) and in the Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QoL-DN) score, at 9 months. Secondary endpoints include the change from baseline in key clinical evaluations including the timed 10-meter walk test (10-MWT), modified body mass index (mBMI), and Rasch-built Overall Disability Scale (R-ODS). The percent reduction in serum transthyretin (TTR) levels in the vutrisiran arm will be compared to the within-study patisiran arm. Additional exploratory endpoints will be assessed to determine the effect of vutrisiran on other aspects of the multisystem nature of this disease, including manifestations of cardiac amyloid involvement.

About HELIOS-B Phase 3 Study HELIOS-B will evaluate the efficacy of vutrisiran versus placebo toward the composite outcome of all-cause mortality and recurrent cardiovascular hospitalizations at 30 months, the primary study endpoint. The study protocol includes an optional interim analysis to be conducted at the Companys discretion. HELIOS-B complements the ongoing HELIOS-A Phase 3 study in patients with hereditary ATTR amyloidosis with polyneuropathy, creating a comprehensive clinical development program to evaluate the safety and efficacy of vutrisiran across the entire disease spectrum of ATTR amyloidosis.

ONPATTRO Important Safety Information Infusion-Related Reactions Infusion-related reactions (IRRs) have been observed in patients treated with ONPATTRO (patisiran). In a controlled clinical study, 19% of ONPATTRO-treated patients experienced IRRs, compared to 9% of placebo-treated patients. The most common symptoms of IRRs with ONPATTRO were flushing, back pain, nausea, abdominal pain, dyspnea, and headache.

To reduce the risk of IRRs, patients should receive premedication with a corticosteroid, acetaminophen, and antihistamines (H1 and H2 blockers) at least 60 minutes prior to ONPATTRO infusion. Monitor patients during the infusion for signs and symptoms of IRRs. If an IRR occurs, consider slowing or interrupting the infusion and instituting medical management as clinically indicated. If the infusion is interrupted, consider resuming at a slower infusion rate only if symptoms have resolved. In the case of a serious or life-threatening IRR, the infusion should be discontinued and not resumed.

Reduced Serum Vitamin A Levels and Recommended Supplementation ONPATTRO treatment leads to a decrease in serum vitamin A levels. Supplementation at the recommended daily allowance (RDA) of vitamin A is advised for patients taking ONPATTRO. Higher doses than the RDA should not be given to try to achieve normal serum vitamin A levels during treatment with ONPATTRO, as serum levels do not reflect the total vitamin A in the body.

Patients should be referred to an ophthalmologist if they develop ocular symptoms suggestive of vitamin A deficiency (e.g. night blindness).

Adverse Reactions The most common adverse reactions that occurred in patients treated with ONPATTRO were upper respiratory tract infections (29%) and infusion-related reactions (19%).

Indication ONPATTRO is indicated for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults.

For additional information about ONPATTRO, please see the full Prescribing Information.

About Transthyretin (ATTR) Amyloidosis Transthyretin (ATTR) amyloidosis is a rare, progressively debilitating, and fatal disease caused by misfolded TTR proteins that accumulate as amyloid deposits in multiple tissues including the nerves, heart and gastrointestinal (GI) tract. There are two types of ATTR amyloidosis: hereditary ATTR (hATTR) amyloidosis and wild-type (wtATTR) amyloidosis. hATTR amyloidosis is an inherited disease resulting in intractable peripheral sensory-motor neuropathy, autonomic neuropathy, and/or cardiomyopathy. It is estimated to affect 50,000 people worldwide. The condition can have a debilitating impact on a patients life and may lead to premature death within 4.7 years of diagnosis. wtATTR amyloidosis is a nonhereditary, progressive type of the disease with undefined etiology. It affects an estimated 200,000-300,000 people worldwide. It primarily manifests as cardiomyopathy, which leads to heart failure and mortality within 2 to 6 years.

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 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 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, Switzerland and Brazil, and GIVLAARI (givosiran), approved in the U.S. and EU. Alnylam has a deep pipeline of investigational medicines, including five 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. 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.

Forward Looking Statements Various statements in this release, including, without limitation, Alnylam's views and plans with respect to the potential for RNAi therapeutics, including vutrisiran, its expectations with respect to the encouraging safety profile of vutrisiran in the Phase 1 study, timing for reporting topline results from its HELIOS-A Phase 3 study, its commitment to developing multiple therapeutic options for the treatment of ATTR amyloidosis, the intended goals of the HELIOS-A and -B studies to demonstrate the broad impact of vutrisiran across the multisystem manifestations of disease and the full spectrum of patients with ATTR amyloidosis, 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: potential risks to Alnylams business, activities and prospects as a result of the COVID-19 pandemic, or delays or interruptions resulting therefrom; 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 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 inclisiran and 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 achieve net product revenues for ONPATTRO within our 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 our expected guidance and 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 Regeneron, for development, manufacture and distribution of certain products, including eye and CNS products, and Ironwood, for assistance with the education about and promotion of GIVLAARI; 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 Annual Report on Form 10-K 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.

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Alnylam Receives Fast Track Designation for Vutrisiran for the Treatment of the Polyneuropathy of hATTR Amyloidosis - BioSpace