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Re: ALN-COV Endpoints article. Some interesting stuff: Alnylam, Sarepta jump into Covid-19 game, as pandemic rekindles antiviral hopes of RNA-targeting technologyJason MastAssociate EditorThe idea had been there from the beginning. Scientists, studying plants and worms at the turn of the 21st century, discovered a mechanism cells used to cut up the RNA of invading viruses. Why not rejig the mechanism, called RNA interference (RNAi), to spear the viruses that attacked humans? “Even way, way at the beginning, it was one of the areas of interest,” John Maraganore, CEO of RNAi biotech Alnylam, told Endpoints News. Now the pandemic is throwing that idea back to the forefront of the field. Last month, after a decade focused primarily on rare genetic diseases, Alnylam announced a partnership with Vir Biotechnology to develop RNAi drugs for Covid-19. Today, the pair released their lead drug candidate, called ALN-COV or VIR-2703. An inhalant, It could offer treatment for those infected and work as a prophylaxis, potentially offering protection for those at high risk of exposure. The plan is to test the drug in humans by the end of the year. advertisementadvertisement “That’s very quick,” Maraganore said, noting they started the program in January. “That’ll be filing an IND for a brand new medicine in record time.” Alnylam joins at least two other companies that, with the advent of one of the worst viruses in a century, are trying to bring back RNA-targeting approaches they had long since devoted primarily for genetic ills. The idea is to directly target SARS-CoV-2, the virus that causes Covid-19, by directly targeting its genetic code, sending custom-made nucleotides to disrupt the strands of RNA at its center. Doug Ingram Last week, Sarepta signed a research agreement with the Department of Defense to design and build antisense sequences — essentially mirror-images of an RNA sequence that binds to and silences it — to prevent SARS-CoV-2 from replicating. Ionis, the other major antisense company, hasn’t announced a program, but told Endpoints they were building sequences for SARS-CoV-2, relying on data from an old SARS program they had run in 2003. For Sarepta, it’s a return after years away from the field. The company spent 30 financially-troubled years trying to develop antisense sequences to target SARS, HIV, and hepatitis C, among others, before they changed their name and focused on Duchenne muscular dystrophy. “We haven’t been focused on antivirals in a very long time,” CEO Doug Ingram told Endpoints. For Alnylam, though, the transition has been smoother and more aggressive. The company never fully abandoned antivirals, signing a pact with infectious disease-focused Vir in 2017 for hepatitis B and four other undisclosed programs. If successful, Alnylam’s will belong to something of a third wave of experimental therapies, after the repurposed drugs doctors have worked with so far and the first monoclonal antibodies from Vir and Regeneron that researchers hope will show promise when put into clinical trials this summer. It offers a new way to treat viruses, but one that, like many of the other scientific insights leveraged in the fight against Covid-19, remains unproven. Stephen Floor “It was a very natural extension,” Stephen Floor, who studies RNA expression at the University of California, San Francisco and is not affiliated with Alnylam, Ionis, or Sarepta, told Endpoints. “Short RNAs are used in many organisms as an antiviral defense, so it seemed pretty natural to use short RNAs as an antiviral therapy.” “Historically, I think the promise has been large,” Floor added. “The promise has been there and it’s waned.” SareptaSarepta’s Covid-19 program began with a surprise phone call from the US government. Patrick Iversen, who spent 18 years as a top scientist at the company, much of them back when it was focused on antivirals, now ran the countermeasures division at the United States Army Medical Research Institute of Infectious Diseases (USAMRIID) in Fort Detrick, Maryland. Although it’s been nearly a decade since Sarepta had made antivirals, Iversen had helped develop a platform that could create virus-combating sequences in a number of days or weeks. The idea was to take an important sequence in a virus’ code and build a mirror image that would bind to and neutralize the sequence. It was a disastrously unprofitable business — a 2005 Forbes report cited them as having lost $156 million and made $5 million, over 25 years without an approved drug — but it could reap benefits. In 2015, under a defense contract, Sarepta showed in the New England Journal of Medicine, their drug could be protective against Marburg virus disease, a deadly cousin of Ebola. Now, again, Iversen thought it might be useful. “We literally just got an inbound call from USAMRIID, asking if we would be willing to lend our technology,” Ingram, who by then was working from home, said. “Of course we said yes.” Working by phone, government and Sarepta scientists settled on the sequences of the virus they wanted to target. They haven’t announced how many constructs they’ll test preclinically or which ones, but like many other antiviral approaches, they will target sequences the virus uses to replicate itself. One way, Ingram said, could be to create an antisense sequence, also known as an oligonucleotide, that will bind to the genes the virus uses to begin replication, jamming it at the starting line. The program is low-risk for Sarepta. After building the nucleotide chains letter by letter over a couple weeks, the biotech freeze dried them and sent them overnight from Massachusetts to Maryland. USAMRIID will now be responsible for in-vitro testing. There’s no timeline yet for clinical trials. “These are early days,” Ingram said. AlnylamAlnylam began working on a sequence that could cut up the once-novel coronavirus shortly after its genome became available in January. The process for making an RNAi drug is different and is in some ways conceptually simpler than building most other treatments or vaccines. Generally those involve finding and targeting a part of the virus that is essential for either invasion or replication. Antivirals, such as remdesivir, go after the RNA-dependent polymerase the virus uses to copy its genome. Vaccines and antibodies have targeted the spike protein SARS-CoV-2 uses to enter cells. RNAi, though, acts like a knife (the enzyme involved is literally called DICER). You feed a cell short RNA strands that match sequences of the virus and the cell cuts the matching sequences. Cut any part of the virus’ genome and the rest falls apart. In its early years Alnylam landed government contracts for Ebola — “not the most robust market,” CEO John Maraganore acknowledged — and developed RSV and hepatitis C programs. They eventually shifted focus to the potential of RNAi to silence genes that cause genetic disorders, but, with Vir, they kept a hepatitis B program and a larger antiviral program alive. Over three months, Alnylam and Vir developed 350 potential sequences to match parts of the SARS-CoV-2 genome. They picked sites that consistently appeared in sequences of the virus — a sign they were essential for survival and mutation or interference could be deadly — and, to prevent side effects, avoided sites that matched human RNA sequences. Vir, equipped with a bio-safety level 3 lab, tested 24 sequences against a virus isolated from a patient in Washington. Five worked. They picked one, ALN–CoV, or VIR-2703. The sequence, the company said, is present in at least 4,000 of the viral genomes scientists have isolated, or 99.9% of them. It “is a complete disruption of the virus,” Maraganore told Endpoints. “As long as you’re targeting a naturally conserved site and it’s not mutated, you’re basically destroying the whole virus.” An earlier pioneer in the field unaffiliated with the biotechs said either approach, RNAi or antisense, had clear advantages over other technologies. Along with a handful of other prominent researchers, he expressed concerns that antibody treatment, while promising, could cause antibody-dependent enhancement, whereby the virus uses the antibodies to infect and influence a patient’s immune cells. Kevin Morris “An antisense oligo or siRNA has way more potential to work as a therapy,” Kevin Morris, a professor at the Gene Therapy Center at City of Hope, told Endpoints in an email. “It won’t be a cure, but it will be a way to treat infected individuals to help them clear the infection.“ DeliveryThe big challenge, the biotechs acknowledge, is delivery. Since the beginning of RNA therapies, it’s been difficult to get them anywhere besides the liver, where the body filters out foreign substances. Both of Alnylam’s FDA-approved drugs target the organ, along with a third — Novartis’s inclisiran — they helped develop and expected to be approved. Both Sarepta and Alnylam will try new delivery systems that have yet to be used in approved drugs. Sarepta will be adding an additional peptide to the chemical constructs, making it positively charged and, in theory, better able to penetrate cells. Alnylam will use an inhalant form of RNAi, Maraganore said, that scientists had just finished developing when Covid-19 broke out. That should allow it to reach lung cells where the virus takes root. “We just happened to be at a point where technologically we had addressed one of the key technical hurdles for treating a respiratory virus,” Maraganore said. Getting RNAi to the right part of the body is only part of the battle. It’s not clear how the RNA therapies will interact with infected cells, Morris said. Floor, the UCSF microbiologist, explained that the coronavirus forms a protective membrane around itself inside a human cell. It’s not clear where the antisense or RNAi will penetrate that membrane, although advances in packaging made it more likely, notably by encasing the genetic sequence in a tiny nub of fat called a lipid nanoparticle. He said RNAi probably has better odds than antisense, but it’s early to tell. “We’ll figure out what works and then we’ll figure out why,” Floor said. Governments and biotechs are trying to get a vaccine approved by the end of the year, when Alnylam plans to enter the clinic, but even if that happens, odds of having of billions of doses is slim. The biotech will be testing the drug in part as a therapy for those already infected, but Maraganore said it could also have a “vaccine-like” effect, potentially protecting healthy patients from the virus for a month or more. In theory, you could give it to healthcare workers or others at-risk, similar to the emergency uses under consideration for some vaccine candidates. The longtime CEO, though, isn’t betting on beating a vaccine or a different effective treatment. They’ve designed the drug to not only match all sequences from SARS-CoV-2, but also those from the original SARS virus. After three deadly coronaviruses have appeared in just 20 years, the plan is to finish developing this treatment, regardless of whether Covid-19 is under control by that time that happens. They want it ready for next time. “Everyone knows this is going to happen again,” Maraganore said. |
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Msg # | Subject | Author | Recs | Date Posted |
34823 | Re: ALN-COV | Aspector | 0 | 5/9/2020 10:07:34 AM |