Having recent success in lung delivery, short interfering RNA (siRNA) is poised to be a powerful new modality to treat COVID-19. Alnylam and Vir Biotechnology expanded their 2017 partnership earlier this month – leveraging Alnylam’s lung delivery technology of novel conjugates of siRNA with Vir’s expertise and extensive capabilities in infectious disease – to target SARS-CoV-2. Alnylam has already identified siRNA that targets highly conserved regions of coronaviruses, thus offering the prospects of broad coronavirus application.

Because the discovery of RNA interference (RNAi) was considered so profound in understanding how genes are regulated in cells, a Nobel Prize in Medicine was awarded to Craig Mello and Andrew Fire just eight years later. Yet the translation of these fundamental findings into the first FDA-approved RNAi-based therapeutic, patisiran, took more than a decade. Discovered and developed by Alnylam, patisiran’s approval represented a crucial milestone for this transformational technology.                              

John Maraganore is CEO of Alnylam, which he co-founded in 2002 with Phil Sharp, Phil Zamore, Paul Schimmel, Dave Bartel, and Tom Tuschl. Under his leadership, Alnylam has built a deep portfolio of drugs and drug candidates created by the platform—and has formed numerous alliances using RNAi to solve industry-wide problems.

Rich Soll and the WuXi AppTec Content Team discussed Maraganore’s quest to apply this technology to stop the COVID-19 pandemic.

WuXi AppTec: What motivated you to apply your RNAi experience to the fight against the coronavirus?

John Maraganore: We have a technology that is very exciting and has great potential to target RNA as a way of developing novel therapies, and we’ve been successful in bringing these medicines to the market. Because our technology targets RNA and because the SARS-CoV-2 virus (the virus that mediates COVID-19), is an RNA virus, our technology is incredibly well-suited for developing a direct antiviral therapy.

As the outbreak was being reported in China very early in the year, our scientists already began to start an effort to develop RNAi therapeutics that target the SARS-CoV-2 genome with the goal of developing a therapeutic for the treatment of COVID-19. The SARS-CoV-2 program builds a lot on what we learned from earlier experiences in virology programs on Hepatitis B and RSV.

WuXi AppTec: Your Covid-19 program is partnered with Vir Biotechnology. Can you describe the relationship and recent expansion of Alnylam’s partnership with Vir in more detail?                                                                        

John Maraganore: The Vir collaboration was started a couple years back when Vir was being established. ARCH Venture Partners, whom we know well through their investment in Alnylam was an investor in Vir. Vir CEO, George Scangos is a friend dating back to when he was at Exelixis and Biogen. The concept was to partner our infectious disease programs to Vir’s dedicated effort on antivirals. We can’t do everything at Alnylam, so Vir was the right fit for us.

The key thing about this 50/50 partnership is that we give them development candidates, they do all the clinical testing through to the end of Phase II where we have the right to opt into the program on a 50/50 basis for free. Basically, we’re retaining half the value of the program to go into that collaboration after a lot of the risk is taken out of the program in even Phase I and Phase II.

WuXi AppTec: Alnylam had designed and synthesized more than 350 siRNAs that target SARS-CoV and SARS-CoV-2 genomes in 48 hours, and Alnylam had been expecting to deliver 50-100 potent molecules. Did you achieve your goal and how was this enabled?

John Maraganore: It’s the power of a platform that uses RNA sequence as a design element. We hope to select a development candidate within the next few months. As soon as that RNA sequence is around, we can begin to design these molecules and find very, very close molecules very quickly.

WuXi AppTec: So it is clear you can design potent siRNA, but delivery has been a problem until more recently?

John Maraganore: Yes, that’s fair to say. The company was started in 2002 yet up until 2010 or so, we were working on delivery and not really building our pipeline. However, when we finally conquered delivery to the liver, we learned a lot about how this delivery could be achieved to other cell types and other tissues in the body; for example, the CNS (central nervous system) and more recently the lungs. Fortunately, the lung delivery results came in recently so the timing was good with respect to siRNA therapy in COVID-19.

The fact that our scientists were able to solve delivery to the lungs in animal models gave us high confidence that we could do this in humans, and therefore gave us high confidence to advance the SARS-CoV-2 program.

WuXi AppTec: Persistence and patience paid off here.

John Maraganore: It really did in our case. I mean, we’re really lucky that it turned out the way it did, and obviously we couldn’t be happier about the success we’ve been able to have. But it did include a number of near-death moments in the company.

WuXi AppTec: What will be the regulatory pathway?

John Maraganore: We will be dealing with the Center for Drug Evaluation and Research, CDER – the arm of the Food and Drug Evaluation (FDA), as the siRNA are prepared via a synthetic process for manufacturing.

Once we have our developing candidates in hand, we’re going to engage with the FDA, the NIAID and the CDC to have the right discussions about what they want to see. We think a relatively truncated approach is going to be important. This will allow for us to bring a molecule into clinical testing as quickly as possible.

It’s worth saying that the way we think this technology may work best is to give it as a preventative agent to people who are or have  been exposed, or to health care workers. As a result, it’s not likely a vaccine that will be given to everybody, but rather to a smaller part of the global population.

WuXi AppTec: We’ve had 3 coronavirus outbreaks in two decades (SARS, MERS, and now COVID-19). How can we use Alnylam’s platform to be better prepared for the next virus?  

John Maraganore: We’re targeting highly conserved sequences that have been 100 percent preserved all the way back to 2003 and the SARS outbreak that happened in 2003. This gives us incredibly high confidence that these molecules that we’re generating will be useful in the future for the next SARS epidemic. I say, the “next” one because I think that at this point we’ve got to realize that history is going to repeat itself.

One thing that we’ve done in the past as a society is that we started initiatives in response to an event like SARS, MERS or Ebola, which then results in a big effort to try to find new therapies. However, in cases where the problems go away, so too does the interest of society – leaving projects in limbo and incomplete. I hope this time that is not the case. We need to finish the job.

WuXi AppTec: For the last few minutes perhaps you can share your perspectives on 2 timely topics: state of innovation, can we reach 100 drugs/year approval rate in 10 years and are these incremental or transformative therapies?

John Maraganore:  My impression on the state of innovation is that we indeed are operating at higher levels of innovation than before, in regards to gene and cell therapies. RNAi technology is a new modality that did not exist even 5 years ago and only now is being realized as novel medicines. The Center for Biological Evaluation and Research (CBER,) the arm of the FDA that approves biologics, has hundreds of applications under review. I would not be surprised if we hit one hundred or more approvals annually based on all the science that I’m seeing in the pipeline, perhaps in as little as 5 years.