With the World Vaccine and Immunotherapy Congress kicking off in San Diego today we are delighted to share another exclusive interview with the community. We were lucky to hear from Dr Ariel Weinberger, founder and CEO of Autonomous Therapeutics since 2017. Autonomous is a “scientist-led company” working on the development of the “first variant-proof RNA therapeutics”. Looking ahead, the team is hoping to create “effective countermeasures” before the next pandemic.
The consequences of the mRNA revolution for therapeutics
As mRNA entered its heyday during the COVID-19 pandemic, scientists and industry leaders rushed to make the most of the emerging potential. We asked Dr Weinberger about how the storming success of the mRNA vaccines might influence therapeutic interventions, and what challenges might be associated with an mRNA-based future. He began by suggesting that the “comparison to mRNA vaccines highlights a number of the challenges faced by mRNA therapeutics”.
Vaccines vs therapeutics
“If you think about vaccines, a core idea is to harness the body’s adaptive immune system for both signal amplification and memory. So, a relatively small vaccine dose can, in principle, confer immunity for years—although, of course, that hasn’t yet been the outcome for COVID-19 vaccines.”
Dr Weinberger explained that “the barriers for mRNA therapeutics arise, in large part, because they cannot leverage the body’s adaptive immune system for amplification and persistence”.
“As a result, you often need to administer far higher therapeutic doses—a recent review noted that mRNA doses are often 100 to 1000-fold higher for therapeutics than vaccines. And you may need to administer those doses repeatedly, because current RNA technologies can degrade in hours to days. And there’s another barrier: current RNAs, including those delivered in lipid nanoparticles, can lead to substantial immunogenicity. This may provide an adjuvant advantage for vaccines, but it’s unfortunately an additional way to accelerate the loss of therapeutic RNA.”
Despite the challenges, Dr. Weinberger believes that mRNA therapeutics are likely to succeed.
“It’s worth noting that these challenges were previously overcome for siRNA therapeutics. The drug that comes to mind is Alnylam’s Onpattro. So, there’s a clear precedent for believing that we’ll find solutions for mRNA therapeutics, too.”
We then asked Dr Weinberger about the opportunities for mRNA therapeutics, and how he understands a next-generation approach will enable us to use them. In his answer he highlighted the importance of “novel technologies” to “tackle the barriers” he explored above. He is particularly excited to encounter some of these next-generation mRNA technologies at the Congress (he gets brownie points for being enthusiastic about other people’s sessions)!
For example, self-amplifying RNAs are being developed to directly amplify RNA in vivo, circular RNAs are being developed to enhance RNA persistence, and novel transcription and purification strategies are being developed to minimise inherent RNA immunogenicity. But I also think that some of the greatest opportunities of mRNA technologies may be paradigmatically different. If you think about it, current mRNA therapies are often focused on producing proteins in vivo. I think a fair question is: “why don’t you just deliver the protein directly’? We may not like asking that question in the mRNA field, but we clearly have to—since some of our competitors are in the protein field.
Asking the right questions
Once this question has been asked, Dr Weinberger has another for his colleagues: “what can we do with mRNA therapeutics that we can’t do with proteins?” He suggests that “if we can answer that question, we have a potential path to developing next-generation drugs that weren’t previously possible”.
“Here are some examples. I think about proteins that are extremely difficult to produce, purify, or effectively deliver—for example, transmembrane proteins. Or therapeutic proteins that you don’t want to express constitutively and systemically, but that are life-saving in certain contexts. Ultimately, I think about how mRNA could be used as a circuit board to precisely control therapeutic protein production both temporally and spatially.
For Dr Weinberger, mRNA “2.0” moves from “plug-and-play production to plug-and-play control”.
“There are a few companies already thinking about this in the cancer context—imagine if we could localise chemotherapies or immunotherapies—and I think there will be more from cancers to autoimmune diseases.”
Autonomous’ pandemic protection against the unknown
We identified on Autonomous’ website the intention to develop countermeasures “before” the next pandemic. So, naturally, we were curious to understand how this works. First and foremost, Dr Weinberger was keen to emphasise that they’re not trying to “predict the future”.
“Before I started Autonomous, I spent years mathematically modelling the evolution and spread of pandemic viruses. And the lesson I kept learning is that you can’t predict a stochastic process with scores of unmeasurable parameters and “heavy” tails to the level of detail that you need to develop an effective precision therapy in advance. And even if we could know the random genotype of a future viral variant, we wouldn’t have a way to map its pandemic potential. Some have proposed using new AI approaches to solve these problems—but the pandemic prediction problem is likely a lot less tractable (and deterministic) than problems in, say, computer vision where AI has changed the world.”
For Dr Weinberger, the solution is “to develop broad-spectrum or variant-proof countermeasures that can control whatever viral variant ultimately emerges—even if the precise genomic confirmation of that variant is frankly unpredictable months to years in advance”.
How can we do this?
“One option is to target the part of the system that doesn’t change from virus to virus: the host. And we’ve seen a ton of recent interest in host-directed therapeutics; I think it’s an extremely promising avenue. The concern has always been that targeting the host means targeting the host, and raises the spectre of toxicity”.
“The other approach is to find the kernels of viral genomes or proteins that don’t change from virus to virus. These conserved viral elements are not likely to be in the Spike or receptor-binding proteins of a virus that vaccines generally target—those proteins are under too much diversifying selection from the immune system. In fact, the conserved regions that we want to target are often the regions that are the least well-suited for vaccine and antibody approaches. But these regions can be targeted using RNA technologies.”
Although there is “too much viral genomic diversity” for us to be able to develop a single virus-targeted drug, Dr Weinberger suggests that we “find elements that are conserved within a viral genus or species”.
“For example, we can find targets that are conserved across all the variants of SARS-CoV-2 or across all influenza variants. And then we have the possibility of developing countermeasures that don’t lose efficacy every 6 months—and that can be effectively administered for lifetimes. More broadly, we have the possibility of pre-developing an armamentarium of pan-variant countermeasures for each major viral family. That’s what Autonomous uses RNA to do.”
As terribly vulgar as it is to discuss money, in some situations curiosity just gets the better of us. Particularly in a post-pandemic world, we wondered what the funding landscape looks like for early-stage companies. Dr Weinberger thinks that “substantial funding will remain in the space, at least in the near term”. Although there is “always some reversion”, as the money moves where the “next hottest thing” is, he believes that “financial incentives are hard to ignore for an investor”.
“You’re talking about $75B that’s likely to be grossed for COVID this year alone by just two companies (and we keep hearing that the pandemic is over). At the same time, these numbers were clear before the pandemic. The market sizes for viral pathogens with pandemic potential are (unfortunately) massive. And there were already blockbuster returns for earlier antivirals and vaccines—from HIV and HCV to HPV.”
“I think that some of the historical shortfalls for antiviral and vaccine funding have also been on us: the companies. We haven’t always been developing new classes of approaches that offer major benefits over state-of-the-art strategies. How many similar monoclonal antibody or Spike vaccine approaches can we keep funding? More fundamentally, some of the issues have been at the Government and academic level. If we keep funding the same sorts of basic science studies, we’ll get more of the same translational products, and less of the same investment funding.”
“My view is that new classes of drugs and vaccines for major market indications will always have substantial investor interest—and that’ll especially be the case in the ID space after COVID. It’s just that you have established biopharma companies that have already developed and clinically tested existing products. The bar is high: you have to disrupt and supplant these existing approaches to enable the kinds of potential returns that would really excite investors.”
Eventually our conversation turned to the future, and what we should be most worried about, or invested in. As Dr Weinberger specialises in viruses, he believes, for “good reason” that these the “critical global health threats”. Previously, he suggested that “we can’t predict the next outcome of a random process”. We don’t know if the next pandemic will be “another flu, COVID, or an entirely different pathogen”.
“I think that we can fairly assume that there are going to be more viral pandemics – we’re still in one. And many of the pandemic strains that emerge will likely be close relatives (i.e. variants) of viruses that have previously infected large numbers of humans. After all, these viruses have already crossed the major evolutionary barrier: transmission across humans. To me, the critical threat is that the next pandemic variant is again untreatable or is resistant to all approved therapeutics and vaccines. In other words, after years of COVID and millions of deaths, we could be back in March 2020 all over again.”
“Sure, new platform technologies (including mRNA) could speed up response times—so maybe we’ll have an authorised vaccine or monoclonal antibody in 6 months. But we know that’s six months too late and that it’s fundamentally impossible to develop, clinically test, and manufacture a new countermeasure faster than a pandemic virus can spread.”
So, fail to prepare and prepare to fail. Thankfully, Dr Weinberger and his colleagues are working to prepare for future threats. It’s encouraging to hear that some of hard lessons from COVID-19 have been taken on board.
“We were based in New York City in March 2020. Being in that environment is something that you never forget. People felt helpless and knew that there were few medical countermeasures for them or their families if an infection took a turn for the worse. It’s incumbent on us to do everything possible to make sure that doesn’t happen again.”
It was a pleasure to hear from Dr Weinberger, and we are so grateful that he put so much thought into his answers. To participate in his roundtable at the World Vaccine and Immunotherapy Congress this week make sure you sign up in advance – it is surely not to be missed!
To read the full interview see here: