Friday, November 5, 2021

Molnupiravir may become the first COVID-19 pill. What took so long?

By Lisa Larrimore Ouellette, Nicholson Price, Rachel Sachs, and Jacob S. Sherkow

On October 1, the developers of the COVID-19 antiviral molnupiravir issued a press release announcing positive Phase 3 clinical trial results, with a 50% reduction in the risk of hospitalization or death. On November 4, the UK’s Medicines and Healthcare products Regulatory Agency authorized molnupiravir for use in the UK. While the results have yet to be reviewed by a scientific journal, they have generated excitement not only because of the potential lives saved but also because molnupiravir can be taken orally in tablet form, greatly reducing the difficulty and cost of administration. (Monoclonal antibodies require intravenous administration, as do the less promising treatments remdesivir and plasma therapy.) While it remains to be seen whether molnupiravir is as effective a weapon as its namesake Mj√∂lnir (Thor’s hammer), the news so far is promising. But why, in a global pandemic where vaccines could be pushed through in record-breaking time, were new treatments like molnupiravir so much slower to find? (It’s worth noting that molnupiravir isn’t the only drug in this situation; as this post was going to press on November 5, Pfizer announced that its experimental antiviral, Paxlovid, reduced COVID-19-related hospital admissions for high-risk adults by 89%.)

In this post, we explore the role of innovation policy in molnupiravir’s development, the FDA’s role in balancing access to promising treatments with the need to generate evidence of their efficacy, questions about molnupiravir access, and the implications for antiviral innovation going forward, for COVID-19 and beyond.

What role did innovation policy play in molnupiravir’s development?

Molnupiravir, also known as EIDD-2801 or MK-4482, is a small-molecule antiviral drug that was initially developed with public funding from the National Institute of Allergy and Infectious Diseases (NIAID) at Emory University’s nonprofit Drug Innovation Ventures at Emory (DRIVE). It works by increasing the frequency of viral RNA mutations, essentially causing viruses to mutate themselves to death.

Early in the COVID-19 pandemic, molnupiravir showed promise at treating coronaviruses in mice (in results eventually published in April 2020), so Emory licensed the drug to Ridgeback Biotherapeutics—led by private investors Wendy and Wayne Holman—in March 2020. Ridgeback rapidly received approval to launch human clinical trials from both the FDA and its UK equivalent, and Phase 1 testing began April 10 (funded directly by the Holmans). 

After the animal study was published in April 2020, Merck also became interested in the drug, and on May 26 Merck and Ridgeback announced a collaboration under which Ridgeback would continue to sponsor Phase 1 and 2 trials and manufacturing campaigns, after which Merck would lead the collaboration. All funds for post-licensing development of the drug have been provided by Ridgeback and Merck.

Phase 2 trials launched in July 2020 as part of the UK’s AGILE drug testing platform (similar to the RECOVERY platform we have described previously). In April 2021, Merck and Ridgeback announced that molnupiravir was unlikely to provide a benefit for hospitalized patients and that further trials would focus on non-hospitalized patients, for whom preliminary evidence seemed more promising.

In June 2021, the Biden Administration announced that Biomedical Advanced Research and Development Authority (BARDA) contracted for an advance purchase of 1.7 million 5-day courses of molnupiravir for $1.2 billion ($700 per course), conditional on the drug receiving emergency use authorization or approval from the FDA. As a comparison, the average cost of COVID-19 hospitalization is around $20,000, and Regeneron’s antibody cocktail can cost $2,000 for the drug and infusion. As in the vaccine context, an advance purchase commitment helps reduce the substantial risk in ramping up manufacturing before trials are completed—although Merck and Ridgeback still bear the downside risk if the drug does not receive authorization or approval.

How should the FDA balance the goals of making molnupiravir quickly available to the public with the need to generate evidence of safety and efficacy?

On October 11, Merck submitted an FDA application for an emergency use authorization (EUA) for molnupiravir. As we have previously explained, the standard for granting an EUA is whether “based on the totality of scientific evidence available,” “it is reasonable to believe that the product may be effective” and that the “known and potential benefits… outweigh the known and potential risks.” The director of the FDA’s Center for Drug Evaluation and Research, Dr. Patrizia Cavazzoni, has praised the “agile and flexible” EUA framework that allowed the agency to both quickly grant and revoke EUAs in response to evolving evidence of therapeutic efficacy throughout the pandemic.

The FDA has announced that molnupiravir will be going through the agency’s advisory committee review process, a process we have previously discussed, with a meeting scheduled for November 30. Although this review process is typical for many FDA-approved drugs and has been followed for every COVID-19 vaccine, it is not typical of the other COVID-19 therapeutics that have received marketing authorization.

As part of this process, the FDA will have to decide not just whether to authorize molnupiravir, but also the scope of that authorization. The clinical trial was limited to unvaccinated adults who began showing symptoms within the previous five days and were at high risk for severe disease (generally people over 60 or younger people with comorbidities including obesity, diabetes, or heart disease). Pregnant people were excluded due to concerns about birth defects. So it is as yet unclear whether authorization will only apply narrowly (such as to high-risk unvaccinated adults who are not pregnant) or will include additional groups (such as vaccinated people with breakthrough cases).

As we explain in a forthcoming chapter, molnupiravir is emblematic of a perennial challenge facing the FDA: how to balance “the goal of making new healthcare technologies quickly available to the public with the need for sufficient evidence that those technologies are safe and effective—evidence which is costly and time-consuming to gather.” Particularly early on in the pandemic, where no other treatment options were available, the FDA was quick to grant EUAs for potentially promising therapies. Even though the agency would revoke (as in the case of hydroxychloroquine) or narrow (as in the case of convalescent plasma) some of these authorizations later on, as the evidence matured, it may still have been the right decision to grant at least some of these authorizations, where the agency had clear plans for the collection of additional clinical trial information that would allow it to confirm or reject its earlier conclusions.

In this case, though, the risk/benefit balance for the agency may be different. In April 2020, even before any clinical trials had been completed, concerns had been raised over potential safety problems with molnupiravir. When coupled with the initial trials’ failure, it is easy to see why the agency may have declined to fast-track its authorization at the time. And although molnupiravir does have administration advantages over the existing effective antibody drugs, the availability of several effective vaccines and therapeutics may reduce agency urgency to speed the drug to market today.

Who will have access to molnupiravir? 

For U.S. patients, the biggest access questions are (1) the scope of any FDA authorization, discussed above, and (2) whether manufacturing and distribution will be sufficient to meet demand effectively. Cost is unlikely to be a significant barrier: $700 per course may sound expensive, but it is less than the U.S. government is paying for other treatments and low compared with the drug’s likely social value (though high compared to the cost of vaccination). In any case, patients won’t face that cost directly: The U.S. government has purchased an initial supply and will provide it free to patients, as is true for many other COVID-19 treatments and vaccines (at least, for now). Distinguishing patient costs and developer rewards matters in discussing the right payments for treatment in innovation policy terms, but whatever one’s views on that issue, cost seems unlikely to decrease patient access in the U.S.

But manufacturing and distribution may raise more important challenges. As with vaccines, scaling up manufacturing will take time; Merck estimates it will be able to produce only 10 million total courses by the end of 2021, of which 1.7 million doses have been pre-purchased by the U.S. government. Ex-FDA Commissioner Scott Gottlieb has questioned why advanced manufacturing wasn’t prioritized more, as was done for vaccines. Wendy Holman claimed in an interview that the company tried and failed to receive manufacturing funding from BARDA. Of course, such questions are a matter of degree; the government did support at-risk manufacturing with its June $1.2-billion advance purchase agreement, which helps address the risk that demand would dry up by the time clinical trials were complete (but not the important risk that the clinical trials would be unsuccessful). 

With respect to distribution, although molnupiravir won’t be subject to the same degree of administration challenges as monoclonal antibodies, getting the drugs to the right people won’t be trivial. The drug is effective in preventing the onset of severe symptoms and hospitalization, which means that getting it to the right patients requires coordination between testing and treatment providers—coordination that is mostly lacking and sorely hampered by continued testing delays. 

For the rest of the world, the advance purchase of 1.7 million 5-day courses by the United States raises similar concerns about hoarding as advance purchases in the vaccine context. But unlike vaccines, for which involvement of the original manufacturer is necessary to expand supply, molnupiravir is a small-molecule drug that is comparatively easy to produce generically. In April 2021, Merck announced licenses to five generics manufacturers in India to supply molnupiravir to India and over 100 low- and middle-income countries; the number of generic manufacturers has since grown to at least eight. And in October 2021, Merck announced a royalty-free license, including technology transfer assistance, to the Medicines Patent Pool, which works with generic drugmakers around the globe. Of course, these countries will also face the same challenge as U.S. healthcare systems in manufacturing a sufficient quantity of drugs at speed and coordinating administration of the drug with sufficient testing capacity. But countries like India, for example, have manufacturing facilities available at their disposal with expertise making the same class of drugs as molnupiravir that should ease most major manufacturing barriers.

Why wasn’t molnupiravir prioritized, and how can policymakers better support antiviral innovation going forward?

Why are we just learning about molnupiravir’s effectiveness now—20 months into the pandemic? The answers lie in cash, concept, and coordination. 

First, throughout the pandemic, the U.S. government has invested less in treatments than in vaccines. For example, as of January 2021, federal funding for treatments was $8.2 billion, compared with $18.5 billion for vaccines. This division is not necessarily problematic: vaccines have a more important role in mitigating the pandemic, and public funding is more important because vaccines are less profitable than treatments, all else equal. In addition, given the difficulties of engaging in a drug development program from scratch during the middle of a rapidly escalating pandemic, much of innovation policy pertaining to therapeutic development focused on repurposing known drugs rather than making brand new ones. While molnupiravir is a nucleoside analog—a well-known class of antivirals—is it a new compound, the efficacy of which was uncertain at the time of its creation. Indeed, other new antivirals, like Atea’s COVID-19 antiviral, have not been effective at stopping COVID-19. Even molnupiravir’s initial trials were not originally succesful.

In addition, focusing on the antivirals in the first instance requires a conceptual leap that seemed almost implausible at the beginning of the pandemic: that a primary source of taming the virus was not preventing people from contracting it, but simply ensuring that they didn’t become seriously ill if they contracted it. The attention paid to masking and social distancing measures that characterized the beginning of the pandemic centered on preventing transmission, not treating the already sick. And indeed, when diagnostic tests were in short supply and asymptomatic transmission feared, preventing the spread of the virus—not its survivability—seemed like the only path forward. Today, with many experts predicting that COVID-19 will become endemic, preventing serious illness has become a more important part of long-term COVID-19 strategy.

Perhaps more than insufficient government funding for treatments, insufficient coordination of government funding has plagued finding treatments for COVID-19. Some of that stems from outsized “enthusiasm for certain treatments . . . including hydroxychloroquine, remdesivir, and convalescent plasma, even where evidence of efficacy has been poor.” Possibly as a result, other potentially promising treatments, like molnupiravir, were delayed funding. Relatedly, even if funding was secured, fully enrolling clinical trials became increasingly problematic as potential subjects either refused to opt-in or could not meet the tests’ screening criteria. 

So: what can be done? The recently announced American Pandemic Preparedness Plan seeks to avoid similar problems by using $3.2 billion to tackle antiviral research against the next pathogen. The Director of National Institute of Allergy and Infectious Diseases, Anthony Fauci, describes this pillar of the Plan as the Antiviral Pandemic Preparedness (APP) program, which includes not simply funding for discovery, but clinical trials, manufacturing, and global distribution. 

After perhaps a slow start, today, other antivirals are currently in the pipeline and we may expect more besides just molnupiravir, such as Pfizer’s Paxlovid drug mentioned above. But ensuring that antiviral development happens the next time around will be a matter of expanding our conceptual understanding of combatting a pandemic, not to mention cash and coordination about how to spend it. 

This post is part of a series on COVID-19 innovation law and policy. Author order is rotated with each post.

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