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Nice article Brian!

> Companies may lack incentives to conduct human clinical trials for drug-free antivirals or repurposed drugs. Drug-free antivirals can enter the market without such trials, while repurposed drugs are often off-patent, which makes clinical trials a high-cost, low-reward proposition for sponsors. And without human clinical trials, we can’t be certain that broad-spectrum antivirals developed in these ways are truly effective. As a result, there remains significant value in navigating traditional regulatory paths for a new broad-spectrum antiviral.

Regarding this point - I agree that there will be low incentives for conducting clinical trials for drug-free antivirals or repurposed off-patent drugs, yet I wonder if something similar to an advance market commitment could be used here. In this case, instead of committing to purchase an approved drug, a public funder could instead commit to running a large clinical trial if a company commercialises an antiviral product that does not require regulatory approval and meets some initial criteria (e.g. a pre-specified efficiency in animals or a pilot-clinical trial). This 'advance research commitment' could incentivise innovation for broad-spectrum antivirals outside traditional regulatory pathways, the company benefits as a successful trial will provide the product with credibility and increase market demand, the public benefits as the antiviral can be sold at a lower price than if the company has to recover the cost of phase 3 clinical trial.

The of idea of public funders paying for clinical trials of pharmaceutical products is from the Chapters 9 and 10 of Against Intellectual Monopoly (free download at http://www.dklevine.com/general/intellectual/againstnew.html), where they argue that the public would benefit from reduced patent protection on drugs, and the monopoly pricing afforded by patent protection wouldn't actually be necessary if the Phase 2 and 3 clinical trials required for regulatory approval were publicly funded. The rational is that clinical trial result submitted to regulators are a public good, and should be paid for directly by the public rather than paid for by the pharmaceutical industry (and then recovered in high product prices).

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Thanks Gavin! Agree that we could use some creative ways to incentivize running clinical trials for these kinds of drugs – or to reward broad-spectrum antiviral activity more broadly. The "advance research commitment" idea is an interesting one and could be extended to products that do require regulatory approval, but where the sponsor only has an incentive to run a clinical trial for a particular disease with commercial appeal. E.g., if you have a broad-spectrum antiviral with proven clinical efficacy against COVID-19, that's great, but without an "advance research commitment" or something else you might not have an incentive to also run clinical trials to test its efficacy against other viruses, even if your preclinical data is promising there.

Even with something like advance research commitments, there's still the problem of trying to demonstrate broad-spectrum efficacy against viruses one by one. Just brainstorming here, but another idea might be to try to develop a whole separate regulatory pathway that breaks out of the "single indication" paradigm – e.g., approval based on trials demonstrating prevention/treatment efficacy for "undiagnosed viral illness." It's possible that trials like these might give you more confidence in a drug for being broad-spectrum enough to be reliable against the next pandemic pathogen. Albeit still not perfect, since undiagnosed viral illnesses are almost certainly a biased subset of total viral diversity. Lots to explore here!

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Well, in terms of the "singe indication" paradigm, maybe the approach here could be working towards efficacy against a disease that has a wide viral etiology. For instance, the clinical guidelines for treating community-acquired pneumonia (CAP) recommend not initially testing for bacterial infection while still prescribing an antibiotic (conversely, influenza antivirals are only recommended after a positive test). Bacteria causes a lot of pneumonia cases and antibiotics are broadly effective against bacteria (well until AMR), so I assume that it just makes sense to prescribe an antibiotic without knowing there is a bacterial etiology, let alone what bacteria (preventing secondary bacterial infection is probably another consideration here). Viruses also cause a lot of pneumonia cases (maybe more than bacteria), so if working towards a broad-spectrum antiviral, perhaps it could just aim for the indication for treating "all CAP cases, without diagnosing etiology" (as antibiotics are used).

There are other respiratory tract infections that are primarily caused by viruses (e.g. bronchiolitis and croup in children, most acute upper respiratory tract infections in adults), so just working towards an indication for treating "all colds" or "all sinusitis cases" might be a useful strategy for developing a broad-spectrum antiviral. As an aside, the etiology of some upper RTIs (and CAP) fully cover the pandemic-prone viral families that the CHS has identified, so they seem like good diseases to target in the context of pandemic preparedness.

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How does your approach compare to that of Kimer Med in New Zealand?

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Great question! They're similar, both being inspired by the same original concept + publication. We haven't spoken with Kimer Med directly, but my sense is that they're sticking closer to the molecular designs reported in the original publication and focusing on bringing it to market. What we're doing has more of a research component up-front, as we're trying to explore as much of the design space around double-stranded RNA-targeting antivirals as possible before settling on a design to push forward into clinical trials.

In addition, we'll be encoding that design in DNA to enable longer-term broad-spectrum antiviral activity, and therefore prophylactic use. This again has a bigger research component associated with it, as there are a lot of uncertainties to tackle in ensuring that our antivirals can be safe + effective for months! But we think that prophylaxis is key for both ensuring that the antivirals can be effective and for opening up different paths to market.

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