Early Stage COVID Treatments: Merck's Molnupiravir Struggles...

Early Stage COVID Treatments: Merck's Molnupiravir Struggles
Dec. 03, 2021 9:10 AM ETMerck & Co., Inc. (MRK)BNTX, SPHRF, SPHRY
Summary

• The treatment window for COVID is very narrow; this limits the value of even effective treatments.
• Molnupiravir effectiveness ~30%; Paxlovid seems more effective in trials, but the real world awaits.
• Molnupiravir is not transforming for Merck, but Paxlovid at worst means a major boost to Pfizer’s 2022 earnings.
• Both Molnupiravir and Paxlovid are expensive, and this will limit their adoption. Starpharma’s Viraleze nasal spray preventative/early treatment is priced for wide adoption.
• Vaccines are still the way to finish the pandemic.

Eoneren/E+ via Getty Images

Viruses get a life by infecting cells, taking them over and turning them into virus-making factories. Viruses have their own cellular targets. One consequence of this is that the time to progression of the disease varies widely for different viruses. For example, infection by the HIV virus often takes 5-10 years if untreated to progress to full blown AIDS. SARS-CoV-2 is different as the progression to COVID-19 is explosive in individuals who are susceptible. There are now a number of drugs used to treat HIV infection and they are often used in combination. These drugs target different aspects of the viral replication so they stop the virus and the slow progression of the disease allows control. For SARS-CoV-2, because of its explosive nature, there is only a narrow window of time before initial virus infection and out of control replication (days). Here I explore why Molnupiravir is proving to be less effective than what was suggested initially in the Phase 3 trial. As I predicted this is not going to be a company changing drug for Merck (MRK).

Merck/Ridgeback Biotherapeutics Molnupiravir

My views about COVID treatments are influenced by my experience as a volunteer bushfire fighter. In the Australian bush it is relatively easy to put out a fire just after it starts, but wait a short time and the fire gets out of control. SARS-CoV-2 causes an explosive infection. Treatment soon after it gets started allows effective treatments to stop the infection, but if you delay treatment, the infection gets out of control. Interim analysis of the Phase 3 study testing risk of hospitalisation and death in COVID patients with mild or moderate disease, who had one or more risk factors for serious COVID disease, and who took antiviral Molnupiravir pills within 5 days of COVID symptoms, showed risk of hospitalisation or death decreased by ~50% compared to treatment with a placebo.
Updated analysis of the results of the MOVE-OUT study on Molnupiravir showed 30% (not 50%) reduction in progression by high-risk patients with mild to moderate COVID. I suspect that timing issues may be part of the explanation for the changed success of this trial. Nevertheless, Merck has secured a commitment from the US Government to purchase 3.1 million doses at a cost of $2.2 billion ($710 for a treatment regime).
Since the timing of treatment commencement is so critical it could be that effectiveness of Molnupiravir for treating early-stage COVID might be even less effective than 30% reduction in serious symptoms in the real world, as issues like getting diagnosed and obtaining a prescription may delay commencement of treatment.
Admittedly Molnupiravir is a pill so it is much easier to deliver than a monoclonal antibody-based treatment that involves delivery by injection and a more formal environment (e.g., hospital). I’m a big fan of new technologies but only if they offer superior outcomes at an affordable price. There have been a number of monoclonal antibody treatments touted as revolutionary. I have trouble comparing a pill with a very expensive option that is delivered in a hospital setting.
Molnupiravir rollout

Merck has planned to produce 10 million doses by the end of 2021 and at least 20 million courses in 2022. This might become an ambitious goal with the advent of Pfizer’s Paxlovid being more effective (see below).
Pfizer’s Paxlovid

Pfizer has a different antiviral pill that is showing more promise as a treatment for early-stage COVID, with 89% reduction in hospitalisation. The US Government has acknowledged the better prospects for Paxlovid compared with Molnupiravir by announcing the order of 13 million doses of the new antiviral pills, which is more than 6x the number of hospitalisations in the US for 2021. The Paxlovid commitment amounts to 10 million doses.

Molnupiravir and Paxlovid are expensive treatments

Medicines are rarely cheap in the US and the pricing of both Molnupiravir and Paxlovid follow that tradition. A treatment course for Molnupiravir is priced at $710, while Paxlovid is priced at $529 for a treatment course.
The Biden administration has just announced a series of new measures to address the burgeoning delta surge and anxiety about what Omicron might bring. It seems that the early-stage treatment pills will be affordable for all US citizens at least in 2022. In addition, the plan is to facilitate ‘at home’ testing to enable rapid diagnosis and hence early treatment for COVID.
Nasal sprays, another approach to prevention and early stage treatment

Given the challenge of rapid viral runaway, there is interest in finding ways to address very early-stage treatment. Since infection is primarily through the nasal passage, an approach that involves treatment in the nasal passage has been discussed. There are a number of companies addressing this area with various antiviral compounds.
Broadly these approaches involve compounds that inactivate the SARS-CoV-2 virus before it enters nasal cells, or killing it when an infected cell releases the virus. Several approaches involve natural products that might be effective in this role.
I’ve been interested in Australian Biotech company Starpharma’s (OTCQX:OTCQX:SPHRY) potent antiviral compound SPL7013 as this compound has been registered for human use in more than 45 countries for treating a vaginal infection (bacterial vaginosis). Key features of SPL7013 include room temperature stability and potent antiviral action against respiratory viruses including all SARS-CoV-2 variants tested, including delta.
Mechanism of action: Viraleze snuffs out through suffocation

Viraleze mechanism of action is suitable as a preventative to enhance protection given by wearing a mask. It acts quickly and irreversibly and stays in the nose for a significant period because it is not absorbed into the bloodstream. It is a coating in the nasal passage in the same way as in the vagina when SPL7013 is used to treat and prevent recurrence of bacterial vaginosis. It is stable at room temperature (keep the dispenser in your handbag) and is easily applied as a nasal spray before going into risky environments or for use after exposure. Viraleze is priced as a consumer product for repeated use in risky environments (e.g., on public transport, etc.).
An interesting aside in the presentation at the recent Starpharma AGM was that paradoxically it seems that Viraleze becomes more potent against the more infective strains of SARS-CoV-2 (e.g., delta) because the changes to the spike protein make the SARS-CoV-2 virus more susceptible to trapping by Viraleze. There is no data yet on Viraleze action on the new Omicron strain.

Viraleze availability

Viraleze was adapted from a Starpharma product VivaGel BV which is a novel antibacterial (and antiviral) based on Starpharma’s dendrimer technology that is approved for use in 45 countries (with FDA application pending). The Australian Government sought expressions of interest for funding to adapt existing medications for use in addressing the COVID pandemic. Starpharma received $A1 million matching funding from the Australian Government MRFF (Medical Research Future Fund) and it quickly developed Viraleze. The Australian TGA (Therapeutic Good Administration) is yet to approve Viraleze despite approval being granted in New Zealand.
Viraleze is now approved for sale in the UK, Europe, India, New Zealand and most recently Vietnam, where it is being made available this week as the first South East Asian country with a supply and distribution agreement. With close to 100 million population, just 50% vaccination and a significant current delta outbreak the Vietnamese market is interesting.
In today’s news, Starpharma announced a 5 year supply and distribution agreement in Vietnam, with a minimum commitment of 1 million doses in the first year. The product launch occurred today.
Conclusion

It is interesting in seeing how acceptance of biotech products work. There has been so much investment in monoclonal antibody products that there is huge pressure for these products to be adopted. The general public is given the impression that these products are superior. There are examples where monoclonal antibody products are a definitive solution (e.g., some of the revolutionary cancer drug treatments), but in many cases, monoclonal antibody drugs are not only much more expensive, less stable and more difficult to administer (injected), they just don’t work as well. I have not emphasised the monoclonal antibody COVID treatments for this reason.
Molnupiravir (Merck) and Paxlovid (Pfizer) are better solutions partly because they are pills that can be administered by the patient and they are likely to suffer less impairment than monoclonal antibody-based drugs when treating new mutant strains of SARS-CoV-2. The Merck and Pfizer drugs are more expensive than they need to be, and that is the story of the US drug pricing system, but President Biden’s announcement yesterday indicates that the early stage treatment pills will be affordable for both those with medical health coverage and those who are uninsured, at least in 2022. It looks like Paxlovid is more effective than Molnupiravir, but I suspect that both drugs will have issues because the time window for treatment is so short. My conclusion about Molnupiravir is that it might be moderately successful but it won’t change the needle for Merck; this is beginning to look like the outcome after initial euphoria. Pfizer’s Paxlovid is a supporting product for its revolutionary mRNA technology vaccine with BioNTech (NASDAQ:BNTX). Even if Paxlovid proves to be less effective than early results show, it seems that 2022 will provide substantial revenue from sales of Paxlovid, with $5.29 billion locked in from the US Government orders and indications of substantial early orders from many countries.

The point is that vaccines are what is going to shutdown SARS-CoV-2, but, and I know I’m a cracked record, I think that a product that has real potential to impact prevention/early infection is Starpharma’s Viraleze. Because Starpharma is unloved at the moment, if the Vietnamese agreement announced today generalises to other countries, the financial impact on Starpharma could be significant. It could be a good opportunity for investors who seek unloved opportunities and who pay attention to substance over style. Of course, I might be wrong about Viraleze for the US because of a pill-popping orientation and resistance to nasal sprays, but there are many markets that might find Viraleze interesting.

I am not a financial advisor but I have experience of biotech from a scientific and commercialisation perspective. I hope my commentary helps give you and your financial advisor some insight into what works for COVID in the prevention/treatment space. I have been a Starpharma investor for longer than I care to admit.
This article was written by

Keith Williams