Ridgeback Biotherapeutics/Merck’s Phase IIa molnupiravir is attractive for outpatient and recently hospitalised Covid-19 patients due to its mechanism and oral administration, experts said. However, many trial success blind spots persist, limiting efficacy judgment, they added.

Encouraging preclinical data is yet to translate into humans, and there is potential for lingering severe side effects due to molnupiravir’s mutagenic mechanism, experts noted. While targeting Covid-19 patients in the earlier part of the disease spectrum is logical, the trial designs may blur molnupiravir’s clinical value, they said.

In July 2020, Miami, Florida-based Ridgeback and Merck announced they had partnered to advance molnupiravir in Covid-19. On Monday (25 January), Merck said it was dropping out of the Covid-19 vaccine race and would instead focus on its therapeutic assets, including molnupiravir. Molnupiravir is in two Phase IIa trials, one in newly hospitalised patients and the other in outpatients, with initial efficacy data expected for both in 1Q.

While molnupiravir has promising animal model data, extrapolation in humans may be fraught due to different enzymes involved in activating the nucleotide analogue, experts said. Gilead Sciences’ Veklury (remdesivir) could be used as an efficacy benchmark since both are polymerase inhibitors, but this may be inappropriate as they are designed for different patients, experts added. There are persistent side-effect concerns with mutagenic molnupiravir, although the fact it is only used for five days in Covid-19 is somewhat reassuring, some noted.

It is logical to investigate molnupiravir in recently hospitalised and outpatients due to its antiviral mechanism, experts said. However, they took issue with the recently hospitalised trial’s primary endpoint of virological clearance, noting it lacks clinical value in the context of lingering side-effect concerns. This trial’s recruitment of patients within seven days of treatment onset will also be challenging to execute due to logistical delays in practice, they added. The Phase IIa inpatient trial is still recruiting, as per ClinicalTrials.gov.

The outpatient trial would have been better-designed if it recruited patients according to their viral load and not symptom onset, as this would have allowed the trial to enroll patients with a consistent patient profile, some experts said. However, others noted recruiting patients according to symptom onset is already challenging enough as it is, as outpatients feel they are not sick enough to participate in trials involving multiple onsite visits.

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Mechanism logical on paper, but yet to prove clinical value

Nucleoside analogue molnupiravir has been investigated previously in other viral diseases, supporting its use versus SARS-CoV-2, said Robert Shafer, research professor, infectious diseases, Stanford University, California. One advantage of its mode of action as a polymerase inhibitor is the limited data showing viruses develop resistance against this approach, added Ashley Brown, PhD, associate professor, Institute for Therapeutic Innovation, University of Florida, Orlando.

There are unique aspects to molnupiravir’s mechanism, Shafer noted. In human immunodeficiency virus (HIV) and herpes viruses, nucleoside analogues are incorporated into a growing DNA chain and would stall its production, he explained. These are called chain terminators. In contrast, molnupiravir would still allow for the viral RNA chain to grow, but wrong nucleosides are attached to the chain, leading to many mutations, he said. Because of this, the chain would be degraded, he noted, adding this is why molnupiravir is a mutagen.

In Covid-19, both molnupiravir and Veklury are incorporated by the viral RNA polymerase, with molnupiravir being a viral genome mutagen and Veklury blocking replication done by the polymerase, explained Ron Swanstrom, PhD, professor, Department of Biochemistry, University of North Carolina, Chapel Hill. So far, both treatments’ preclinical data indicate equivalent potency, Shafer added. Ridgeback declined this news service’s interview request, but forwarded links to publicly available molnupiravir data. In ferrets, molnupiravir significantly reduced the upper respiratory tract load in infected models and suppressed spread to noninfected models (Cox, R., et al., Res Sq. 2020 Oct 12;rs.3.rs-89433). Merck did not respond to a comment request.

There are caveats to extrapolating animal model data to humans, Brown said. With molnupiravir, it needs to be converted into its active triphosphate form in the cell, and enzymes responsible for such conversion may be different between animal models and humans, she said. In fact, dosing data in animals do not relate to humans, as plasma concentrations do not correlate to activity within animal and human cells, she explained. Both placebo-controlled Phase IIa trials are dose-ranging trials, investigating as many as nine different doses.

Comparing molnupiravir and Veklury may be inappropriate as they are intended for different patients, Brown added. Veklury is FDA approved in hospitalised patients, although it has a wider emergency use authorisation. Even if molnupiravir is only as potent as Veklury, its oral formulation will boost its clinical value, as it could be used by more people, Shafer said. As much as 80% of all Covid-19 cases are either asymptomatic or mild, with only 20% of patients sick enough to be hospitalised, added Dr Yvonne Maldonado, professor, infectious diseases in pediatrics and health research and policy, Stanford University, California, and a Phase II Avigan trial investigator in asymptomatic or mild Covid-19 patients. Another oral Covid-19 therapy under investigation is Fujifilm Toyama Chemical’s Avigan (favirpiravir), which is also an oral mutagen, Shafer said, but added Avigan’s preclinical and clinical data in Covid-19 are underwhelming so far.

Due to limited data with highly active viral mutagens like molnupiravir, there is concern its mechanism would negatively impact the host, leading to side effects, Swanstrom said. When considering widespread deployment, toxicity is a major issue, said Dr Saye Khoo, professor, pharmacology and therapeutics, University of Liverpool, UK. How it is utilised will depend on its overall toxicity data, added Khoo, who is studying molnupiravir in a Phase I/II basket trial investigating various Covid-19 treatments.

Side effect concerns have been raised about whether molnupiravir could be metabolised into a precursor of DNA, Swanstrom said, explaining it could enter the host cell nucleus, leading to oncogenesis. Mitochondrial toxicity with such a mechanism has been raised in previous investigations in hepatitis B and HIV, added an investigator in a Covid-19 trial recruiting outpatients and recently hospitalised patients. In the 20-day Phase I molnupiravir trial recruiting healthy volunteers, 93.3% of adverse events were mild, with one patient discontinuing due to rash (Painter, W., et al., Medrxiv. 14 December. https://doi.org/10.1101/2020.12.10.20235747).

Molnupiravir is only used in the short term, twice-daily for five days, as opposed to chronic use, Shafer added. Polymerase inhibitor side effects have improved over the years, and while mutagen side effects were a concern in early development in HIV, they have eased in available hepatitis treatments, Brown added. However, due to the need for longer-term safety data, molnupiravir may be limited to patients at high risk of developing severe disease, Swanstrom said.

Targeted patients ideal but investigation execution challenges present

The value of antivirals is most pertinent in the recently hospitalised and outpatients with high risk of severe disease, considering the host’s inflammatory response is more of a concern later in the disease, Swanstrom and Khoo said.

Molnupiravir’s recent inpatient trial has a primary endpoint of virological clearance. While this endpoint is logical to confirm its mechanism, it is not as clinically valuable as investigating symptom improvement, the Covid-19 investigator added. Due to molnupiravir’s theoretical side-effect risk, underscoring its clinical value in this early stage would have been more important to positively influence its risk-benefit balance, Swanstrom said.

In molnupiravir’s recently hospitalised trial, treatment should be initiated within seven days of symptom onset. However, this seven-day window is challenging to execute in practice, with a 7–9 day window being more realistic, the Covid-19 investigator added. From experience, patients take 2–3 days to wait if symptoms are severe enough to go to the hospital, and a positive result is confirmed by day 5, he said. It takes a couple more days to decide if the patient would be recruited in the trial, he added.

Meanwhile, molnupiravir’s outpatient trial has a primary endpoint of number of days until first nondetectable SARS-CoV-2 load. One limitation of this endpoint is how the viral load baseline could vary among patients, the Covid-19 investigator said. Additionally, people can clear the virus at different timeframes, with some taking 10 weeks, Maldonado added. Outpatients typically clear the virus within 14–21 days without therapeutic intervention, the Covid-19 investigator said.

It may have been more informative if patients were recruited according to their viral load in order to have a more consistent patient profile, the Covid-19 investigator added. Although the trial has a primary endpoint of virologic efficacy, patients are recruited according to symptom onset or when Covid-19 was confirmed.

The trial does use the Kaplan-Meier Method to account for “early” versus “late” time of symptom onset, which is a gold standard methodology, said Khoo. Trial researchers must have believed the early and late groups would have different times to event, leading to stratified randomisation, explained Janet Wittes, a biostatistician, fellow of the society for clinical trials and president and founder of statistics collaborative. One basic underlying assumption is the effect of the intervention in terms of hazard ratio is the same in both groups, but the underlying probability of event differs in the two groups, she added.

However, using viral load as a recruitment criteria would make outpatient trials even more challenging to enroll, said Maldonado. Patients with mild disease do not feel sick enough to participate in trials, particularly those with repeated onsite visits, she explained. Teleconferences can be conducted, but there would be no sample collection, the Covid-19 investigator added.

Merck has a $194.99bn market cap.

Reynald Castaneda is Associate Editor for Clinical Trials Arena parent company GlobalData’s investigative journalism team. A version of this article originally appeared on the Insights module of GlobalData’s Pharmaceutical Intelligence Center. To access more articles like this, visit GlobalData.

Sean Rai-Roche is a Reporter for Clinical Trials Arena parent company GlobalData’s investigative journalism team. A version of this article originally appeared on the Insights module of GlobalData’s Pharmaceutical Intelligence Center. To access more articles like this, visit GlobalData.