Roche's Oral COVID-19 Drug Fails Phase II Trial; Merck, Pfizer, Shionogi, and Kintor Advance in Development Race

Recently, Roche and Atea Pharmaceuticals announced that the global Phase II MOONSONG trial of their oral COVID-19 drug AT-527 failed to meet its primary endpoint. On the day of the announcement, Atea's stock price plummeted 66%, while Roche's shares dipped slightly by 1.64%.

Developed by Atea, AT-527 is an RNA polymerase inhibitor that specifically inhibits viral RNA-dependent RNA polymerase (RdRp), thereby suppressing viral replication and transcription. Consequently, it exhibits a unique dual inhibitory mechanism against SARS-CoV-2. To date, its in vitro and in vivo antiviral activities have been demonstrated against several single-stranded RNA viruses, including human flaviviruses and coronaviruses. Last October, Roche acquired the development and commercialization rights for this drug outside the United States with a $350 million upfront payment.

The Phase II clinical trial of AT-5272 was primarily designed to treat hospitalized patients with moderate COVID-19 and non-hospitalized patients with mild-to-moderate COVID-19, with the primary clinical endpoint being viral RNA levels. The newly released data indicate that, at doses of 550 mg and 1,100 mg, the change in viral load from baseline in patients with mild-to-moderate, low-risk disease did not demonstrate a significant reduction compared to the placebo group, failing to meet the primary endpoint of the study.

However, for high-risk patients with underlying health conditions (comorbidities), the viral load in the 550 mg and 1100 mg dose groups decreased by 0.5 log10 units relative to baseline on day 7.

Roche and Atea believe that the overly broad inclusion criteria for patient enrollment may have contributed to the clinical trial failure, resulting in no significant difference compared to the control group. Both parties currently plan to re-evaluate the clinical trial for non-hospitalized COVID-19 patients after revising the study protocol and target patient population, with trial data expected in the second half of 2022.

Currently, in the development of oral COVID-19 therapeutics, pharmaceutical companies such as Pfizer, Merck, Japan's Shionogi, and Kintor Pharma are all actively expanding their pipelines and have reached late-stage clinical development. Among them, Merck is progressing the fastest. Earlier this month, the company announced the submission of an Emergency Use Authorization (EUA) application to the FDA for molnupiravir (English name: Molnupiravir), and is simultaneously filing applications with regulatory authorities in other countries worldwide. The drug is expected to potentially become the world's first highly effective oral anti-COVID-19 medication. Furthermore, the recent clinical failure of the oral COVID-19 candidate developed by Roche and Atea presents another major opportunity for Merck's molnupiravir to capture the market ahead of its competitors.

Molnupiravir is a small-molecule, broad-spectrum oral antiviral drug targeting RNA viruses that inhibits the replication of SARS-CoV-2. Interim analysis results from the Phase III MOVe-OUT study demonstrated a 50% reduction in the risk of hospitalization or death among non-hospitalized, high-risk patients with mild COVID-19. Based on recommendations from the independent data monitoring committee and communications with the FDA, Merck terminated this Phase III study early and submitted an Emergency Use Authorization (EUA) application to the FDA.

In fact, based on confidence in the study results, Merck has already proceeded with at-risk manufacturing of molnupiravir. It is expected to produce enough of the drug for 10 million treatment courses within 2021, and will further increase the supply in 2022. This June, Merck signed an agreement with the U.S. government to supply 1.7 million treatment courses of molnupiravir, valued at $1.2 billion (approximately 7.7 billion RMB), contingent upon receiving either an Emergency Use Authorization (EUA) or full approval from the FDA.

Regarding Pfizer, Phase III data for the 3CL protease inhibitor PF-07321332 plus ritonavir therapy will be unblinded before the end of the year. PF-07321332 plays a pivotal role in the life cycle of multiple coronaviruses, with the potential advantage of demonstrating efficacy against all currently circulating SARS-CoV-2 variants.

Regarding Japan's Shionogi, S-217622, also a 3CL protease inhibitor, is currently in a Phase 2/3 clinical trial for patients with mild or asymptomatic COVID-19 infection.

Regarding Kintor Pharmaceutical, the androgen receptor antagonist proxalutamide will unblind its Phase III data in mid-November.