EM Coronavirus, causing SARS

Genentech, a member of the Roche Group, said today its marketed arthritis drug Actemra®(tocilizumab) will be studied with Gilead Sciences’ antiviral candidate remdesivir as a combination treatment for hospitalized patients with severe COVID-19, through a Phase III clinical trial the companies have launched.

The global randomized, double-blind, placebo-controlled Phase III trial—to be called REMDACTA—will compare the safety and efficacy of Actemra plus remdesivir to placebo plus remdesivir in severe COVID-19 patients receiving standard of care. The trial’s primary and secondary endpoints will include clinical status, mortality, mechanical ventilation, and intensive care unit (ICU) variables. Patients will be followed for 60 days post-randomization.

REMDACTA is expected to start enrolling patients in June, with researchers estimating they will recruit approximately 450 patients worldwide, including in the U.S.

Actemra and remdesivir are two of 19 “Front Runner” candidates among the 200+ COVID-19 therapeutics under study in GEN’s updated and just-launched “COVID-19 Drug & Vaccine Candidate Tracker.”

“Based on our current understanding, we believe that combining an antiviral with an immune modulator could potentially be an effective approach to treating patients with severe disease,” Levi Garraway, MD, PhD, chief medical officer and head of Global Product Development for Roche and subsidiary Genentech. “We’re pleased to partner with Gilead to determine whether combining these medicines could potentially help more patients during this pandemic.”

REMDACTA is one of two global Phase III trials assessing Actemra.

Data from REMDACTA are expected to supplement those generated by the other Phase III trial, called COVACTA (NCT04320615). The COVACTA study is designed to evaluate the safety and efficacy of intravenous Actemra plus standard of care in hospitalized adults with severe COVID-19 pneumonia, compared to placebo plus standard of care.

COVACTA is expected to generate results this summer. A timeframe for announcement of results from REMDACTA has not been set.

Completing enrollment

Genentech said today it is close to completing patient enrollment in COVACTA after increasing the trial’s patient enrollment from the initial target of 330 to about 450 patients worldwide, including the U.S.

COVACTA’s primary endpoint is clinical status assessed using a 7-Category Ordinal Scale at day 28. The ordinal scale ranges from one (discharged from hospital) to seven (death), and covers different hospital locations such as non-intensive care unit (non-ICU) or ICU, and ventilation/treatment requirements, including not requiring supplemental oxygen, or requiring extracorporeal membrane oxygenation (ECMO) or mechanical ventilation and additional organ support.

Key secondary endpoints include mortality, mechanical ventilation, clinical status at day 14, time to clinical improvement, and time to discharge.

Patients will be followed for 60 days post-randomization, and an interim analysis will be conducted to look for early evidence of efficacy. The COVACTA trial protocol permits the inclusion of patients who are being treated with antivirals, including investigational antivirals.

Actemra is an interleukin-6 (IL-6) receptor antagonist approved by the FDA in 2010, with indications in rheumatoid arthritis, giant cell arteritis, polyarticular juvenile idiopathic arthritis, systemic juvenile idiopathic arthritis, and cytokine release syndrome.

During Q1, Actemra sales jumped 25% (30% at constant exchange rates) from a year earlier, to CHF 666 million ($687 million) from CHF 534 million ($551 million)—a possible result of the drug being studied for COVID-19 in several Chinese cohort studies, plus reports of effective treatment from Italy, Antoine Grey, senior healthcare analyst at GlobalData, said in April.

Also in April, a team of Chinese researchers published a study in PNAS, concluding from preliminary data that Actemra improved clinical outcomes immediately in 20 patients with severe or critical COVID-19, and thus “is an effective treatment to reduce mortality.” Five days after treatment, 15 of the 20 patients (75%) lowered their oxygen intake, and 1 patient needed no oxygen therapy.

U.S., U.K. authorizations

Remdesivir is a nucleotide prodrug that Gilead initially developed as a treatment for Ebola before repositioning the drug as a COVID-19 candidate. Remdesivir is approved by the FDA under emergency use authorization, while the UK has authorized remdesivir as a COVID-19 treatment in selected patients through the Medicines & Healthcare products Regulatory Agency (MHRA)’s Early Access to Medicines Scheme.

Both authorizations came after researchers conducting the 1,063-patient Adaptive COVID-19 Treatment Trial (ACTT; NCT04280705), sponsored by the NIH’s National Institute of Allergy and Infectious Disease (NIAID), published a study in The New England Journal of Medicine consisting of preliminary findings suggesting that suggest that a 10-day course of remdesivir was superior to placebo in treating hospitalized patients with COVID-19.

ACTT researchers cited data showing patients who were treated with remdesivir showed a 31% faster median time to recovery compared with those who received placebo (11 days compared with 15 days). However, William A. Haseltine, PhD, the HIV/AIDS research pioneer and Chairman of ACCESS Health International, has criticized the NIAID trial. “‘Time to discharge” is one of the weakest criteria by which to gauge the success of a drug therapy. Rigorous criteria include reductions in mortality or, at a minimum for antivirals, reduction of viral load before and during treatment. That is how you know an antiviral drug is working as it is supposed to work.

NIAID Director Anthony S. Fauci, MD, initially trumpeted the ACTT results: “Although a 31% improvement doesn’t seem like a knockout 100%, it is a very important proof of concept. What it has proven is that a drug can block this virus,” Fauci said during an April 29 appearance with President Donald Trump. “This will be the standard of care.”

However, testifying May 12 before the U.S. Senate Committee on Health, Education, Labor, & Pensions, Fauci offered a more nuanced view of the ACTT trial results: “The result was statistically significant, but really modest.”

“We hope to build on this modest success with combinations of drugs and better drugs,” Fauci added.

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