Candidate: Bucillamine (N-(mercapto-2-methylpropionyl)-l-cysteine)
Type: Cysteine derivative with 2 thiol groups that has been prescribed in the treatment of rheumatoid arthritis in Japan and South Korea for over 30 years. According to the company, Bucillamine has shown 16-fold more potency than N-acetyl-cysteine (NAC) as a thiol donor in vivo, enabling it to increase glutathione activity and other anti-inflammatory activity, which the company reasons may lessen the effects of SARS-CoV-2 infection in the lungs and attenuate the clinical course of COVID-19.
2021 Status: Revive said July 15 that it is continuing the Phase III RT-003 trial (NCT04504734) at the 600 mg high dose recommended by the study’s independent data and safety monitoring board (DSMB). The next DSMB meetings will occur at 600 and 800 completed patients; both are expected to be held in Q3-2021.
The company is preparing for the potential of filing an Emergency Use Authorization (EUA) with the FDA should blinded results from the trial provide evidence to the DSMB to recommend to pursue EUA for Bucillamine to treat mild to moderate COVID-19. Revive said it is on track to meet its planned enrollment goal for the Study in Q3-2021 and aim to file EUA with the FDA.
The trial has signed up 40 clinical sites in 14 state and Puerto Rico, with plans to increase that number to a minimum 50 sites in those states and COVID-19 hot spot states. To date, the trial has not seen any serious adverse events or safety concerns that require DSMB notification, Revive added.
Revive said May 3 that it entered into a sponsored research agreement with University of California, San Francisco (UCSF) to explore the utility of Bucillamine as a treatment for severe COVID-19. The agreement is intended to support research in the laboratory of John Fahy, MD, director of UCSF’s severe asthma clinic and the UCSF Airway Clinical Research Center, to test the efficacy of Bucillamine in preclinical models of COVID-19 and design protocols that test the utility of Bucillamine in human trials.
Fahy authored a prepreint study posted on bioRxiv December 8, 2020, concluding that Bucillamine and other thiol-based drugs decreased the binding of SARS-CoV-2 spike protein to its receptor, decreased the entry efficiency of SARS-CoV-2 spike pseudotyped virus, and inhibited SARS-CoV-2 live virus infection.
On March 24, Revive said it is on track to meet its goal of enrolling up to 1,000 participants by the end of the second quarter for its Phase III RT-003 trial, designed to evaluate Bucillamine in patients with mild to moderate COVID-19.
As of that date, Revive had partnered with 14 clinical sites in six states—including California, Florida, Illinois, Nevada, North Carolina, and Texas. The company said it was expanding to up to 50 clinical sites in those states as well as in Massachusetts, Michigan, New Jersey, New York, Pennsylvania, and South Carolina.
The double-blind, confirmatory clinical trial will randomize patients to Bucillamine or placebo for up to 14 days, with the aim of comparing the frequency of hospitalization or death in patients with mild-to-moderate COVID-19 receiving Bucillamine therapy with those receiving placebo.
The trial’s primary endpoint is the proportion of patients meeting a composite endpoint of hospitalization or death from the time of the first dose through Day 28 following randomization. Efficacy will be assessed by comparing clinical outcomes (death or hospitalization), disease severity using the 8-category NIAID COVID ordinal scale, supplemental oxygen use, and progression of COVID-19 between patients receiving standard-of-care plus Bucillamine (high dose and/or low dose) and patients receiving standard-of-care plus placebo.
2020 Status: Revive Therapeutics said December 23 that it was is on track to meet its enrollment goals for a Phase III trial of Bucillamine, enabling the Independent Data and Safety Monitoring Board (“DSMB”) to review the safety and efficacy data from the study’s first 210 patients as part of the first interim analysis of patients treated and followed up for 28 days after randomization. The company said its clinical safety team found there had been no safety concerns and no severe adverse events during the interim analysis enrollment period.
Nine clinical sites are participating in the Phase III trial, with six more sites set to join in January in order to satisfy the overall enrollment goal of up to 1,000 patients. Revive plans to file for an emergency use authorization of Bucillamine for mild to moderate COVID-19 with the FDA.
Revive said September 29 that it selected and finalized with five clinical sites in Florida, Texas and California for enrollment of patients in the Phase III clinical study, and was finalizing agreements with an additional 10 clinical sites in these states including Arizona and Ohio where patient enrollment should start in October within these other locations.
On July 31, Revive received FDA approval for a confirmatory Phase III trial to evaluate the safety and efficacy of Bucillamine in patients with mild-moderate COVID-19. The randomized, double-blind, placebo-controlled trial will enroll up to 1,000 patients (up from earlier plans for 800 patients) who will be randomized 1:1:1 to receive Bucillamine 100 mg three times a day (TID), Bucillamine 200 mg TID or placebo TID for up to 14 days.
The trial’s primary objective is to compare frequency of hospitalization or death in patients with mild-moderate COVID-19 receiving Bucillamine therapy with those receiving placebo. The primary endpoint is the proportion of patients meeting a composite endpoint of hospitalization or death from the time of first dose through Day 28 following randomization.
According to Revive, efficacy will be assessed by comparison of clinical outcome (death and hospitalization), disease severity using the eight-category National Institute of Allergy and Infectious Diseases (NIAID) COVID ordinal scale, supplemental oxygen use, and progression of COVID‑19 between patients receiving standard-of-care plus Bucillamine (high dose and/or low dose) and patients receiving standard-of-care plus placebo. Revive submitted its IND application to the FDA for the Phase III trial in June.
An Independent Data and Safety Monitoring Board will carry out an interim analysis after 210 patients have been treated and followed up for a total of 28 days after randomization. Additional interim analyses will be performed after 400, 600, and 800 patients reach the same post-treatment timepoint, Revive said.
Revive disclosed plans to study Bucillamine in COVID-19, as well as influenza and other infectious diseases, in March. The company has completed a U.S. Phase II study of Buicillamine in the treatment of acute gout flares. (NCT02330796).
COVID-19: 200 Candidates and Counting
To navigate through the >200 potential therapeutic and vaccine options for COVID-19, GEN has grouped the candidates into four broad categories based on their developmental and (where applicable) clinical progress:
● FRONT RUNNER – the most promising therapeutics/vaccines based on clinical progress, favorable data or both.
● DEFINITELY MAYBE – earlier phases with promising partners, or more advanced candidates in development that have generated uneven data.
● KEEPING AN EYE ON… – interesting technology, attracting notable partners, or both, but preliminary data.
● TOO SOON TO TELL – longshots pending additional experimental and/or clinical data.
GEN has also tagged the most common treatment types: