Moderna and the NIH’s National Institute of Allergy and Infectious Diseases (NIAID) have launched an approximately 30,000-patient Phase III trial of the company’s front-running COVID-19 messenger RNA (mRNA) vaccine candidate mRNA-1273—a study being funded among late-stage clinical activity for which the company has won an additional up-to-$472 million from the Biomedical Advanced Research and Development Authority (BARDA).
The additional funding nearly doubles the original up-to-$483 million commitment made by BARDA to Moderna in April, bringing the agency’s funding to a potential of approximately $955 million.
Moderna said the extra funding followed the company decision to expand the patient population of the Phase III study, following talks with the FDA and officials with Operation Warp Speed, the federal effort through which President Donald Trump’s administration has committed the nation to delivering 300 million vaccine doses protecting against SARS-CoV-2 by January 2021.
“We thank BARDA for this continued commitment to mRNA-1273, our vaccine candidate against COVID-19,” Moderna CEO Stéphane Bancel said in a company statement.
Appearing on CNBC’s Squawk Box yesterday, Bancel added that he expects the trial will be fully enrolled within four to six weeks, with results coming as soon as October in a “really optimistic” scenario. However, on CNBC’s Squawk on the Street, Jim Cramer cautioned that results may take longer to emerge: “I also don’t like the idea that you can put any time frame on it. October optimistic? Then don’t talk about October. Just say, ‘Listen, we hope to have something by the first quarter.’”
The Phase III COVE trial (NCT04470427) is designed to evaluate the safety of mRNA-1273 in 30,000 adult volunteers who do not have COVID-19. The primary endpoint will be the prevention of symptomatic COVID-19 disease. Key secondary endpoints include prevention of severe COVID-19 disease, as defined by the need for hospitalization), and prevention of infection by SARS-CoV-2.
Participants in the trial will receive two intramuscular injections approximately 28 days apart. Participants will be randomly assigned 1:1 to receive either two 100 µg injections of mRNA-1273 or two shots of a saline placebo.
First “Warp Speed” trial
The COVE trial is the first trial launched through Operation Warp Speed, which funds and coordinates development of vaccines, drugs, and diagnostics across agencies of the departments of Defense and Health and Human Services (HHS)—the latter agency including the FDA, the NIH, the Centers for Disease Control and Prevention (CDC), and BARDA.
“Operation Warp Speed is supporting a portfolio of vaccines like the NIH/Moderna candidate so that, if the results of clinical trials meet FDA’s gold standard, these products can reach Americans without a day’s delay,” HHS secretary Alex Azar II said in a statement. “Thanks to President Trump’s leadership and the hard work of American scientists, the investigational vaccine developed by NIH and Moderna has reached this Phase III trial at record pace.”
The NIH and other HHS agencies and government partners also collaborated with representatives from academia, philanthropic organizations, and biopharmaceutical companies to advise Moderna and NIAID on the trial protocol design and endpoints, the NIH said, to ensure a harmonized approach across multiple vaccine efficacy trials.
“Having a safe and effective vaccine distributed by the end of 2020 is a stretch goal, but it’s the right goal for the American people,” said NIH director Francis S. Collins, MD, PhD.
Investors responded to Moderna’s Phase III trial launch by sending shares up 10% in trading as of 3:05 pm, to $80.55 from Friday’s close of $73.21. Moderna shares have roller-coasted in recent days, having fallen 9.5% on Thursday after the company lost its challenge to a patent covering an earlier version of the delivery technology used in mRNA-1273.
The COVE trial comes just two weeks after researchers from Moderna, NIAID, and their clinical research partners announced plans for the Phase III trial after publishing additional, mostly positive data in The New England Journal of Medicine (NEJM) from their interim analysis of Phase I study (NCT04283461) results showing that mRNA-1273 induced rapid and strong immune responses against SARS-CoV-2.
The findings were based on data through Day 57 from a two-dose vaccination schedule of mRNA-1273 given 28 days apart across three dose levels (25, 100, 250 µg) in 45 healthy adults ages 18–55 years—15 adults in each dose cohort.
At the 100 µg dose, researchers reported, the geometric mean titers seen among patients were 2.1-fold higher than those seen in convalescent sera obtained from 38 individuals with confirmed COVID-19 diagnoses (and 4.1-fold above those seen in reference convalescent sera).
Severe adverse events reported
However, at the highest 250 µg dose level, three of 14 participants (21%) reported one or more severe adverse events. “That’s not good. That is a warning sign,” William A. Haseltine, Ph.D., the HIV research pioneer and chairman of ACCESS Health International, told Clinical OMICs’ sister publication GEN last week.
Moderna and partners reported that the adverse events were not trial-limiting. While a fourth severe event, a fever of 39.6°C (103.3°F), was reported in a patent in the 100 µg group, the systemic adverse events after the first vaccination were all graded mild or moderate. Lesser solicited systemic adverse events were more common after the second vaccination.
The NEJM study reaffirmed and elaborated upon initial findings from the Phase I, dose-escalation, open-label trial that Moderna announced on May 18 via press release, showing that all 45 participants across the study’s three dose levels produced antibodies of the virus by day 15 following treatment, with eight of the participants in two of the dose levels reaching or exceeding neutralizing antibody titers generally seen in convalescent sera.
“Encouraged by the Phase I data, we believe that our mRNA vaccine may aid in addressing the COVID-19 pandemic and preventing future outbreaks,” Bancel added.
Moderna is also studying mRNA-1273 in a NIAID-led Phase II trial (NCT04283461) designed to assess the safety, reactogenicity, and immunogenicity of two vaccinations given 28 days apart. The placebo-controlled, dose-confirmation study has enrolled a total 600 healthy participants across two cohorts: 300 adults ages 18–55 years, and 300 adults ages 55 years and up. Participants are assigned to placebo, a 50 μg, or a 100 μg dose at both vaccinations, and will be followed through 12 months after the second vaccination.
The Phase II study was “active, not recruiting” patients as of the most recent update July 10 on ClinicalTrials.gov.
“Results from early-stage clinical testing indicate the investigational mRNA-1273 vaccine is safe and immunogenic, supporting the initiation of a Phase III clinical trial,” added NIAID director Anthony S. Fauci, M.D.. “Although face coverings, physical distancing, and proper isolation and quarantine of infected individuals and contacts can help us mitigate SARS-CoV-2 spread, we urgently need a safe and effective preventive vaccine to ultimately control this pandemic.”