Moderna said today it is on track to advance its COVID-19 vaccine candidate mRNA-1273 into Phase II and Phase III trials—the latter set to start in July—after reporting positive interim Phase I data 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.
The NIH’s National Institute of Allergy and Infectious Diseases (NIAID) is leading the Phase II trial (NCT04283461) of mRNA-1273, a novel lipid nanoparticle (LNP)-encapsulated mRNA vaccine encoding for a prefusion stabilized form of the Spike (S) protein.
The NIAID-led study is assessing three doses of the vaccine in healthy participants ages 18-55: 25 µg and 100 µg, based on two doses as of day 43; and 250 µg, based on one dose as of day 29.
All participants across all three dose levels seroconverted by day 15 after a single dose, Moderna said. At day 43, two weeks following the second dose, levels of binding antibodies for the 15 participants dosed at the 25 µg level were at levels seen in blood samples from people who have recovered from COVID-19. At day 43, 10 participants at the 100 µg level showed levels of binding antibodies that significantly exceeded the levels seen in convalescent sera.
Samples are not yet available for the remaining participants, Moderna said.
Consistent with the binding antibody data, mRNA-1273 vaccination elicited neutralizing antibodies in the first four participants in each of the 25 µg and 100 µg dose level cohorts—the only participants for which neutralizing antibody data was available—as measured by plaque reduction neutralization assays against live SARS-CoV-2.
Levels of neutralizing antibodies at day 43 were at or above levels generally seen in convalescent sera, the company said.
The first participant in the Phase I study was dosed on March 16, 63 days from sequence selection to Phase 1 study dosing.
Amending clinical dose cohorts
The NIAID-led Phase I study is being amended to include a 50 µg dose level cohort across each of the three age groups studied. Based on the interim Phase I data, Moderna said, its planned Phase II trial will be amended to study two dose levels, 50 µg and 100 µg, with the aim of selecting a dose for pivotal Phase III studies that are expected to begin in July, subject to finalization of a clinical trial protocol.
Moderna received FDA clearance to begin a Phase II trial of mRNA-1273 on May 6. Moderna said it intends to enroll 600 healthy participants across two cohorts of adults ages 18-55 years (n=300) and older adults ages 55 years and above (n=300) for the Phase II study, designed to assess the safety, reactogenicity, and immunogenicity of two vaccinations of mRNA-1273 given 28 days apart. Each subject will be assigned to receive placebo, a 50 μg or a 250 μg dose at both vaccinations.
The dose for the Phase III study is expected to be between 25 µg and 100 µg, Moderna said.
mRNA-1273 is among 18 candidates designated as “Front Runners” among 160+ COVID-19 therapeutics under study in GEN’s updated A-List published April 13, “Vanquishing the Virus: 160+ COVID-19 Drug and Vaccine Candidates in Development.” An updated edition of the list is set for publication this week.
Moderna also announced positive preclinical results from a viral challenge study in mice conducted with NIAID and its academic partners. That study showed that vaccination with mRNA-1273 prevented viral replication in the lungs of animals challenged with SARS-CoV-2—and that neutralizing titers in Phase I participants at the 25 µg and 100 µg dose levels were consistent with neutralizing titers that were protective in the mouse challenge model.
“With today’s positive interim Phase I data and the positive data in the mouse challenge model, the Moderna team continues to focus on moving as fast as safely possible to start our pivotal Phase III study in July and, if successful, file a BLA,” said Stéphane Bancel, Chief Executive Officer at Moderna. “We are investing to scale up manufacturing so we can maximize the number of doses we can produce to help protect as many people as we can from SARS-CoV-2.”
Ramping up manufacturing
Moderna accelerated its manufacturing capacity for mRNA-1273 and additional future products through a 10-year agreement with Lonza announced by the companies on May 1.
The companies agreed to establish manufacturing suites at Lonza’s facilities in the U.S. and Switzerland for the production of mRNA-1273. Technology transfer is expected to begin in June, with the first batches of mRNA-1273 set to be manufactured at Lonza’s U.S. site in July.
Moderna and Lonza said they intend to establish additional production suites across Lonza’s worldwide facilities, ultimately allowing for the manufacture of material equivalent to up to 1 billion doses of mRNA-1273 per year for use worldwide, based on an expected dose at the time of 50 µg.
An unspecified portion of funding for establishing manufacturing operations at Lonza U.S. is covered by Moderna’s contract with the Biomedical Advanced Research and Development Authority (BARDA), announced April 16. BARDA committed up to $483 million toward supporting development and manufacturing of mRNA-1273 through FDA licensure.
mRNA-1273 received the FDA’s Fast Track designation on May 12.
The company acknowledged that a single participant at 100 µg experienced grade 3 erythema (redness) around the injection site, while at the 250 µg dose level, three participants showed grade 3 systemic symptoms, but only following the second dose. All adverse events have been transient and self-resolving. No grade 4 or serious adverse events were reported.