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Product development

Moderna says Warp Speed improved quality, but not speed of its COVID-19 vaccine development

Company expects to unblind trial within weeks of EUA, predicts NIH and FDA will certify correlates of protection in 2H21

Moderna plans to unblind its Phase III COVE trial within weeks of gaining emergency use authorization of mRNA-1273 and predicts NIH and FDA will certify correlates of protection in 2H21.

Nov 30, 2020 | 12:02 PM GMT

It took 322 days from the day Moderna produced the first dose of mRNA-1273 for the company to announce Monday that in a Phase III trial its vaccine had prevented 94.1% of symptomatic and 100% of severe cases of COVID-19. Moderna is now applying to FDA for emergency use authorization of the mRNA-based vaccine and the agency announced it will convene an advisory committee meeting to discuss the application on Dec. 17.

In addition to the EUA application, Moderna has rolling submissions under way for conditional approvals from EMA and other regulatory agencies.

That timeline was not accelerated by Operation Warp Speed, but the quality of the development program was greatly enhanced by the U.S. government’s collaboration and investment, Tal Zaks, CMO of Moderna Inc. (NASDAQ:MRNA), told BioCentury.

Warp Speed’s contributions were especially important for designing and implementing the 30,000-person COVE trial that was enriched for individuals with risk factors for severe COVID-19 and succeeded in enrolling a mix of participants that closely matches the racial, gender and ethnic composition of the U.S., Zaks said.

The trial results, especially the 30 cases of severe COVID-19 and the death of one participant among those who received placebo, underline the urgency of the vaccine development program. In a conversation with BioCentury, Zaks said Moderna feels an ethical obligation to unblind the COVE trial soon after an EUA is issued so participants who received a placebo can be given the opportunity to be vaccinated.

Zaks also said he is hopeful that NIH and FDA will certify correlates of protection in 2H21 that would facilitate assessment of future COVID-19 vaccine candidates.

Clinical results from mRNA and viral vector vaccines “underpin the underlying correlation between neutralizing antibody levels and clinical effectiveness,” he said.  Data from trials of Moderna’s vaccine candidate and from the vaccine candidate developed by Pfizer Inc. (NYSE:PFE) and BioNTech SE (NASDAQ:BNTX) validate the mRNA platform, Zaks said.

For COVID-19, he suggested that mRNA is likely to produce stronger efficacy than adenoviral vector vaccines. “If you look at the data in totality for the adenovectors, it is clear from the Phase I trials that the level and consistency of neutralizing antibody responses they see are not as consistent and robust as mRNA.” 

High-risk, diverse 

A total of 196 cases of COVID-19 occurred in the COVE trial, which Moderna conducted together with NIH and BARDA. All but 11 cases occurred in the placebo arm, and 100% of the 30 severe cases were observed in the placebo groups.

The efficacy of Moderna’s vaccine did not fall from its earlier interim readout at 95 cases, and with Monday’s result the efficacy is now based on more cases than that of other leading COVID-19 vaccines.

Moderna and its government collaborators set out to not only demonstrate safety and efficacy quickly, but also to enroll individuals who were at high risk of developing severe COVID-19, and to make the trial demographics match the demographics of the U.S.

When NIH and Moderna looked at the enrollment data in August, “we saw in the metrics that we were doing better week over week in terms of minority enrollment,” Zaks said. “It was clear we could complete the trial sooner, but we would have had fewer minorities, so we and NIH took the approach of making sure we kept the door open a little longer.”

He added, “a significant effort went into making sure the trial was available to minorities who don’t typically put their trust in these kinds of activities.”

The delay paid off, according to Zaks.

Trial participants included more than 11,000 volunteers from communities of color, representing 37% of the study population, Zaks said, noting that is similar to the diversity of the U.S. at large. The participants including more than 6,000 volunteers who identify as Hispanic or LatinX, and more than 3,000 participants who identify as Black or African American, he said.

Moderna said that the 196 COVID-19 cases included 33 adults aged at least 65 and 42 participants identifying as being from diverse communities, including 29 Hispanic or LatinX, six Black or African Americans, four Asian Americans and three multiracial participants.

The roughly 30,000 individuals in COVE included more than 7,000 people over the age of 65, as well as more than 5,000 under 65 who had chronic diseases that put them at high risk for severe COVID-19. These high-risk groups accounted for 42% of the trial enrollment.

As a result of the time taken to ensure diverse enrollment and enrichment for high-risk individuals, Moderna “can confidently say there was a consistent effect on all the risk groups,” as well as on all racial and ethnic groups, Zaks said.

He added Moderna “hit the secondary endpoint of severe disease with unimpeachable effectiveness.”

Shares of Moderna rose $25.71 (20%) to $152.74, adding $10.1 billion in market cap.

20M in 2020

In addition to the EUA submission to FDA, Moderna has started rolling submissions for an EMA conditional marketing authorization and for product licensing by Health Canada, SwissMedic, the U.K. Medicines and Healthcare products Regulatory Agency (MHRA), Israel’s Ministry of Health, and Health Sciences Authority in Singapore. The company intends to seek prequalification and/or emergency use listing with the WHO.

Moderna expects to have about 20 million doses of its mRNA-1273 available for distribution in the U.S. by year-end. The vaccine is administered in two doses 28 days apart, which translates to protection for 10 million individuals.

The company said it is on schedule to produce 500 million to 1 billion doses globally next year.

It is manufacturing mRNA-1273 in the U.S. Its partner Lonza Group Ltd. (SIX:LONN) will manufacture the product at sites in the U.S. and Switzerland.

Operation Warp Speed has procured 100 million doses of mRNA-1273 and has an option to acquire more.

The European Commission has contracted for an initial purchase of 80 million doses on behalf of all EU member states and has an option to request up to a further 80 million doses. The U.K. has a deal in place for 5 million doses.

Moderna is in talks with COVAX to ensure access to other countries and regions, Zaks told BioCentury.

Unblinding

Zaks made it clear that it is a question of when, not if, Moderna will unblind the COVE trial. “We have to do this in a way that is responsible, that respects the data FDA needs to see.”

Zaks said Moderna has a commitment to trial participants. “When we see we prevent severe disease with such high efficacy, it is untenable” to continue to withhold the vaccine from participants who received placebo.

“I think there is going to be an operational gap but not an intentional one” between FDA issuing an EUA for mRNA-1273 and unblinding the trial, Zaks said. “We are already designing the protocol amendment” to give placebo participants the option to be vaccinated. He predicted that it will take “a few weeks” after emergency use authorization is granted. “Once we reach alignment with FDA on what and how to do in this space you will see us move very quickly.”

The COVE trial will continue after it has been unblinded and will provide insights into the durability of protection and safety, Zaks said.

Whether Moderna and other sponsors unblind their Phase III trials, authorization and approval of the first cohort of COVID-19 vaccines could make it difficult or impossible to conduct placebo-controlled trials of a second wave of vaccines.

Operation Warp Speed and FDA are working on the development of correlates of protection that could make large-scale, placebo-controlled trials unnecessary, Zaks told BioCentury. All the sponsors who are receiving R&D support from Warp Speed-sponsored trials have committed to share blood samples from trial participants with NIH, he said.

“I am hopeful by the time the dust settles on the Phase III trials that are running now — ours, AstraZeneca’s, J&J’s, maybe Novavax’s — that there will be enough” data to establish correlates of protection, Zaks said.

He expressed confidence that FDA and the National Institute of Allergy and Infectious Diseases (NIAID) will be able to certify a correlate of protection by 2Q21. “That would be a huge achievement.”

Better, not faster

Moderna’s COVID-19 vaccine development was much better as a result of the company’s collaboration with Operation Warp Speed, but it was not faster, Zaks said.

“I think if we had to do it alone it wouldn’t have taken a day longer,” he told BioCentury. He noted that Pfizer and BioNTech developed a similar mRNA vaccine without participating in the Operation Warp Speed on a timeline that was similar to Moderna’s.

“The ability of the government to backstop the investment was a reassurance to our shareholders and that was important,” Zaks said.

While Warp Speed’s financial support was important, he said the most important contribution was scientific collaboration. 

In terms of timelines, the U.S. government’s most important contribution was quickly creating a standardized assay for neutralizing assays, according to Zaks.

“When we put this vaccine into production on January 13, if by some magic I had been able to dose someone on January 14 and collect their blood on February 1, nobody in the world could have told me if my vaccine worked,” Zaks said. While Moderna and other vaccine developers worked with academic labs to create assays, the work of NIAID to support development of Phase I assays was critical, he added.

Zaks said NIAID’s contributions, including with trial design and conduct, made it possible to collect better data, and to have more credibility with the public than Moderna could have achieved on its own. “The NIAID collaboration in the Phase III trial improved the quality of the trial and the quality of the results. The quality of the partnership with them allowed us to get results that were beautiful.”

Zaks added that the credibility conferred by close association with NIH is important for overcoming skepticism about COVID-19 vaccines. This is especially valuable “in the current political environment when earning the public trust is so important,” he said.

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