'Learned a lot last year': After Covid-19 success, Moderna's Stéphane Bancel plans to give rest of pipeline a big push
A year ago, Stéphane Bancel would have described Moderna as cautious — walking step-by-step to investigate whether mRNA vaccines could prevent a host of viruses. Then the pandemic hit, and the Cambridge, MA-based biotech got a multibillion-dollar windfall to produce the world’s second-ever authorized mRNA vaccine in a matter of months.
What’s next? Bancel is planning a big acceleration and expansion of the rest of the pipeline, including the company’s Phase III-ready candidate for cytomegalovirus (CMV), which was the lead program before Covid-19 came around.
“We have a financial means that we never had before,” Bancel said. The company’s stock $MRNA, which sold for under $20 for most of 2019, is now flying at close to $150 apiece.
“The appetite to invest in innovative vaccines is, I would say, almost limitless,” he added.
As part of its second annual Vaccines Day Wednesday, Moderna offered updates on its key programs, including vaccines for respiratory syncytial virus (RSV), CMV, HIV and the flu. It also read out 6-month data for its Covid-19 vaccine, and preclinical results that suggest its booster candidates produce a sufficient immune response against new variants.
“For 10 years, we believed mRNA vaccines could be high-efficacy, fast and with great manufacturing scale-up. Now we know that,” Bancel said.
First up is Moderna’s CMV vaccine, which is scheduled to enter Phase III later this year. The candidate combines six mRNAs in a single vial; the mRNAs encode for two antigens located on the surface of CMV. Why so many mRNAs? To provide a broad spectrum of neutralizing antibodies, thus maximizing the chance of efficacy, Bancel explained.
“Some biology is straightforward like Covid. The spike protein, as we’ve shown, is enough,” he said. “But for very complex viruses, what we need to do to help educate the immune system is to make a lot of different antibodies.”
Seven-month data from a Phase II study show the candidate, mRNA-1647, was generally well-tolerated, according to Moderna. In CMV-seronegative participants who received three doses, neutralizing antibody geometric mean titers (GMTs) against epithelial cell infection were at least 20-fold higher than the baseline GMT of the CMV-seropositive group, the biotech said. And in CMV-positive patients who received three doses, neutralizing antibody GMTs increased to at least 6.8-fold over baseline.
CMV is a common virus that infects more than half of adults by the time they’re 40, according to the CDC. Most people show no symptoms — but about 1 in 5 babies born with the infection suffer long-term health problems.
Once you’re infected with CMV, you have it for life, Bancel said. And it’s believed that while your immune system spends a lot of energy fighting CMV, it’s spending less energy on other things, like fighting cancer, he added.
“I already believe that CMV could have a very profound both midterm impact on birth defects, and potentially long-term impact on cancer incidence and overall health of people,” Bancel said.
Moderna also read out interim Phase I data for its RSV vaccine, mRNA-1345. There’s currently no vaccine approved for RSV, the leading cause of respiratory illness in young children, although several drugmakers, including GlaxoSmithKline, are racing to develop one. The Phase I study is assessing mRNA-1345 in younger adults (18 to 49 years old), older adults (65 to 79 years old) and children (between 1 and just under 5 years old).
The interim analysis came from the younger adult cohorts, which are fully enrolled. At one-month post-vaccination, a single shot of either 50 μg or 100 μg was well-tolerated, and the candidate boosted neutralizing antibody titers against both serotypes of RSV with “no apparent dose response,” Moderna said.
The geometric mean fold rise in neutralizing antibody relative to baseline was at least 20.5 for RSV-A and at least 11.7 for RSV-B, the company added. It plans on exploring potential combinations of the candidate with its other vaccines against other respiratory pathogens in children and older adults.
As for HIV, Moderna plans to launch three Phase I trials this year, including one in collaboration with the International AIDS Vaccine Initiative (IAVI) and the Bill and Melinda Gates Foundation. That candidate, mRNA-1644, will aim to use a “novel approach” to elicit HIV neutralizing antibodies, Moderna said, with the study aiming to identify and use multiple antigens for germline targeting and immuno-focusing. A second vaccine hopeful, mRNA-1574, a collaboration with the NIH, will use a similar approach with multiple native-like trimeric antigens.
Bancel said mRNA has the potential to overcome the unique challenges of developing a vaccine for HIV — including its ability to rapidly mutate — by combining high efficacy with speed and flexibility of manufacturing.
“If you think about old technology like protein technology, it takes so long to make a product. It is so expensive to develop a single drug that it limits what you can do,” he said. But mRNA is like a piece of software — it’s always the same manufacturing process.
“We can move in 30 days from a sequence to a product ready to go into clinical trial, we can move very quickly for variants of virus evolution, and that increases again the efficacy of a product and allows you to adapt to biology,” Bancel said.
Bancel also has a high-efficacy flu vaccine in the works, which is expected to enter Phase I this year. Eventually, he hopes to explore combination candidates that protect against the flu, SARS-CoV-2, RSV and human metapneumovirus (hMPV).
“This is really the big issue. If you could have a product that had high-efficacy in Covid, high-efficacy in flu and high-efficacy in RSV, you will have a massive impact on public health, and hospitalization and mortality of elderly,” he said.
Yesterday, Moderna announced that its Covid jab — the company’s crown jewel — proved more than 90% effective against all cases after an updated review of 900-plus cases from the Phase III COVE study. It was 95% effective against severe cases, and a study with 33 Phase I participants showed that antibodies persisted 6 months after the second dose.
The company is now pushing forward with booster candidates to address concerning variants, which were shown to elicit neutralizing titers in mice that were similar to those produced against the original virus.
“There’s a lot of things that I think we are doing differently as we look forward, which is why I think we can really compress the timelines of vaccine development,” Bancel said. “I think the agency and the industry learned a lot last year.”