Type: Novel lipid nanoparticle (LNP)-encapsulated mRNA vaccine encoding for a prefusion stabilized form of the Spike (S) protein.
Status: Moderna said via Twitter on July 8 that it completed enrollment of its Phase II trial of mRNA-1273 (NCT04405076). The study is designed to evaluate the safety, reactogenicity and immunogenicity of two vaccinations of mRNA-1273, given 28 days apart. Moderna enrolled 600 healthy participants across two cohorts: 300 adults ages 18-55 years, and 300 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 trial does not include a 250 μg dosage, Moderna has said, since the dosages under study showed neutralizing antibody titers at or above convalescent sera and were generally well tolerated in the company’s Phase I trial.
Six days earlier, Moderna said via Twitter on July 2 that its planned 30,000-patient Phase III trial of mRNA-1273 is still expected to begin in July, “and we expect to be the first to start a Phase III trial,” despite changes to the trial’s protocol following talks with the NIH that pushed back the start from an expected July 9 launch.
A day earlier, The Wall Street Journal reported CEO Stéphane Bancel’s projection that mRNA-1273 could be available for limited use as soon as this fall in a profile of the company that recounted its meteoric rise and included a description of him as being “very rigorous, and he’s very demanding at the same time.”
World Health Organization (WHO) Chief Scientist Soumya Swaminathan, MD, MBBS, told reporters June 26 she considered mRNA-1273 “not far behind” what she called “probably the leading candidate” among COVID-19 vaccine candidates in development worldwide, AZD1222 by AstraZeneca, University of Oxford and Vaccitech. WHO counts more than 200 such candidates worldwide, of which 15 are in clinical trials.
A day earlier, Moderna said it would partner for large-scale, commercial fill-finish manufacturing of mRNA-1273 with Catalent at its biologics facility in Bloomington, IN. Undert the agreement, whose value was not disclosed, Catalent agreed to provide packaging capacity and vial filling work under barrier isolator technology, as well as additional staffing required for 24×7 manufacturing operations at the site to support production of an initial 100 million doses of the vaccine candidate, which are intended to supply the U.S. market starting in the third quarter.
The companies are in talks to secure fill-finish capacity for continued production of hundreds of millions of additional doses, Moderna said, while Catalent also agreed to provide clinical supply services from its facilities in Philadelphia—including packaging and labeling, as well as storage and distribution to support Moderna’s Phase III clinical study for mRNA-1273.
Moderna on June 12 said it finalized the study protocol for its planned Phase III trial of mRNA-1273, based on feedback from the FDA. The randomized, 1:1 placebo-controlled trial is expected to be conducted in collaboration with the National Institute of Allergy and Infectious Diseases (NIAID), and is set to include approximately 30,000 participants enrolled in the U.S.
“We know our platform. It works on MERS, Zika and CMV and so on. When you have the right sequence … you will get neutralizing antibodies,” Moderna CEO Stephane Bancel told CNBC, predicting mRNA-1273 had an 80% to 90% chance of success.
Earlier in June, the Biomedical Advanced Research and Development Authority (BARDA) said it was expanding its collaboration with Moderna in order to increase the domestic manufacturing capacity of mRNA-1273 by accelerating manufacturing scale-up. “While large investments in manufacturing and vaccine supplies before FDA approval presents a financial risk, continuing to make these investments is critical to shave months to years off the vaccine development timeline and meet the Administration’s directive to make vaccine available more rapidly,” BARDA stated.
mRNA-1273 will be the first COVID-19 product to be shifted for advanced development from NIH to BARDA, which said expansion activities are expected to begin with delivering material for manufacturing “mid-year,” with the vaccine available as early as the end of 2020. The expansion is expected to increase BARDA’s commitment made in April of up to $483 million to Moderna toward supporting development and manufacturing of mRNA-1273 through FDA licensure.
On June 3, The New York Times reported that Moderna was among developers of five COVID-19 vaccines identified by President Donald Trump’s administration as most likely to produce a vaccine for the virus, citing unnamed “government officials.” According to the report, the five will receive additional government funding, assistance with clinical trials, and financial and logistical support for manufacturing. A formal announcement is expected in coming weeks.
Moderna said in May it was partnering with NIAID on its planned Phase III trial, which is expected to study a dosage between 25 µg and 100 µg—and recruit approximately 30,000 patients, NIAID Director Anthony S. Fauci, MD, told JAMA Editor-in-Chief Howard Bauchner, MD, in June. The trial is expected to start in July subject to finalization of the clinical trial protocol. The company has said it aims to gain BLA approval for the vaccine “as soon as 2021.”
Earlier in May, Moderna reported 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 data disclosed by Moderna touched off a 911.95 (3.85%) surge of the Dow Jones Industrial Average. But the following day, after several doctors told STAT the data was not sufficient to assess the efficacy of mRNA-1273, the report triggered a 390.51 (1.59%) decline. Moderna said additional data would emerge in future peer-reviewed studies and presentations.
The NIH’s National Institute of Allergy and Infectious Diseases (NIAID) is leading the Phase I trial (NCT04283461), an open-label, dose-ranging study in males and non-pregnant females, 18 to 55 years old. The 45-patient study is assessing the safety and reactogenicity of a 2-dose vaccination schedule of mRNA-1273, given 28 days apart, across 3 dosages in healthy adults.
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.
Joshua Schimmer, a senior managing director on Evercore ISI’s biotech team, said in an investor note that mRNA-1273 may be “good enough” to be first among COVID-19 candidates to win FDA approval, but is unlikely to be better than other candidates that appeared likely to offer higher immunogenicity, fewer doses and less reactogenicity, according to Seeking Alpha.
The same day as the interim Phase I data release, Moderna announced plans to raise about $1.34 billion in gross proceeds through an underwritten public offering. Morgan Stanley is acting as sole book-running manager for the offering, from which the company said it intended to use proceeds toward working capital needs (raw materials, labor and capital equipment purchases) related to manufacturing mRNA-1273 for distribution in and outside the U.S. upon receiving approvals.
Moderna said any remaining proceeds will fund clinical development and drug discovery in existing and new therapeutic areas; further development of its mRNA technology platform; the creation of new modalities; or working capital and other general corporate purposes.
The public offering consisted of 17.6 million shares of common stock at a public offering price of $76.00 per share, before underwriting discounts and commissions. Moderna also granted the underwriters a 30-day option to purchase up to an additional 2.64 million shares of common stock at the public offering price, less underwriting discounts and commissions.
Earlier in May, Moderna received the FDA’s Fast Track designation for mRNA-1273, six days after the company received FDA clearance to begin a Phase II trial of mRNA-1273.
The Phase II trial, “expected to begin shortly” according to Moderna, will be 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. 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). Participants will be followed through 12 months after the second vaccination.
The company has set a goal of gaining BLA approval for the vaccine “as soon as 2021.”
That goal may be overly ambitious, an analyst warned: “With plans to start Phase III trials in early summer, Moderna’s ambitious timeline leaves some skepticism, as no data has been published to date,” cautioned Philipp Rosenbaum, PhD, Infectious Diseases Analyst at GlobalData. “mRNA-based vaccines have yet to be proven to work in humans, and the history of vaccine development shows that setbacks and roadblocks are almost certain.”
However, Anthony S. Fauci, MD, Director of the NIH’s National Institute for Allergy and Infectious Diseases, told National Geographic in an interview published May 4 that mRNA-1273 and University of Oxford-led vaccine candidate ChAdOx1 nCoV-19 have generated “rather substantial immune responses, particularly the mRNA vaccine. When we look at the immune response that you can induce with a modest dose—one that’s feasible to be translated into humans—and the amount of time it takes to get to that level of immunity, it is really quite impressive.”
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 the currently expected dose 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.
“Our ability to design our antigens in silico allows us to rapidly produce and test antigens and move vaccine development candidates quickly into the clinic,” Tal Zaks, MD, PhD, Moderna’s chief medical officer, told GEN in April. “Multiple mRNAs encoding for multiple viral proteins can be combined in a single vaccine, permitting production of complex multimeric antigens that are more difficult to achieve with traditional technologies.”
Also in April, Moderna also launched a partnership with Ginkgo Bioworks, which agreed to provide resources for potential optimizations to Moderna’s processes for generating some of the key raw materials used in the manufacturing of mRNA-1273 and other Moderna mRNA vaccines. Ginkgo agreed to contribute its microbial discovery, production, and fermentation infrastructure to companies and academic researchers working on coronavirus response. The company said it intended to provide $25 million in free work at its Boston-area location.
In March, Moderna said it was accelerating work on mRNA-1273 and was engaged in discussions for outside funding of such activities. CEO Stéphane Bancel detailed that acceleration during a Synbiobeta “town hall” presentation. He said a reason the SARS-CoV-2 vaccine development had been so fast was the work Moderna had done over the past two years in an existing collaboration with the NIH’s National Institute of Allergy and Infectious Diseases (NIAID) Dale and Betty Bumpers Vaccine Research Center (VRC) to develop a vaccine against MERS-CoV.
Moderna’s platform is based on injecting mRNA into cells to produce protein in human cells—an idea Bancel first viewed as crazy before realizing that making a human protein in a human cell is probably not going to be worse than making it in bacteria: “We don’t guess the biology—we use the biology of nature.”
Moderna was among developers of COVID-19 drug and vaccine candidates highlighted March 22 on CBS’ “60 Minutes.”
Also in March, Moderna disclosed in a regulatory filing that Bancel told Goldman Sachs representatives that while a commercially-available vaccine probably won’t be available for 12-18 months, a vaccine might be available in the fall of 2020 under emergency use authorization. He also said the Company was scaling up manufacturing capacity toward producing millions of doses per month, in the potential form of individual or multi-dose vials.
The first batch of mRNA-1273 was shipped in February to the VRC, which partnered with Moderna in designing the vaccine.
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: