Candidate: mRNA-1273

Category: RNAVAX

Type: Novel lipid nanoparticle (LNP)-encapsulated mRNA vaccine encoding for a prefusion stabilized form of the Spike (S) protein.

Status: Moderna disclosed in a September 18 regulatory filing that it anticipates producing approximately 20 million doses of mRNA-1273 by the end of 2020, and restated earlier estimates that it expects to manufacture “in the range of between 500 million and 1 billion doses” in 2021.

A day earlier at its R&D Day, Moderna said that as of September 16, 25,296 participants have been enrolled in the Phase III COVE trial (NCT04470427), being conducted by the company and the NIH’s National Institute of Allergy and Infectious Diseases (NIAID). COVE is designed to evaluate the safety of mRNA-1273 in 30,000 adult volunteers who do not have COVID-19.

Of patients enrolled in COVE, 10,025 have received their second vaccination. Approximately 28% of participants enrolled cumulatively are from diverse communities, the company said. The protocol for the COVE trial has been posted online.

Also that day, Moderna said it established its first regional hub and commercial organization outside of North America in Switzerland. The company’s activities in Sewitzerland will be overseen by Dan Staner, who was appointed Vice President and General Manager, Switzerland, effective that day. Staner will build a team to cover functions for the Swiss market that include medical, regulatory, pricing, reimbursement, market access, government affairs, and commercial operations, Moderna said. Staner will also work closely with Nicolas Chornet, who the company recently named SVP International Manufacturing, Europe, based in Basel.

Switzerland has been a focus of Moderna activity in recent months. The country’s federal government has agreed to procure 4.5 million vaccine doses of mRNA-1273, while Moderna partners with Basel-based Lonza on larger scale global manufacturing of mRNA-1273 and said it will do so with future Moderna products.

On August 24, Moderna confirmed that it was in advanced talks with the European Commission to supply 80 million doses of mRNA-1273. The potential purchase agreement provides for an option for EU Member States to purchase an additional 80 million doses for a total of up to 160 million doses.

The company said it is scaling up global manufacturing to be able to deliver approximately 500 million doses per year—and possibly up to 1 billion doses per year beginning in 2021. In Europe, Moderna’s strategic manufacturing partners include Lonza and ROVI, which will oversee manufacturing and fill-finish outside of the U.S.

Of those enrolled in COVE as of August 21, approximately 18% were Black or African American, Latinx, American Indian, or Alaskan Native, four groups that account for a combined 33% of the U.S. population, according to U.S. Census data: “Working together with collaborators, the company hopes to achieve a shared coal that the participants in the COVE study are representative of the communities at highest risk for COVID-19 and of our diverse society,” the company also tweeted August 21.

A day earlier, NIAID Director Anthony S. Fauci, MD, said on CNN that he wanted COVE and other Phase III trials for COVID-19 vaccine candidates to enroll minorities at levels that are at least double their percentages in the population.

The COVE trial’s primary endpoint is 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. Enrollment is expected to be completed in September, Moderna has said.

Moderna on August 11 joined the U.S. government in announcing that the company was awarded an additional up to $1.525 billion toward manufacturing and delivering 100 million doses of mRNA-1273. The new funding, combined with up to $955 million previously committed to Moderna, more than doubles Washington’s investment in the company to potentially up to $2.48 billion. The new funding includes an unspecified amount of incentive payments “for timely delivery of the product,” Moderna added. The company did say, however, that the U.S. government holds an option to purchase from it up to an additional 400 million doses of mRNA-1273.

Also on August 11, Moderna disclosed in its Form 10-Q quarterly regulatory filing that it “cannot be certain that we were the first to make the inventions claimed in our patents or pending patent applications, or that we were the first to file for patent protection of such inventions, including mRNA-1273,” since “third parties may have filed patent applications for technology covered by our pending patent applications without our being aware of those applications, and our patent applications may not have priority over those applications,” In addition, “publications of discoveries in the scientific literature often lag behind the actual discoveries, and patent applications in the United States and other jurisdictions are typically not published until 18 months after filing, or in some cases not at all.”

The disclosure—which had not been included in earlier filings—followed a report by Axios and Public Citizen that the NIH may hold joint ownership claims to the vaccine, had filed a patent application to that effect, and had maintained that “mRNA coronavirus vaccine candidates [are] developed and jointly owned” by NIH and Moderna.

On August 5, Moderna CEO Stéphane Bancel told analysts on the quarterly conference call that the company will charge some “small-order” customers seeking “in the millions” of doses between $32 and $37 per dose for mRNA-1273, adding that Moderna is in talks with some governments worldwide for larger-volume agreements at lower per-dose prices: “We are working with governments around the world and others to ensure a vaccine is accessible regardless of ability to pay.” Pfizer and BioNTech, by comparison, agreed to a $19.50 per-dose price with the U.S. government.

Moderna disclosed in its second-quarter results that it received approximately $400 million of customer deposits as of July 31, 2020 for potential supply of mRNA-1273.

Also on August 5, researchers from Moderna, the NIH’s National Institute for Allergy and Infectious Diseases (NIAID), and collaboration partners published a preclinical study in Nature showing that mRNA-1273 protected mice from infection with SARS-CoV-2. mRNA-1273 induced neutralizing antibodies in mice when given as two intramuscular injections of a 1-microgram (mcg) dose three weeks apart. Mice given two injections of the 1-mcg dose and later challenged with SARS-CoV-2 virus either 5 or 13 weeks after the second injection were protected from viral replication in the lungs and nose.

mRNA-1273 also induced robust CD8 T-cell responses in mice—but did not induce the type of cellular immune response linked to vaccine-associated enhanced respiratory disease (VAERD). In addition, mice challenged 7 weeks after only a single dose of 1 mcg or 10 mcg of mRNA-1273 were also protected against viral replication in the lung.

The investigators also vaccinated mice with sub-protective doses of mRNA-1273, then challenged the mice with SARS-CoV-2. The mice showed no evidence of enhanced lung pathology or excessive mucus production, indicating the vaccine did not cause enhanced disease, the researchers reported.

Wang Wenbin, a spokesman for China’s foreign ministry, on July 31 denied a Reuters report that hackers linked to the Chinese government attempted to steal data from Moderna earlier this year—a report Reuters attributed to “a U.S. security official tracking Chinese hacking” speaking on condition of anonymity.

The report and denial came a week after the U.S. Justice Department made public its indictment of two Chinese nationals on charges of spying on the U.S. that entailed three unnamed U.S.-based targets involved in medical research to fight the novel coronavirus. Moderna confirmed to Reuters that it was in contact with the FBI and informed of the suspected “information reconnaissance activities” by the hacking group.

“Moderna remains highly vigilant to potential cybersecurity threats, maintaining an internal team, external support services and good working relationships with outside authorities to continuously assess threats and protect our valuable information,” the company stated July 31.

Three days earlier, researchers for Moderna and the NIH’s National Institute of Allergy and Infectious Diseases (NIAID) published a study in The New England Journal of Medicine (NEJM)  reporting that two doses of mRNA-1273 induced robust immune responses and rapidly controlled the coronavirus in the upper and lower airways of rhesus macaques exposed to SARS-CoV-2.

Three groups of eight rhesus macaques received two injections of 10 or 100 micrograms (µg) of mRNA-1273 or a placebo. Injections were spaced 28 days apart. Vaccinated macaques produced high levels of neutralizing antibodies directed at the surface spike protein used by SARS-CoV-2 to attach to and enter cells. The researchers also noted that macaques receiving the 10-µg or 100-µg dose vaccine candidate produced neutralizing antibodies in the blood at levels well above those found in people who recovered from COVID-19.

On July 27, Moderna and the NIH’s National Institute of Allergy and Infectious Diseases said July 27 that they launched an approximately 30,000-patient Phase III trial  of 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 toward supporting development and manufacturing of mRNA-1273 through FDA licensure, 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.

Phase III trial participants will receive two intramuscular injections approximately 28 days apart, and will be randomly assigned 1:1 to receive either two 100 µg injections of mRNA-1273 or two shots of a saline placebo. Moderna disclosed plans for the Phase III trial in mid-July on ClinicalTrials.gov the same day that researchers from NIAID, Moderna, and their clinical research partners reported that mRNA-1273 induced rapid and strong immune responses against SARS-CoV-2, in an interim analysis of results from their Phase I study (NCT04283461).

“These safety and immunogenicity findings support advancement of the mRNA-1273 vaccine to later-stage clinical trials,” the researchers concluded in “An mRNA Vaccine against SARS-CoV-2 — Preliminary Report,” published in The New England Journal of Medicine (NEJM).

At the 100 µg dose, they 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. Also at 100 µg, the geometric mean titer levels were 4.1-fold above those seen in reference convalescent sera.

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.

Also in July, 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.

“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,” CEO Bancel told CNBC, predicting mRNA-1273 had an 80% to 90% chance of success.

Earlier in June, 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 was 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.” BARDA has partially supported the research and development of mRNA-1273 with federal funding under Contract no. 75A50120C00034.

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.

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.

NIAID led 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.

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 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:

● ANTIVIRAL
● VAX
● ANTIBODY
● RNA

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