Arriving For An Ongoing Clinical Trial: EUA Vaccination Station

  • Arriving For An Ongoing Clinical Trial: EUA Vaccination Station

  • TheRealRestoreInc.

    Member
    July 22, 2021 at 3:21 pm

    Moderna: “Our company trade secrets and know-how are appropriately guarded to maintain our business advantage.”

    Many of the hopeful people arrive at a clinic, hospital, pharmacy or other COVID-19 vaccination stations looking for safety and protection. While not volunteering for a true clinical trial these people are participating in Emergency Use Authorization (EUA). You might receive a fact sheet and a consent form.

    https://www.cdc.gov/vaccines/covid-19/eua/index.html

    The decentralized clinical trials are hidden in plain sight.

    https://www.sec.gov/Archives/edgar/data/0001682852/000168285221000006/mrna-20201231.htm

    Excerpt:

    Table of Contents

    PART I

    Item 1. Business

    THE mRNA OPPORTUNITY

    mRNA, the software of life

    Messenger RNA, or mRNA, transfers the information stored in our genes to the cellular machinery that makes all the proteins required for life. Our genes are stored as sequences of DNA which contain the instructions to make specific proteins. DNA serves as a hard drive, safely storing these instructions in the nucleus until they are needed by the cell.

    When a cell needs to produce a protein, the instructions to make that protein are copied from the DNA to mRNA, which serves as the template for protein production. Each mRNA molecule contains the instructions to produce a specific protein with a distinct function in the body. mRNA transmits those instructions to cellular machinery, called ribosomes, that make copies of the required protein.

    We see mRNA functioning as the “software of life.” Every cell uses mRNA to provide real time instructions to make the proteins necessary to drive all aspects of biology, including in human health and disease. This was codified as the central dogma of molecular biology over 50 years ago, and is exemplified in the schematic below.

    mRNA is used to make every type of protein, including secreted, membrane, and intracellular proteins, in varying quantities over time, in different locations, and in various combinations. This is shown in the figure below.

    6

    <hr>

    Table of Contents

    Since our founding in 2010, we have been inspired by the belief that mRNA could be used to create a new class of medicines, with significant potential to improve the lives of patients. In 2020, mRNA technology emerged as a new class of medicine, with the potential to help treat the ongoing global pandemic. In the span of just over 11 months, we designed a vaccine against COVID-19 (mRNA-1273) using mRNA-based technology, conducted Phase 1, Phase 2 and Phase 3 clinical trials, which demonstrated that the vaccine was highly effective at preventing COVID-19, and obtained an Emergency Use Authorization (EUA) for the vaccine from the U.S. Food and Drug Administration on December 18, 2020, followed a few days later by an Interim Order from Health Canada authorizing the distribution of the vaccine in Canada. By December 31, 2020, we had delivered nearly 17 million doses of the Moderna COVID-19 Vaccine to the U.S. government, and several hundred thousand doses to the Canadian government to help fight the pandemic. As of December 31, 2020, we had committed orders for approximately 520 million doses of the vaccine to be delivered in 2021 to governments around the world.

    The success we experienced in 2020 builds on over 40 years of progress in the biotechnology industry. Our approach fundamentally differs from traditional approaches to medicine. Rather than introduce a protein or chemical to the body, we send tailored mRNA into cells to instruct them to produce specific proteins. We built Moderna on the guiding premise that if mRNA can be used as a medicine for one disease, it could work for many diseases. Instead of starting from scratch for each new vaccine or therapy, our mRNA approach leverages the technology and fundamental components that we have been researching and developing since our founding. By building off our prior research and learning, we believe we can improve how we discover, develop, and manufacture medicines.

    Our success in developing the Moderna COVID-19 Vaccine further underpins our belief that mRNA-based medicines have the potential to help patients in ways that could equal or exceed the impact of traditional approaches to medicine.

    Our strategic priorities

    Our first priority for 2021 is to maximize the impact of our COVID-19 vaccine, both in terms of access and value creation of this product between now and the end of 2021. We are closely monitoring emerging variants of the SARS-CoV-2 virus as it continues to evolve and testing the performance of our vaccine against them. We are also studying potential booster shots, either of the existing vaccine or of a version that has been adjusted to address significant variants, as well as conducting further clinical trials in younger populations, with the hope of being able to provide the vaccine to adolescents aged 12 to 18 by fall 2021. Executing on this first priority will allow us to pursue our second priority, to accelerate vaccine development to advance our pipeline and bring new vaccines to market. In turn, this will make way for our third priority, to generate human proof-of-concept data in autoimmune diseases, cardiovascular diseases, oncology and rare diseases. And this will allow for our fourth priority, to continue to expand the use of mRNA technology to maximize the potential impact we can have on patients. We continue to believe that over time we will have a number of commercial products within our different modalities, which are described in more detail below.

    In January 2021, we announced the expansion of our pipeline of prophylactic vaccines with three new development programs: mRNA vaccine candidates against seasonal flu, human immunodeficiency virus (HIV) and the Nipah virus. We also announced our intent to expand our respiratory syncytial virus (RSV) vaccine program into older adults. We currently have 24 mRNA development programs in our portfolio, with 13 having entered the clinic.

    As of February 15, 2021, we had received additional regulatory authorizations for use of our COVID-19 vaccine in Europe, the United Kingdom, Israel, Switzerland, Singapore and Qatar. We continue forging ahead with the rolling reviews of our COVID-19 vaccine that have already been initiated with several regulatory agencies across the globe and the WHO, which is important for obtaining regulatory authorization to distribute the vaccine in many middle- and low-income countries.

    The early investment we made in our manufacturing and digital capabilities prepared us to rapidly scale our production. At present, we believe we will be able to produce between 700 million and 1 billion doses of our COVID-19 vaccine in 2021. We are continuing to invest and add staff to make this production possible. We are also working on increasing our potential supply to up to 1.4 billion doses for 2022. Much of the production for the supply of the U.S. market will be completed at our Moderna Technology Center facility, or MTC South, in Norwood, Massachusetts, with additional production by Lonza Ltd. for the U.S. market. We have also partnered with Lonza to complete all production in Switzerland of our COVID-19 vaccine (generally referred to as COVID-19 Vaccine Moderna outside the U.S.) for markets other than the U.S. Fill-finish services for our COVID-19 vaccine are provided by Catalent Inc. in the U.S., and by ROVI and Recipharm outside the U.S. We have also partnered with other contract manufacturing organizations for the production of and fill-finish services for our COVID-19 vaccine, and expect that we will enter into additional collaborations as we scale production.

    The structure of mRNA

    Messenger RNA is a linear polymer comprising four monomers called nucleotides: adenosine (A), guanosine (G), cytosine (C), and uridine (U). Within the region of the molecule that codes for a protein, or the coding region, the sequence of these four nucleotides forms a language made up of three-letter words called codons. The first codon, or start codon (AUG), signals where the ribosome

    7

    <hr>

    Table of Contents

    should start protein synthesis. To know what protein to make, the ribosome then progresses along the mRNA one codon at a time, appending the appropriate amino acid to the growing protein. To end protein synthesis, three different codons (UAA, UAG, and UGA) serve as stop signals, telling the ribosome where to terminate protein synthesis. In total, there are 64 potential codons, but only 20 amino acids that are used to build proteins; therefore multiple codons can encode for the same amino acid.

    The process of protein production is called translation because the ribosome is reading in one language (a sequence of codons) and outputting in another language (a sequence of amino acids). As shown in the figure below, the coding region is analogous to a sentence in English. Much like a start codon, a capitalized word can indicate the start of a sentence. Codons within the coding region resemble groups of letters representing words. The end of the sentence is signaled by a period in English, or a stop codon for mRNA.

    The intrinsic advantages of using mRNA as a medicine

    mRNA possesses inherent characteristics that we believe provide it with a strong foundation as a new class of medicines. These characteristics include:

    1.mRNA is used by every cell to produce all proteins: Cells in the human body use mRNA to make all types of proteins, including secreted, membrane, and intracellular proteins. mRNA is used by cells to vary the quantities of protein produced over time, in different locations, and in various combinations. Given the universal role of mRNA in protein production, we believe that mRNA medicines could have broad applicability across human disease.

    2.Making proteins inside one’s own cells mimics human biology: Using a person’s own cells to produce protein therapeutics or vaccine antigens provides certain advantages over existing technologies such as recombinant proteins, which are manufactured using processes that are foreign to the human body. These advantages include the ability to:

    •use multiple mRNAs to produce multiple proteins;

    •reduce or eliminate immunogenicity;

    •create multi-protein complexes;

    •produce therapeutic or vaccine proteins locally;

    •harness native protein folding and glycosylation; and

    •make proteins that are unstable outside the body.

    3.mRNA has a simple and flexible chemical structure: Each mRNA molecule comprises four chemically similar nucleotides to encode proteins made from up to 20 chemically different amino acids. To make the full diversity of possible proteins, only simple sequence changes are required in mRNA. A vast number of potential mRNA medicines can be developed, therefore, with only minor changes to the underlying chemical structure of the molecule or manufacturing processes, a significant advantage over small molecule or protein therapeutics.

    4.mRNA has classic pharmacologic features: The intrinsic properties of mRNA translate into attractive pharmacologic features, including:

    •each mRNA encodes for a specific protein and no other protein;

    •each mRNA molecule can produce many copies of a protein in the cell before being degraded;

    •increasing mRNA levels in a cell generally leads to increasing protein levels; and

    8

    <hr>

    Table of Contents

    •the effects of mRNA in a cell can be transient and limits risk of irreversible changes to the cell’s DNA.

    As a result, mRNA possesses many of the attractive pharmacologic features of most modern medicines, including reproducible activity, predictable potency, and well-behaved dose dependency; and the ability to adjust dosing based on an individual patient’s needs, including stopping or lowering the dose, to seek to ensure safety and tolerability.

    mRNA as a new class of medicines

    Based on these and other features, we have developed four core beliefs about the value drivers of mRNA as a new class of medicines:

    1.mRNA has the potential to create an unprecedented abundance and diversity of medicines. Although only two infectious disease vaccines using mRNA technology have been authorized to date for emergency use, or other provisional, interim or conditional use in response to the COVID-19 pandemic, we believe this success further demonstrates the potential for mRNA medicines to provide patients or healthy individuals with any therapeutic protein or vaccine, including those targeting intracellular and membrane proteins. This breadth of applicability has the potential to create an extraordinary number of new mRNA-based medicines that are currently beyond the reach of recombinant protein technology.

    2.Advances in the development of our mRNA medicines can reduce risks across our portfolio. mRNA medicines share fundamental features that can be used to learn quickly across a portfolio. We believe that once safety and proof of protein production has been established in one program, the technology and biology risks of related programs that use similar mRNA technologies, delivery technologies, and manufacturing processes will decrease significantly. We believe that the progress of our COVID-19 vaccine has helped mitigate risk associated with our prophylactic vaccine modality.

    3.mRNA technology can accelerate discovery and development. The software-like features of mRNA enable rapid in silico design and the use of automated high-throughput synthesis processes that permit discovery to proceed in parallel rather than sequentially. We believe these mRNA features can also accelerate drug development by allowing the use of shared manufacturing processes and infrastructure.

    4.The ability to leverage shared processes and infrastructure can drive significant capital efficiency over time. We believe the manufacturing requirements of different mRNA medicines are dramatically more similar than traditional recombinant protein-based drugs across a similarly diverse pipeline. When manufacturing at commercial scale, we believe a portfolio of mRNA medicines will benefit from shared capital expenditures, resulting in lower program-specific capital needs and an advantageous variable cost profile.

    We believe that the development of mRNA as a new class of medicines, as evidenced by the development of mRNA-based vaccines during 2020, represents a significant breakthrough for patients and our industry.

    OUR STRATEGIC PRINCIPLES AND APPROACH TO MANAGING RISK

    Our strategy is designed to deliver on the full scope of the mRNA opportunity over the long-term. Reaching patients with mRNA medicines requires us to make complex choices, including: how much capital we devote to technology creation, drug discovery, drug development, commercial and global marketing and infrastructure; which programs we advance and how; whether we advance programs alone or with strategic collaborators; and which capabilities we build internally versus outsource.

    To navigate these choices, we established five strategic principles that guide our approach to creating long-term value for patients and investors. No single strategic principle dominates our choices. Embedded in every decision we make is also our assessment of the most important risks inherent in our business. We believe these risks fall into four categories: technology, biology, execution, and financing.

    To increase our chances of success, we often find it necessary to balance our near-to-mid-term risks against the strategic principles that guide our approach to long-term value creation.

    Our strategic principles

    1.We seek to discover and develop a large pipeline in parallel.

    Our goal is to address or prevent as many human diseases as our technology, talent, capital, and other resources permit. We do so as rapidly as we can, understanding both the urgency for patients and the need to be disciplined in our approach. We have a diverse pipeline of 24 development programs, with 13 of them having entered the clinic, many of which have the potential to be

    9

    <hr>

    Table of Contents

    first-in-class or best-in-class medicines. We have one commercial product, our COVID-19 vaccine, that is being distributed globally.

    2.We undertake sustained, long-term investment in technology creation. We aim to improve the performance of mRNA medicines in our current modalities, and to unlock new modalities, through investments within basic and applied science. We are committed to remaining at the forefront of mRNA science.

    3.We focus on the pace and scale of our learning. We believe that time is a critical resource. We seek to accelerate our progress by solving numerous technical problems in parallel rather than in sequence. Our scientists pursue experiments based on how much we can learn from the results, not just the probability of a positive outcome. We believe negative information is valuable and we can learn from our setbacks. We make significant investments in digital assets and research infrastructure to accelerate the pace and scale of our learning.

    4.We integrate across the most critical parts of our value chain. mRNA is a complex multicomponent system and we believe it demands integration. We believe that we must be directly engaged in research, drug discovery, drug development, process and analytical development, and manufacturing to accelerate our learning, reduce our risk, and protect our critical know-how. Where appropriate, we seek out strategic collaborators that can augment our capabilities or expand our capacity in specific therapeutic areas, while being careful to resist the fragmentation of our core technology.

    5.We forward invest in core enabling capabilities and infrastructure. To execute across a broad pipeline, we need to invest at risk before we have all the answers. Our forward investments focus on areas where lead times are long and where early investments can reduce execution risk and accelerate future progress. We proactively invested in a dedicated manufacturing facility, Moderna Technology Center (MTC), in Norwood, MA, to support the anticipated growth of our pipeline, and this early investment greatly facilitated our ability to respond to the COVID-19 pandemic by allowing us to begin production of our vaccine even before we received regulatory authorization for its distribution.

    Our approach to managing risk

    In conjunction with the strategic principles that guide our approach to long-term value creation, we actively manage the risks inherent in our business. At present, these categories of risk include: technology, biology, execution, and financing. We summarize our approach to managing these risks below:

    1.Technology risk encompasses the challenges of developing the product features of mRNA medicines, including delivery, controlling interactions with the immune system, optimizing therapeutic index, and manufacturing. We believe the best way to mitigate technology risk is to sustain long-term investments in our platform. In addition, we diversify our technology risk by compartmentalizing our pipeline into groups of programs with shared product features, which we call modalities. Lastly, we stage program development within a modality, leveraging the first program, whether successful or not, to generate insights that accelerate and reduce the risk of subsequent programs within the modality.

    2.Biology risk entails the risk unique to each program based on its mechanism of action and of clinical development in the target patient population. We believe the best way to manage biology risk is to diversify it by pursuing multiple programs in parallel. In addition, within a modality we seek to initially pursue programs with well-understood biology. Lastly, we may seek strategic collaborators to share risk and upside in disease areas with high inherent biology risk, such as cancer and heart disease.

    3.Execution risk refers to the challenge of executing against the scale of our mission. We solve for this risk by seeking to hire the right people, the best talent in the industry. We seek to foster a culture of execution with a focus on quick review cycles and high velocity decision-making. We make forward investments in infrastructure, including manufacturing. Lastly, we have created a digital backbone to track all aspects of our programs and anticipate challenges before they arise.

    4.Financing risk refers to our ability to access the capital required to fund the current breadth of our endeavor, as well as new opportunities. We manage this risk by attempting to maintain a strong balance sheet with several years of cash runway. As of December 31, 2020, we had cash, cash equivalents, and investments of $5.25 billion. This balance represents a significant increase in our liquidity over the prior year, driven primarily by customer deposits for the sale of our COVID-19 vaccine, as well as two equity offerings during the first half of the year (in February and May).

    There is no single strategic principle nor single category of risk that dominates our decision-making, and universal rules do not exist across our portfolio. Our trade-offs generally involve balancing near-term risks and long-term value creation. Because development cycles are long, our choices are complex. We expect the weighting and types of risk we face will evolve as our business matures. We

    10

    <hr>

    Table of Contents

    believe that disciplined capital allocation across near- and long-term choices must be a core competency if we are to maximize the opportunity for patient impact and shareholder value creation.

    […]

    We also sought strategic alliances with the Defense Advanced Research Projects Agency (DARPA), the Biomedical Advanced Research Development Authority (BARDA) and Merck & Co. (Merck), to allow us to rapidly expand our pipeline and complement our capabilities with their expertise. This early work in the prophylactic vaccines modality led to the ability to introduce our COVID-19 vaccine during 2020 in response to the ongoing pandemic.

    Over time, we have taken on more challenging applications and technological hurdles with each successive modality, but we have also tried to build upon our prior experiences to manage risk.

    […]

    Since
    we nominated our first program in late 2014, we and our strategic
    collaborators have advanced in parallel a diverse development pipeline
    which currently consists of 27 development candidates across our 24
    programs, with 13 having entered the clinic and an additional
    development candidate subject to an open investigational new drug
    application (IND). Aspects of our pipeline have been supported through
    strategic alliances, including with AstraZeneca, Merck, and Vertex
    Pharmaceuticals, or Vertex, and government-sponsored organizations and
    private foundations focused on global health initiatives, including
    BARDA, DARPA, the National Institute of Allergy and Infectious Diseases
    (NIAID), the National Institutes of Health (NIH), the Coalition for
    Epidemic Preparedness Innovations (CEPI), and the Bill & Melinda
    Gates Foundation.

    […]

    COVID-19 vaccine (mRNA-1273)

    Moderna’s COVID-19 vaccine has already been administered in millions of patients and is authorized for use in more than 30 countries

    Our COVID-19 vaccine (mRNA-1273) was designed, subject to Phase 1, Phase 2 and Phase 3 clinical trials, delivered clinical trial results, and received emergency use and other conditional authorizations in less than a year, and has been and continues to be a key tool in fighting the global SARS-CoV-2 pandemic. The vaccine is referred to as the Moderna COVID-19 Vaccine in the U.S. and Canadian markets, and is generally referred to as the COVID-19 Vaccine Moderna in other markets. Forward-looking references to our COVID-19 vaccine in this Annual Report on Form 10-K may include future modifications to mRNA-1273 or other development candidates that are designed to provide protection against variants of the SARS-CoV-2 virus.

    24

    <hr>

    Table of Contents

    We worked throughout 2020 to expand our manufacturing capacity and partnered with other companies to supplement that production, and currently anticipate that we will be able to produce between 700 million and 1 billion doses of our COVID-19 vaccine in 2021. Our COVID-19 vaccine is a two-dose course, meaning this production will be sufficient to vaccinate between 350 million and 500 million people against COVID-19 at the current 100 microgram (µg) dose. As of December 31, 2020, we had committed orders for approximately 520 million doses of the COVID-19 vaccine to be delivered in 2021, for total contract consideration of $11.7 billion. We are conducting a Phase 2/3 study of mRNA-1273 in adolescents 12 to 17 years of age. Additional studies are planned to evaluate our COVID-19 vaccine in children younger than 12 years and immunocompromised populations. We are also conducting a field effectiveness trial in the United States to gather additional data in other populations, including older adults and individuals with co-morbidities that place them at increased risk for the complications of COVID-19.

    On February 25, 2021, we announced that the Company is developing a next-generation vaccine against COVID-19, mRNA-1283. This vaccine candidate encodes for the portions of the SARS-CoV-2 spike protein that are critical for neutralization, specifically the Receptor Binding Domain (RBD) and N-terminal Domain (NTD). The encoded mRNA-1283 antigen is shorter than mRNA-1273, and is being developed as a potential refrigerator stable mRNA vaccine that we anticipate will facilitate easier distribution and administration by healthcare providers. mRNA-1283 is intended to be evaluated for use as a booster dose for previously vaccinated or infected individuals as well as in a primary series for seronegative individuals.

    COVID-19: Disease overview

    SARS-CoV-2 is the virus that causes COVID-19 disease, which has led to over 2.4 million global deaths

    Coronaviruses are a large family of viruses that can cause illness in animals or humans. In humans there are several known coronaviruses that cause respiratory infections. These coronaviruses range from the common cold to more severe diseases such as severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and COVID-19. SARS-CoV-2 is the novel coronavirus first identified in humans in December 2019 and is the cause of COVID-19.

    COVID-19 is the most severe global pandemic since the influenza pandemic of 1918. As of February 18, 2021, there have been over 110 million confirmed cases and over 2.4 million global deaths from COVID-19. The risk of mortality increases with age (estimated to be ~0.1% for individuals aged 0-19, ~6% for individuals over age 60). Risk of severe disease and mortality increase for persons with pre-existing diseases or comorbid conditions (e.g. cardiovascular disease, diabetes, chronic lung disease, obesity).

    As the pandemic has continued variants of the original SARS-CoV-2 virus first detected in Wuhan, China, have continued to evolve. Certain of these variant strains of SARS-CoV-2 have already proven to lead to increased rates of transmission of the virus, and as the virus continues to evolve, future strains or those already in circulation could cause more severe forms of disease. Some variant strains have also demonstrated resistance to existing vaccines and therapeutics for COVID-19. Data from the primary efficacy analysis announced November 30, 2020 suggested that mRNA-1273—which was designed based upon the genetic sequence of the virus first detected in Wuhan, China—is 94.1% efficacious against symptomatic COVID-19 disease with a clinically-acceptable safety profile. However, while the neutralization titers are comparable for most variant strains tested, including the B.1.1.7 strain first identified in the United Kingdom, there are data to suggest a 6.4-fold reduction in neutralization titers against the B.1.351 strain which was first identified in South Africa. While the titers against B.1.351 remain higher than those found to be protective against viral challenge in animal models, we have nonetheless announced a proactive strategy to address variants of the virus. We are continuing to collaborate with the NIH to study the evolution of the SARS-CoV-2 virus and the effectiveness of mRNA-1273 against new strains. As one part of this strategy, we are testing additional boosters of mRNA-1273 to further increase protection against emerging strains. Additionally, we are advancing an emerging strain booster, referred to as mRNA-1273.351 (named for the B.1.351 strain) to assess protection against that strain. On February 24, 2021, doses of mRNA-1273.351 were shipped to the NIH for a Phase 1 clinical trial that will be led and funded by NIAID.

    COVID-19 vaccine (mRNA-1273): Product concept

    Our vaccine is an mRNA vaccine against COVID-19 encoding for a prefusion stabilized form of the Spike (S) protein, which was co-developed by Moderna and investigators from NIAID’s Vaccine Research Center.

    The Spike protein complex is necessary for membrane fusion and host cell infection and has been the target for the majority of vaccines against COVID-19. Our COVID-19 vaccine encodes a stabilized version of the SARS-CoV-2 full-length spike glycoprotein trimer, S-2P, which has been modified to include two proline substitutions at the top of the central helix in the S2 subunit (S-2P).

    25

    <hr>

    Table of Contents

    COVID-19 vaccine (mRNA-1273): Preclinical data

    mRNA-1273 led to protection against SARS-CoV-2 infection in the lungs and nose of non-human primates

    On July 29, 2020, we announced the publication in The New England Journal of Medicine of data from a preclinical study of mRNA-1273, demonstrating that two doses of mRNA-1273 provided protection against lung inflammation following viral challenge with SARS-CoV-2 in non-human primates at both the 10 µg and 100 µg dose levels. In addition, both the 10 µg and 100 µg dose groups demonstrated protection against viral replication in the lungs, with the 100 µg dose also protecting against viral replication in the nose of the animals. Of note, none of the eight animals in the 100 µg group showed detectable viral replication in the nose compared to six out of eight in the placebo group on day 2.

    COVID-19 vaccine (mRNA-1273): Clinical data

    Phase 1 trial. A Phase 1 open-label study of mRNA-1273 is being conducted by the NIH. This study, which began on March 16, 2020, originally enrolled 45 healthy adult volunteers ages 18 to 55 years and is evaluating three dose cohorts (25 µg, 100 µg and 250 µg). An additional seven cohorts were subsequently added in the Phase 1 study: a 50 µg cohort in adults 18-55 (n=15), three cohorts of older adults (n=30, ages 56-70, 25 µg, 50 µg, and 100 µg) and three cohorts of elderly adults (n=30, ages 71 and above, 25 µg, 50 µg, and 100 µg).

    On July 14, 2020, we announced the publication in The New England Journal of Medicine of an interim analysis of data from the original cohorts obtained through Day 57 in the Phase 1 study. This interim analysis demonstrated that mRNA-1273 induced binding antibodies to the full-length SARS-CoV-2 Spike protein (S) in all participants after the first vaccination, with all participants seroconverting by Day 15. Dose dependent increases in binding titers were seen across the three dose levels, and between prime and boost vaccinations within the dose cohorts. After two vaccinations, at Day 57, geometric mean titers exceeded those seen in convalescent sera obtained from 38 individuals with confirmed COVID-19 diagnosis. Of the 38 individuals in the convalescent sera group, 15% were classified as having severe symptoms (hospitalization requiring intensive care and/or ventilation), 22% had moderate symptoms and 63% had mild symptoms. Convalescent sera samples were tested using the same assays as the study samples. mRNA-1273 was generally well-tolerated, with no serious adverse events reported through Day 57. Adverse events were generally transient and mild to moderate in severity.

    Evaluation of the durability of immune responses is ongoing, and participants will be followed for one year after the second vaccination, with scheduled blood collections throughout that period. On December 2, 2020, a letter to the editor was published in The New England Journal of Medicine reporting that participants in the Phase 1 study of mRNA-1273 retained high levels of neutralizing antibodies through 119 days following first vaccination (90 days following second vaccination). The study was led by NIAID.

    Phase 1 older adult cohort. On September 29, 2020, we announced the publication in The New England Journal of Medicine of the second interim analysis of data from 40 healthy adult participants across two dose levels (25 µg and 100 µg) in two age cohorts (ages 56-70 and ages 71+), and reports results through Day 57 (1 month after the second dose). Both the 25 µg and 100 µg dose levels of mRNA-1273 were generally well-tolerated, with no serious adverse events reported through Day 57.

    26

    <hr>

    Table of Contents

    At both the 25 µg and 100 µg dose levels, after two vaccinations, mRNA-1273 induced dose-dependent binding antibody responses reaching the upper quartile of the distribution of convalescent sera. At Day 57 (1 month post-dose 2), geometric mean titers (GMT) exceeded the median of those seen in convalescent sera from 41 individuals with confirmed COVID-19 diagnosis.

    Phase 3 trial. The Phase 3 COVE trial for mRNA-1273 is a randomized, 1:1 placebo-controlled study testing the vaccine at the 100 µg dose level in 30,000 participants in the U.S., ages 18 and older. The primary endpoint of the COVE study, which is ongoing, is the prevention of symptomatic COVID-19 disease. Key secondary endpoints include prevention of severe COVID-19 disease and prevention of infection by SARS-CoV-2. The Phase 3 COVE study was designed in collaboration with the FDA and NIH to evaluate vaccine efficacy in Americans at risk of severe COVID-19 disease and completed enrollment of more than 30,000 participants ages 18 and older in the U.S. on October 22, 2020, including those at high risk of severe complications of COVID-19 disease. In early September 2020, we announced that we were slowing enrollment in the trial to ensure representation of communities of color in the COVE study. Final enrollment in the study included more than 11,000 participants from communities of color, representing 37% of the study population.

    On December 30, 2020, interim safety and primary efficacy results from the Phase 3 trial of mRNA-1273 were published in The New England Journal of Medicine. The primary endpoint of the Phase 3 COVE study was based on the analysis of COVID-19 cases confirmed and adjudicated starting two weeks following the second dose of vaccine. This final analysis was based on 196 cases, of which 185 cases of COVID-19 were observed in the placebo group versus 11 cases observed in the Moderna COVID-19 Vaccine group, corresponding to a 94% vaccine efficacy (95% CI 89.3-96.8%; p<0.0001). This efficacy is highlighted in the chart below. The most common solicited adverse reactions (ARs) after the two-dose series was injection site pain (86.0%). Solicited systemic adverse events occurred more often in the Moderna COVID-19 vaccine group (54.9% and 79.4%) than in the placebo (42.2% and 36.5%) group after both the first dose and the second dose respectively and were most commonly headache, fatigue and myalgia. While the majority of these ARs were mild (grade 1) or moderate (grade 2), there was a higher occurrence of severe (grade 3) reactions in the Moderna COVID-19 Vaccine group after the first (2.9%) and second (15.8%) injections. The majority of local solicited ARs occurred within the first one to two days after injection and generally persisted for a median of one to two days. Safety data continues to accrue, and the study continues to be monitored by an independent Data Safety Monitoring Board (DSMB) appointed by the NIH. All participants in the COVE study will be monitored for two years after their second dose to assess long-term protection and safety. Additional data to be collected will include longer term safety follow-up, duration of protection against COVID-19, and efficacy against asymptomatic SARS-CoV-2 infection. All placebo recipients in the Phase 2 and Phase 3 trials have been offered our COVID-19 vaccine. As of February 15, 2020, over 80% of placebo recipients have received at least one dose of our COVID-19 vaccine.

    We are also conducting a Phase 2/3 study of mRNA-1273 in adolescents 12 to less than 18 years of age and a Phase 2/3 pediatric study in children less than 12 years old is expected to begin in April 2021. Finally, to assess the ability of a third vaccination with mRNA-1273 to further boost antibody titers, participants in the active arms (100 and 50ug) of our Phase 2 adult study will be offered a 50ug booster dose. Additional studies are planned to evaluate mRNA-1273 in special risk groups, such as the immunocompromised.

    27

    <hr>

    Table of Contents

    COVID-19 vaccine (mRNA-1273): Regulatory updates

    On December 18, 2020, the U.S. Food and Drug Administration authorized the emergency use of mRNA-1273, Moderna’s vaccine against COVID-19, in individuals 18 years of age or older. Our COVID-19 vaccine has also been authorized for emergency or conditional use by regulatory authorities in Canada, Israel, the United Kingdom, the European Union, Switzerland, Singapore and Qatar. Additional authorizations are currently under review in additional markets and by the World Health Organization (WHO). We expect to submit a biologics license application, or BLA, to the FDA for approval of mRNA-1273, and to submit applications with other regulatory authorities for similar approvals, which will allow for the commercial sale and distribution of the vaccine after the pandemic subsides and conditions are no longer met for emergency or conditional use authorizations.

    COVID-19 vaccine (mRNA-1273): Commercial, manufacturing and supply updates

    As of December 31, 2020, we have signed supply agreements to deliver approximately 520 million doses of mRNA-1273 in 2021, for total contract consideration of $11.7 billion. We have confirmed the following supply agreements as of that date: United States: 200 million doses, with option for an additional 300 million doses; European Union: 160 million doses; Japan: 50 million doses; Canada: 40 million doses, with option for an additional 16 million doses; South Korea: 40 million doses; United Kingdom: 17 million doses; Switzerland: 7.5 million doses; Israel: 6 million doses. We also signed agreements with Qatar, Singapore, and other countries for which order amounts were not disclosed.

    During 2021, and through the date of this Annual Report on Form 10-K, we have agreed to additional supply agreements, or received option exercises, for additional doses as follows: United States: 100 million doses, with an option remaining for 200 million doses; European Union: 150 million doses, with an option remaining for 150 million doses in 2022 (subject to final execution of the Purchase Agreement following the expiration of the opt out period for EU Member States); Canada: 4 million doses; Colombia: 10 million doses; and Taiwan: 5 million doses.

    Our base case global production estimate is 700 million to 1 billion doses for 2021. We are continuing to invest and add staff as we meet production at the high end of this range. We are also working on increasing our potential supply to up to 1.4 billion doses for 2022 based upon the current 100 µg dose. Much of the production for the supply of the U.S. market will be completed at our MTC facility in Norwood, Massachusetts, with additional production by Lonza Ltd. for the U.S. market. We have also partnered with Lonza to complete all production of mRNA-1273 for markets other than the U.S. in Switzerland. Fill-finish services for mRNA-1273 are provided by Catalent Inc. in the U.S., and by ROVI and Recipharm outside the U.S.

    We believe that the conditions under which mRNA-1273 can be shipped and stored are a key feature of our vaccine as such conditions provide for greater flexibility in distributing the vaccine to markets where special handling may be a barrier to distribution. mRNA-1273 does not require dilution prior to use and remains stable at 2° to 8°C (36° to 46°F), the temperature of a standard home or medical refrigerator, for 30 days. mRNA-1273 remains stable at -20° C (-4°F) for up to six months, at refrigerated conditions for up to 30 days and at room temperature for up to 12 hours.

    […]

    Defense Advanced Research Projects Agency (DARPA)

    In October 2013, DARPA awarded Moderna up to approximately $24.6 million under Agreement No. W911NF-13-1-0417 to research and develop potential mRNA medicines as a part of DARPA’s Autonomous Diagnostics to Enable Prevention and Therapeutics, or ADEPT, program, which is focused on assisting with the development of technologies to rapidly identify and respond to threats posed by natural and engineered diseases and toxins. As of December 31, 2020, $19.7 million of the award amount has been funded. This award followed an initial award from DARPA of approximately $1.4 million given in March 2013 under Agreement No. W31P4Q-13-1-0007. The DARPA awards have been deployed primarily in support of our vaccine and antibody programs to protect against Chikungunya infection.

    In September 2020, we entered into an agreement with DARPA for an award of up to $56.4 million to fund development of a mobile manufacturing prototype leveraging our existing manufacturing technology that is capable of rapidly producing vaccines and therapeutics. As of September 30, 2020, the committed funding was $5.0 million, with an additional $51.4 million available under Agreement No. HR0011-20-9-0118 if DARPA exercises additional contract options.

    79

    <hr>

    Table of Contents

    Biomedical Advanced Research and Development Authority (BARDA)

    In September 2016, we received an award of up to approximately $125.8 million under Agreement No. HHSO100201600029C from BARDA, a component of the Office of the Assistant Secretary for Preparedness and Response (ASPR), within the U.S. Department of Health and Human Services (HHS), to help fund our Zika vaccine program. Under the terms of the agreement with BARDA, an initial base award of approximately $8.2 million supported toxicology studies, a Phase 1 clinical trial, and associated manufacturing activities. Additionally, four contract options were awarded under the agreement with BARDA. Three out of four of these options have been exercised, bringing the total current award to approximately $117.3 million to support an additional Phase 1 study of an improved Zika vaccine candidate, Phase 2 and Phase 3 clinical studies, as well as large-scale manufacturing for the Zika vaccine.

    In April 2020, we entered into an agreement with BARDA for an award of up to $483.3 million to accelerate development of mRNA-1273, our COVID-19 vaccine. In July 2020, we amended our agreement with BARDA to provide for an additional commitment of up to $471.6 million to support late-stage clinical development of mRNA-1273, including the execution of a 30,000 participant Phase 3 study in the U.S. The amendment increased the maximum award from BARDA from $483.3 million to $954.9 million. Under the terms of the agreement, BARDA will fund the advancement of mRNA-1273 to FDA licensure. All contract options have been exercised. As of December 31, 2020, the remaining available funding net of revenue earned was $444.3 million.

    The Bill & Melinda Gates Foundation

    In January 2016, we entered a global health project framework agreement with the Bill & Melinda Gates Foundation to advance mRNA-based development projects for various infectious diseases. The Bill & Melinda Gates Foundation has committed up to $20.0 million in grant funding to support our initial project related to the evaluation of antibody combinations in a preclinical setting as well as the conduct of a first-in-human Phase 1 clinical trial of a potential mRNA medicine to help prevent human immunodeficiency virus, or HIV, infections. Follow-on projects which could bring total potential funding under the framework agreement up to $100.0 million (including the HIV antibody project) to support the development of additional mRNA-based projects for various infectious diseases can be proposed and approved until the sixth anniversary of the framework agreement, subject to the terms of the framework agreement, including our obligation to grant to the Bill & Melinda Gates Foundation certain non-exclusive licenses.

    INTELLECTUAL PROPERTY

    Our patent estate and approach, a strategic asset

    Since our inception, we have considered the creation and building of our intellectual property, or IP, portfolio as a critical part of our mission. In a relatively short amount of time, we have built a significant patent estate that includes over 600 world-wide pending patent applications and over 270 issued or allowed U.S. and foreign patents covering key components of our proprietary platform technology, investigational medicines, and development candidates. The figure below shows our internally developed estate and indicates the number of patents approved since 2010.mrna-20201231_g45.jpg

    We regularly identify inventions and trade secrets as we surmount various challenges with our platform to create modalities. We seek to protect our proprietary position by, among other means, filing U.S. and certain foreign patent applications related to our platform, modality, and program inventions. Our company trade secrets and know-how are appropriately guarded to maintain our business advantage […]

Viewing 1 of 1 replies

Log in to reply.

Original Post
0 of 0 posts June 2018
Now