First year after launch: Surprise, it’s COVID!
By Joshua Slatko
COVID may have shut down the better part of the known world, but it clearly didn’t shut down pharma. Less than a year after the virus first spread into the United States, FDA had already granted emergency use authorizations (EUA) for two vaccines, and those two vaccines promptly transformed the top lines of their respective companies, with Comirnaty helping to push Pfizer from $41.7 billion in 2020 to more than $100 billion in 2022 and Spikevax taking Moderna from close to zero in 2020 to $18.4 billion two years later. Alongside Pfizer’s COVID treatment Paxlovid, the two vaccines have dominated the sales charts of the industry’s most recent launches as few products have before; the three together generated more than $75 billion in sales in 2022, while no other non-COVID new brand even reached $500 million.
Pfizer and BioNTech’s Comirnaty was authorized for emergency use against COVID-19 in individuals 16 years of age and older by FDA on December 11, 2020. The agency’s authorization was based on the totality of scientific evidence shared by the companies, including data from a pivotal Phase III clinical study announced the previous month. The Phase III data demonstrated a vaccine efficacy rate of 95 percent in participants without prior SARS-CoV-2 infection (first primary objective) and also in participants with and without prior SARS-CoV-2 infection (second primary objective), in each case measured from seven days after the second dose. Efficacy was consistent across age, gender, race, and ethnicity demographics. A similar authorization was granted by the European Commission
10 days later.
The day after FDA’s initial EUA was announced, the U.S. Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices voted to recommend the use of Comirnaty in people 16 years of age and older.
“Today’s ACIP recommendation marks a momentous step in this historic journey and the beginning of another, as we work jointly with the U.S. government, other vaccine companies, and our many partners to execute the largest mass vaccination program in our nation’s history,” said Albert Bourla, Pfizer’s chairman and CEO, upon announcement of the recommendation. “Collectively, we aim to vaccinate hundreds of millions of Americans by the end of 2021. With vaccinations set to begin this week, I feel a sense of tremendous pride at what we have collectively achieved over the past nine months. I now look forward to the day that this devastating and deadly pandemic is finally behind us.”
In March 2021, the Israel Ministry of Health, Pfizer, and BioNTech announced real-world evidence demonstrating dramatically lower incidence rates of COVID-19 disease in individuals fully vaccinated with Comirnaty, underscoring the observed substantial public health impact of Israel’s nationwide immunization program. The data showed that vaccine effectiveness was at least 97 percent against symptomatic COVID-19 cases, hospitalizations, severe and critical hospitalizations, and deaths. Furthermore, the analysis found a vaccine effectiveness of 94 percent against asymptomatic SARS-CoV-2 infections. For all outcomes, vaccine effectiveness was measured from two weeks after the second dose.
That same month, the two companies announced that, in a Phase III trial in adolescents 12 to 15 years of age with or without prior evidence of SARS-CoV-2 infection, Comirnaty demonstrated 100 percent efficacy and robust antibody responses, exceeding those recorded earlier in vaccinated participants aged 16 to 25 years old, and was well tolerated. The trial enrolled 2,260 adolescents 12 to 15 years of age in the United States. In the trial, 18 cases of COVID-19 were observed in the placebo group versus none in the vaccinated group. Vaccination with Comirnaty elicited SARS-CoV-2–neutralizing antibody geometric mean titers of 1,239.5, demonstrating strong immunogenicity in a subset of adolescents one month after the second dose. FDA subsequently expanded its EUA for Comirnaty to include individuals 12 to 15 years of age in May 2021; the European Commission did the same a few days later.
In April 2021 the two companies announced updated topline results from analysis of 927 confirmed symptomatic cases of COVID-19 observed in their pivotal Phase III study through March 13, 2021, showing that Comirnaty, was 91.3 percent effective against COVID-19, measured seven days through up to six months after the second dose. The vaccine was 100 percent effective against severe disease as defined by the U.S. Centers for Disease Control and Prevention, and 95.3 percent effective against severe COVID-19 as defined by the FDA. Safety data from the Phase III study was also collected from more than 12,000 vaccinated participants who have a follow-up time of at least six months after the second dose, demonstrating a favorable safety and tolerability profile.
In August 2021, FDA approved the Biologics License Application for Comirnaty to prevent COVID-19 in individuals 16 years of age and older. For FDA approval, Pfizer and BioNTech submitted a comprehensive data package that included longer-term follow-up data from the Phase III trial, where the vaccine’s high efficacy and favorable safety profile were observed up to six months after the second dose. The BLA submission package also included the manufacturing and facilities data required for licensure. Pfizer and BioNTech completed submission of the BLA in May 2021, and the BLA was granted Priority Review in July 2021.
That same month, Pfizer and BioNTech announced the initiation of a supplemental Biologics License Application to FDA for the approval of a booster (third) dose of Comirnaty to prevent COVID-19 in individuals 16 years of age and older. The sBLA included data from a Phase III clinical trial of 306 participants 18-55 years of age who received a booster (third) dose of Comirnaty between 4.8 and 8 months after completing the two-dose primary regimen, with a median follow-up time of 2.6 months post-booster. The booster (third) dose of Comirnaty elicited robust neutralizing antibodies to the wild-type strain in participants who were without evidence of SARS-CoV-2 infection through one-month post-dose-three. SARS-CoV-2 50 percent neutralizing titers after the third dose were 3.3 times the titers after the second dose. The post-dose-three neutralizing titers met the pre-specified 1.5-fold non-inferiority criterion for success and were statistically superior. Moreover, 99.5 percent of participants had a four-fold response after the third dose, compared to 98 percent after the second dose. The titers after dose three met the pre-specified 10 percent non-inferiority margin for the difference in the four-fold seroresponse rates.
In September 2021 the two companies announced results from a Phase II/III trial showing a favorable safety profile and robust neutralizing antibody responses in children 5 to 11 years of age using a two-dose regimen of 10 µg administered 21 days apart, a smaller dose than the 30 µg dose used for people 12 and older. The antibody responses in the participants given 10 µg doses were comparable to those recorded in a previous Pfizer-BioNTech study in people 16 to 25 years of age immunized with 30 µg doses. The 10 µg dose was carefully selected as the preferred dose for safety, tolerability, and immunogenicity in children 5 to 11 years of age. The following month, FDA granted an EUA for the vaccine in children 5 through 11 years of age.
In November 2021 FDA expanded its EUA for a booster dose of Comirnaty to include all individuals 18 years of age and older. The change was based on results from a Phase III randomized, controlled trial evaluating the efficacy and safety of a 30-µg booster dose of the vaccine, which enrolled more than 10,000 participants during a period when the Delta variant was the prevalent strain. The booster dose had previously been authorized for emergency use in individuals 65 years of age and older, individuals 18 through 64 years of age at high risk of severe COVID-19, and individuals 18 through 64 years of age with frequent institutional or occupational exposure to SARS-CoV-2. FDA subsequently expanded its EUA for the booster to individuals 12 years of age and older in January 2022, and for children 5 through 11 years of age in May 2022.
Also in November 2021, Pfizer and BioNTech announced topline results from a longer-term analysis of the safety and efficacy of their COVID-19 vaccine in individuals 12 through 15 years of age. The updated findings from the companies’ pivotal Phase III trial showed that a two-dose series of Comirnaty (30-µg per dose) was 100 percent effective against COVID-19, measured seven days through over four months after the second dose.
In June 2022, FDA granted EUA of Comirnaty as a three 3-µg dose series for children 6 months through 4 years of age. The 3-µg dose was carefully selected as the preferred dose for children under 5 years of age based on safety, tolerability, and immunogenicity data.
Pfizer’s Paxlovid received an EUA from FDA in December 2021 for the treatment of mild-to-moderate COVID-19 in adults and pediatric patients (12 years of age and older weighing at least 40 kilograms or about 88 pounds) with positive results of direct SARS-CoV-2 testing, and who are at high risk for progression to severe COVID-19, including hospitalization or death. This represented the first treatment for COVID-19 in the form of a pill taken orally.
FDA based its decision on clinical data from the Phase II/III EPIC-HR (Evaluation of Protease Inhibition for COVID-19 in High-Risk Patients) trial, which enrolled non-hospitalized adults aged 18 and older with confirmed COVID-19 who were at increased risk of progressing to severe illness. The data demonstrated an 89 percent reduction in the risk of COVID-19-related hospitalization or death from any cause in adults treated with Paxlovid, compared to placebo, within three days of symptom onset (primary endpoint). No deaths occurred in the treatment group compared to nine deaths in the placebo group by Day 28. Similar results were seen in those treated within five days of symptom onset (secondary endpoint), with an 88 percent reduction in risk and no deaths observed in the treatment group.
In May 2023, FDA approved Paxlovid for the treatment of mild-to-moderate COVID-19 in adults who are at high risk for progression to severe COVID-19, including hospitalization or death. The FDA approval of Paxlovid was based on the totality of scientific evidence shared by Pfizer, including safety and efficacy data from the EPIC (Evaluation of Protease Inhibition for COVID-19) clinical development program. This included results from the Phase II/III EPIC-HR (Evaluation of Protease Inhibition for COVID-19 in High-Risk Patients) study, which enrolled unvaccinated, non-hospitalized adults, aged 18 years and older, with confirmed COVID-19 who were at increased risk of progressing to severe disease. The data showed an 86 percent reduction in risk of COVID-19-related hospitalization or death from any cause through Day 28 in patients who initiated treatment with Paxlovid within five days of symptoms onset, compared to placebo. The FDA approval was further supported by the results from a secondary endpoint of the Phase II/III EPIC-SR (Evaluation of Protease Inhibition for COVID-19 in Standard-Risk Patients) study, which showed a numerical reduction in COVID-19-related hospitalizations or death from any cause through Day 28 in a sub-group of non-hospitalized adults, aged 18 years and older, with confirmed COVID-19 who had at least one risk factor for progression to severe disease and who were fully vaccinated.
Recent real-world studies of Paxlovid supported the efficacy conclusions from Pfizer’s EPIC clinical program, providing additional data on the use of Paxlovid in the post-authorization setting of Omicron sub-lineage predominance and where high levels of pre-existing immunity occur. These real-world studies also have shown that Paxlovid is effective amongst both vaccinated and unvaccinated high-risk patients.
Moderna’s Spikevax COVID-19 vaccine was authorized for emergency use by FDA on December 18, 2020 in individuals 18 years of age or older. FDA based its decision on the totality of scientific evidence shared by the company, including a data analysis from the pivotal Phase III COVE clinical study. The primary efficacy analysis conducted on 196 cases indicated a vaccine efficacy rate of 94.1 percent. The next day, CDC’s Advisory Committee on Immunization Practices voted 11-0 to recommend the use of Spikevax in people 18 years of age and older. On January 6, 2021, the European Commission granted a conditional marketing authorization to Spikevax as well.
“I want to thank the thousands of participants in our clinical trials and the staff at our clinical trial sites who have been on the front lines of the fight against the virus,” said Stéphane Bancel, CEO of Moderna, in the company’s announcement of FDA’s authorization. “I want to thank the NIH and NIAID for their scientific leadership and our partners at BARDA and Operation Warp Speed who have been instrumental to accelerating our progress to this point. I also want to thank the Moderna team, our suppliers and our partners for their tireless work across research, development, and manufacturing of our vaccine. I am proud of what the Moderna team has achieved in collaboration with our partners. We were able to create and manufacture the Moderna COVID-19 Vaccine in 11 months from sequence to authorization, while advancing clinical development with a Phase I, Phase II, and pivotal Phase III study of 30,000 participants. It has been a 10-year scientific, entrepreneurial, and medical journey, and I am thankful to all those who have helped us get here today. We remain focused on scaling up manufacturing to help us protect as many people as we can from this terrible disease.”
In March 2021, Moderna announced that the first participants had been dosed with the company’s modified COVID-19 vaccines, designed to address the potential need for booster vaccine candidates, in an amendment to the ongoing Phase II clinical study. Moderna’s mRNA-1273.351 encodes for the prefusion stabilized Spike protein of the SARS-CoV-2 variant B.1.351, first identified in the Republic of South Africa, and was assessed as a booster vaccine to increase the breadth of response to emerging variants with key-receptor-binding domains mutations. mRNA-1273.211 was a multivalent candidate that combined mRNA-1273 (Spikevax) against ancestral strains, and mRNA-1273.351 in a single vaccine, designed to elicit a broad immune response as both a primary series and when administered as a boost to those who have previously received mRNA-1273.
That same month, the first participants were dosed in the Phase II/III study, called the KidCOVE study, of Spikevax in children ages 6 months to less than 12 years. This two-part, open label, dose-escalation, age de-escalation (Part 1) and randomized, observer-blind, placebo-controlled expansion study (Part 2) evaluated the safety, tolerability, reactogenicity, and effectiveness of two doses of Spikevax given 28 days apart.
In August 2021, FDA approved an update to the EUA for Spikevax to include a third dose for immunocompromised individuals 18 years of age or older in the United States who have undergone solid organ transplantation, or who are diagnosed with conditions that are considered to have an equivalent level of immunocompromise. A double-blind, randomized controlled trial of 120 individuals who had undergone solid organ transplant procedures (heart, kidney, kidney-pancreas, liver, lung, pancreas) had demonstrated that a third dose of the Moderna COVID-19 vaccine improved immune response compared to placebo. The European Commission granted a similar update to its own authorization of the vaccine in October 2021, with an expanded age range of 12 years and older.
Also in October 2021, FDA authorized for emergency use a booster dose of Spikevax at the 50 µg dose level for people aged 65 and older; people aged 18 to 64 who are at high risk of severe COVID-19; and people aged 18 to 64 with frequent institutional or occupational exposure to SARS-CoV-2. The booster dose was to be administered at least six months after completion of the primary series. FDA also authorized a single booster dose of the Moderna COVID-19 vaccine for individuals who have completed a primary vaccination with other authorized or approved COVID-19 vaccines. The following month, FDA expanded the authorization to all adults aged 18 and older.
FDA based the October EUA on the totality of scientific evidence shared by the company and reviewed by the FDA’s Vaccines and Related Biological Products Advisory Committee, including a data analysis from the Phase II clinical study of Spikevax, which was amended to offer a booster dose of Spikevax at the 50 µg dose level to interested participants 6-8 months following their second dose. Neutralizing antibody titers had waned prior to boosting, particularly against variants of concern, at approximately 6 months. Notably, a booster dose of mRNA-1273 at the 50 µg dose level boosted neutralizing titers significantly above the Phase III benchmark. After a booster dose, a similar level of neutralizing titers was achieved across age groups including in older adults (ages 65 and above).
In January 2022, FDA approved the Biologics License Application for Spikevax to prevent COVID-19 in individuals 18 years of age and older. FDA based its decision on the totality of scientific evidence shared by the company in its submission package, which included follow-up data from the Phase III COVE study showing high efficacy and favorable safety approximately six months after the second dose. Moderna also submitted manufacturing and facilities data required by FDA for licensure. By the time of this approval Spikevax had already received approvals by regulators in more than 70 countries, including Canada, Japan, the European Union, the UK, and Israel.
In March 2022 FDA approved Moderna’s amendment to its EUA to allow for a second booster dose of Spikevax at the 50 µg dose level in adults 50 years of age and older who have received an initial booster of any of the authorized or approved COVID-19 vaccines and adults 18 years of age and older with certain kinds of immunocompromise. The application to amend the EUA was based on published data from Israel indicating the safety and effectiveness of administering a fourth dose of vaccine during the Omicron variant surge.
In June 2022, FDA granted an EUA for Spikevax in young children ages 6 months through 5 years of age at a dose level of 25 µg. The vaccine also received EUA for a 50 μg two-dose regimen for children ages 6 through 11 years old and a 100 μg two-dose regimen for adolescents aged 12 through 17 years old. The two-dose regimens, with doses tailored for each age group given one month apart, were well-timed to initiate protection for the start of the school year, as children return to higher-risk classroom and daycare settings.
Spikevax for children and adolescents showed protection starting 14 days after the second dose. Protection was statistically significant, with data coming from large, well-controlled trials of more than 14,000 children and adolescents and a median follow-up of more than 2 months for 6 months through 5 years of age, 5.6 months for 6 through 11 years of age, and 11.1 months for adolescents. Positive interim results from the Phase II/III KidCOVE study showed a robust neutralizing antibody response in the 6 months through 5 years of age group consistent with young adults, even at the lower 25 μg dose, along with a favorable safety profile consistent with other age groups. The antibody titers in the pre-specified 6 months to 23 months and 2 years to 5 years age sub-groups met the success criteria for similarity to the adults in the COVE study, which satisfied the primary objective of the study. The secondary endpoint of vaccine efficacy was observed to be 51 percent and 37 percent based on RT-PCR confirmed COVID-19 and CDC case definition in the 6 months through 23 months and 2 years through 5 years age groups, respectively, comparable to the vaccine efficacy observed in adults receiving Spikevax during the same Omicron prevailing period.
In August 2022, FDA granted an EUA for Moderna’s BA.4/.5 Omicron-targeting bivalent COVID-19 booster vaccine, mRNA-1273.222. Authorization was given for a 50 µg booster dose for adults over 18 years of age who had received either a primary series or an initial booster of any of the authorized or approved COVID-19 vaccines. The 50 µg booster dose of mRNA-1273.222 includes 25 µg of mRNA encoding for the spike protein of BA.4/.5 and 25 µg encoding for the original strain of the SARS-CoV-2 virus. This authorization was expanded to children and adolescents 6 to 17 years of age in October 2022.
|Josh Slatko is contributing editor of Med Ad News and PharmaLive.com.|