Regeneron Pharmaceuticals and Moderna on Tuesday released encouraging preliminary data on their therapeutic and vaccine candidates targeting COVID-19. Regeneron’s candidate REGN-COV2—an antibody combination therapy—is enrolled in a Phase I/II/III trial, while Moderna’s mRNA-1273 is a vaccine candidate enrolled in a Phase I clinical study.
Researchers from Moderna and clinical partners published a second interim analysis of data in The New England Journal of Medicine (NEJM) from the open-label Phase I trial (NCT04283461) of its mRNA-1273 that is being conducted by the NIH’s National Institute of Allergy and Infectious Diseases (NIAID). The analysis assessed a two-dose vaccination with mRNA-1273 with the doses given 28 days apart in 40 healthy adult participants across two dose levels (25 and 100 µg) in two age cohorts (ages 56–70 and ages 71) with the results reported through Day 57, one month after the second dose.
At both the 25 µg and 100 µg dose levels, mRNA-1273 induced dose-dependent binding antibody responses after two vaccinations that reached the upper quartile of the distribution of convalescent sera. At Day 57, geometric mean titers (GMT) exceeded the median of those seen in convalescent sera from 41 individuals with confirmed COVID-19 diagnosis, Moderna said.
“These interim Phase I data suggests that mRNA-1273, our vaccine candidate for the prevention of COVID-19, can generate neutralizing antibodies in older and elderly adults at levels comparable to those in younger adults,” Tal Zaks, M.D., Ph.D., Moderna’s chief medical officer, said in a statement.
The researchers reported that both the 25 µg and 100 µg dose levels were generally well-tolerated in both age cohorts, with no serious adverse events reported through Day 57. Immune responses were dose-dependent with the 100 µg dose eliciting higher binding and neutralizing antibody titers, supporting the selection of the 100 µg dose for further study in Moderna’s Phase III COVE trial (NCT04470427).
NIAID and Moderna assessed neutralizing activity through multiple assays that included a pseudovirus neutralization assay (pseudotyped lentivirus reporter single-round-of-infection neutralization assay [PsVNA]) against the two most common SARS-CoV-2 variants (614D and 614G) and three live-virus neutralization assays (SARS-CoV-2 nanoluciferase high-throughput neutralization assay [nLUC HTNA], a focus reduction neutralization test mNeonGreen [FRNT-mNG], and the 80% plaque-reduction neutralization test [PRNT80]). At Day 43, PRNT80 GMT in the 100 ug dose groups was 878 in the 56–70 and 317 in the 71+ age cohort, representing 5.5 and 2.0-fold above convalescent sera respectively, and 4.1-fold above convalescent sera in the 18–55 age group (GMT 654).
No participants had detectable neutralizing responses by any assay prior to vaccination, and robust neutralizing activity was observed in all participants 14 days after the second vaccination, Moderna said.
The most common solicited adverse events were headache, fatigue, myalgia, chills, and pain at the injection site, most of which were mild-to-moderate and of self-limited duration, according to the company. Local and systemic reactogenicity were more common and more frequently moderate in severity after the second dose. Two severe solicited systemic adverse events occurred following the second vaccination: fever in one participant in the ages 56-70 cohort who received the 25 µg dose and fatigue in one participant in the ages 71+ cohort who received the 100 µg dose. Clinical laboratory values of Grade 2 or higher revealed no pattern of concern. Participants will continue to be followed through 13-months to allow for a longer assessment of vaccine-related adverse events.
“Overall, these preliminary findings show that in a small group of participants, adverse events associated with the mRNA-1273 vaccine were mainly mild or moderate in older adults, a group that is particularly at risk for illness and death from COVID-19,” the researchers concluded. “The 100-μg dose induced higher binding- and neutralizing-antibody titers than the 25-μg dose, findings that support the continued evaluation of the 100-μg dose level and two-dose regimen in a large Phase III trial with a more diverse population to ascertain the safety and efficacy of the mRNA-1273 vaccine and to assess its level of protection against COVID-19.
Moderna and NIAID in July launched the COVE trial, designed to evaluate the safety of mRNA-1273 in 30,000 adult volunteers who do not have COVID-19. The primary endpoint will be 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.
Viral Load Reduction
Regeneron said REGN-COV2 rapidly reduced viral load as well as time to alleviate symptoms in non-hospitalized patients with COVID-19, and also reduced medical visits for patients, in the Phase I/II/III trial. The ongoing, randomized, double-blind trial measures the effect of adding REGN-COV2 to standard-of-care, compared to adding placebo to standard-of-care.
“The greatest treatment benefit was in patients who had not mounted their own effective immune response, suggesting that REGN-COV2 could provide a therapeutic substitute for the naturally-occurring immune response. These patients were less likely to clear the virus on their own, and were at greater risk for prolonged symptoms,” stated George D. Yancopoulos, MD, PhD, Regeneron’s president and chief scientific officer. “We are highly encouraged by the robust and consistent nature of these initial data, as well as the emerging well-tolerated safety profile, and we have begun discussing our findings with regulatory authorities while continuing our ongoing trials.”
In addition to having positive implications for REGN-COV2 trials and those of other antibody therapies, Yancopoulos added, the data generated by Regeneron also support vaccines targeting the SARS-CoV-2 spike protein.
Regeneron announced results from the first 275 patients enrolled in the trial, which was designed to evaluate anti-viral activity with REGN-COV2 and identify patients most likely to benefit from treatment. At least 1,300 patients will be recruited into the Phase II/III portion of the outpatient trial. They will be followed for 29 days, with viral shedding in the upper respiratory tract assessed approximately every 2–3 days in the Phase II portion of the trial and clinical endpoints assessed via investigator and patient-reported data throughout.
Patients in the trial were randomized 1:1:1 to receive a one-time infusion of 8 grams of REGN-COV2 (high dose), 2.4 grams of REGN-COV2 (low dose) or placebo. Of those first 275 patients, approximately 56% were Hispanic, 13% were African American and 64% had one or more underlying risk factors for severe COVID-19, including obesity (more than 40%). Patients were 44 years of age on average, with 49% of participants being male and 51%, female.
Patients were prospectively characterized prior to treatment by serology tests to see if they had already generated antiviral antibodies on their own and were classified as seronegative (no measurable antiviral antibodies) or seropositive (measurable antiviral antibodies). Approximately 45% of patients were seropositive, 41% were seronegative and 14% were categorized as “other” due to unclear or unknown serology status, Regeneron said.
All patients entering the trial had laboratory-confirmed COVID-19 that was being treated in the outpatient setting—though Regeneron added that the patients consisted of two different populations: those who had already mounted an effective immune response, and those whose immune response was not yet adequate, based on being seropositive or seronegative for SARS-CoV-2 antibodies, and/or by high viral loads at baseline. Seropositive patients had much lower levels of virus at baseline, and rapidly achieved viral loads approaching lowest levels quantifiable (LLQ), even without treatment—while seronegative patients had substantially higher viral levels at baseline, and cleared virus more slowly in the absence of treatment.
“We are encouraged by REGN-COV2 data and see a strong need in the seronegative patient population,” Canaccord Genuity biotechnology analyst John Newman, PhD, wrote in a note to investors. “We also believe that the drug can be used at a lower dose, extending dosing capacity. We look forward to additional cohort data, as well as hospitalized patient data. In addition, the recent agreement with Roche allows REGN to significantly expand manufacturing capacity.”
Meeting Key Virologic Endpoint
Regeneron said REGN-COV2 met its key virologic endpoint of rapidly reducing viral load through Day 7 in seronegative patients. The mean time-weighted-average change from baseline nasopharyngeal (NP) viral load through Day 7 in the seronegative group was a 0.60 log10 copies/mL greater reduction (p=0.03) in patients treated with high dose, and a 0.51 log10 copies/mL greater reduction (p=0.06) in patients treated with low dose, compared to placebo.
In the overall population, Regeneron said, there was a 0.51 log10 copies/mL greater reduction (p=0.0049) in patients treated with high dose, and a 0.23 log10 copies/mL greater reduction (p= 0.20) in patients treated with low dose, compared to placebo.
“Since this study consists of 275 patients, we believe it will be difficult for the FDA to resist granting REGN’s product an EUA approval, although making it available for the population treated in this study (non-hospitalized, early symptomatic disease) would be an impossible task,” Geoffrey C. Porges, MBBS, Director of Therapeutics Research and a senior research analyst at SVB Leerink, wrote in a research note this morning. “Regulators and investigators are likely to push Regeneron to provide an early look at the results of their hospitalized, moderate to severe COVID study. If that study is trending in the same direction, then an EUA would seem to be justified.”
According to Regeneron, patients with increasingly higher baseline viral levels had correspondingly greater reductions in viral load at Day 7 with REGN-COV2. The mean log10 copies/mL reduction in viral load compared to placebo were:
- Viral load higher than 105copies/mL: high dose (-0.93); low dose (-0.86) (p=0.03 for both); approximately 50–60% reduction compared to placebo
- Viral load higher than 106copies/mL: high dose (-1.55); low dose (-1.65) (p<0.002 for both); approximately 95% reduction compared to placebo
- Viral load higher than 107copies/mL: high dose (-1.79); low dose (-2.00) (p<0.0015 for both); approximately 99% reduction compared to placebo
Among seronegative patients, median time to symptom alleviation was 13 days in placebo, 8 days in high dose (p=0.22), and 6 days in low dose (p=0.09). Patients with increasing viral loads at baseline had correspondingly increasing benefit in time to symptom alleviation.
The company said it has already enrolled the trial’s next cohort, which could be used to rapidly and prospectively confirm these results.
“While we were encouraged to see Regeneron’s antibody cocktail lead to reductions in patient’s viral loads, data surrounding the ability of this treatment to reduce patient’s symptoms and improve clinical outcomes remains limited,” Baird Senior Research Analyst Brian P. Skorney, CFA, and two colleagues wrote in a research note. “That said, we do anticipate an EUA is likely, though with only ~300K doses expected to become available by ~YE20, we don’t expect REGN-COV2 will have a substantial near-term impact on the course of the pandemic.”
The 300,000 figure is the maximum number of potential treatment doses available from bulk lots of REGN-COV2 that Regeneron agreed to manufacture and supply under a $450 million contract awarded in July by the Biomedical Advanced Research and Development Authority (BARDA). BARDA awarded the funding through its involvement in Operation Warp Speed, 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.
Skorney and colleagues also noted that Regeneron executives have anticipated being able to produce up to 250,000 doses per month next year, through an increase in manufacturing capacity enabled under a partnership with Roche announced in August, and whose value was not disclosed.
Regeneron said it would quickly publish more detailed data based on what it announced in a press release: “We plan rapidly to submit detailed results from this analysis for publication in order to share insights with the public health and medical communities,” stated David Weinreich, MD, Regeneron’s senior vice president and head of global clinical development.
Regeneron is partnering with NIAID to conduct a 2,000-patient Phase III trial (NCT04452318) designed to assess REGN-COV2’s ability to prevent infection among uninfected people who have had close exposure to a COVID-19 patient, such as a patient’s housemate.
Regeneron has also advanced REGN-COV2 into the Phase II/III portion of two adaptive Phase I/II/III trials designed to evaluate the antibody cocktail’s ability to treat hospitalized and non-hospitalized patients with COVID-19. One Phase II/III study (NCT04426695) is designed to assess the safety, tolerability, and efficacy of Regeneron’s antibody cocktail in hospitalized adult patients with COVID-19, with an estimated enrollment of 1,860 participants. The other study (NCT04425629) will evaluate the safety, tolerability, and efficacy of Regeneron’s antibody cocktail in ambulatory adult patients with COVID-19, with an estimated enrollment of 1,054 participants.
To date, Regeneron said, more than 2,000 people have been enrolled across the overall REGN-COV2 development program. No unexpected safety findings have been reported by the program’s Independent Data Monitoring Committee.