Three antibody candidates designed to fight COVID-19, including two that are authorized for emergency use by the FDA, have shown positive late-stage clinical results according to separate studies released by their developers, Eli Lilly and Regeneron Pharmaceuticals.
Lilly said its authorized bamlanivimab (LY-CoV555), in combination with another of its antibody candidates, etesevimab (LY-CoV016), met the primary endpoint of the Phase III BLAZE-1 trial (NCT04427501) by significantly reducing COVID-19-related hospitalizations and deaths in high-risk patients recently diagnosed with COVID-19.
Of the 10 patients who died during the study, all were randomized to placebo, Lilly added.
Lilly reported 11 events (2.1%) in patients receiving its antibody combination, compared with 36 events (7%) in placebo patients—a 70% risk reduction among the study’s 1,035 patients. That decrease was consistent with the reduction in risk of hospitalization or ER visits seen with bamlanivimab alone in the Phase II portion of BLAZE-1, the company said.
The bamlanivimab-etesevimab combo also showed statistically significant improvements on all four key secondary endpoints—the change from baseline to day 7 in SARS-CoV-2 viral load, persistently high SARS-CoV2 viral load on day 7, time to sustained symptom resolution, and COVID-related hospitalization, ER visit or death from any cause from baseline by day 29.
By generating positive results in the secondary endpoints, Lilly said, bamlanivimab-etesevimab offered strong evidence that the combination shrunk viral load and accelerated symptom resolution.
“These exciting results, which replicate positive Phase II data in a much larger set of patients, add valuable clinical evidence about the role neutralizing antibodies can play in fighting this pandemic,” Daniel Skovronsky, MD, PhD, Lilly’s chief scientific officer and president of Lilly Research Laboratories, said yesterday in a statement. “These data further support our belief that bamlanivimab and etesevimab together have the potential to be an important treatment that significantly reduces hospitalizations and death in high-risk COVID-19 patients,” Skovronsky added.
The results marked the second time in less than a week that Lilly announced a positive clinical outcome for bamlanivimab.
On January 21, the company trumpeted findings from its BLAZE-2 trial (NCT04497987), saying that bamlanivimab significantly reduced the risk of contracting symptomatic COVID-19 among residents and staff of long-term care facilities compared with placebo after eight weeks. Lilly said that 299 SARS-CoV-2 negative residents randomized to bamlanivimab had up to an 80% lower risk of contracting COVID-19 versus residents in the same facility randomized to placebo.
BLAZE-2 enrolled 965 participants who tested negative for SARS-CoV-2 at baseline (299 residents and 666 staff), and 132 participants (41 residents and 91 staff) who tested positive. Lilly is conducting BLAZE-2 with the NIH’s National Institute of Allergy and Infectious Diseases (NIAID) and the COVID-19 Prevention Network (CoVPN).
Bamlanivimab is a recombinant, neutralizing human immunoglobulin G1 (IgG1) monoclonal antibody first identified in a blood sample from one of the first U.S. patients who recovered from COVID-19. The antibody was discovered through the rapid pandemic response platform of partner AbCellera, in collaboration with NIAID’s Vaccine Research Center. Lilly and AbCellera partnered in March 2020 to identify the most promising of 500+ antibodies discovered through the platform.
Etesevimab is a recombinant fully human monoclonal neutralizing antibody designed to specifically bind to the SARS-CoV-2 surface spike protein receptor-binding domain with high affinity, while blocking the binding of the virus to the ACE2 host cell surface receptor.
The FDA is reviewing Lilly’s request for an Emergency Use Authorization (EUA) for the bamlanivimab-etesevimab combination. The FDA granted an EUA to bamlanivimab on November 9, allowing for distribution and emergency administration via a single intravenous infusion at the lowest IV dose studied, 700 mg. Nearly two weeks later on November 21, the FDA authorized REGEN-COV (casirivimab and imdevimab) for emergency use, with administration via a single intravenous infusion at 2,400 mg—consisting of 1,200 mg of casirivimab and 1,200 mg of imdevimab. Casirivimab and imdevimab were the two most potent, non-competing, and virus-neutralizing antibodies selected from thousands produced through Regeneron’s monoclonal antibody discovery platform VelocImmune®, part of the company’s VelociSuite™ technologies. Regeneron has said it has produced two distinct antibody cocktails, an initial cocktail and a backup.
Both the Regeneron and Lilly antibody treatments are indicated for adults and youths ages 12 years and older with mild-to-moderate COVID-19. In granting the companies their EUAs, the FDA emphasized that the antibody therapies are not authorized for patients who are hospitalized due to COVID-19 or require oxygen therapy due to COVID-19, since no benefit to the treatments has been shown in those patients.
Bamlanivimab and REGEN-COV2 are also among 21 “Front Runner” leading candidates among the more than 300 COVID-19 therapeutics under study in GEN’s “COVID-19 Drug & Vaccine Candidate Tracker.”
Regeneron’s passive cocktail
Fifteen minutes after Lilly released its data, Regeneron Pharmaceuticals announced positive initial results from an ongoing Phase III clinical trial assessing its two-antibody “cocktail” REGEN-COV (casirivimab and imdevimab) as a passive vaccine for preventing COVID-19 in people at high risk of infection due to household exposure to a patient with SARS-CoV-2.
“Passive” vaccines provide immediate short-term or passive immunity by delivering protective virus-neutralizing antibodies directly to patients, either through antibody treatments or from mother to child through breast milk.
Regeneron said passive vaccination with REGEN-COV resulted in full 100% prevention of symptomatic infection (zero of 186 REGEN-COV patients) compared with the eight patients with symptomatic infections among the 223 randomized to placebo in the study, which was jointly conducted with NIAID.
“The 100% reduction in symptomatic COVID-19 with prophylactic use of REGEN-COV is striking,” Geoffrey C. Porges, MBBS, director of therapeutics research and a senior research analyst at SVB Leerink, wrote yesterday in a research note.
REGEN-COV also resulted in approximately 50% lower overall rates of symptomatic and asymptomatic infection—10 of 186 patients, compared with 23 of 223 placebo patients. The lower number of infections occurring with REGEN-COV therapy were all asymptomatic, with decreased peak virus levels and short duration of viral shedding, Regeneron said.
The increased rate of SARS-CoV-2 infections in the placebo group in turn drove more frequent adverse events, Regeneron observed. According to its data, 18% of placebo patients experiencing adverse events, compared with 12% of patients treated with REGEN-COV.
Infections in the REGEN-COV group lasted no more than one week, the company added, compared with the 3-to-4 week duration of approximately 40% of infections in the placebo group. Also, none of the asymptomatic infected individuals in the REGEN-COV group (0 of 9) showed high viral loads (>10^4 copies/mL), compared to the 62% of infected patients (13 of 21) in the placebo group.
Additionally, REGEN-COV was associated with lower disease burden by showing:
- Fewer total viral shedding weeks (44 weeks placebo vs. 9 weeks REGEN-COV)
- Fewer total high viral shedding weeks (>10^4 copies/mL) (22 weeks placebo vs. 0 weeks REGEN-COV)
- Fewer total symptomatic weeks (18 weeks placebo vs. 0 weeks REGEN-COV)
“These data using REGEN-COV as a passive vaccine suggest that it may both reduce transmission of the virus as well as reduce viral and disease burden in those who still get infected,” George D. Yancopoulos, MD, PhD, Regeneron’s president and chief scientific officer, said in a statement.
Distribution, manufacturing “boon”
As significant as the findings of the dosage of the antibody cocktail, Porges said, was the administration of REGEN-COV at a dosage of 1,200 mg—not the 2,400 mg infusion authorized by the FDA EUA. That “should be a boon to both distribution and manufacturing,” Porges predicted.
Regeneron’s data came from an exploratory analysis conducted on the first 409 evaluable individuals enrolled in the trial. They were randomized to receive passive vaccination with REGEN-COV (1,200 mg via subcutaneous injections) or placebo.
Confirmatory Phase III results are expected in the second quarter.
“We look forward to seeing the full dataset early next quarter and will discuss the current results with regulatory authorities, including the potential to expand the Emergency Use Authorization,” stated David Weinreich, MD, executive vice president and head of global clinical development at Regeneron.
Weinreich also noted that REGEN-COV was administered via injections rather than infusion, which he said “makes administration much more convenient and efficient for patients and overburdened healthcare providers and facilities.”
Both REGEN-COV2 and bamlanivimab are indicated for administration as soon as possible after a positive COVID-19 test and within 10 days of symptom onset. Before patients can be treated with either treatment, according to their EUAs, they must weigh at least 40 kilograms (about 88 pounds) and be deemed at high risk for progressing to severe COVID-19 and/or hospitalization. That high-risk category includes adults who are ages 65 or older, or who have chronic medical conditions.
“Even with the emerging availability of active vaccines, we continue to see hundreds of thousands of people infected daily, actively spreading the virus to their close contacts,” Yancopoulos added. “The REGEN-COV antibody cocktail may be able to help break this chain by providing immediate passive immunity to those at high risk of infection, in contrast to active vaccines which take weeks to provide protection.”