This article was originally published by GEN.

Clinical setbacks reported this past week by Regeneron Pharmaceuticals and Eli Lilly have raised questions about the effectiveness of antibody therapies in patients with severe COVID-19 compared to patients with mild-to-moderate forms of the virus. Regeneron said Friday it agreed to hold off on further enrollment of patients requiring high-flow oxygen or mechanical ventilation in the Phase II/III portion (NCT04426695) of an adaptive Phase I/II/III trial assessing its two-antibody “cocktail” REGN-COV2 in hospitalized adult patients with COVID-19. In pausing enrollment of the sickest patients, Regeneron said it is following the recommendation of the trial’s independent data monitoring committee (IDMC) “based on a potential safety signal and an unfavorable risk/benefit profile at this time.” Regeneron did not disclose the potential safety signal that triggered the pause in patient enrollment—but did say it would inform the FDA of its findings, since the agency is evaluating the company’s request for an emergency use authorization (EUA) of REGN-COV2 for in mild-to-moderate outpatients at high risk for poor outcomes. Regeneron is the second developer of a leading antibody candidate against COVID-19 to suffer a clinical setback this past week. On October 26, the NIH’s National Institute of Allergy and Infectious Diseases (NIAID) halted the up-to-10,000 patient Phase III ACTIV-3 trial (NCT04501978) it was conducting to assess the safety and effectiveness of Lilly’s LY-CoV555, recently renamed bamlanivimab, compared with Gilead Sciences’ Veklury (remdesivir) and placebo in people who have been hospitalized with COVID-19.

“Disappointing replication”

“A disappointing replication: monoclonal antibodies to #SARSCoV2 don’t provide benefit to hospitalized patients w/ moderate-severe illness,” tweeted Eric Topol, MD, founder and director of the Scripps Translational Research Institute, on Friday. Topol, who is also professor, molecular medicine and executive vice president of Scripps Research, added that the Regeneron and Lilly disappointments reflected “the need to treat #COVID19 early or preventatively.” Florian Krammer, PhD, professor at the department of microbiology, Icahn School of Medicine at Mount Sinai, also noted in a Twitter thread that early in COVID-19, monoclonal antibodies and other antivirals are likely to help infected patients. “Late in infection, our own immune system does the damage, and immunomodulatory drugs likely help at this stage (like dexamethasone),” Krammer said. “Using mAbs late (like in the trials stopped by Eli Lilly and Regeneron) was unlikely to work. But using them early is very promising.” Reflecting that promise, the IDMC in Regeneron’s hospitalized patient trial of REGN-COV2 also recommended continuing enrollment of the less severely injured hospitalized patients—namely those requiring either no or low-flow oxygen, “as the risk/benefit remains acceptable in these cohorts.” The trial has an estimated enrollment of 2,970 participants.

No changes

Regeneron added that its other three late-stage trials will proceed with no changes. One of those trials is the Phase II/III portion (NCT04425629) of an adaptive Phase I/II/III trial evaluating the safety, tolerability, and efficacy of REGN-COV2 in ambulatory adult outpatients with COVID-19. The randomized, double-blind trial has an estimated enrollment of 2,104 participants. On Wednesday, Regeneron trumpeted data from a second group of 524 patients showing that the antibody cocktail met its primary endpoint of significantly reducing viral load and medical visits. However, Regeneron disclosed that it was reviewing a possible change to dosages in that study after finding no significant difference in efficacy between REGN-COV2’s low dose of 2.4 g, and its high dose of 8 g. That finding differed with initial data from the trial’s first 275 patients that was announced by the company in September, which showed that the 8 g dose showed better results than the 2.4 g low dose and placebo. The results from the first 275 patients also showed REGN-COV2 significantly reducing viral load and medical visits. Based on those positive results, Regeneron said October 7 it will seek an EUA for the antibody cocktail.

Symptomatic benefit?

Brian P. Skorney, a senior research analyst with Baird, observed in a research note that while data from the first group of patients showed a symptomatic benefit, data from the second did not—by Regeneron’s design. “There was no planned formal statistical analysis of symptom alleviation in this analysis; descriptive analyses did not reveal robust associations with viral load, serology status or treatment,” the company stated on Wednesday. Concluded Skorney: “Unfortunately, it seems that the symptomatic benefit Regeneron highlighted in its top-line release of the early data from this study has waned.” The other two late-stage trials with which Regeneron is proceeding:

• A portion of the 15,000-patient open-label, Phase III RECOVERY (Randomized Evaluation of COVid-19 thERapY) trial (NCT04381936) that is examining the effectiveness of the cocktail plus standard of care in at least 2,000 hospitalized COVID-19 patients to be chosen at random in the U.K., and comparing that to another 2,000 patients who already receive standard of care alone.
• A 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. The trial has an estimated enrollment of 2,000 participants.

REGN-COV2 is a combination of two monoclonal antibodies, REGN10933 and REGN10987, that are designed to both treat people with COVID-19 and to prevent SARS-CoV-2 infection. Both antibodies are designed to bind non-competitively to different sides of the receptor-binding domain (RBD) of SARS-CoV-2’s spike protein. Bamlanivimab is an anti-SAR-CoV-2 antibody first identified in a blood sample from a recovered COVID-19 patient, and discovered through the rapid pandemic response platform of partner AbCellera, in partnership with NIAID’s Vaccine Research Center.

Front runners

Both REGN-COV2 and bamlanivimab are among 19 “front runner” candidates among the 230+ COVID-19 therapeutics detailed in GEN’s updated “COVID-19 Drug & Vaccine Candidate Tracker.” On October 13, NIAID paused patient enrollment in the Phase III ACTIV-3 trial, citing an undisclosed safety concern. The trial had recruited 326 participants before the pause, which NIAID said was recommended by its independent data safety monitoring board after “an overall difference in clinical status between the group receiving LY-CoV555 and the group receiving saline placebo” was found during a planned interim analysis of safety data for the first 300 participants enrolled in the trial. The board followed up by reviewing data October 26 at a scheduled meeting. The data suggested that bamlanivimab was unlikely to help hospitalized COVID-19 patients recover from the advanced stage of their disease, NIAID and Lilly stated. Eli Lilly’s antibody therapy is the first of several COVID-19 candidates set to be evaluated in ACTIV-3. The multicenter, adaptive, randomized, blinded, controlled trial is governed by a master protocol is designed to allow for the study of multiple candidates compared to placebo in adults hospitalized with COVID-19. Participants in ACTIV-3 were randomized to treatment with LY-CoV555 plus current standard of care (SOC), remdesivir plus current SOC, or placebo plus current SOC. Lilly said all other trials of LY-CoV555 were continuing, and noted that ACTIV-3 focused on hospitalized patients who were being treated with other drugs and were more severely ill than those in its other trials. The other trials include:

• ACTIV-2 (NCT04518410), an NIH-sponsored study in recently diagnosed mild to moderate COVID-19 patients;
• BLAZE-1 (NCT04427501), Lilly’s ongoing Phase II trial in people recently diagnosed with COVID-19 in the ambulatory (non-hospitalized) setting, studying bamlanivimab as monotherapy and in combination with etesevimab;
• BLAZE-2 (NCT04497987), Lilly’s Phase III study of bamlanivimab for the prevention of COVID-19 in residents and staff at long-term care facilities.

“Insufficient evidence”

“While there was insufficient evidence that bamlanivimab improved clinical outcomes when added to other treatments in hospitalized patients with COVID-19, we remain confident based on data from Lilly’s BLAZE-1 study that bamlanivimab monotherapy may prevent progression of disease for those earlier in the course of COVID-19,” Lilly said October 28 in a  statement. The following day, Derek Lowe, PhD, a drug discovery chemist who authors the blog “In the Pipeline” published by Science Translational Medicine, opined on Twitter: “I have to be honest: I was expecting more from the monoclonal antibodies than we’re seeing now from Lilly and Regeneron.” “It looks like you need to give the mAbs early, to people who have risk factors,” Lowe added. In September, Lilly announced positive proof of concept data from an interim analysis of the Phase II BLAZE-1 trial showing a reduced rate of hospitalization for mild-to-moderate recently diagnosed COVID-19 patients treated with bamlanivimab. The trial’s pre-specified primary endpoint, change from baseline in viral load at day 11, was met at the middle of three dose levels studied (2800 mg), but not the other three groups studied (700 mg, 7000 mg, and placebo). According to Lilly, most patients—including those randomized to placebo—showed near-complete viral clearance by day 11. Bamlanivimab also improved viral clearance at an earlier time point (day 3) and reduced the proportion of patients with persistently high viral load at later time points. Another pre-specified endpoint, COVID-19-related hospitalization or ER visit, occurred in 1.7% (5/302) of bamlanivimab patients, pooled across dose groups, compared to 6% (9/150) of placebo patients—a 72% risk reduction, Lilly said. Most study hospitalizations occurred in patients with underlying risk factors (age or body mass index), suggesting a more pronounced treatment effect for patients in these higher-risk groups, a finding that Lilly said it will seek to confirm through ongoing studies. BLAZE-1 is enrolling a larger, confirmatory cohort of higher risk patients, testing the ability of the antibody combination to reduce the number of patients with persistently high viral load and reduce COVID-19 related hospitalizations.

Positive combination data

Earlier this month, Lilly promoted positive interim data from BLAZE-1 showing that a combination of LY-CoV555 and LY-CoV016—another Lilly antibody that binds a different epitope in the SARS-CoV-2 spike region—reduced viral load, symptoms, and COVID-related hospitalization and ER visits. A day later, Lilly announced additional BLAZE-1 data from an exploratory analysis which showed that the proportion of patients with persistent high viral load at day 7 for the combination therapy was lower (3.0%) vs. placebo (20.8%). Based on that positive data, Lilly submitted a request to the FDA for an EUA of bamlanivimab as a monotherapy in higher-risk patients who have been recently diagnosed with mild-to-moderate COVID-19. However, Lilly did not furnish baseline viral load data in its announcement of interim results: “The lack of baseline viral load data for LLY is not helpful,” Canaccord Genuity analyst John Newman, PhD, fumed in a research note. The randomized, double-blind, placebo-controlled BLAZE-1 assessed the two neutralizing antibodies for the treatment of symptomatic COVID-19 in the outpatient setting. The combination cohort enrolled recently diagnosed patients with mild-to-moderate COVID-19, of which 112 were assigned to 2800 mg of each antibody, while the other 156 patients were randomized to placebo. At day 11, the combination therapy met the trial’s primary endpoint by “significantly” reducing viral load at day 11, while “most” patients, including those receiving placebo, showed near-complete viral clearance by day 11. Lilly said it plans to publish data for the combination therapy and LY-CoV555 monotherapy in peer-reviewed journals “as soon as possible.” Lilly added that the combination treatment reduced viral levels at day 3 and day 7, while also significantly reducing the time-weighted average change from baseline from day 1 to 11. An exploratory analysis showed that the proportion of patients with persistent high viral load at day 7 for combination therapy was lower (3.0%) vs. placebo (20.8%). The post Regeneron, Lilly Setbacks Raise Questions on the Effectiveness of Antibodies in Severe COVID-19 appeared first on GEN - Genetic Engineering and Biotechnology News.