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Product Development

COVID mAb data from Lilly, AbCellera suggest monotherapy may soon be superseded by Lilly’s combo 

Shaky argument for monotherapy is undermined by strength of the two-mAb combo

The shaky argument for the monotherapy is undermined by the strength of two-mAb combo.

Nov 12, 2020 | 12:58 AM GMT

Whether the spike-targeting mAb bamlanivimab from Eli Lilly and AbCellera will have a substantial impact on the COVID-19 pandemic boils down to two factors: the strength of its efficacy and its availability. The former isn’t fully characterized, nor are the initial data overwhelming, and the latter will be limited, at least initially.

Moreover, the strength of the pharma’s next candidate — a  combination of mAbs — undermines its explanation for the monotherapy’s weak effect on viral load.

Eli Lilly and Co. (NYSE:LLY) has reported stronger clinical data from a combination of bamlanivimab, which is partnered with AbCellera Biologics Inc., and a second mAb from Shanghai Junshi Biosciences Co. Ltd. (HKEX:1877; Shanghai:688180). Lilly said in an October presentation that it plans to apply for emergency use authorization of the bamlanivimab/etesevimab combo this month.

Regeneron Pharmaceuticals Inc. (NASDAQ:REGN) has an EUA pending for its two-mAb cocktail REGN-COV2, meaning Lilly’s monotherapy could have company in the armamentarium soon. 

FDA granted bamlanivimab an EUA on Nov. 9 to treat COVID-19 outpatients based on data from the Phase II BLAZE-1 trial, in which the middle, 2,800 mg dose of the mAb — but not the authorized dose of 700 mg or the high dose of 7,000 mg — met the primary endpoint of lowering viral loads at day 11 vs. placebo.

The mAb’s small effect and lack of dose response on the primary endpoint cast doubt on its effect on viral clearance. Secondary endpoints, however, suggest it may keep a subset of patients out of the hospital, and could alleviate some symptoms. It’s likely those clinical outcomes, combined with a post hoc analysis of patients with “persistently high viral load,” are what persuaded FDA.

At a briefing on Tuesday, Janet Woodcock, leader of Operation Warp Speed’s therapeutics program,  defended the dosing in bamlanivimab’s EUA. She said the low dose didn’t perform better on the primary endpoint because “most people can clear the virus on their own and giving them additional antibody isn't doing very much.”

Woodcock added that the mAb “reduced the virus very rapidly” in a subset of individuals who hadn’t mounted an immune attack against the virus — a claim that likely rests on the company’s post hoc analysis, as it is not directly addressed by any of the prespecified analyses. 

However, data from the combo arm of the same trial contradict the idea that additional antibody won’t create a detectable difference on the grounds that many people can clear the virus without therapy. When given together, bamlanivimab and etesevimab produced statistically significant reductions in viral load at all three time points monitored in the trial. 

“We are confident in the growing body of evidence supporting bamlanivimab 700 mg for the treatment of COVID-19. In BLAZE-1, the primary endpoint of reduction of viral load on Day 11 was a starting point based on limited data,” Lilly told BioCentury in an emailed statement.

The pharma also invoked the argument that “most patients (including those receiving placebo) demonstrated near complete viral clearance by day 11,” and added “when the total body of virology data is evaluated, there is no evidence of important differences between the doses.”

Through Operation Warp Speed, the U.S. government has contracted to purchase 300,000 doses of bamlanivimab this year and has an option to purchase an additional 650,000 doses through June 2021.

According to the CDC, there were over 120,000 new cases in the U.S. last week.

In Tuesday’s briefing, Woodcock said “The goal during this EUA should be to treat high-risk individuals.”

Bamlanivimab will initially be distributed only to hospitals and hospital-affiliated facilities such as emergency rooms and urgent care centers. Safely delivering the mAb will likely require alternative administration sites to avoid sending infected people into infusion centers where cancer and autoimmune patients are receiving treatment.

It’s clear that the viral reductions alone aren’t what persuaded FDA to grant an EUA. In a statement to BioCentury, Lilly said, “The more clinically meaningful evidence came from the predefined secondary endpoint of COVID-19-related hospitalizations or emergency room visits.” And Woodcock’s comments suggested that secondary endpoints lent support to the efficacy of the monotherapy. 

The same BLAZE-1 trial produced more convincing viral reduction data for the two-mAb cocktail, suggesting that it may fast upstage the monotherapy as an agent of choice. 

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