Two Weeks Ago, We Had No Treatment for COVID -19. Now There are Two

By Andrew Dahl, M.D.

Two weeks ago, there were no effective therapeutics to treat COVID-19 infection. Despite being highly touted initially, convalescent plasma is basically worthless and remdesivir may shorten the length of a hospital stay but likely does nothing for the 96+% of patients contracting the disease who, at least on initial presentation, do not require hospital care. Decadron (steroid) therapy should be reserved for critically ill patients within the hospital setting.

There are now two effective monoclonal neutralizing antibody therapies for patients who are infected with COVID-19 and become symptomatic. Regeneron reported impressive clinical trial results of their “antibody cocktail” less than two weeks ago, just in time for President Trump to receive the drug when he became ill. Lilly released some early unimpressive data for a single antibody trial a month ago, but today provided additional data on a two-antibody approach, revealing significant effectiveness and safety. Both companies are in the process of meeting with the FDA to secure emergency authorization use, Regeneron for their dual antibody combination and Lilly for its initial one antibody treatment. Both companies’ optimism in the potential for these antibodies is illustrated by Regeneron partnering in production of the treatment with their competitor, Roche. The two have sparred in the lucrative anti-angiogenesis macular degeneration treatment landscape for years. Lilly is doing the same with Amgen in attempting to rapidly produce larger amounts of their biologic agent.

Let us examine the preliminary public data from the two companies, which have neither been published in a journal nor peer reviewed.

Regeneron:

On September 29, 2020, Regeneron provided an interim analysis of their Phase 1/2/3 randomized, double-blind, placebo-controlled trial of its investigational antibody cocktail, REGN-COV2, for the treatment of symptomatic COVID-19 in the outpatient setting. The trial enrolled mild-to-moderate recently diagnosed COVID-19 patients and treated them with either placebo or a combination of two different monoclonal antibodies by intravenous infusion. This interim analysis involved the first 275 patients enrolled in the trial, randomized 1:1:1 to placebo, high dose (8 grams) or low dose (2.4 grams). Prior to treatment, patients were classified as seronegative or seropositive, dependent on whether they had already produced endogenous antibodies (approximately 50% in each group). Furthermore, they were also classified as having either a “high” viral load or a” low” viral load. These classifications did not influence placement within a specific arm of the study. The analysis found, as might be expected, that there was a strong correlation between seronegativity and a high viral load and a similar strong correlation between seropositivity and a low viral load prior to treatment. In the untreated (placebo) patients, seropositive patients had a median time to alleviation of symptoms of 7 days, compared to seronegative patients who had a median time to alleviation of symptoms of 13 days. Patients with increasingly higher baseline viral levels had correspondingly greater reductions in viral load at Day 7 with REGN-COV2 treatment. Reduction in viral loads at day 7 in treated patients versus placebo were statistically significant (p=0.03 or better, depending on initial viral load) for both high and low dose REGN-COV-2. Patients receiving the antibody cocktail who were seronegative with higher baseline viral levels also had greater benefits in terms of symptom alleviation when compared to placebo. Among these patients, median time to symptom alleviation was 13 days with placebo, 8 days with high dose treatment and 6 days in low dose treated patients. The number of patients requiring hospitalization or medical visits was small in both treated and placebo patients, but significantly less in treated patients. The vast majority of symptomatic patients with mild to moderate disease do not go to the emergency room or need hospitalization under any circumstances. Treatment was well-tolerated.

Regeneron is prepared to have up to 300,000 doses of the antibody cocktail available this year..

Eli Lilly:

On September 16, 2020, Lilly provided an interim analysis of their BLAZE-1 clinical trial, a randomized, double-blind, placebo-controlled Phase 2 study to evaluate their investigational monoclonal antibody, LY-CoV555, for the treatment of symptomatic COVID-19 in the outpatient setting. The trial enrolled mild-to-moderate recently diagnosed COVID-19 patients and treated them with either placebo or one of three doses of the antibody (700 mg, 2800 mg, or 7000 mg). by intravenous infusion. The interim analysis involved 452 patients, 1/3 of whom were treated with placebo. In this population, the primary endpoint, change from baseline in viral load at day 11, was statistically different from placebo in only the 2800 mg dosage group, not in the lower or higher dose group. This was a somewhat confusing and unimpressive result, but likely predictable in that most patients, including those receiving placebo, “demonstrated near complete viral clearance by day 11.” The other, softer, endpoint was that of COVID-19-related hospitalization or ER visits. 1.7% of treated patients reached this endpoint while six percent of treated patients sought an ER visit or “required” hospitalization. Not a large number in either group should have been expected since most symptomatic patients with mild to moderate disease choose not to go to the emergency room or need hospitalization under any circumstances. Treated patents had an 8% development of viral resistance. Treatment was well-tolerated.

These results do not represent significant progress in disease treatment, perhaps because of study design. I have difficulty fathoming why Lilly went to the FDA today with these results to ask for emergency use authorization (EUA) for the single LY-CoV555 antibody. Perhaps it was to counter Regeneron’s move. I do not think they will get EUA for the single antibody based on this data.

Today, Lilly released additional data from an interim analysis of an additional 112 patients who were treated in BLAZE-1 with a combination of two Lilly SARS-CoV2 antibodies, the same LLYCoV555 together with and a second antibody, LLY CoV016, each at a dosage level of 2800 mg in the 112 treated patients. The same 156 patients were used as a placebo group as in the earlier study. Most patients in both treated and placebo groups achieved the primary end point of near total viral clearance at 11 days. More importantly, there was reduced viral levels at day 3 (p=0.016) and day 7 (p=<.001) in the treated group versus placebo. There were no resistance variants observed in patients receiving the two antibodies. ER and hospitalization was again reduced with the combination therapy (0.9 percent) versus placebo (5.8 percent), a relative risk reduction of 84.5 percent (p=0.049). Most likely these again were small numbers. Lilly may feel that it is premature to ask for EUA for their dual antibody approach, given the relatively small number of patients reported today.

Of note, Lilly also announced today that they were prepared to supply 1 million doses of monotherapy in 2020 and 50,000 doses of combination therapy this year. It seems a shame that most of that million doses of monotherapy will not achieve much or go to waste, given the data released so far for single antibody treatment.

Both Regeneron and Lilly have additional ongoing studies of their antibodies in hospitalized patients. Regeneron is also involved in a Phase 3 open-label RECOVERY trial of hospitalized patients in the UK and a Phase 3 trial for the prevention of COVID-19 in household contacts of infected individuals. Recruitment in all trials of both companies is ongoing.

This is genuinely exciting news in the battle against the pandemic. Any vaccine is still a long way from approval, much less distribution to a large portion of the population. In addition, the vaccine likely will be only 50–65% effective, meaning that 35 to 50% of those immunized will not have sufficient neutralizing antibodies to combat the disease. If people can be confident that should they contract Covid-19, dual monoclonal therapy is available to keep them alive and out of the hospital, reduce their symptoms, and get back to normal more quickly, then Covid-19 can be viewed as just another flu-like illness, and we can get back to our normal unmasked lives.