Regeneron’s COVID-19 Antibody Cocktail Shows Early Promise, But Does It Merit An EUA?

Early data from Regeneron Pharmaceuticals, Inc.’s REGN-COV2 shows the antibody cocktail has promise in treating non-hospitalized COVID-19 patients, with the most significant results in individuals who have not mounted an antibody response against the infection.

The first data from a descriptive analysis of the first 275 patients treated in a seamless Phase I/II/III trial showed the targeted antibody therapy reduced viral load and the time to alleviation of symptoms in non-hospitalized patients – but only showed clear benefits in ‘seronegative’ individuals ie, those patients who had not generated their own antibodies to fight the infection.

Perhaps one of the most illuminating findings of the study, which could help to develop COVID-19 treatment more broadly, was the surprisingly high number of patients with confirmed infection found to be seronegative, which was around 41%. Approximately 45% of patients were seropositive, and 14% were categorized as "other" due to unclear or unknown serology status.

The study also found that this serological status was highly correlated with baseline viral load (p<0.0001) – in other words those patients who had generated their own antibodies cleared the virus without the need for assistance, while those seronegative patients had the highest viral loads, and were at greater risk of prolonged symptoms.

Among seronegative patients, median time to symptom alleviation (defined as symptoms becoming mild or absent) was 13 days in placebo, eight days in high dose (p=0.22), and six days in low dose (p=0.09). This contrasted with seropositive patients, who saw symptoms disappear on average after seven days.

However, the trial was not powered to show if the treatment could keep these patients out of hospital. Seronegative patients were at higher risk of this however, 10 of the 12 medically attended visits (either hospitalizations, or emergency room, urgent care or telemedicine visits for COVID-19) occurred in patients who were seronegative at baseline. In the seronegative group, 15.2% of placebo-treated patients, 7.7% of patients treated with high dose and 4.9% of patients treated with low dose required additional medical visits.

Patients in the trial were randomized 1:1:1 to receive a one-time infusion of 8g of REGN-COV2 (high dose), 2.4g of REGN-COV2 (low dose) or placebo. All patients entering the trial had laboratory-confirmed COVID-19 that was being treated in the outpatient setting. 

The descriptive analysis was designed to evaluate anti-viral activity with REGN-COV2 and identify patients most likely to benefit from treatment. Regeneron said that the next cohort of 1,3000 patients has already been enrolled and could be used to rapidly and prospectively confirm these early results.

Regeneron's George Yancopoulos

George Yancopoulos, president and chief scientific officer of Regeneron, welcomed the initial results and said the treatment showed promise in helping these patients who had not mounted their own effective antibody response, and could provide a therapeutic substitute for the naturally occurring immune response.

“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."

Reviewing the results with analysts and the media, he indicated the company was willing to discuss Emergency Use Authorization with the US Food and Drug Administration.

"We think there's a lot of evidence here to suggest that this is a therapeutic solution that could really benefit quite a number of individuals. And it's up to regulators and society to try to figure out how to best, and when to employ this solution pending the sort of data [from patients] we've already enrolled."

He added that the results had positive implications not only for REGN-COV2, but also for other antibody therapies and vaccines which target the SARS-CoV-2 spike protein. 

However the preliminary nature of the data, and its benefits being limited to a subset of patients who first require a serology test meant that medical experts are cautious about an EUA.

That caution is heightened by the controversies around previous EUAs, including hydroxychloroquine (granted and then withdrawn because of lack of evidence) and convalescent blood plasma, where the clinical benefits are far from clear cut.

On Twitter, Eric Topol, director of the Scripps Research Translational Institute commented: “I don’t see how the data would support that [an EUA]. It’s a step in the right direction but we need to see more.”

Steven Joffe, chief, division of medical ethics at Pennsylvania University, responded: “Completely agree. The last thing we need is emergency-authorized products based on preliminary data. Priority has to be figuring out what really works and more EUAs just make that harder to do.”

The trial generates lots more questions about how the antibody cocktail might be used in the frontline against SARS-CoV-2. The company is studying its use in several other settings, including as a prophylactic to prevent infection, and also in hospitals, where the hope is that it could help save lives of patients with a high viral load and the most severe illness. In this setting it could be combined with Gilead Sciences, Inc.'s Veklury (remdesivir) or dexamethasone, which have also demonstrated their value in these patients.

Commercial Potential

If REGN-COV2 were to be given the green light, eligible patients in the US would be given the treatment free of charge during the pandemic, under an deal agreed between the company and the US government's Operation Warp Speed program.

Another issue is the need for high volumes of antibody production to meet potential demand, and Regeneron recently entered into a partnership with Roche Holding AG to help it boost manufacturing capacity and serve non-US markets. Yancopoulos said his company would be able to meet a commitment to provide 300,000 doses of the treatment by the end of 2020, with a "substantial fraction" of this already available. The partnership with Roche would then allow capacity to be scaled up to 250,000 doses a month in 2021.

Analysts see significant commercial potential for REGN-COV2 and other antibody therapies, Morningstar recently forecasting revenues of up to $6bn in 2021 for the partners, with potential for similar candidates from AstraZeneca PLCand Eli Lilly and Company – although the approval and uptake of the first COVID-19 vaccines is just one hard-to-predict factor which will impact this picture. (Also see "Regeneron and Roche Await Data On Potential COVID-19 Blockbuster" - Scrip, 3 Sep, 2020.)

The Regeneron results come just two weeks after initial data from Lilly's LY-CoV555, which many analysts judged to be inconclusive. The company told Scrip that it was too early to say what its next steps might be, and whether or not it would seek an EUA.  (Also see "Lilly Claims Proof Of Concept For Neutralizing Antibodies In COVID-19 Therapy" - Scrip, 16 Sep, 2020.)