Oct 14 2020 - A Look At Regeneron's Antibody Cocktail

REGN recently reported initial results from a trial of REGN-COV2, the company's antibody cocktail for COVID-19.

The results so far look fairly promising but the market may want more.

REGN plans to report additional results and has filed for Emergency Use Approval.

Back in June, I wrote about Regeneron Pharmaceuticals (REGN), highlighting one of their plays in the COVID-19 space, a drug called REGN-COV2. REGN has now produced some initial results, which are the focus of this article, the drug itself having come into focus as President Trump received it as part of his treatment regime for a case of COVID-19.

A brief refresher

REGN-COV2 is a cocktail of two antibodies. Both antibodies, REGN10933 and REGN10987, bind to the receptor binding domain (RBD) of the SARS-CoV-2 spike protein (Figure 1). Targeting two separate parts of the spike protein makes it harder for a mutation to render the cocktail ineffective. For example, a mutation found on one virion might lead to REGN10933 being no longer effective at binding to that virion. Elsewhere, another virion might have a mutation that leads to REGN10987 no long being effective. The chances of a virion having both mutations however, are pretty slim, meaning that the odds of resistance developing to REGN-COV2 are much smaller than would be achieved with one antibody alone.

Figure 1: Molecular model of REGN-COV2, consisting of REGN10933 (cyan and green) and REGN10987 (red and yellow) binding to the spike RBD of SARS-CoV-2 (dark blue). This binding prevents binding to the ACE2 receptor (straw colour) on human cells. Source: REGN presentation of REGN-COV2 results.

Trial results

On September 29, REGN provided results from an analysis of the first 275 patients in a placebo-controlled, randomized, double-blind Phase 1/2/3 trial, of REGN-COV2 in non-hospitalized COVID-19 patients. REGN-COV2 both reduced viral loads and improved symptoms in these patients. REGN noted greater treatment benefit was seen in patients with a weak immune response of their own against SARS-CoV-2, suggesting REGN-COV2 can substitute for the body's own immune response.

REGN assessed whether patients had already produced their own antibodies at baseline (seropositive) or had not (seronegative). Seropositive patients tended to have lower viral loads even at baseline, and those levels tended to soon become even lower, even in the placebo group. These patients then only stand to benefit so much from REGN-CoV-2. In seronegative patients, the high dose of REGN-COV2 (8 grams) resulted in a more rapid decline in viral load through day seven when compared to placebo (p=0.03). The low dose group was not significantly better than placebo in seronegative patients at reducing viral load (p=0.06, a near miss). President Trump received the 8 gram dose, for those who are interested.

REGN is seeking Emergency Use Approval (EUA) and has already enrolled the next cohort in its Phase 1/2/3 trial. Results from this cohort could be used to "rapidly and prospectively confirm" results seen so far, according to REGN.

Figure 2: REGN-COV2 is being assessed in multiple clinical trials providing the company with multiple opportunities to demonstrate the value of the drug. Source: REGN presentation of REGN-COV2 results.

Given the p-values above represent results from subgroups, first the seronegative subgroup and then the 8 gram or 2.4 gram dose, it is worth considering the results in the entire population. In that population, the drug achieves statistical significance with the 8 gram dose but not the 2.4 gram dose.

In the overall population, there was a 0.51 log10 copies/mL greater reduction (p=0.0049) in patients treated with high dose, and a 0.23 log10 copies/mL greater reduction (p= 0.20) in patients treated with low dose, compared to placebo.

REGN September 29 press release.

The fact that the 8 gram dose was better than the 2.4 g dose, shows a dose-response relationship, an indication the existing results represent a true positive, and not a false positive due to luck. Further, the fact that the drug works best in seronegative patients (who tend to have higher viral loads) is also biologically plausible, it makes sense. Indeed, REGN was expecting such an effect, so the fact that many of REGN's p-values come from subgroups is of less concern.

We prospectively hypothesized that many patients would recover based upon their own individual immune response, and that any anti-virus effect and/or associated clinical benefit would most likely be greatest in patients who had not yet mounted a strong immune response.

REGN comments from REGN presentation of REGN-COV2 results (slide 8).

On the safety front, REGN-COV2 was also quite impressive. There were no serious adverse events in the 8 gram dose group (N=88) and the rate of treatment-emergent adverse events (2.3%) was lower than in the placebo group (4.3%).

Conclusions

REGN has come up with a promising treatment for COVID-19. The company has additional readouts ahead, which will give it an opportunity to further impress the market. Perhaps it is a EUA that the market wants to see for the stock to trade at an even higher multiple as initial results didn't spark a lasting rally.