CytoDyn digs deep for signs of efficacy in COVID-19 trial flop

A phase 3 clinical trial of CytoDyn’s leronlimab in COVID-19 patients has missed its primary and all major secondary endpoints. However, CytoDyn zeroed in on a subgroup of patients and performed an “age adjustment” analysis to hail the study as evidence of the efficaciousness of leronlimab.

The clinical trial randomized 384 patients with severe or critical COVID-19 to receive CCR5 antagonist leronlimab or placebo once a week. CytoDyn chose all-cause mortality at Day 28 as the primary endpoint.

In a statement issued late Friday, CytoDyn shared no data on the performance of leronlimab in the overall study population, focusing instead on a subset of 62 mechanically ventilated, critically ill COVID-19 patients. The biotech said leronlimab was associated with a 24% reduction in all-cause mortality in the subgroup as well as a six-day reduction in hospital stay and improved probability of being “discharged alive” at Day 28. CytoDyn only provided a p-value for the reduction in hospital stay. 

Late Saturday, CytoDyn issued a second press release about the data. The second statement explained that the treatment arm contained a higher proportion of people aged 65 years and older than the control group did. As the mortality rate in the 267 people aged under 65 was lower than in the 117 people over that threshold, CytoDyn performed an “age adjustment” analysis on the data.

The analysis associated the use of leronlimab plus “commonly used COVID-19 treatments” with a statistically significant improvement in all-cause mortality at Day 28 compared to placebo plus “commonly used COVID-19 treatments.” The p-value was 0.0319. CytoDyn also calculated a p-value of 0.0552 for mortality in an age-adjusted analysis of a subgroup of patients who took dexamethasone.

Even after applying the age adjustment, the study missed its primary endpoint and all other major secondary endpoints among all patients in the modified intent-to-treat population. CytoDyn said the primary endpoint “was much closer to statistically significant value” after adjusting for age. Similarly, CytoDyn said some secondary endpoints approached statistical significance after the adjustment. 

What, if anything, can be concluded from CytoDyn’s analysis is unclear. Neither of the CytoDyn releases state the analyses were prespecified. Post hoc analyses of small subgroups of patients can generate results that appear to show a drug is efficacious, only for more rigorous assessments of the molecule to reveal the signs of efficacy to be a mirage. That story, of post hoc promise being crushed by later assessments, has played out repeatedly in drug development. 

CytoDyn will need stronger data to win even emergency use authorization in the U.S. The biotech has filed to run a clinical trial that will enroll 140 critically ill COVID-19 patients and is awaiting comments from the FDA. CytoDyn plans to use the same sites as the earlier trial but another primary endpoint, namely length of hospital stay. 

In Canada, CytoDyn thinks the regulator could allow the sale of leronlimab while additional data from critically ill patients are being generated. CytoDyn said the U.K. regulator will accept data from an open-label extension to the current trial but made no comment on what evidence will be needed to get leronlimab to market in that jurisdiction. 

Clinical failures and regulatory rejections could deal hammer blows to a biotech that has ridden high, by its recent standards, during the pandemic. CytoDyn’s share price fell below $1 in 2016 and stayed below that threshold until early 2020. Since the pandemic hit the West, CytoDyn shares have rarely traded below $2.50 and rose toward $7 last summer. Its shares were down more than 22% Monday morning on the news, trading at around $4 a share.