Hope for Critically Ill Covid-19 Patients-Hanging on a pValue
On March 29th, CytoDyn Inc., a small US biotech, released results from a Covid-19 study indicating an unprecedented 82% reduction in death measured at Day 14 in a group of 62 critically ill patients (ie, on a
ventilator) who received a drug called leronlimab compared with a placebo. This marks the first time any therapy has demonstrated a signal of improving survival in this patient population in a randomized, doubleblind, placebo-controlled study, the gold-standard of clinical medicine. This striking result aligns with published reports of other critically ill Covid-19 patients successfully treated with leronlimab under
compassionate use programs.
Unfortunately, this is where things get a bit complicated. The “pvalue”, or test of statistical significance of the 82% survival benefit, was reported as 0.023 which, being less than 0.05, would normally indicate the
result had a less than 1 in 20 chance of having randomly occurred. However, the critically ill patients were only a “subgroup” within the larger CytoDyn study. In order to prove the claim, CytoDyn will need to enroll a new study of just critically ill patients that will take months to complete. In the meantime, the FDA has refused to approve CytoDyn’s request for an Emergency Use Authorization (EUA). The consequences of this decision for critically ill Covid -19 patients, their ICU medical teams, and the US economy during a potential 4th wave of infection due to mutant strains of virus could be disastrous.
The FDA is given the authority and flexibility to exercise judgement and grant an EUA in the setting of an urgent unmet medical need when available evidence suggests the potential benefit of a treatment outweighs its potential risk. The agency has granted EUAs for other Covid-19 therapies that are thought to directly attack the virus but are potentially effective only if given early in the course of illness. None of the antiviral therapies have proven to help patients during the latter or “hyperinflammatory” stage of the illness during which a disordered immune response, rather than the virus itself, appears to drive complications including death. Dexamethasone, a potent steroid, is thought to help but has not been tested in a double-blind, placebocontrolled trial in this patient population. In contrast to antiviral approaches, leronlimab is a monoclonal antibody that treats the latter stages of Covid-19 illness including Covid pneumonia by disrupting the signaling within the body that brings inflammatory cells into the lungs and other tissues. Importantly, since the proposed mechanism of action is independent of the virus, leronlimab should remain effective in patients harboring mutant strains.
On the other side of the EUA calculation is the important question of safety. Here too, the FDA’s inaction is difficult to understand. Leronlimab has been safely administered to more than 1200 patients, including
patients in studies of HIV, cancer, and Covid-19. Some patients with HIV have received the drug by injection under the skin weekly for up to six years without any discernable safety issues.
Crucial questions remain. The survival benefit in the CytoDyn study disappointedly tapered off from 82% compared to placebo at Day 14 down to 24% at Day 28. The tapering of benefit may have occurred because
patients were not given the drug for the final two weeks of the study per FDA guidance. What will overall survival be when critically ill patients are permitted to receive the full 4 weeks of dosing as originally proposed? Studies are underway to answer these urgent questions.
In the meantime, the future of the pandemic remains deeply uncertain. Even as the US starts to reopen, we are confronting a growing surge of mutant strains that appear to be more infectious, possibly more
lethal, and likely a greater threat to younger individuals. The FDA has the authority and mandate to act with common sense in a crisis. Janet Woodcock, the acting Commissioner of the FDA, has opined on “the cost
of failing to approve an effective therapy” when “there may be thousands of lives to be lost if you delay.” Commissioner Woodcock tellingly added “people say they want placebo-controlled trials, but I always ask them would you be willing to die to give a p-value?”
The current evidence is clear: leronlimab is safe and can save the lives of critically ill patients with Covid-19. The FDA should issue an EUA now while further studies are completed. Hope and relief for the sickest
and most vulnerable among us cannot be held hostage to a p-value any longer.
Jacob Lalezari, MD, Medical Director, Quest Clinical Research, San Francisco, CA
Nicholas Agresti, MD, Southeast Georgia Health, Brunswick, GA
Harish Seethamraju, MD,Professor of Medicine, Pulmonary Critical Care, Mount Sinai School of Medicine