Humanigen is vowing to continue pursuing approvals for lenzilumab following the FDA’s rejection of its application for emergency use authorization (EUA) of the antibody as a treatment for patients hospitalized with COVID-19—a setback that has sent the company’s stock plunging more than 50%.

The FDA stated in a letter that it was unable to conclude that the known and potential benefits of lenzilumab outweighed known and potential risks of its use as a treatment for COVID-19, Humanigen said in a statement.

Humanigen applied for the EUA in May. Despite its rejection, the FDA has invited Humanigen to submit additional data as it becomes available, the company added.

“We remain committed to bringing lenzilumab to patients hospitalized with COVID-19,” Humanigen CEO Cameron Durrant, MD, stated on Thursday.

Humanigen also said it remained committed to completing regulatory processes underway seeking marketing authorization for lenzilumab to treat hospitalized COVID-19 patients in the U.K. and elsewhere in the world.

Durrant cited the ongoing ACTIV-5/Big Effect Trial (BET-B; NCT04583969), sponsored by the NIH’s National Institute of Allergy and Infectious Diseases (NIAID): “We believe the ongoing ACTIV-5/BET-B trial, which has been advanced to enroll up to 500 patients, may provide additional safety and efficacy data sufficient to support our efforts to obtain an EUA to treat hospitalized COVID-19 patients.”

Humanigen’s reassurances did not appear to comfort investors, who responded to the FDA rejection with a selloff that sent the company’s shares plummeting 54%. From a closing price of $15.11 on Wednesday, Humanigen shares fell 47% to $7.97 on Thursday and a further nearly 14% on Friday, when shares closed at $6.88.

Humanigen shares were downgraded due to the EUA rejection by firms that included J.P. Morgan (from “Neutral” to “Underweight”) and Jefferies (from “Buy” to “Hold”). GEN moved lenzilumab from “Front Runner” to “Definitely Maybe” status on its COVID-19 Drug & Vaccine Tracker, which lists more than 300 COVID-19 drugs and vaccines.

Lenzilumab is a “humaneered” monoclonal antibody designed to prevent or minimize the cytokine release syndrome that precedes lung dysfunction and acute respiratory distress syndrome (ARDS) in serious cases of SARS-CoV-2 infection. It does so by targeting and neutralizing granulocyte macrophage-colony stimulating factor (GM-CSF), a key cytokine in the initiation of cytokine storm.

“We think that lenz is, or has the potential to be, a leading treatment near term for patients that could have serious and potentially fatal outcomes, who are high risk and hospitalized,” Durrant told GEN last year.

Enough patients?

Kelly Shi, PhD, equity analyst with Jefferies, reported in a research note that Humanigen management believed the FDA may have rejected its EUA application because lenzilumab’s clinical trials studied a smaller number of patients (500) compared with other COVID-19 drugs the FDA has approved or authorized for emergency use, most of which have been studied in more than 1,000 patients.

For example, Actemra® (tocilizumab), an interleukin-6 (IL-6) receptor antagonist marketed by previously approved for rheumatoid arthritis and other indications, received an EUA on June 24 based on data from four trials with a combined patient population of 5,606, according to the FDA.

However, the FDA also acknowledges that data supporting Sotrovimab®, a dual-action SARS-CoV-2 monoclonal antibody marketed by GlaxoSmithKline (GSK) and Vir Biotechnology, came from an interim analysis of an ongoing, randomized, double-blind, placebo-controlled clinical trial in 583 non-hospitalized adults with mild-to-moderate COVID-19 symptoms at increased risk for COVID-19 progression due to age or other medical conditions. That trial met its primary endpoint—progression of COVID-19 at Day 29—by showing an 85% reduction in patients randomized to sotrovimab compared with placebo.

Sotrovimab and lenzilumab were among “Seven Up-and-Coming COVID-19 Drugs” highlighted by GEN in June.

Sotrovimab and Actemra are the two most recent of 10 drug and biological therapeutic products the FDA has approved or authorized for COVID-19-related indications.

In July, NIAID expanded the ACTIV-5/BET-B trial into Phase II/III study, increased the patient population from the original 200, and modified the primary endpoint to survival without ventilation (SWOV)—the same endpoint used in the Phase III LIVE-AIR trial (NCT04351152). Data from LIVE-AIR showed lenzilumab improved the likelihood of SWOV with a 54% relative improvement in the likelihood of SWOV vs. placebo, according to a preprint  posted May 5 on medRxiv by researchers from Humanigen and clinical partners that included the Mayo Clinic and Emory University.

Humanigen reasoned at the time that the study modification may enable it to use ACTIV-5/BET-B as a confirmatory study to support a future Biologics License Application (BLA). Data is expected to come out next year from ACTIV-5/BET-B, which has yet to reach full enrollment.

“Given the uncertainty of enrollment pace for ACTIV-5, emerging oral COVID drugs and the diminishing COVID risks over time, market oppy [opportunity] for Lenz in COVID appears largely uncertain,” Shi concluded.

Premium pricing

Eric Joseph, PhD, biotechnology analyst at J.P. Morgan, wrote in a research note that the FDA’s rejection of Humanigen’s EUA application “is likely to irrevocably undermine the company’s planned premium pricing strategy,” which envisioned charging patients $10,000-plus per patient course of lenzilumab, “leaving us with doubts as to whether lenzilumab could ultimately be a meaningfully profitable product given its high administration volumes and cost of manufacture.”

Joseph contrasted the pricing of lenziuluimab with the approximately $4,000-per-course price of another antibody that is authorized for emergency use, Eli Lilly’s Olumiant® (baricitinib). Olumiant received authorization—originally in combination with Gilead Sciences’ Veklury® (remdesivir), amended to Olumiant alone on July 28—based on data from two clinical trials:

  • NIAID’s Phase III Adaptive COVID-19 Treatment Trial 2 (ACTT-2; NCT04401579) in 1,033 hospitalized patients, which showed that patients treated with baricitinib in combination with Veklury had a significant reduction in median time to recovery from 8 to 7 days (12.5% improvement) compared to remdesivir.
  • The 764-patient COV-BARRIER trial (NCT04421027), which showed that COVID-19 patients on mechanical ventilation or extracorporeal membrane oxygenation (ECMO) who received Olumiant plus standard of care were 46% less likely to die by Day 28 compared to patients who received placebo plus standard of care.

“We see little potential for lenzilumab commercialization in the United States within the next six to nine months via EUA, and similarly low approval prospects via BLA (which we anticipate being a 2023+ event),” Joseph wrote.

As for the FDA’s rejection of lenzilumab, he added: “While disappointing, we’re not terribly surprised by the decision given the length of the review cycle and, in our view, a fairly modest benefit in the prevention of progression to ventilation.”

That benefit was more than modest, according to Durrant, who led the company out of bankruptcy in 2016 under its old name KaloBios after it was briefly owned and run by “Pharma Bro” Martin Shkreli, now serving a seven-year prison sentence following conviction on security fraud and conspiracy charges.

While lenzilumab showed a 54% relative improvement in the likelihood of SWOV compared to placebo, additional data released by Humanigen in May showed that SWOV likelihood improved 92% in participants receiving both corticosteroids and Veklury; and three-fold in patients who had a C-reactive protein level of <150 mg/L and were under 85 years of age.

“These new data are very encouraging, and it means that we plan to continue to progress with our U.S. submission,” Durrant told GEN in May. “We think it’s important, if possible, to define the patients that are more likely to receive the benefit and I thought we’ve been able to do with this analysis.

“This gives physicians over healthcare professionals, better and more explicit guidance as to the kinds of patients are more likely to receive benefit from lenz,” Durant added. “We’re not a company that would claim our therapy is a panacea, that it’s all things to everyone.”

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