Two COVID-19 drug developers said they will seek emergency use authorizations (EUAs) from the FDA for their therapeutics following positive late-stage clinical results.

Humanigen disclosed topline Phase III results showing that hospitalized patients who received lenzilumab and other treatments—including steroids and/or Gilead Sciences’ marketed drug Veklury® (remdesivir)—had a 54% greater relative likelihood of survival without needing invasive medical ventilation (IMV), compared with patients who received placebo and other treatments.

Separately, NeuroRx released 60-day results from a Phase II/III trial showing that its Zyesami™ (aviptadil acetate) for respiratory failure in critically-ill patients with COVID-19, which is being developed with Relief Therapeutics, met the study’s primary endpoint for successful recovery from respiratory failure at days 28 and 60.

Zyesami also showed a meaningful benefit in survival after controlling for ventilation status and treatment site, NeuroRx said.

Should Zyesami and lenzilumab be granted EUAs, they would join Veklury and four other therapies and therapeutic combinations in gaining FDA emergency authorization to treat COVID-19:

  • Eli Lilly’s antibody bamlanivimab (LY-CoV555);
  • The combination of bamlanivimab and another Lilly antibody, etesevimab (LY-CoV016);
  • Regeneron Therapeutics’ two-antibody combination or “cocktail” REGEN-COV™ (casirivimab and imdevimab); and
  • The combination of Veklury and Lilly’s Olumiant (baricitinib).

Humanigen’s lenzilumab is an engineered or “Humaneered®” anti-human granulocyte macrophage-colony stimulating factor (GM-CSF) monoclonal antibody designed to prevent and treat cytokine storm.

In the Phase III trial (NCT04351152), Humanigen said, lenzilumab achieved its primary endpoint of significant improvement in ventilator-free survival through day 28 following treatment—to 84.4% from 77.9% among placebo patients. As a result, the percentage of lenzilumab patients who died or needed IMV was 15.6% compared with 22.1% of placebo patients, a 54% improvement in the relative likelihood of survival without the need for IMV.

Favorable mortality trend

The trial was not powered to demonstrate a difference in mortality—though Humanigen said a favorable trend was observed: the percentage of lenzilumab patients that died was 9.6% compared with 13.9% of placebo patients.

“The results from our Phase III clinical trial with lenzilumab treatment were associated with better outcomes in hospitalized hypoxic COVID-19 patients who had not yet progressed to the point of requiring IMV,” Humanigen CEO Cameron Durrant, MD, said in a statement.

Investors responded to the news by sending Humanigen shares surging 54% on Monday, to $21.61 at the close of trading from $13.99 at Friday’s close.

“We think Lenz is well positioned to capture COVID opportunity for several reasons,” Kelly Shi, PhD, equity analyst with Jefferies, and three colleagues wrote Monday in a research note. “1) Vaccination is still not available to children <16 years old; 2) ~25% of US population declines to get vaccinated; 3) new variants could continue to emerge, with mutations (e.g., B.1.351 South Africa variant) at risk to reduce the efficacy of vaccines. In addition, we expect demands of government purchase for emergency use.”

Shi noted that Humanigen aims to reach a manufacturing capacity of 100,000 doses in 12 months for the US.

The trial enrolled 520 patients in 29 sites in the U.S. and Brazil who were at least 18 years of age; experienced blood oxygen saturation (SpO2) of less than or equal to 94%; or required low-flow supplemental oxygen, or high-flow oxygen support, or non-invasive positive pressure ventilation (NIPPV); and were hospitalized but did not require IMV. Following enrollment, subjects were randomized to receive three infusions of either lenzilumab or placebo, each infusion separated by eight hours over a 24-hour period with other treatments.

Results of the trial are planned to be submitted for potential publication in a peer-reviewed journal, Humanigen said.

The results help validate Durrant’s assertion expressed to GEN last summer: “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.”

NeuroRx is privately held but is being acquired for $500 million by publicly-traded Big Rock Partners Acquisition, whose shares climbed nearly 15% on the news Monday, to $41.12 at the close from $35.89 on Friday.

Approximately 88% of patients received dexamethasone or other steroids, 62% received Veklury, and 57% received both, balanced across both arms of the study, Humanighen noted. Also balanced, according to the company, was the number of serious adverse events (SAEs) seen in both study arms, and the SAE profile was similar to that previously documented in prior lenzilumab studies.

No new SAEs were identified, and none were attributed to lenzilumab, Humanigen added.

Durrant added that the trial incorporated a diverse population with various comorbidities—most commonly a body mass index above 30 which is considered obese, and thus representative of a real-world, high-risk population, according to Humanigen.

“The data strongly suggest that lenzilumab improved outcomes for hospitalized patients with COVID-19 pneumonia,” said Zelalem Temesgen, MD, professor of medicine at Mayo Clinic and principal investigator of the Phase III trial.

Lenzilumab is also under study in the Phase II ACTIV-5/BET trial (NCT04583969), alone and with Veklury, compared to placebo plus Veklury; along with Skyrizi® (risankizumab-rzaa), the Boehringer Ingelheim/AbbVie monoclonal antibody now marketed for moderate to severe plaque psoriasis, plus Veklury, compared to a placebo plus Veklury.

Lenzilumab and Zyesami are two of 21 “front runners” among the more than 300 drug and vaccine candidates tracked on GEN’s COVID-19 Drug & Vaccine Candidate Tracker.” Zyesami was upgraded from a “Definitely Maybe” candidate as of Monday.

Zyesami is a synthetic human vasoactive intestinal polypeptide (VIP). VIP is known to reduce inflammation in the lungs by inhibiting inflammatory cytokines and protecting the alveolar type II cells that are believed to be an entry route for the SARS-CoV-2 to invade the lungs.

“Robust” significance

NeuroRx said Zyesami showed “robust” overall significance across all 196 treated patients at all 10 clinical sites in the Phase IIb/III COVID-AIV trial (NCT04311697).

COVID-AIV was originally approved as a 28-day study at FDA’s direction. In December, NeuroRx added a 60-day endpoint based on FDA guidance recognizing that the traditional 28-day endpoint adopted in the 1990s for trials in Acute Respiratory Distress Syndrome was not appropriate for critically ill patients with COVID-19, who are frequently maintained in the ICU with advanced technologies well beyond that time point.

NeuroRx said the study’s pre-specified analysis of recovery from respiratory failure was clinically and statistically significant in the 127 patients treated by High Flow Nasal Cannula (HFNC), compared to those treated with mechanical or non-invasive ventilation at tertiary care hospitals.

In that group, Zyesami patients showed a 71% chance of successful recovery by day 28 vs. 48% of placebo patients. Zyesami patients also showed a 75% rate of successful recovery by day 60, compared with 55% of placebo patients.  Of HFNC patients treated at tertiary medical centers with Zyesami, 84% survived to day 60, compared with 60% of those treated with placebo.

Patients were treated with Zyesami or placebo in addition to standard of care treatment that included steroids, convalescent plasma, antiviral therapy, anticoagulants, and various anti-cytokine drugs.

NeuroRx has also launched another Phase IIb/III trial, AVICOVID-2 (NCT04360096), designed to evaluate inhaled Zyesami in patients with moderate and severe COVID-19, with the aim of preventing progression to respiratory failure. Zyesami is also among drugs under study in the 1,500-patient Phase II I-SPY COVID-19 trial (NCT04488081) being conducted by NeuroRx, Relief, and the Quantum Leap Healthcare Collaborative of San Francisco, and designed to assess multiple drugs for the treatment of patients with critical COVID-19 who are hospitalized or in intensive care units.

“In exactly 12 months, a lifesaving drug has advanced from concept to clinical success in partnership with Relief Therapeutics in the midst of a public health emergency that has claimed the lives of millions,” Jonathan C. Javitt, MD, NeuroRx’s founder, chairman, and CEO, said in a statement. “[Monday’s] findings confirm the often dramatic clinical success that has been seen in numerous patients treated in the U.S. and abroad under emergency use protocols.”