Burlingame, California-based Humanigen reported positive data from its Phase Ib ZUMA-19 trial of lenzilumab in patients treated with CAR-T in diffuse large B-cell lymphoma (DLBCL). Lenzilumab is being investigated for its ability to tamp down the hyper-immune response known as a cytokine storm. The cytokine storm and neurotoxicity are known potential side effects of CAR-T immuno-oncology therapies.

On March 29, Humanigen reported positive topline results from a Phase III trial of lenzilumab in hospitalized COVID-19 patients. One of the deadlier aspects of COVID-19 is the cytokine storm, where the immune system overreacts, causing enormous damage to cells and tissues in the process. This trial demonstrated that patients receiving lenzilumab and other therapies, including steroids and/or Gilead’s antiviral drug remdesivir, had a 54% better chance of survival without the need for intermittent mandator ventilation (IMV).

“Mayo Clinic is pleased to have been part of the investigation of lenzilumab from the earliest days of the development program in COVID-19 and are excited by these data,” said Andrew Badley at the time, professor of Infectious Diseases, and professor and chair of the Department of Molecular Medicine at Mayo Clinic. “If lenzilumab is authorized for emergency use by FDA, and based on our clinical trial experience to date, it may then be considered a part of our treatment armamentarium for newly hospitalized patients with COVID-19.”

In cancer, the ZUMA-19 study evaluated the efficacy and safety of lenzilumab and CAR-T, specifically Gilead’s Yescarta (axicabtagene ciloleucel) in patients with relapsed or refractory (r/r) DLBCL. The study was a standard 3+3 design, with three patients receiving 600 mg lenzilumab (cohort 1) and three given 1,800 lenzilumab (cohort 2) just before receiving CAR-T. The study determined that the recommended Phase II dose was 1,800 mg.

In the six patients in the study, the objective response rate (ORR) was 83%, including four complete responses (CR). In cohort 1, no patients had severe cytokine release syndrome (CRS) of grade 3 or higher. One patient experienced grade 3 neurotoxicity (NT) that lasted for two days. 

At the recommended dose for Phase II, ORR was 100%, and the toxicity-free CR was 66%. No severe CRS or severe NT was observed at the recommended Phase II dose. No adverse events associated with lenzilumab were seen in the study.

“These encouraging results from ZUMA-19 provide further proof of concept that lenzilumab may break the linkage between efficacy and toxicity (CRS and NT) widely associated with CAR-T, and may improve durability of response,” said Dale Chappell, chief scientific officer of Humanigen. “We believe these data warrant a larger study involving multiple CAR-T therapies.”

The company plans to launch a potentially registrational Phase II study to evaluate lenzilumab combined with all commercially available CD19 CAR-T therapies in DLBCL. It will enroll about 150 patients. The protocol is currently being submitted to the U.S. Food and Drug Administration (FDA).

The company has terminated the clinical agreement with Kite/Gilead related to ZUMA-19, and both groups are working to wind down the current study.

“Humanigen is pleased to be in a position to proactively develop lenzilumab across the CAR-T landscape and further expand its pipeline,” said Cameron Durrant, chief executive officer of Humanigen. “We thank Kite for their sponsorship and contribution that has allowed Humanigen to progress to this exciting point.”

The company closed on its initial public offering of common stock on April 6, raising about $92.5 million. The funds raised are to be used for manufacturing and commercial preparation for a possible Emergency Use Authorization for lenzilumab in hospitalized COVID-19 patients, as well as working capital and general corporate purposes.

Interestingly, although company shares spiked by more than 50% after the announcement of the COVID-19 data, shares dropped after the pricing of the public offering of common stock. According to The Motley Fool, this was associated with investors’ concerns over diluting its shareholders. However, regulatory authorization for the drug would likely send the company’s shares soaring. Humanigen has no other products on the market.