Humanigen Inc., the Burlingame, Calif.-based developer of an anti-human-GM-CSF monoclonal antibody for preventing and treating cytokine storms, is urgently working to spin up a phase III trial of the candidate, lenzilumab, for COVID-19 patients whose immune systems have gone into overdrive. Meanwhile, its team is trying to get the drug added to open protocols of NIH-administered trials of other potential therapies and into the hands of individual patients by opening up compassionate use requests.

Cytokine storm, or cytokine release syndrome (CRS), appears to be "a key trigger" in acute respiratory distress syndrome (ARDS) associated with COVID-19, the company said. The question now is whether lenzilumab can offer a therapeutic benefit for patients with the most serious cases of the infection. Getting to an answer fast, on something other than "pre-COVID-19 time," has become a top priority for Humanigen, said CEO Cameron Durrant, who has taken to working 15-hour-plus days over the last week.

There's "an abundance of data demonstrating that GM-CSF is upstream in the cytokine cascade and that the neutralization of GM-CSF is known to inhibit the release of key downstream cytokines known to be associated with CRS and neurotoxicity," Humanigen said in its most recent annual report. Put more simply, "if you have a leaky faucet in your house, you could either mess about with the faucet or you can switch off the water mains," Durrant told BioWorld.

With results from multiple phase II trials already showing lenzilumab can prevent CRS, and ongoing tests looking to bolster that evidence in the context of treatment with the CAR T cancer therapy Yescarta (axicabtagene ciloleucel, Gilead Sciences Inc.), demand is now rising to test lenzilumab in ARDS associated with COVID-19. Key opinion leaders from the U.K., Australia, Spain, Italy, Switzerland, Slovenia and the U.S. have already sought an opportunity to trial lenzilumab in serious cases of COVID-19.

Meanwhile, at a time when Gilead has had to reconsider its handling of individual compassionate use requests for remdesivir, Humanigen is just opening the door to such requests for lenzilumab. With the drug already in inventory, Humanigen is ready to supply limited amounts of it through that channel, Durrant said.

Humanigen's team is also preparing to imminently submit a protocol for the phase III study to the FDA soon while pursuing a third path: trying to piggyback on existing studies that are looking at antiviral therapies. Though lenzilumab itself isn't an antiviral or a vaccine, it could potentially prevent people from requiring ICU care and ventilator support when those drugs fail to prevent deteriorating health, Durrant suggested.

Now "we need NIH and other agencies to open up to the idea of adding lenz to existing protocols," he said, expressing frustration with the pace of regulatory response to the pandemic. "In what world is standard operating procedure going to be helpful here? In what world are usual timelines going to be helpful?" he asked.

Other companies focused on ARDS in patients with respiratory distress caused by COVID-19 include Apeiron Biologics GmbH, Aqualung Therapeutics Corp., Cellenkos Inc., Lattice Biologics Ltd., Mallinckrodt plc and Mesoblast Ltd.

Only one other company appears to be targeting GM-CSF: Roivant Sciences Ltd. On March 18, the Basel, Switzerland-based company announced its team is seeking to test gimsilumab, a fully human monoclonal antibody that has been tested in numerous nonclinical studies and two clinical studies, including an ongoing four-week phase I study of a subcutaneous formulation in healthy volunteers.

Both Roivant and Humanigen have pointed to a pre-print study finding that "excessive activated immune response caused by pathogenic GM-CSF+ Th1 cells and inflammatory CD14+CD16+ monocytes may connect pulmonary immunopathology leading to deleterious clinical manifestations and even acute mortality after 2019-nCoV infections."

Shares of Humanigen (NASDAQ:HGEN), formerly known as Kalobios Pharmaceuticals Inc., rose 4.4%, closing at $1.20 on March 23.

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