Shares of immunotherapy developer Enlivex Therapeutics Ltd. (NASDAQ:ENLV) climbed as much as 69% Dec. 3 after interim data showed the apparent benefits of its lead candidate, Allocetra, for severe and critical COVID-19 patients. Though the program's lead indication is sepsis, a positive final outcome in the phase II COVID-19 study might lead to conversations with regulators exploring emergency use authorizations, Executive Chairman Shai Novik told BioWorld. Full enrollment in the study could be completed as soon as January, he said.
For patients whose immune systems have kicked into high gear in response to pathogenic intrusion, Allocetra is designed to "rebalance" that response from one of cytokine "storm" to more normal operation. However, rather than seeking to neutralize certain cytokines, the elevations of which can vary from patient to patient, Enlivex is focused on a more basic biology: luring macrophages and other phagocytes into going after the billions of semi-apoptotic, dying, mononuclear cells it sources from donor blood to create Allocetra. As the macrophages and other cells engage in the removal of those cells, "several therapeutic responses are induced, such as inflammation suppression, modulation of macrophage-directed deletion of invading pathogens and regulation of immune responses," the company said in a recent regulatory filing.
"We're not targeting specific cytokines," Novik explained. "Our theory is, if you have a very effective therapy that can rebalance and bring macrophages back into homeostasis, everything else will take care of itself," he said.
But could that approach lead to a meaningful improvement for patients with COVID-19? An investigator-initiated phase Ib study in COVID-19 patients at Hadassah Hospital was run to find out.
Though Israeli regulators allowed just five COVID-19 patients to be enrolled in the trial, all of them – three in severe condition and two in critical condition – completely recovered. Each was released from the hospital after an average of five days (severe) and nine days (critical) following administration of Allocetra, the company reported in October. PCR testing confirmed each to be negative for SARS-CoV-2 virus.
Convinced by that positive outcome to build further evidence, an ongoing investigator-initiated phase II trial was designed. It first began dosing patients in October. So far, the Nes Ziona, Israel-based company has reported data on eight COVID-19 patients who received infusions of Allocetra in a phase II study, six in severe and two in critical condition, both according to U.S. NIH standards. Following an infusion of Allocetra, seven of the patients recovered and were discharged from the hospital after an average of 4.7 days. The remaining patient, in critical condition at enrollment, improved to moderate/severe condition following treatment with Allocetra, but remained hospitalized.
What happens next for Allocetra in COVID-19 will be driven, of course, by the clinical data generated by the phase IIb, but also shaped by unmet need that's likely to remain for treating patients with the SARS-CoV-2 infection even after vaccines enter the market.
"From our vantage point, even in a best-case scenario involving the successful development of multiple effective vaccines against the SARS-CoV-2 virus, we anticipate a situation where patient compliance is relatively low," H.C. Wainwright & Co. analyst Raghuram Selvaraju wrote in a Nov. 11 research note on the company. "We believe that now – more than ever – there is an acute need for effective therapeutic interventions as well as vaccines to appropriately manage the COVID-19 crisis," he said.
Meanwhile, Enlivex will continue to push ahead with Allocetra's chief development focus, sepsis, which kills at least 250,000 Americans each year, according to the CDC.
To date, the company has run a few small trials in sepsis, including a phase Ib trial of Allocetra in 10 patients with dysregulated immune modulators of all classes which "returned to, or trended towards, levels consistent with immune homeostasis, despite the heterogeneous baseline in cytokine storm profile," according to a company report in May. None of the patients given the cellular therapy candidate died vs. a mortality rate of 27% in a 37-patient matched historical control group.
Based on those data, the company has submitted a request to the EMA to run a randomized controlled phase IIb study, designed to recruit up to 160 sepsis patients. Its team plans to initiate that trial this month.
Competition, too, will carry ahead, with Burlingame, Calif.-based Humanigen Inc. continuing to advance lenzilumab, its lead candidate focused on preventing and treating cytokine storms. Following recent news that COVID-19 patients treated with the granulocyte macrophage-colony stimulating factor ligand inhibitor fared well in terms of recovery, the company is planning to file an emergency use authorization request with the FDA in the first quarter of 2021.