On December 1, 2021 Humanigen, Inc. (Nasdaq:HGEN) ("Humanigen"), a clinical-stage biopharmaceutical company focused on preventing and treating an immune hyper-response called ‘cytokine storm’ with its lead drug candidate, lenzilumab, reported The Lancet Respiratory Medicine ("Lancet"), an internationally trusted, peer-reviewed source of clinical, public health, and global health knowledge, published positive results from Humanigen’s LIVE-AIR Phase 3 randomized, controlled trial of lenzilumab in hospitalized COVID-19 patients, as well as an independent expert commentary (Press release, Humanigen, DEC 1, 2021, View Source [SID1234596361]). The Lancet paper concludes "LIVE-AIR showed that lenzilumab treatment of hospitalised patients with COVID-19 can improve the likelihood of survival without the need for mechanical ventilation, with a safety profile similar to that of placebo."2

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"Publication of LIVE-AIR results in this peer-reviewed medical journal is a major achievement. Our goal was to demonstrate that lenzilumab, a variant-agnostic therapy, could address the unmet need in treatment of COVID-19 patients by reducing death or mechanical ventilation. The results describe the positive impact lenzilumab has on improving survival without the need for invasive mechanical ventilation in COVID-19 patients upon hospitalization," said Cameron Durrant, Chairman and CEO, Humanigen. "As the paper describes ‘60% of LIVE-AIR patients were on room air or low-flow oxygen support. … (Raising) the possibility that lenzilumab might be positioned for use before ICU admission and progression of respiratory failure requiring high-flow oxygen and non-invasive or invasive ventilation.’"2

"This study of the treatment to prevent hyperinflammatory immune response that occurs in some patients infected with SARS-CoV-2 is important," said Zelalem Temesgen, M.D., Mayo Clinic infectious disease researcher and principal investigator. "The need is great for more therapies for newly hospitalized patients prior to respiratory failure to reduce mortality or mechanical ventilation."

Lenzilumab is not authorized, or approved, in any country.

"One of the key components of the detrimental hyperinflammatory response in COVID-19 is granulocyte-macrophage colony-stimulating factor (GM-CSF). … excessive GM-CSF production can contribute to the dysregulated immune response in severe COVID-19, in which, upstream of IL-1 and IL-6, activated T cells target neutrophils and macrophages. Agents that interfere with its actions have high plausibility for benefit, not just in COVID-19, but in other acute inflammatory conditions,"1 noted the commentary.

The Lancet paper notes differences in CRP levels for LIVE-AIR patients compared to those of clinical trials for another immunomodulator to suggest these "findings might indicate the therapeutic potential of targeting a single upstream cytokine earlier in the disease process, guided by baseline CRP. … The study contributes to the emerging body of evidence about how CRP concentrations relate to the pathogenesis of COVID-19 and to patient and treatment selection."2 Related to the value of a CRP-guided approach to treatment of COVID-19 patients, the commentary noted "further study of a CRP-guided approach, possibly targeting patients with lower CRP concentrations, earlier in their disease course, … could therefore be warranted."1

For hospitalized patients, "we now know that targeting the dysregulated host response is of greater value than targeting the virus."1 The high level of uncertainty and concern surrounding the emergence of the Omicron variant highlights the ongoing need for variant-agnostic therapies.

About the LIVE-AIR, Phase 3 Study of Lenzilumab

This study was a randomized, double-blind, placebo-controlled, multi-center Phase 3 trial for the treatment and prevention of serious and potentially fatal outcomes in patients hospitalized with COVID-19 pneumonia. The primary objective was to assess whether lenzilumab, in addition to other treatments, which included dexamethasone (or other steroids) and/or remdesivir, could prevent or alleviate the immune-mediated ‘cytokine storm’ and improve survival without ventilation, or ‘SWOV’ (sometimes referred to as ‘ventilator-free survival’). SWOV is a composite endpoint of time to death and time to invasive mechanical ventilation (IMV) and SWOV is an important clinical endpoint that measures not only mortality, but the morbidity associated with mechanical ventilation. Approximately 94% of patients received dexamethasone (or other steroids), 72% received remdesivir, and 69% received both.

The LIVE-AIR study enrolled 520 patients in 29 sites in the US 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; and were hospitalized but did not require IMV. Following enrollment, subjects were randomized to receive three infusions of either lenzilumab or placebo, with each infusion separated by eight hours over a 24-hour period. The LIVE-AIR study achieved its primary endpoint of survival without ventilation measured through day 28 following treatment (HR: 1.54; 95%CI: 1.02-2.32, p=0.040).

About Lenzilumab

Lenzilumab is a proprietary Humaneered first-in-class monoclonal antibody that has been proven to neutralize GM-CSF, a cytokine of critical importance in the hyperinflammatory cascade, sometimes referred to as cytokine release syndrome, or cytokine storm, associated with COVID-19 and other indications. Lenzilumab binds to and neutralizes GM-CSF, consequently improving outcomes for patients hospitalized with COVID-19. Humanigen believes that its GM-CSF neutralization has the potential to reduce the hyper-inflammatory cascade known as cytokine release syndrome common to chimeric antigen receptor T-cell (CAR-T) therapy and acute Graft versus Host Disease (aGvHD).

In CAR-T, lenzilumab successfully achieved the pre-specified primary endpoint at the recommended dose in a Phase 1b study with Yescarta in which the overall response rate was 100% and no patient experienced severe cytokine release syndrome or severe neurotoxicity. Based on these results, Humanigen plans to test lenzilumab in a randomized, multicenter, potentially registrational, Phase 2 study to evaluate its efficacy and safety when combined with other commercially available CD19 CAR-T therapies in non-Hodgkin lymphoma. Lenzilumab will also be tested to assess its ability to prevent and/or treat aGvHD in patients undergoing allogeneic hematopoietic stem cell transplantation.

A study of lenzilumab is also underway for patients with chronic myelomonocytic leukemia (CMML) exhibiting RAS pathway mutations. This study will build on evidence from a Phase 1 study, conducted by Humanigen, that showed RAS mutations are associated with hyper-proliferative features, which may be sensitive to GM-CSF neutralization.