Humanigen, Inc. (Nasdaq: HGEN), a clinical-stage biopharmaceutical company focused on preventing and treating an immune hyper-response called ‘cytokine storm’ with its lead drug candidate, lenzilumab, today announced a late-breaking (LB) presentation of results from the Company’s randomized, double-blind, placebo-controlled LIVE-AIR Phase 3 study at the CHEST Annual Meeting 2021, which is being hosted by the American College of Chest Physicians® (CHEST) virtually from October 17th to October 20th. CHEST includes more than 19,000 physicians, nurses, and respiratory therapists among its members, including more 15,500 U.S-based members and 3,500 members from more than 100 other countries.
The presentation will be delivered by Zelalem Temesgen, MD, Professor of Medicine at Mayo Clinic and Principal Investigator of the LIVE-AIR Phase 3 trial, highlighting the potential utility of CRP as a means to optimize outcomes with lenzilumab in hospitalized COVID-19 patients. The LB abstract entitled: “C-Reactive Protein as a Biomarker for Improved Efficacy of Lenzilumab in COVID-19 Patients: Results from the LIVE-AIR Trial” has been published in the journal CHEST® and can be accessed via this link.1
Lenzilumab has not been authorized or approved for use in any indication by any regulatory agency.
“Our analysis of LIVE-AIR data using CRP<150 mg/L as a cut-off suggests that early use of lenzilumab in COVID-19 patients upon hospitalization can significantly reduce progression of these patients to a hyperinflammatory state that independent research has already shown results in higher rates of invasive mechanical ventilation and death,” said Dale Chappell, Chief Scientific Officer of Humanigen.2 “Our LIVE-AIR study data show lenzilumab reduces CRP levels, and improves clinical outcomes, and this analysis suggests utilization of CRP as a biomarker may offer an effective way to optimize lenzilumab treatment in hospitalized COVID-19 patients, if authorized or approved for use. In our LIVE-AIR trial, 78% of the LIVE-AIR study population had a baseline CRP less than 150mg/L, representing a substantial population.”
Exploratory analysis of LIVE-AIR results in patients with CRP<150 mg/L and aged <85 years of age, which represented 74% of patients with an evaluable CRP at baseline, show lenzilumab improved the likelihood of survival without ventilation by more than 3-fold (OR 3.04; 95% CI: 1.68-5.51, nominal p=0.0003) compared with placebo and mortality was improved by more than 2-fold (OR: 2.22; 95%CI: 1.07-4.67, p=0.034). Response to lenzilumab was observed in the first through third quartiles of baseline CRP with the greatest response observed in those patients treated earlier in the inflammatory process (<41 mg/L, HR:8.33; 41-<79 mg/L, HR:1.60; 79-<137 mg/L, HR: 2.12; >137 mg/L, HR: 1.17)
Overall, 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=0.0403).
About use of CRP to identify immune phenotypes in hospitalized COVID-19 patients
Numerous studies in COVID-19 have published data showing CRP levels are strongly associated with severity of disease and worsening clinical outcomes such as respiratory failure and death.2,3,4,5 As an example, last year, independent researchers established an operational definition of COVID-19 hyperinflammation (COV-HI) from emerging evidence that there was an association between biomarkers of inflammation such as CRP and severe disease. To test this hypothesis, these UK-based researchers conducted a retrospective longitudinal cohort study of 269 consecutive patients admitted to study hospitals in March 2020. Results of the study support the concept that a subset of COVID-19 that meet the definition of the hyperinflammatory phenotype, 82% of which met the criteria due to elevated CRP (CRP>150 mg/L), suffer from worse outcomes than those who do not. The study also showed 74% of those requiring elevated respiratory care met the definition of COV-HI by the time they needed the additional support. In addition, meeting the definition of COV-HI (CRP > 150 mg/L) was significantly associated with next-day escalation of respiratory support or death supporting the concept that therapeutic intervention prior to CRP > 150 mg/L may be necessary to provide an adequate therapeutic window in order to prevent progression to mechanical ventilation and death.4
While the LIVE-AIR results, reported above, suggest an improved treatment outcome for patients treated with lenzilumab with CRP<150 mg/L, other studies of immunotherapies like tocilizumab show a differential benefit in patients with CRP>150 mg/L. A large observational study in Spain showed tocilizumab was associated with decreased risk of death (adjusted hazard ratio 0.34, 95% confidence interval 0.16–0.72, p 0.005) and ICU admission or death (adjusted hazard ratio 0.39, 95% confidence interval 0.19–0.80, p 0.011) among patients with baseline CRP >150 mg/L but not among those with CRP ≤150 mg/L.6 Another study of tocilizumab reported the primary endpoint (the proportion of patients who required noninvasive ventilation or intubation or who died at day 14) was achieved in the overall patient population as a result of the disproportionate benefit seen in patients with CRP>150 mg/L, as no benefit was reported in patients with baseline CRP<150 mg/L. Likewise, a survival benefit was observed at day 90 in this same study for those treated with tocilizumab who had baseline CRP>150 mg/L, but not for those with baseline CRP <150 mg/L.7 This suggests CRP as a biomarker may help physicians to determine which immunotherapeutic may be most beneficial for a particular patient.
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=0.0403). Results of the trial have been submitted for publication in a peer-reviewed journal.
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 (“CRS”) or cytokine storm (CS), associated with COVID-19 and other indications. Lenzilumab binds to and neutralizes GM-CSF, consequently improving outcomes for hypoxic 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 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 DLBCL. Lenzilumab will also be tested to assess its ability prevent and/or treat aGvHD in patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT).
A study of lenzilumab is also being prepared 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.
Humanigen, Inc. (Nasdaq: HGEN) (“Humanigen”), is a clinical-stage biopharmaceutical company focused on preventing and treating an immune hyper-response called ‘cytokine storm’. Lenzilumab is a first-in class antibody that binds to and neutralizes granulocyte-macrophage colony-stimulating factor (GM-CSF). Results from preclinical models indicate GM-CSF is an upstream regulator of many inflammatory cytokines and chemokines involved in the cytokine storm. Early in the COVID-19 pandemic, investigation showed high levels of GM-CSF secreting T cells were associated with disease severity and intensive care unit admission. Humanigen’s Phase 3 LIVE-AIR study suggests early intervention with lenzilumab may prevent consequences of a full-blown cytokine storm in hospitalized patients with COVID-19. Humanigen has submitted lenzilumab to Medicines and Health Regulatory Agency in the United Kingdom for a rolling review towards potential Marketing Authorization. Humanigen is developing lenzilumab as a treatment for cytokine storm associated with COVID-19 and CD19-targeted CAR-T cell therapies and is also exploring the effectiveness of lenzilumab in other inflammatory conditions such as acute Graft versus Host Disease in patients undergoing allogeneic hematopoietic stem cell transplantation, eosinophilic asthma, and rheumatoid arthritis. For more information, visit www.humanigen.com and follow Humanigen on LinkedIn, Twitter, and Facebook.
All statements other than statements of historical facts contained in this press release are forward-looking statements. Forward-looking statements reflect management's current knowledge, assumptions, judgment, and expectations regarding future performance or events. Although management believes that the expectations reflected in such statements are reasonable, they give no assurance that such expectations will prove to be correct, and you should be aware that actual events or results may differ materially from those contained in the forward-looking statements. Words such as "will," "expect," "intend," "plan," "potential," "possible," "goals," "accelerate," "continue," and similar expressions identify forward-looking statements, including, without limitation, statements regarding the potential of lenzilumab being optimized in patients with CRP<150 mg/L; statements regarding tocilizumab being less effective in patients with CRP<150 mg/L and optimized in patients with CRP>150 mg/L; statements regarding use of lenzilumab as a therapy for the treatment of patients hospitalized with COVID-19; and statements regarding our plans to develop lenzilumab for CAR-T and other indications and our other plans relating to lenzilumab.
Forward-looking statements are subject to a number of risks and uncertainties including, but not limited to, the risks inherent in our lack of profitability and need for additional capital to grow our business; our dependence on partners to further the development of our product candidates; the uncertainties inherent in the development, attainment of the requisite regulatory authorizations and approvals and launch of any new pharmaceutical product; the outcome of pending or future litigation; and the various risks and uncertainties described in the "Risk Factors" sections of our latest annual and quarterly reports and other filings with the SEC.
All forward-looking statements are expressly qualified in their entirety by this cautionary notice. You should not rely upon any forward-looking statements as predictions of future events. We undertake no obligation to revise or update any forward-looking statements made in this presentation to reflect events or circumstances after the date hereof or to reflect new information or the occurrence of unanticipated events, except as required by law.
- Temesgen, Z., et al. (2021). C-reactive protein as a biomarker for improved efficacy of LENZILUMAB in patients with COVID-19: Results from the live-air trial. Chest, Oct. 11, 2021;160(4). https://doi.org/10.1016/j.chest.2021.08.029
- Chen, W., et al. (2020). Plasma CRP level is positively associated with the severity of COVID-19. Annals of Clinical Microbiology and Antimicrobials, May 15, 2020;19(1):18. https://doi.org/10.1186/s12941-020-00362-2
- Herold, T., et al. (2020). Elevated levels of IL-6 and CRP predict the need for mechanical ventilation in COVID-19. Journal Allergy Clinical Immunology, May 18, 2020. https://doi.org/10.1016/j.jaci.2020.05.008
- Manson, J., et al. (2020). Covid-19-associated hyperinflammation and escalation of patient care: A retrospective longitudinal cohort study. The Lancet Rheumatology, Aug. 21, 2020;2(10), e594–e602. https://doi.org/10.1016/s2665-9913(20)30275-7
- Sharifpour, M., et al. (2020). C-Reactive protein as a prognostic indicator in hospitalized patients with COVID-1. PLOS One Nov. 20, 2020. https://doi.org/10.1371/journal.pone.0242400
- Martinez-Sanz, J., et al. (2020). Effects of tocilizumab on mortality in hospitalized patients with COVID-19: a multicentre cohort study. Clinical Microbiology and Infection Sep. 23, 2020. https://doi.org/10.1016/j.cmi.2020.09.021
- Mariette, X., et al. (2021). Effectiveness of tocilizumab in patients hospitalized with COVID-19 a follow-up of the CORIMUNO-TOCI-1 randomized clinical trial. Jama Internal Medicine May 24, 2021;181(9):1241-1243. https://doi.org/10.1001/jamainternmed.2021.2209