• CRISPR/Cas9-Mediated GM-CSF knock-out (GM-CSF^ko) CAR-T cells demonstrate reduced apoptosis and enhanced in vivo anti-tumor activity in preclinical models
• Phase 3 SHIELD study utilizing lenzilumab to prophylactically neutralize GM-CSF in CAR-T to begin 1H22

Humanigen, Inc. (Nasdaq: HGEN) (“Humanigen”), a clinical-stage biopharmaceutical company focused on preventing and treating an immune hyper-response called ‘cytokine storm,’ announced today a peer-reviewed publication in Leukemia, a leading oncology and hematology journal, entitled “GM-CSF disruption in CART cells modulates T cell activation and enhances CART cell anti-tumor activity.”

This publication is a significant addition to the findings from a previous article in the leading hematology journal, blood, which demonstrated that neutralization of GM-CSF with lenzilumab (LENZ^®) was able to break the efficacy/toxicity linkage by reducing cytokine release syndrome (CRS) and neuroinflammation (ICANS) while enhancing CAR-T function.¹ The Leukemia publication demonstrates that CRISPR/Cas9-mediated GM-CSF knockout in CAR-T cells directly ameliorates CAR-T cell early activation, reduces activation-induced cell death, and results in enhanced anti-tumor activity in vivo in a xenograft model.²

Enhancing CAR-T cell in vivo efficacy by using strategies to non-specifically stimulate CAR-T cell proliferation utilizing synthetic biology or combination therapy to edit exhaustion pathways or prevent apoptosis is an important goal and is the subject of substantial ongoing research. However, while this may improve CAR-T efficacy, it is often at the cost of an increase in important toxicities, such as CRS and ICANS. In contrast, these data published in Leukemia indicate that GM-CSF^ko CAR-T cells result in enhanced CAR-T cell proliferation and anti-tumor activity while being associated with a marked reduction in GM-CSF levels, which have been linked to CAR-T associated toxicities.

CAR-T therapies have resulted in significant advances for patients. However, for up to one-third of patients, toxicities such as severe ICANS and CRS occur, and tumor relapse is still a frequent occurrence.³ Currently, the widespread adoption of CAR-T therapy is limited, in part, by the requirement for treatment in centers that are experienced in managing the common toxicities of ICANS and CRS and by the financial and health burden that this creates. “CRS, ICANS, and tumor relapse remain challenges for physicians and patients treated with CAR-T therapy,” said Saad Kenderian, M.B., Ch.B., hematologist at Mayo Clinic Cancer Center, an author of the Leukemia paper and the primary investigator for the SHIELD study (Study on How to Improve Efficacy and toxicity with Lenzilumab in DLBCL and other NHL patients treated with CAR-T therapy). He added, “They result in additional morbidity for patients, as well as significantly increased costs for healthcare providers. Treatments that can prevent ICANS and CRS while potentially improving CAR-T efficacy could address a critical unmet need.”

This publication adds to the body of knowledge of GM-CSF depletion in CAR-T. The upcoming Phase 3 CAR-T study, known as SHIELD, will determine the efficacy and safety of prophylactic lenzilumab on the rates of ICANS, CRS, and CAR-T efficacy. “The SHIELD trial has been designed to build on the positive results from the ZUMA-19 study. The primary endpoint of SHIELD will focus on demonstrating a significant improvement in neurotoxicity associated with both Yescarta® and Tecartus®. We will also seek to explore the beneficial impact that lenzilumab may have CAR-T efficacy,” stated Dale Chappell, M.D., MBA, Chief Scientific Officer, Humanigen.

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, potentially improving outcomes for patients hospitalized with COVID-19. Humanigen believes that GM-CSF neutralization with lenzilumab also 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 (ZUMA-19) 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 3 study (“SHIELD”) to evaluate its efficacy and safety when combined with Yescarta and Tecartus CAR-T therapies in non-Hodgkin lymphoma. Lenzilumab will also be tested to assess its ability to prevent and/or treat acute Graft versus Host Disease (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 builds 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.

Lenzilumab is an investigational product and is not approved or authorized in any country.

About Humanigen

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 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.

Forward-Looking Statements

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 SHIELD and LIVE-AIR studies, and other statements regarding improving the safety and efficacy of CAR-T and our plans relating to lenzilumab and ifabotuzumab.

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 press release to reflect events or circumstances after the date hereof, to reflect new information or the occurrence of unanticipated events, or to update the reasons why actual results could differ materially from those anticipated in the forward-looking statements, in each case, except as required by law.

References

1. Sterner, R. et al. (2019). GM-CSF inhibition reduces cytokine release syndrome and neuroinflammation but enhances CAR-T cell function in xenografts. blood. https://doi.org/10.1182/blood-2018-10-881722
2. Cox, M. et al. (2022). GM-CSF disruption in CART cells modulates T cell activation and enhances CART cell anti-tumor activity. Leukemia. https://doi.org/10.1038/s41375-022-01572-7
3. Morris, E. et al. (2021). Cytokine release syndrome and associated neurotoxicity in cancer immunotherapy. Nature Reviews Immunology. https://doi.org/10.1038/s41577-021-00547-6

LENZ® is a trademark of Humanigen, Inc.

Yescarta® and Tecartus® are trademarks of Gilead Sciences, Inc., or its related companies.

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