Humanigen Inc (NASDAQ:HGEN): results from the Phase 1/2 multi-center study of lenzilumab and axicabtagene ciloleucel in patients with relapsed or refractory large B cell lymphoma

Phase III may not be necessary for approval in ZUMA-19; precedent is CAR-Ts to date have been approved on Phase II data

It is a Phase 1b/2

1 Phase III may not be necessary for approval in ZUMA-19; precedent is CAR-Ts to date have been approved on Phase II data

In mid-2019, Gilead paid Galapagos (NASDAQ:GLPG) almost $4 billion plus $1.1 billion in equity for exclusive rights to its portfolio of compounds. The deal left Galapagos an independent company. CEO O'Day offered reasoning in the earnings call shortly after the deal, stating "innovation requires independence." In addition to future developments, Gilead gained rights to commercialize products outside of Europe. The three primary assets of interest were for idiopathic pulmonary fibrosis (IPF), osteoarthritis, and rheumatoid arthritis.

Patients refractory to tocilizumab and corticosteroids remain difficult to treat, and new strategies for the management or prevention of CRS are ongoing. Given the success of tocilizumab in treating CRS, there is a strong rationale for the selective inhibition of additional key cytokines involved in CART-related toxicities. GM-CSF has been implicated in the stimulation of myeloid cells, which greatly contribute to CRS development. Preclinical studies have shown that treatment with the anti-GM-CSF antibody, lenzilumab, had no negative effects on CART cell function in vitro or in vivo and even improved leukemic disease control in mice. Furthermore, GM-CSF neutralization reduced CRS symptoms in a patient-derived xenograft model. GM-CSF was also genetically nullified by using a CRISPR-Cas9 platform; GM-CSF knockout CART cells led to improved overall survival in mice, indicating additional potential for next-generation gene-edited CART cells (62). Another study demonstrated that GM-CSF neutralized by antibodies or knocked out with TALEN technology ablated macrophage-associated cytokines linked to CRS development, including MCP-1, IL-6, and IL-8 (63). A clinical trial has been designed using lenzilumab to prevent toxicities in patients receiving axicabtagene ciloleucel.

As with CRS, targeting key cytokines has shown promise in preventing or reducing ICANS after CART cell therapy. GM-CSF secretion contributes to pro-inflammatory myeloid cells, which are associated with ICANS occurrence. Not only did GM-CSF neutralization dampen CRS, but it also resulted in decreased myeloid and T-cell infiltration in the central nervous system and reduction of neuroinflammation in a patient-derived xenograft model. IL-1 secreted by activated myeloid cells has been associated with ICANS. In addition to preventing CRS, the IL-1 antagonist anakinra abolished ICANS symptoms in mice treated with CART cells (57) and is being evaluated in the clinic.

Humanigen, Inc., (Nasdaq: HGEN) (“Humanigen”), a clinical stage biopharmaceutical company focused on preventing and treating an immune hyper-response called ‘cytokine storm,’ today announced that the first patient has been dosed at the Emory University School of Medicine in Atlanta, Georgia as part of the in the ACTIV-5 “Big Effect Trial” (ACTIV-5/BET) evaluating lenzilumab with remdesivir, compared to placebo and remdesivir, in patients hospitalized with COVID-19. Lenzilumab is the Company’s lead product candidate and proprietary Humaneered® anti-human granulocyte macrophage-colony stimulating factor (GM-CSF) monoclonal antibody designed to optimize antibody properties.

ACTIV-5/BET, which is being conducted by the National Institute of Allergy and Infectious Diseases (NIAID), part of the U.S. National Institutes of Health (NIH), is designed to determine whether certain approved therapies or investigational drugs in late-stage clinical development show promise against COVID-19 and, therefore, merit advancement into larger clinical trials.

The adaptive, randomized, double-blind placebo-controlled trial evaluating lenzilumab with remdesivir will include up to 200 patients across as many as 40 treatment centers in the U.S. There will be approximately 100 patients assigned to each study arm.

“Nearly 90% of hospitalized COVID-19 patients progress to severe disease including the cytokine storm for some patients,” said Vincent C. Marconi, MD, professor of medicine and global health in Emory University School of Medicine and Emory’s Rollins School of Public Health. “There is a critical need for a novel COVID-19 therapeutic with potential to reduce patients’ time to recovery, and this study aims to streamline the pathway to finding these urgently needed treatments.”

“We are encouraged by lenzilumab’s efficacy and safety data demonstrated in hospitalized COVID-19 patients to date and believe we have a game-changing treatment with frontline potential,” said Cameron Durrant, MD, MBA, chief executive officer of Humanigen. “We are eager to put lenzilumab through further rigorous testing in this NIH ACTIV-5 study as we continue to advance our lead candidate in the next phases of development.”

ACTIV-5/BET is being conducted in collaboration with the NIH’s public-private partnership Accelerating COVID-19 Therapeutic Innovations and Vaccines (ACTIV) program. The ACTIV partnership has evaluated approximately 400 therapeutic agents with a potential application for COVID-19 and developed a collaborative framework for prioritizing the most promising candidates, streamlining clinical trials, coordinating regulatory processes, and leveraging assets among all partners to rapidly respond to the COVID-19 and future pandemics. To date, ACTIV has designed five adaptive master protocols for ACTIV clinical trials, and selected numerous NIH-supported networks to launch these clinical trials to test prioritized therapeutic candidates.

More details on Humanigen’s programs in COVID-19 can be found on the company’s website at www.humanigen.com under the COVID-19 tab, and details on ACTIV-5/BET can be found at www.clinicaltrials.gov using Identifier NCT04583969.

About ACTIV-5/BET

The primary purpose of ACTIV-5/BET, a randomized, double-blind, placebo-controlled trial, is to evaluate the clinical efficacy of the different investigational therapeutics relative to the control arm in hospitalized adults based on the patients’ clinical status at day 8. The study’s secondary point of evaluation is to evaluate the clinical efficacy of the different investigational therapeutics as assessed by the amount of time it takes for each patient to recover from COVID-19.

About Humanigen, Inc.

Humanigen, Inc. is developing its portfolio of clinical and pre-clinical therapies for the treatment of cancers and infectious diseases via its novel, cutting-edge GM-CSF neutralization and gene-knockout platforms. We believe that our GM-CSF neutralization and gene-editing platform technologies have the potential to reduce the inflammatory cascade associated with coronavirus infection. The company’s immediate focus is to prevent or minimize the cytokine release syndrome that precedes severe lung dysfunction and ARDS in serious cases of SARS-CoV-2 infection. The company is also focused on creating next-generation combinatory gene-edited CAR-T therapies using strategies to improve efficacy while employing GM-CSF gene knockout technologies to control toxicity. In addition, the company is developing its own portfolio of proprietary first-in-class EphA3-CAR-T for various solid cancers and EMR1-CAR-T for various eosinophilic disorders. The company is also exploring the effectiveness of its GM-CSF neutralization technologies (either through the use of lenzilumab™ as a neutralizing antibody or through GM-CSF gene knockout) in combination with other CAR-T, bispecific or natural killer (NK) T cell engaging immunotherapy treatments to break the efficacy/toxicity linkage, including to prevent and/or treat graft-versus-host disease (GvHD) in patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT). Additionally, Humanigen and Kite, a Gilead Company, are evaluating lenzilumab in combination with Yescarta® (axicabtagene ciloleucel) in patients with relapsed or refractory large B-cell lymphoma in a clinical collaboration. For more information, visit www.humanigen.com.

Published scientific evidence links GM-CSF expression to serious and potentially life-threatening outcomes in respiratory conditions such as COVID-19 pneumonia. Evidence also indicates a potential role of GM-CSF expression in serious and potentially life-threatening side-effects associated with CAR-T therapy, and reduced efficacy in CAR-T therapies approved by the US Food and Drug Administration (“FDA”). As a result, while we believe our leadership position in GM-CSF pathway science and cytokine storm presents us with a diverse set of development opportunities, we currently are focused on developing lenzilumab for three primary indications:

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As a therapy treating severe and critical hospitalized patients with confirmed COVID-19 pneumonia, which is the majority of hospitalized patients who are hypoxic and not yet on invasive mechanical ventilation (“IMV”);

As a prophylactic therapy ahead of CAR-T administration in CD19 targeted CAR-T therapies; and

As an early treatment or potential prophylaxis for acute GvHD following HSCT in high and intermediate risk patients.

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In addition to these programs with lenzilumab, we are also exploring the effectiveness of our GM-CSF neutralization technologies (either through the use of lenzilumab as a neutralizing antibody, or through GM-CSF gene knockout) in combination with other CAR-T, T-cell engaging, and immunotherapy treatments to break the efficacy/toxicity linkage.

Our clinical-stage pipeline also comprises a further Phase I study with ifabotuzumab (“ifab”) in glioblastoma multiforme (“GBM”). The GBM study is nearly fully enrolled. We believe ifab may have potential in other solid cancers. We also have a focus on creating safer and more effective CAR-T therapies in hematologic malignancies and solid tumors via three key modalities:



Combining FDA-approved and development stage CAR-T therapies with lenzilumab;

Creating next-generation gene-edited CAR-T therapies using GM-CSF gene knockout technologies; and

Exploring the effectiveness of our GM-CSF neutralization technologies (either through the use of lenzilumab as a neutralizing antibody or through GM-CSF gene knockout) in combination with other CAR-T, T-cell engaging, and immunotherapy treatments, including allogeneic HSCT.

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These product candidates are in the early stage of development and will require substantial time, resources, research and development, and regulatory approval prior to commercialization. Furthermore, none of these product candidates have been approved for marketing and it may be years, if this occurs at all.

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We believe that we have built an intellectual property position in the area of GM-CSF neutralization through multiple approaches and mechanisms, as they pertain to COVID-19, CAR-T, GvHD and multiple other oncology/transplantation, inflammation, fibrosis and autoimmune conditions which may be driven by GM-CSF.

Humanigen is in advanced planning for a Phase 2 study of lenzilumab in combination with azacitidine in newly-diagnosed CMML patients who express NRAS/KRAS/CBL mutations, which are known to be hypersensitive to granulocyte macrophage-colony stimulating factor (GM-CSF) and therefore may lend themselves to responsiveness to lenzilumab treatment. CMML is a rare form of hematologic cancer with no FDA-approved treatment options and a three-year overall survival rate of 20% and median overall survival of 20 months.1,2 The study is funded by grant from the Australian Government's Medical Research Future Fund and is expected to commence in 2021.

Ifabotuzumab in glioblastoma multiforme (GBM)