San Francisco Bay Area biotech venture Humanigen, Inc. (HGEN), formerly known as KaloBios Pharmaceuticals, is a clinical stage company focused on preventing and treating cytokine storm with lenzilumab, their proprietary Humaneered® anti-human granulocyte macrophage-colony stimulating factor (GM-CSF) monoclonal antibody. They recently announced additional analysis on the first clinical use of lenzilumab in 12 COVID-19 patients. With accumulating evidence, the company is also conducting a Phase III clinical trial investigating the anti-GM-CSF therapy in high risk, COVID-19 patients with pneumonia. The stakes are monumental for the company as it has accumulated over $280 million in operating losses since its inception with no commercial successes. Rising out of bankruptcy in 2016 as it was once led by reviled investor and pharma executive Marin Shkreli, the Company changed its name in 2018; and as of today, they possibly can contribute significant medical value should the evidence from clinical trials make the case for the technology platform.
The Hypothesis behind the Therapy
Most deaths in COVID-19 patients result from respiratory distress, which appears to be driven large in part by a cytokine release syndrome (CRS) mediated hyper-immune reaction (‘cytokine storm’) that may occur even in patients who appear to be resolving their infection by viral titers. In addition, granulocyte-macrophage colony stimulating factor (GM-SF) and T cells are highly correlated with severity and ICU admission in the setting of COVID-19. For this reason, it is critical to intervene prior to the initiation of CRS and severe respiratory distress in patients at high risk of progression. Up to 238 patients with high risk COVID-19 involving pneumonia could benefit from this treatment—if the current Phase III clinical trial goes well, a powerful new therapy for those most at risk from COVID-19 could be on its way to a regulatory filing and hopefully commercialization.
The Investigational Therapy
Lenzilumab is a humanized monoclonal antibody (class IgG1 kappa) that targets colony stimulating factor 2 (CSF2)/granulocyte-macrophage colony stimulating factor (GM-SF). The therapy was first designed for the treatment of chronic myelomonocytic leukemia (CMML) and juvenile myelomonocytic leukemia (JMML).
Pre-clinical evidence and clinical data implicate GM-CSF as a crucial initiator in systemic inflammatory pathway driving the serious life-threatening chimeric antigen receptor T cell (CAR-T) associated cytokine release syndrome (CRS). GM-CSF is produced by CAR-T cells upon recognition of target cells, which activates myeloid cells and compels them to produce monocyte chemoattractant protein 1 (MCP-1) and its receptor (CCR2).
GM-CSF knockout CAR-T cells protect mice from CRS, but IL-6 knockout mice receiving wild type CAR-T cells were not protected from CRS. Moreover, mice infused with GM-CSF knockout CAR-T cells have significantly lower serum levels of MCP-1, IL-6, MIG and MIP-1 than mice receiving wild-type CAR-T cells, demonstrating the impact of GM-CSF signaling early in the inflammatory crisis. The company has demonstrated that the use of Lenzilumab in a patient-derived xenograft model reduced CRS and neurotoxicity in mice while maintaining anti-leukemic efficacy.
Published recently on a preprint server, the manuscript is titled ‘First Clinical Use of Lenzilumab to Neutralize GM-CSF in Patients with Severe Critical COVID-19 Pneumonia.’ A secondary analysis was conducted by the company comparing patients with similar baseline characteristics treated with lenzilumab to patients treated with remdesivir. Patients treated with lenzilumab evidenced rapid clinical improvement with a median time to improvement of five days and a medium time to recovery of five days. In comparison, patients treated with remdesivir demonstrated a median time to improvement of 10 to 11 days and median time to recovery of 10 to 11 days. Remdesivir was granted emergency use authorization based on time to recovery of 11 days in the Adaptive COVID-19 Treatment Trial (ACT-1).
The company has already published results evidencing that lenzilumab has the ability to prevent and/or treat cytokine storm. The company believes a combination of this lenzilumab to treat cytokine storm and direct-acting antiviral may be synergistic in the treatment of patients with COVID-19, given the differing mechanisms of action of these two drug categories. Thus far, the investigational product has been shown to overall exhibit safe properties while evidencing that it is well tolerated in 113 patents in Phase I and two Phase II studies conducted for other purposes including severe respiratory illness and a form of leukemia reported the company in a recent S1 investor disclosure.
Limitations of the Latest Data
This most recent data has limitations, including the fact that it is a small initial cohort actually treated with the drug. Moreover, neither data set included a placebo arm, and the inherent problems of making cross trial comparisons .
More details on the company’s programs in COVID-19can be found at the company’s website under the COVID-19 tab, while details of the Phase III potential registration study follow.
Phase III Study
Currently disclosed in Clinicaltrials.gov, the company reported on May 6 that the first patient was dosed in the Phase III pivotal study for the anti-GM-CSF therapy in COVID-19 patients. The company announced it was the first U.S. randomized, double-blind, placebo-controlled, multi-center, Phase III study with an anti-GM-CSF monoclonal antibody, which, if successful, may lead to lenzilumab product approval for COVID-19 with a target of severe to critical hospitalized patients with COVID-19 pneumonia. The study is planned to conclude September 2020. The company is collaborating with the following research sites for this pivotal Phase III study: Mayo Clinic (MN, AZ, FL), AdventHealth (FL), Emory University (GA), Dartmouth-Hitchcock (NH), Atrium Health (NC) and Texas Health (TX). The Company contracted with contract research organization (CRO) CTI Clinical Trial and Consulting Service for the management of the clinical trial.
Humanigen, Inc. is developing its portfolio of clinical and pre-clinical therapies for the treatment of inflammation and cancers via its novel, cutting-edge GM-CSF neutralization and gene-knockout platforms. The company believes its GM-CSF neutralization and gene-editing platform technologies have the potential to reduce the inflammatory cascade associated with coronavirus infection as well as the serious and potentially life-threatening CAR-T therapy-related side effects while preserving and potentially improving the efficacy of the CAR-T therapy itself, thereby breaking the efficacy/toxicity linkage.
The company’s immediate focus is to prevent or minimize the cytokine storm that precedes severe lung dysfunction and ARDS in serious cases of SARS-CoV-2 infection and also in combining FDA-approved and development stage CAR-T therapies with lenzilumab, the company’s proprietary Humaneered® anti-human-GM-CSF immunotherapy, which is its lead product candidate. A potential registrational Phase III study in COVID-19 patients is currently enrolling. 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).
Technology Value Proposition
The company describes its patented “Humaneered” technology platform as a method for essentially converting existing antibodies (typically murine) into engineered, high-affinity human antibodies designed for therapeutic use with an emphasis on chronic conditions. The company has accumulated intellectual property via its own internal development as well as from in-license deals from academic institutions and thereafter applied their proprietary Humaneered technology. Their investigational product portfolio includes candidate Lenzilumab (COVID-19 is latest focus) as well as two other targets named ifabotuzumab and HGEN005. They position that their Humaneered antibodies are closer to human antibodies than chimeric or conventionally humanized antibodies plus exhibit a high affinity for their target coupled with low immunogenicity. They position their Humaneered technology as superior as it generates an antibody from an existing antibody with the required specificity as a starting point and, they articulate, a list of advantages from high potency and solubility to high antibody expression yields, attractive cost-of-goods and a list of other positioned advantages.
Their lead candidate Lenzilumab, a monoclonal antibody, has been proven in animal models to neutralize CSF, a cytokine that they believe is of critical importance in the inflammatory cascade known as the cytokine release storm (“CRS”) or cytokine storm associated with COVID-19, chimeric antigen receptor T-cell (“CAR-T”) therapy and acute Graft versus Host Disease (“GvHD”) related side-effects.
Business & Finance
Founded in 2001, the company has raised over $120 million, including a recent financing of $71 million led by JP Morgan Securities LLC organizing a financing syndicate that included Venrock Healthcare Capital Partners, Surveyor Capital (a Citadel Company), HealthCor, Valiant Capital Partners, First Light Assessment Management and Ghost Tree Capital. A TrialSite News analyst reviewed their latest SEC Form S-1 investor disclosure.
Importantly, the company went through a major restructuring when it changed its name and historically, has burned through $287.4 million and expect losses for the foreseeable future as they develop their drug candidates. It should be noted the company was formerly called KaloBios Pharmaceuticals and declared bankruptcy back in 2015, emerging out of this process in 2016. By mid-2017, the company announced it would change its name.
This company represents considerable investor risk, like most small biotech firms. With a history of operating losses, the entire dependence on the current product platform and candidates exposes high amounts of risk. It could turn out that the cause of the COVID-19 cytokine storm are factors other than elevated GM-CSF levels, which would most likely eliminate lenzilumab as part of a COVID-19 therapy recommendation. A long list of risks can be reviewed in their financial disclosures, including their dependence on a collaboration with Kite (Gilead).
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