We are currently enrolling patients in a Phase III multi-center, randomized, placebo-controlled, double-blinded, clinical trial in the setting of COVID-19. The Phase III trial will assess the safety and efficacy of lenzilumab in improving time to recovery and reducing severe outcomes in hospitalized adult patients with confirmed severe or critical COVID-19 pneumonia and may serve as the basis for EUA and/or submission of a Biologics License Application (“BLA”) for approval of lenzilumab for COVID-19 pneumonia. The first patient was dosed in May 2020. There are currently 17 clinical sites across the US and we are targeting 12 clinical sites in Brazil.
In April 2020, Lenzilumab was granted emergency single use Investigational New Drug Application (“IND”) authorization from FDA (often referred to as compassionate use) to treat patients with COVID-19. On June 15, 2020, we announced that Mayo Clinic published data derived from the compassionate use of lenzilumab in the treatment of 12 patients hospitalized in the Mayo Clinic system. Under applicable FDA rules, a patient cannot receive a compassionate use drug unless FDA has issued an individual patient emergency IND authorization, which the Mayo Clinic requested from FDA prior to each individual patient dosing of lenzilumab. Accordingly, there was no randomized control group in the Mayo Clinic program and, instead, a contemporaneous group of patients at the same centers treated with standard of care acted as matched controls. We did not pre-select patients to receive lenzilumab through the compassionate use program and did not deny any requests for compassionate use. Mayo Clinic clinicians solely determined which patients for which they would request emergency IND authorization from the FDA. As discussed below the results of the compassionate use lenzilumab compared to the control group were recently published in the Mayo Clinic Proceedings.
The patients receiving lenzilumab had severe or critical pneumonia as a result of COVID-19. They were also viewed as being at high risk of further disease progression. All patients required oxygen supplementation and had elevation in at least one inflammatory biomarker prior to receiving lenzilumab. All patients had at least one co-morbidity associated with poor outcomes in COVID-19 and several patients had multiple co-morbidities.
On September 1, 2020, we announced that Mayo Clinic Proceedings, a premier peer-reviewed journal, had published a manuscript reporting the first case-control data of lenzilumab in COVID-19 patients, demonstrating an 80% reduction in relative risk of invasive mechanical ventilation (“IMV”) and/or death for patients treated with lenzilumab compared to the matched control group. Control patients were identified from an electronic registry of COVID-19 patients in the same centers as cases and matched for age, sex, disease severity, and baseline oxygen requirements. At the time of selection, the clinical outcomes for the matched control patients were not known.
The study involved a total of 39 patients, 12 treated with lenzilumab, and 27 contemporaneous matched control patients who received standard of care treatment. Lenzilumab treatment was associated with a reduction in risk of progression to IMV and/or death compared to matched controls (8% vs. 41%, p=0.07). Median time to a 2-point clinical improvement on the 8-point hospital ordinal scale was five days versus 11 days in the control arm (p=0.006). Ventilator-free survival favored lenzilumab versus controls (p=0.06) Median time to resolution of acute respiratory distress syndrome (ARDS) was one day in the lenzilumab treatment arm versus eight days in the control group (p<0.001). Mean SpO2/FiO2 ratios post-therapy were significantly improved in the lenzilumab patients versus controls (p<0.001). Patients treated with lenzilumab were discharged in a median of five days versus 11 days in the control arm (p=0.008).
Lenzilumab treatment was also associated with a significant reduction in the inflammatory marker CRP relative to the control group (p=0.01) and an improvement in lymphocyte counts relative to the control group (p=0.04). There were no treatment-emergent adverse events attributable to lenzilumab.
The data from the case-control study suggest that GM-CSF neutralization with lenzilumab may have an effect through a dual mechanism of action to restore balance to dysregulated immune response induced by SARS-CoV-2 by suppressing myeloid inflammatory response and improving T-cell counts thought to be responsible for viral clearance.
Table 1. Demographics and baseline characteristics
Table 2. Clinical Outcomes
Table 3. Laboratory Markers
On July 27, 2020, we announced that the National Institute of Allergy and Infectious Diseases (“NIAID”), a part of the National Institutes of Health (“NIH”), which is part of the United States Government Department of Health and Human Services (“HHS”) as represented by the Division of Microbiology and Infectious Diseases (“DMID”), in partnership with Humanigen have executed a clinical trial agreement for lenzilumab as an agent to be evaluated in the NIAID-sponsored Big Effect Trial (“BET”) in hospitalized patients with COVID-19. BET will help advance NIAID’s strategic plan for COVID-19 research, which includes conducting studies to advance high-priority therapeutic candidates. Identification of agents with novel mechanisms of action for therapy is a strategic priority.
This trial builds on initial data from NIAID’s Adaptive COVID-19 Treatment Trial (ACTT-1) that demonstrated Gilead’s investigational antiviral, remdesivir, may improve time to recovery in hospitalized patients with COVID-19. BET will evaluate the combination of lenzilumab and remdesivir on treatment outcomes versus placebo and remdesivir in hospitalized COVID-19 patients. Given the differing mechanisms of action, lenzilumab and remdesivir may be synergistic. We believe that, if the BET is successful, lenzilumab may become part of an antiviral “cocktail” approach in combination with remdesivir that could be used treat hospitalized patients with COVID-19. The trial is expected to enroll 100 patients in each arm of the study with an interim analysis for efficacy after 50 patients have been enrolled in each arm. According to Genetic Engineering News, NIAID has awarded contracts totaling approximately $26 million to support the BET. Site selection for the BET is currently underway, and we anticipate minimal overlap with the sites conducting our Phase III trial. The first patient is expected to be dosed in September 2020.
With data from the BET and our ongoing Phase III study, including the component being conducted in Brazil, we expect to have data from approximately 500 hospitalized COVID-19 patients.
We believe that the ongoing Phase III study has the potential to serve as a basis for lenzilumab to receive EUA from FDA. The FDA’s authority to grant EUAs emanates from the Pandemic and All Hazards Preparedness Reauthorization Act of 2013, which authorizes and enhances FDA’s ability to support emergency preparedness and foster the development and availability of medicinal products (drugs, biologics and medical devices) for use in emergencies. EUAs permit marketing and use of medicinal products in response to declared, public health emergencies before the products are approved by FDA under the Food, Drug, & Cosmetic Act. FDA, however, holds authority to limit, restrict or condition the amount of promotional activity that accompanies EUA-approved medicinal products. An EUA, if issued in respect of lenzilumab, would be temporary; if an EUA were issued, that would not take the place of our need to complete the formal BLA submission, review and approval process.
On September 10, 2020, the independent data safety monitoring board (“DSMB”) responsible for analyzing the data generated by the Phase III study met to review the trial data for safety, futility, and sample size re-estimation after 50% of the expected events occurred. An event, per the primary endpoint of the trial is a recovery (defined as discharge from the hospital or a patient that is no longer receiving medical care for COVID-19). The DSMB unanimously recommended that the trial continue according to the existing trial protocol without modification.
We recently announced that the Brazilian Health Regulatory Agency, Anvisa, has granted permission to commence the Phase III study of lenzilumab in patients with COVID-19. Brazil has the third highest reported rates of COVID-19 infection in the world, following only the US and India. As of September 6, 2020, more than 4 million cases of COVID-19 had been confirmed in Brazil, causing more than 125,000 deaths. The expansion of the phase III study, which we expect will be conducted in a target of 12 sites located in current hot spots in Brazil, will follow the same protocol approved by FDA – a multicenter, randomized, placebo-controlled, double-blinded clinical trial focused on hospitalized severe and critical adult COVID-19 patients at high risk of disease progression. Data generated from patients in Brazil will be aggregated with that generated from patients in the US. We expect the first patient to be dosed in Brazil in September 2020, and currently expect that we will complete enrollment of the 300 patients in total from sites in the US and Brazil by the end of September 2020. Topline data is expected to be available in Q4 2020.
Based on the promising data generated from the Mayo Clinic case-control study, we are actively pursuing the commercial preparation of lenzilumab in the event we receive EUA for COVID-19 patients from FDA. We believe we may be able to apply for an EUA before the end of 2020 and for a BLA in 2021. To that end, we have undertaken significant efforts and expended resource to secure US-based production capacity to meet anticipated demand, including through the expansion of capacity offered by Catalent Biologics and the addition of Lonza.
Our current clinical and regulatory development plan in the CAR-T setting is focused on a collaboration agreement we executed with Kite in May 2019, which we refer to as the “Kite Agreement”. Pursuant to the Kite Agreement, the parties have agreed to conduct and are currently enrolling patients in a multi-center Phase Ib/II study (“ZUMA-19”) of lenzilumab with Kite’s YESCARTA in patients with relapsed or refractory B-cell lymphoma, including DLBCL. Kite is the sponsor of ZUMA-19 and is responsible for its conduct. The primary objective of ZUMA-19 is to determine the effect of lenzilumab on the safety of YESCARTA. In addition, efficacy and healthcare resource utilization will be assessed. On June 30, 2020, we announced that the first patient had been infused with lenzilumab and YESCARTA in the ZUMA-19 study.
Kite’s YESCARTA is one of three CAR-T therapies that have been approved by FDA and is the leading CAR-T by revenue. We believe our collaboration with Kite is the only current clinical collaboration that is enrolling patients with the potential to improve both the safety and efficacy of CAR-T therapy. The Kite Agreement is non-exclusive. Depending upon FDA feedback, we believe that the results from the ZUMA-19 trial may serve as the basis for registration for lenzilumab in the CAR-T setting.
We are collaborating with IMPACT, a clinical trial partnership of 23 transplant centers in the United Kingdom, in planning a potential randomized, placebo controlled, double-blind, Phase II/III study focused on early intervention with lenzilumab in patients at high risk or intermediate risk for steroid refractory acute GvHD based on the Mt. Sinai acute GvHD international consortium (MAGIC) biomarkers. The goal of the trial, as it is currently contemplated, would be to determine the efficacy and safety of lenzilumab in reducing non-relapse mortality at six months.