LENZILUMAB DEVELOPMENT
COVID-19
LIVE-AIR Phase 3 Study
In March 2021, we announced topline results in a Phase 3 multi-center, randomized, placebo-controlled, double-blinded clinical trial in the setting of COVID-19. The positive results from the study served as the basis for the filing of an Emergency Use Authorization ("EUA") submission in May 2021.
The primary endpoint of this Phase 3 trial evaluated the safety and efficacy of lenzilumab in improving survival without ventilation (SWOV) in COVID-19 patients. Secondary measures included duration of ICU stay, time to death, and time to recovery. The first patient was dosed in May 2020. There was a total of 29 clinical sites across the United States and Brazil.
Mayo Clinic Case-Control Study
In April 2020, lenzilumab was granted emergency single use Investigational New Drug Application (“IND”) authorization from the 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 cohort of patients at the same centers treated with standard of care as matched controls. 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. 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 of lenzilumab compared to the control cohort were recently published in the Mayo Clinic Proceedings.
The COVID-19 patients receiving lenzilumab were hospitalized and required supplemental oxygen but were not on invasive mechanical ventilation (“IMV”). They were also viewed as being at high risk of further disease progression. All patients 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 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).
The results showed that the primary clinical outcome –– time to clinical improvement –– was shorter in the lenzilumab group. The median time to a 2-point clinical improvement on the 8-point hospital ordinal scale was 5 days in the lenzilumab group versus 11 days in the control arm (p=0.006). Ventilator-free survival favored lenzilumab over the control but was not statistically significant (p=0.06). The proportion of patients who were free of ARDS (with SpO2/FiO2 of 315 or higher) at the end of the trial was higher in the lenzilumab group (p<0.001). Patients treated with lenzilumab were discharged in a median of 5 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-cohort 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.
The results of this case-control study were published in Mayo Clinic Proceedings, a premier peer-reviewed journal, on September 1, 2020, illustrating the 80% reduction in relative risk of IMV and/or death for patients treated with lenzilumab compared to the matched control group.
Table 1. Demographics and baseline characteristics
Lenzilumab group (n=12) | Control group (n=27) | P-value | |
|---|---|---|---|
Age, y | 65 (52-70) | 68 (61-76) | 0.25 |
Male | 8 (67%) | 19 (70%) | > .99 |
Female | 4 (33%) | 8 (30%) | > .99 |
Race | |||
White | 9 (75%) | 17 (63%) | 0.79 |
Asian | 2 (17%) | 5 (19%) | > .99 |
American Indian/Native American | 1 (8%) | 0 (0%) | 0.36 |
Comorbidities | |||
Diabetes mellitus | 7 (58%) | 14 (52%) | > .99 |
Hypertension | 7 (58%) | na | na |
Obesity (BMI > 30) | 6 (50%) | 9 (33%) | 0.54 |
Coronary artery disease | 2 (17%) | 4 (15%) | > .99 |
Kidney transplantation | 1 (8%) | na | na |
Obstructive lung disease | 4 (33%) | na | na |
Chronic obstructive pulmonary disease | 2 (17%) | 11 (41%) | 0.47 |
Reactive airway disease | 1 (8%) | na | na |
Temperature (degrees Celsius) | 38 (37.25-38.5) | 37.5 (37.1-38.4) | 0.76 |
Inflammatory markers before treatment | |||
CRP (<= 8.0 mg/L) | 103.2 (52.7-159.9) | 74.4 (42.2-131.5) | 0.25 |
Ferritin (24-336mcg/L) | 596.0 (358.3-709.0) | 673.0 (406.8-1012.8) | 0.75 |
IL-6 (<= 1.8 pg/mL) | 30.95 (24.18-34.05) | 29.20 (13.55-40.70) | 0.87 |
D-dimer (<=500 ng/mL) | 829 (513.5-1298.5) | 916.0 (585.0-1299.0) | 0.84 |
Lymphocyte count before treatment (0.95-3.07x10^9/L) | 0.75 (0.55-1.04) | 0.76 (0.59-1.01) | 0.91 |
Oxygen therapy before treatment | |||
Nasal cannula (=4 clinical ordinal endpoint scale) | 8 (67%) | 20 (74%) | > .99 |
High-flow oxygen/NIPPV (=3 clinical ordinal endpoint scale) | 4 (33%) | 7 (26%) | 0.73 |
Invasive ventilation (=2 clinical ordinal endpoint scale) | 0 (0%) | 0 (0%) | > .99 |
SpO2/FiO2 before treatment | 280.9 (252.5-317.9) | 289.1 (254.9-342.0) | 0.98 |
Table 2. Clinical Outcomes
Lenzilumab group (n=12) | Control group (n=27) | P-value | |
|---|---|---|---|
Incidence of clinical improvement | 11 (92%) | 22 (81%) | 0.43 |
Days to clinical improvement | 5 (1 - 14) | 11 (4 - 42) | 0.006 |
Days to discharge from hospital | 5 (3-19) | 11 (4 - 42) | 0.008 |
Mean temperature reduction | 1.075 | 0.459 | 0.02 |
Days to resolution of fever | 2 (1-6) | 1 (1-3) | 0.22 |
Incidence of IMV | 1 (8%) | 10 (37%) | 0.1 |
Incidence of death | 1 (8%) | 5 (19%) | 0.43 |
Incidence of IMV and/or death | 1 (8%) | 11 (41%) | 0.07 |
Table 3. Laboratory Markers
Lenzilumab group (n=12) | Control group (n=27) | P-value | |
|---|---|---|---|
CRP reduction | 135.8 | -0.95 | 0.01 |
IL-6 reduction | 20.1 | na | na |
ALC increase | 0.46 x 10^9/L | 0.03 x 10^9/L | 0.04 |
PLT increase | 52.5 | 63.2 | 0.61 |
ACTIV-5/Big Effect Trial (“BET”) Study
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 to be evaluated in the NIAID-sponsored ACTIV-5/Big Effect Trial (“BET”) in hospitalized COVID-19 patients. ACTIV-5 will help advance NIAID’s strategic plan for COVID-19 research, which includes conducting studies to advance high-priority therapeutic candidates. Identification of agents such as lenzilumab 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. ACTIV-5 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 ACTIV-5 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 ACTIV-5. Sites have been selected for ACTIV-5 and enrollment is underway. The first patient was dosed in October 2020.
With data from ACTIV-5 and our Phase 3 lenzilumab COVID-19 study, we expect to have data from over 700 hospitalized COVID-19 patients in the aggregate.
We believe that the Phase 3 study has the potential to serve as a basis for lenzilumab to potentially receive an 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.
We are actively pursuing the commercial preparation of lenzilumab in the event we receive an EUA. To that end, we have undertaken significant efforts and expended resource to secure production capacity to meet anticipated demand.
CAR-T THERAPIES
Humanigen has announced positive data from the Phase 1b portion of ZUMA-19 evaluating the efficacy and safety of lenzilumab in patients treated with CAR-T in diffuse large B-cell lymphoma (DLBCL). At the recommended Phase 2 dose of lenzilumab, the objective response rate (“ORR”) was 100% and no patient experienced severe cytokine release syndrome (“CRS”) or severe neurotoxicity (“NT”).
ZUMA-19 was a clinical study designed to evaluate the efficacy and safety of lenzilumab and CAR-T (axicabtagene ciloleucel, Axi-Cel) in patients with relapsed or refractory DLBCL.
This study was a standard 3+3 design with three patients administered 600 mg lenzilumab (cohort 1) and three patients administered 1,800 mg lenzilumab (cohort 2) just prior to CAR-T. The recommended Phase 2 dose was determined to be 1,800 mg.
In the six study patients, the ORR was 83% (n=5) which included four complete responses (“CR”). In cohort 1, there was no severe CRS (≥ grade 3). One patient experienced grade 3 NT with a two-day duration. At the recommended Phase 2 dose (cohort 2), ORR was 100% (n=3) and the toxicity-free CR (CRS and NT < grade 2) was 66% (n = 2). There was no severe CRS or severe NT at the recommended Phase 2 dose. There were no adverse events attributed to lenzilumab across the study.
Inflammatory markers were correlated with reduced rates of CRS and NT. Lenzilumab dose-dependently reduced myeloid cytokines IL-6, IL-8, MCP-1, and IP-10 (CXCL-10) and systemic inflammatory markers CRP, ferritin, and SAA.
We are currently initiating a randomized, multicenter, Phase II study to investigate the efficacy and safety of lenzilumab in CD19 Car-T therapies in DLBCL.
GRAFT VERSUS HOST DISEASE (“GvHD”)
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 2/3 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.