Type: Engineered (Humaneered®) anti-human granulocyte macrophage-colony stimulating factor (GM-CSF) monoclonal antibody designed to prevent and treat cytokine storm.
2021 Status: FDA REJECTS EUA APPLICATION—Humanigen acknowledged September 9 that the FDA has rejected its application for emergency use authorization (EUA) of lenzilumab for the treatment of patients hospitalized with COVID-19. In its letter of rejection, Humanigen said, the FDA stated that it was unable to conclude that the known and potential benefits of lenzilumab outweigh the known and potential risks of its use as a treatment for COVID-19.
“We remain committed to bringing lenzilumab to patients hospitalized with COVID-19,” stated Humanigen CEO Cameron Durrant, MD.
Humanigen also said it remained committed to completing regulatory processes underway seeking marketing authorization for lenzilumab to treat hospitalized COVID-19 patients in the U.K. and elsewhere in the world.
Durrant cited the ongoing ACTIV-5/Big Effect Trial (BET-B; NCT04583969): “We believe the ongoing ACTIV-5/BET-B trial, which has been advanced to enroll up to 500 patients, may provide additional safety and efficacy data sufficient to support our efforts to obtain an EUA to treat hospitalized COVID-19 patients.”
NIH Advances ACTIV-5 to Phase II/III—Humanigen said July 30 that the NIH has advanced its ACTIV-5/Big Effect Trial (BET-B; NCT04583969) into Phase II/III, and modified the primary endpoint to survival without ventilation (SWOV), the same endpoint used in the Phase III LIVE-AIR trial (NCT04351152). HUmanigen reasons that the study modification may enable it to use ACTIV-5/BET-B as a confirmatory study to support a future Biologics License Application (BLA).
The amended ACTIV-5/BET-B study now includes 400 patients overall. Up to 60 U.S. sites will participate in the study, which is sponsored and funded by the NIH. The trial’s primary endpoint focuses on survival without ventilation by day 28 in patients with baseline C-reactive protein (CRP) levels less than 150 mg/L.
EUA application submitted to FDA—Humanigen said May 28 that it submitted an application to the FDA seeking an Emergency Use Authorization (EUA) for lenzilumab for the treatment of patients hospitalized with COVID-19. The EUA application followed positive results from the Phase III LIVE-AIR trial (NCT04351152) evaluating the ability of lenzilumab to improve the likelihood of survival without ventilation (SWOV) in newly hospitalized COVID-19 patients (See LIVE-AIR Trial Data, below).
Humanigen said May 17 that it entered into a manufacturing services agreement with Chime Biologics to produce lenzilumab bulk drug substance and drug product for Humanigen for commercial sale following receipt of the requisite regulatory authorizations or approvals in regions outside of the U.S., including Europe, the United Kingdom, India, and Brazil. Chime is the first foreign CDMO selected by Humanigen to supply lenzilumab to ex-U.S. markets.
Under the agreement, whose value was not disclosed, Chime will produce lenzilumab at the modular single use KuBio (Cytiva) biologics facility in China. The cell culture capacity at the facility is 24,000L with planned expansion to 140,000L. Chime has expressed willingness to commit at least 56,000L for Humanigen manufacture annually, Humanigen said. As of the announcement date, technical transfer work had already begun, and commercial product was planned to be available in 2022.
LIVE-AIR Trial Data—Researchers from Humanigen and clinical partners that included the Mayo Clinic and Emory University posted a preprint May 5 on medRxiv reporting data from the Phase III LIVE-AIR trial (NCT04351152). LIVE-AIR was a randomized, double-blind, placebo-controlled trial designed to evaluate the efficacy and safety of lenzilumab to assess its potential to improve the likelihood of ventilator-free survival (also called survival without ventilation or SWOV), beyond standard supportive care, in hospitalized subjects with severe COVID-19.
The data showed lenzilumab improved the likelihood of SWOV by 54% in the modified intent to treat (mITT) population, and by 90% in the ITT population compared to placebo. SWOV also relatively improved by 92% in subjects who received both corticosteroids and Gilead Sciences’ Veklury® (remdesivir); by 2.96-fold in subjects with CRP<150 mg/L and age <85 years; and by 88% in subjects hospitalized ≤2 days prior to randomization. Survival was improved by 2.17-fold in subjects with CRP<150 mg/L and age <85 years.
“This study demonstrates that early neutralization of GM-CSF with lenzilumab, a key initiator and orchestrator of CS, in newly hospitalized hypoxic subjects can improve their likelihood of survival without the need for mechanical ventilation and defines a targeted patient population most likely to derive the greatest benefit over and above that of steroids and/or remdesivir,” the researchers concluded.
On March 29, Humanigen disclosed topline Phase III results showing that hospitalized patients who received lenzilumab and other treatments—including steroids and/or Gilead Sciences’ marketed drug Veklury® (remdesivir)—had a 54% greater relative likelihood of survival without needing invasive medical ventilation (IMV), compared with patients who received placebo and other treatments.
In the Phase III trial, Humanigen said, lenzilumab achieved its primary endpoint of ventilator-free survival measured through day 28 following treatment. The percentage of lenzilumab patients who died or needed IMV was 15.6% compared with 22.1% of placebo patients, a 54% improvement in the relative likelihood of survival without the need for IMV. The trial was not powered to demonstrate a difference in mortality—though Humanigen said a favorable trend was observed: the percentage of lenzilumab patients that died was 9.6% compared with 13.9% of placebo patients.
Humanigen said January 29 that it has completed enrollment for its pivotal Phase III trial (NCT04351152) of lenzilumab for COVID-19. The company expects to announce top-line data in March. The Phase III randomized, double-blind, placebo-controlled clinical study, which has enrolled 520 patients, is designed to determine whether lenzilumab plus current standard of care can alleviate the immune-mediated cytokine release syndrome (CRS) and improve ventilator-free survival in hospitalized and hypoxic patients with COVID-19 pneumonia.
2020 Status: Humanigen said November 6 that lenzilumab generated positive interim data from the company’s Phase III trial (NCT04351152) in patients hospitalized with COVID-19. The data suggested that lenzilumab had a clinically meaningful impact on patient recovery, with an estimated 37% more recoveries observed in the lenzilumab arm of the randomized, placebo-controlled, double-blinded study versus current standard of care (SOC). “These interim data demonstrate the potential of lenzilumab as a frontline treatment option for patients hospitalized with COVID-19,” said Humanigen CEO Cameron Durrant, MD, MBA.
The trial’s data safety monitoring board (DSMB) recommended increasing the target number of events (recoveries) from 257 to 402 (approximately 515 patients) to maintain the power of the study at 90%, after conducting an interim analysis of the unblinded data. The next DSMB interim analysis for efficacy is planned when the study reaches 75% events (302 events) which will require approximately 390 patients to be enrolled in the trial.
Humanigen also said it intends to file for an emergency use authorization (EUA) in the first quarter of 2021 either following interim data at 75% or at study completion. The Phase III trial evaluating patients hospitalized with COVID-19 is enrolling at sites across the U.S. and Latin America. Current enrollment stands at 285 patients.
Also on November 6, Humanigen and the Department of Defense Joint Program Executive Office for Chemical, Biological, Radiological and Nuclear Defense (JPEO-CBRND or JPEO) entered into a Cooperative Research and Development Agreement (CRADA) in collaboration with the Biomedical Advanced Research and Development Authority (BARDA), designed to support Operation Warp Speed (OWS) by assisting in the development of lenzilumab in advance of a potential Emergency Use Authorization (EUA) for COVID-19. Operation Warp Speed is the Trump administration’s program aimed at delivering 300 million doses of a COVID-19 vaccine by January 2021.
The CRADA will provide access to a full-scale, integrated team of OWS manufacturing and regulatory subject matter experts, decision makers and statistical support in anticipation of applying for EUA and subsequently a Biologics License Application for lenzilumab as a potential treatment for COVID-19. The CRADA also provides that OWS regulatory experts will work hand in hand with Humanigen on FDA communications, meetings and regulatory filings.
On November 3, Humanigen inked its first Asia-Pacific licensing deal for lenzilumab with Telcon RF Pharmaceutical and KPM Tech, covering for development and commercialization rights to lenzilumab for COVID-19 for South Korea and the Philippines. Both companies invested in Humanigen’s private investment in public equity or “PIPE” financing of approximately $71.8 million of common stock, completed in June 2020.
RF and KPM agreed to pay Humanigen up to $20 million—$6 million upfront and $14 million in two payments tied to Humanigen achieving milestones in the US. Telcon and KPM Tech will be responsible for gaining regulatory approval and subsequent commercialization of lenzilumab in its territories. Subsequent to commercialization, Humanigen would earn double-digit royalties on net sales.
On October 30, MedStar Washington Hospital Center in Washington, D.C. treated its first COVID-19 patient with lenzilumab in the Phase III trial. MedStar Washington Hospital Center is one of 18 sites in the U.S. approved to enroll eligible patients in the randomized, double-blind, multicenter, placebo-controlled clinical trial is to determine if lenzilumab can help hospitalized patients with COVID-19 recover faster.
A day earlier, Humanigen dosed its first patient at Atlanta’s Emory University School of Medicine in the fifth trial conducted through the public-private Accelerating COVID-19 Therapeutic Innovations and Vaccines program (ACTIV-5), also known as the Big Effect Trial (BET). The Phase II ACTIV-5/BET trial (NCT04583969) is a proof-of-concept study designed in part to evaluating lenzilumab with Gilead Sciences’ Veklury® (remdesivir), compared to placebo and remdesivir, in patients hospitalized with COVID-19.
The adaptive, randomized, double-blind placebo-controlled trial 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. The trial’s primary endpoint is clinical efficacy in adults hospitalized with COVID-19 on day 8 compared with remdesivir and placebo, according to clinical status on an 8-point ordinal scale.
ACTIV-5/BET will enroll adult volunteers hospitalized with COVID-19 at as many as 40 U.S sites, twice as many as originally planned. Approximately 100 hospitalized volunteers will be assigned to each study arm—200 participants total—with each study site testing no more than three investigational treatments at once.
H.C. Wainwright on October 14 initiated coverage of Humanigen with a “buy” rating, a day after the NIH’s National Institute of Allergy and Infectious Diseases (NIAID) said it launched ACTIV-5/BET, designed to evaluate remdesivir in combination with lenzilumab and another late-stage antibody treatment candidate—Humanigen’s Skyrizi® (risankizumab-rzaa), the Boehringer Ingelheim/AbbVie monoclonal antibody now marketed for moderate to severe plaque psoriasis—to assess if they show enough promise against COVID-19 to be advanced into larger clinical trials.
Volunteers assigned to receive risankizumab will be administered a single intravenous dose on day 1 of the study. Study participants assigned to receive lenzilumab will be given a 600 mg intravenous infusion every eight hours, for a total of three doses. The study is set to start on October 30, with an estimated primary completion date of January 8, 2021, and an estimated completion date for the full study of July 1, 2021.
Humanigen said September 23 it launched a collaboration with Thermo Fisher Scientific to expand the manufacturing capacity for lenzilumab, in order to support a potential Emergency Use Authorization (EUA). Thermo Fisher began technical transfer of the lenzilumab bulk drug substance process, with commercial scale production potentially starting before the end of 2020.
The multi-year manufacturing partnership, whose value was not disclosed, added to large scale commercial production efforts that include partnerships with Lonza and Catalent, in advance of the potential EUA this year and subsequent commercialization of lenzilumab.
On September 4, Humanigen’s board decided to carry out a 1-for-5 reverse split of its outstanding common stock shares, citing the need to meet corporate objectives that include satisfying the minimum bid price requirement in connection with the company’s application to list its common stock on the Nasdaq Capital Market and making additional shares available for issue in the future. The split will take effect with the start of trading on September 14, and reduce the company’s outstanding shares of common stock from approximately 211 million shares to approximately 42 million shares.
Holders of a majority of the company’s outstanding shares agreed in July to a reverse stock split, and gave the company authority to determine the split ratio before July 29, 2021. Humanigen stock is quoted on the OTC Markets (OTCQB) Venture Market with only limited trading.
Humanigen Chairman and CEO Cameron Durrant, MD, MBA, told GEN August 25 that the company will “shortly” recruit its first patient in Brazil, where regulatory agency Anvisa earlier that month approved the company’s launch of a Phase III study of lenzilumab in COVID-19 patients in Brazil.
The multicenter, randomized, placebo-controlled, double-blinded clinical trial—similar to a Phase III trial (NCT04351152) being conducted in the U.S.—focuses on hospitalized severe and critical adult COVID-19 patients at high risk of disease progression. Humanigen is working with the contract research organization Clinical Trial & Consulting (CTI) to conduct the potential registrational trial, which is about halfway through enrollment, and expected to finish by end of September or early October, with data expected to be released about a month later.
Should the trials prove positive, Humanigen envisions applying for a BLA, and based on the strength of tits data obtaining emergency use authorization (EUA) for lenzilumab, followed by a launch of initial commercial activities as soon as the fourth quarter. Within six months, the company envisions an expanded product launch and commercialization, followed by work on additional dose formulations and further international studies.
“At some point, provided those [Phase III and BET] studies read out positively—and we’re confident that they will—we could see ourselves going into earlier stages of the disease as well. But right now, the highest unmet medical need is in the severe and critical stages, we believe,” Durrant told GEN. “We think that lenz is, or has the potential to be, a leading treatment near term for patients that could have serious and potentially fatal outcomes, who are high risk and hospitalized.”
In July, Humanigen signed a clinical trial agreement with the NIH’s National Institute of Allergy and Infectious Diseases (NIAID), Division of Microbiology and Infectious Diseases (DMID) to evaluate lenzilumab in the NIAID-sponsored Big Effect Trial (BET) in hospitalized patients with COVID-19.
The NIH confirmed to GEN it has awarded contracts totaling $25.8 million to Leidos Biomedical Research toward managing, overseeing, and conducting the trial, the most recent being $14.3 million awarded on August 4.
BET is intended to build on initial data from NIAID’s Adaptive COVID-19 Treatment Trial (ACTT), which showed that Gilead’s remdesivir may improve time to recovery in hospitalized patients with COVID-19. BET is designed to assess the combination of lenzilumab and remdesivir on treatment outcomes versus placebo and remdesivir in hospitalized COVID-19 patients. 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, Humanigen said.
“With data from the BET and our ongoing Phase III study, we will have data from approximately 500 hospitalized COVID-19 patients,” Durrant stated.
In June, Mayo Clinic researchers published a preprint study at medRxiv.org showing positive data associated with a Phase III potential registration study (NCT04351152) that the company said was the first clinical use of lenzilumab in 12 COVID-19 patients hospitalized in Mayo’s system with severe or critical pneumonia due to the virus. Lenzilumab led to rapid clinical improvement with a median time to recovery of five days, median time to discharge of five days, and 100% survival to the data cutoff date. Patients also showed rapid improvement in oxygenation, temperature, inflammatory cytokines, and key hematological parameters consistent with improved clinical outcomes, Humanigen added.
At the data cut-off point, according to Humanigen CEO Cameron Durrant, MD, MBA, 11 of the 12 patients were discharged from the hospital. All 12 had at least one risk factor associated with poor outcomes, such as age, smoking history, cardiovascular disease, diabetes, chronic kidney disease, chronic lung disease, high BMI, and elevated inflammatory markers, with several patients having multiple such risk factors. The patients, who were hospitalized in the Mayo Clinic system, all 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, with several patients having multiple co-morbidities: 58% had diabetes mellitus, 58% had hypertension, 58% had underlying lung diseases, 50% were obese (defined as a BMI greater than 30), 17% had chronic kidney disease and 17% had coronary artery disease. The median age was 65 years.
On June 16, Humanigen released additional analysis of the data comparing patients with similar baseline characteristics treated with lenzilumab to patients treated with Gilead Sciences’ remdesivir. Patients treated with lenzilumab for a single day showed rapid clinical improvement with a median time to improvement of five days and a median time to recovery of five days—compared with a median time of 10 days for both measures in patients treated with remdesivir over 5 days, and a median of 11 days for both measures in patients treated 11 days with remdesivir.
Neither data set included a placebo arm, and the lenzilumab cohort was small, Humanigen acknowledged.
COVID-19: 300 Candidates and Counting
To navigate through the >300 potential therapeutic and vaccine options for COVID-19, GEN has grouped the candidates into four broad categories based on their developmental and (where applicable) clinical progress:
● FRONT RUNNER – the most promising therapeutics/vaccines based on clinical progress, favorable data or both.
● DEFINITELY MAYBE – earlier phases with promising partners, or more advanced candidates in development that have generated uneven data.
● KEEPING AN EYE ON… – interesting technology, attracting notable partners, or both, but preliminary data.
● TOO SOON TO TELL – longshots pending additional experimental and/or clinical data.
GEN has also tagged the most common treatment types: