Burlingame, CA-based Humanigen is testing whether its engineered antibody or “Humaneered” technology developed over two decades can catapult the company to a leading role in the scramble to conquer COVID-19. This coming four years since its emergence from a bankruptcy, touched off by the arrest of its former CEO, “Pharma Bro” Martin Shkreli.

The company is currently testing whether its engineered antibody or “Humaneered” technology developed over two decades can catapult the company to a leading role in the scramble to conquer COVID-19 and has started recruiting patients in Brazil for an expanded Phase III trial (NCT04351152) of its lead product lenzilumab in hospitalized adults with severe or critical COVID-19. Brazil will account for between 50 and 100 of the 300 patients to be enrolled in the Phase III trial, Humanigen Chairman and CEO Cameron Durrant, M.D.,  said.

The Phase III study, which won FDA approval in April, is one of two key tests for lenzilumab in the sickest COVID-19 patients. The other is the Big Effect Trial (BET), a 200-patient study sponsored by the NIH’s National Institute of Allergy and Infectious Diseases (NIAID) to evaluate lenzilumab in combination with Gilead Sciences’ Veklury (remdesivir) versus remdesivir and placebo in hospitalized patients that include those on invasive mechanical ventilation.

BET is expected “shortly” to recruit its first patient, Durrant said.

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. As for the Phase III study, it 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 its 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.”

Upstream Target

Lenzilumab is a “Humaneered” monoclonal antibody designed to prevent or minimize the cytokine release syndrome that precedes lung dysfunction and acute respiratory distress syndrome (ARDS) in serious cases of SARS-CoV-2 infection. It does so by targeting and neutralizing granulocyte macrophage-colony stimulating factor (GM-CSF), a key cytokine in the initiation of cytokine storm.

When a virally-infected cell interfaces with CD4 T cells, it leads to production of GM-CSF, which acts directly on myeloid cells to cause expansion and activation, as well as to initiate and promote production of other cytokines and chemokines as part of the body’s immune response. These include interleukin (IL) 6, IL-1, tumor necrosis factor-α (TNF-α), monocyte chemoattractant protein 1 (MCP-1), macrophage inflammatory protein 1-α (MIP1-α), and interferon-γ-inducible protein 10 (IP-10).

Humanigen cites published data showing that GM-CSF is a key triggering cytokine, with elevated levels in ICU patients, and that GM-CSF inhibition prevented, and potentially could treat, cytokine storm and reduce levels of inflammatory myeloid cells—suggesting a role in treating COVID-19.

Because GM-CSF is a critical upstream and early regulator of many inflammatory cytokines known to be important in the pathophysiology of cytokine release storm (see a study published last year in Blood), Humanigen reasons that lenzilumab will succeed where two FDA-approved IL-6-targeting antibodies—Kevzara® (sarilumab) by Regeneron Pharmaceuticals and Sanofi, and Actemra® (tocilizumab) by Roche and its Genentech subsidiary—recently failed in clinical trials against COVID-19.

“The horse is out of the barn by the time you have to tackle IL-6 as an individual cytokine rather than the master switch, which is GM-CSF,” Durrant said.

Lenzilumab is one of one of 19 “Front Runner” candidates among the nearly 300 COVID-19 therapeutics included in GEN’s updated “COVID-19 DRUG & VACCINE CANDIDATE TRACKER.” Lenzilumab has climbed in recent weeks from “Keeping an Eye On” and “Definitely Maybe” rankings: “We are not a ‘Definitely Maybe.’ We’re more than a maybe. We’re a definitely,” Durrant asserted, adding: “In any event, we’re keeping an eye on you.”

Big-Name Competition

Humanigen is among the smaller companies testing the premise that antibody treatments hold potential as vital tools against COVID-19. Regeneron has launched two Phase III trials for its REGN-COV2 antibody “cocktail,” while Eli Lilly is partnering with AbCellera to develop LY-CoV555, a neutralizing Immunoglobulin G1 (IgG1) monoclonal antibody directed against the spike protein of SARS-CoV-2, based on AbCellera’s rapid pandemic response platform.

More recently, AstraZeneca advanced its COVID-19 combination AZD7442 into the clinic, while GlaxoSmithKline (GSK) and Vir Biotechnology said this week they had dosed the first patient in a Phase II/III trial of their monoclonal antibody VIR-7831 (GSK4182136), with plans to bring a second antibody (VIR-7832) into the clinic.

Durrant counters that Humanigen has something that the leading biopharmas do not — two decades of data for Humaneered antibodies. That includes positive data on a dozen hospitalized severe or critical COVID-19 patients treated with lenzilumab earlier this year through Humangen’s compassionate use program.

In a study published in Mayo Clinic Proceedings this week, Mayo Clinic researchers showed that lenzilumab led to rapid clinical improvement with a median time to recovery of five days (vs 11 days in the control arm), median time to discharge of five days (vs. 11 for the control group), 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. The patients all required oxygen supplementation and had elevation in at least one inflammatory biomarker prior to receiving lenzilumab.

“The better outcomes in patients who received lenzilumab compared to patients in the matched cohort are very encouraging,” the Mayo researchers concluded.

At the data cut-off point, 11 of the 12 patients were discharged from hospital. All 12 had at least one risk factor associated with poor outcomes: 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.

The Mayo study did not include a placebo arm, and the lenzilumab cohort was small, researchers acknowledged.

Rescue, Ruin, and Revival

Humanigen’s current challenges are a far cry from November 2015, when under its former name of KaloBios Pharmaceuticals, it averted liquidation through an investor share purchase agreement that sent the share price rocketing from $2.07 a share to more than $40, once it became known that the investors included Shkreli. He gained notoriety earlier that year when his former company, Turing Pharmaceuticals, sparked a furor with a 5000% price hike, from $13.50 to $750 per tablet, for toxoplasmosis drug Daraprim.

Shkreli took over as CEO as part of rescuing KaloBios, which was incorporated in 2000 and re-incorporated under that name the following year. A month later, Shkreli was arrested on securities fraud charges related to another company he founded years earlier, Retrophin. He is currently serving a seven-year prison sentence following conviction on security fraud and conspiracy charges.

While none of the charges related to KaloBios, the arrest and global publicity surrounding Shkreli plunged KaloBios into Chapter 11 bankruptcy—from which it emerged in 2016 led by Durrant.

The company renamed itself Humanigen a year later, then restructured its debt through transactions completed in February 2018. Today the company focuses on infectious diseases as well as cancer. In addition to the COVID-19 related indication, lenzilumab is also in development for chronic myelomonocytic leukemia (CMML), both as monotherapy and in combination with chemotherapy drug azacitidine.

Other indications for which Humanigen aims to develop lenzilumab include preventing or reducing serious and potentially life-threatening side effects associated with chimeric antigen receptor T-cell (CAR-T) therapy; preventing or treating graft-versus-host disease (GvHD) in patients undergoing allogeneic hematopoietic stem cell transplantation; eosinophilic asthma (EA), and relapsed or refractory diffuse large B cell lymphoma—for which it is partnering with Kite, a Gilead Company, to study the combination of lenzilumab and Kite’s Yescarta® (axicabtagene ciloleucel) in the Phase I/II ZUMA-19 trial (NCT02348216).

Also in Humanigen’s pipeline are two other Humaneered monoclonal antibodies. One is Ifabotuzumab, an anti-Eph Type-A receptor 3 antibody that has shown positive Phase I results in recurrent Glioblastoma Multiforme highlighting its potential to kill tumor cells by targeting the tumor, tumor stroma, and tumor vasculature. The other is HGEN005, a preclinical anti-EMR1 antibody being developed for EA and other eosinophilic diseases.

PIPE Funds Pipeline

Advancing development of Humanigen’s pipeline, and funding the Phase III and ZUMA-19 trials, are among intended uses of proceeds from the private placement of approximately $71.8 million of common stock completed in June. J.P. Morgan Securities acted as placement agent for the private investment in public equity or “PIPE” financing, which saw participation from investors that included Venrock Healthcare Capital Partners, Surveyor Capital (a Citadel company), HealthCor, Valiant Capital Partners, First Light Asset Management, and Ghost Tree Capital.

Humanigen stock is quoted on the OTC Markets (OTCQB) Venture Market with only limited trading. The company has applied for listing on the Nasdaq Capital Market: “We’re very actively working on plans to secure that,” Durrant said.

Humanigen finished the second quarter with a $24 million net loss, compared with a $3.3 million net loss in Q2 2019. While the company’s reported cash and cash equivalents jumped from $143,000 as of December 31, 2019, to $41.7 million as of June 30, so too did its operating expenses, particularly R&D, which ballooned during Q2 to $21.1 million from $1.2 million—primarily due to increased clinical trial and clinical material manufacturing costs related to the Phase III trial in COVID-19.

“Considering the company’s current cash resources and its current and expected levels of operating expenses, management expects to need additional capital to fund the Company’s planned operations for the next twelve months,” Humanigen disclosed in its Form 10-Q filing for the second quarter.

According to the regulatory filing, Humanigen’s cash and cash equivalents fell from $41.7 million as of June 30 to approximately $30.8 million as of August 13—though the company is well above the $143,000 reported as of December 31, 2019, and $1.1 million as of June 30, 2019.

Humanigen does not disclose its number of staffers, except to say they are “in the double digits,”  However, the company has announced a series of top executive appointments—most recently that of Edward P. Jordan, MBA, to Chief Commercial Officer, who reports directly to Durrant. Omar Ahmed, PharmD, was promoted to Senior Vice President, Clinical, Medical and Scientific Affairs, while four executives have recently joined the company in new positions:

• Timothy E. Morris, Chief Operating Officer and Chief Financial Officer.
• Dale Chappell, MD, MBA, Chief Scientific Officer.
• Bob Atwill, MBA, Head of Asia-Pacific, focused on regional clinical development, commercialization, business, and corporate development. (He will initially serve on a consultancy basis.)
• David L. Tousley, CPA, MBA, Chief Accounting and Administrative Officer, Corporate Secretary and Treasurer.

“We’re making active preparations for launch and commercial readiness,” Durrant said.

This story originally appeared in GEN Edge, a premium content service of Clinical OMICs’ sister publication Genetic Engineering & Biotechnology News (GEN).