Thanks to unprecedented development speed and mostly strong safety and efficacy data, vaccines have dominated the response to COVID-19. But ending the pandemic will also require development of numerous therapeutics.
Seven COVID-19 drugs have shown promise recently. Positive signs include the accumulation of encouraging data, participation in the Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) trials, and/or progress toward regulatory authorizations.
With operations in China and the United States, Brii Biosciences (Durham, NC, and Beijing) jumped into fighting COVID-19 shortly after SARS-CoV-2 emerged. Brii partnered with Tsinghua University and Third People’s Hospital of Shenzhen to discover, develop, manufacture, and commercialize fully human neutralizing monoclonal antibodies against SARS-CoV-2 in March 2020.
Soon after, as cases declined in China, Brii pivoted to the United States, reaching out to the National Institute of Allergy and Infectious Diseases (NIAID). A combination therapy consisting of Brii’s BRII-196 and BRII-198 was initially studied in the NIAID’s ACTIV-3 trial (NCT04501978) in hospitalized patients, but failed to meet prespecified efficacy criteria needed to enter Phase III.
However, in April 2021, the NIAID advanced BRII-196 and BRII-198 into Phase III of another of its platform trials, ACTIV-2 (NCT04518410) in ambulatory COVID-19 patients at high risk for disease progression, after the antibodies showed safety and efficacy in Phase II.
“We are a smaller company and lack the bandwidth to just go out and set up global clinical trials ourselves,” said Zhi Hong, PhD, Brii’s CEO. “[But] this is a great public-private partnership where we are focused on public health.”
Cerecor (Rockville, MD) was given Fast Track status from the Food and Drug Administration (FDA) in May for CERC-002, a biologic designed to treat hospitalized SARS-CoV-2 patients. CERC-002 is a first-in-class fully human monoclonal antibody that targets tumor necrosis factor superfamily member 14 (TNFSF14), a cytokine that is also known as lymphotoxin-like inducible protein that competes with glycoprotein D for binding herpesvirus entry mediator on T cells (LIGHT).
In final efficacy data from a Phase II trial (NCT04412057), Cerecor showed that more COVID-19 patients with acute respiratory distress syndrome who received a single dose of CERC-002 instead of a placebo were alive and free of respiratory failure over the 28-day study period. Efficacy was highest in patients over age 60, who often have other underlying inflammatory conditions.
“We think it’s that underlying baseline information and then the resultant increase in cytokines with COVID-19 infection that really leads to this immunological dysregulation,” H. Jeffrey Wilkins, MD, Cerecor’s chief medical officer, told GEN. He said Cerecor tests for LIGHT through a validated, high-sensitivity serum/plasma-free assay developed with Myriad RBD.
Cerecor licenses CERC-002 from Kyowa Kirin through an agreement of undisclosed value. The agreement was expanded in March, giving Cerecor exclusive worldwide rights to develop, manufacture, and commercialize CERC-002 for all indications.
Humanigen (Burlingame, CA) applied in May for FDA emergency use authorization (EUA) for lenzilumab to treat patients hospitalized with COVID-19. Lenzilumab is an engineered (or, as the company says, “Humaneered”) anti-human granulocyte-macrophage colony-stimulating factor (GM-CSF) monoclonal antibody designed to prevent and treat cytokine release syndrome preceding lung dysfunction and acute respiratory distress syndrome in serious SARS-CoV-2 infection cases.
Lenzilumab aced the Phase III LIVE-AIR trial (NCT04351152) by meeting its primary endpoint with a 54% relative improvement in the likelihood of survival without ventilation (SWOV) vs. placebo. SWOV likelihood improved 92% in participants receiving both corticosteroids and Gilead Sciences’ remdesivir (Veklury); and three-fold in patients who had a C-reactive protein level of <150 mg/L and were under 85 years of age.
Lenzilumab is under study to prevent and treat cytokine storm in the NIAID-sponsored, placebo-controlled Phase II ACTIV-5 Big Effect Trial (NCT04583969), alone and with Veklury. Lenzilumab is also under study for numerous additional indications.
“We saw the pandemic wreaking havoc, and felt that we had a potentially valuable therapeutic, which appears to be proving out based on the Phase III data,” said Cameron Durrant, MD, Humanigen’s CEO.
Organicell Regenerative Medicine (Miami, FL) showed positive results in April for an initial COVID-19 trial in India to evaluate Zofin, an acellular biologic therapeutic that is derived from perinatal sources and that is manufactured to retain naturally occurring microRNAs. The results pertain to the first 10 patients in the trial, all of whom had moderate to severe COVID-19. They were treated in hospitals in Bangalore, Kozhikode, and Chennai, and they all recovered. Recently, 65 additional patients with moderate-to-severe COVID-19 enrolled in the trial, which Organicell is conducting in partnership with CWI India.
In May, Pakistan’s Drug Regulatory Authority approved a request to use Zofin on compassionate grounds to treat a COVID-19 patient, a physician who had been admitted to an intensive care unit. “Healthcare providers are the ones that have been hit the most all over the world, so we’re very excited that we are able to participate and collaborate,” said Mari Mitrani, MD, PhD, Organicell’s co-founder and chief science officer.
Instances of compassionate use of Zofin have also been documented for COVID-19 patients in the United States, where Organicell recently completed enrollment in a U.S. trial offering expanded access to Zofin for patients showing mild-to-moderate COVID-19 or deemed at high risk of progression to moderate COVID-19. At the Landmark Hospital of Athens, in Athens, GA, emergency, compassionate use IND requests to administer Zofin were granted in three cases of severe COVID-19.
“The patients showed improvements in ICU clinical status and experienced respiratory improvements,” a case report in Frontiers in Medicine indicated. “Acute delirium experienced by patients completely resolved and inflammatory biomarkers improved.” The report also noted that the administration of Zofin was associated with decreased levels of inflammatory biomarkers, such as C-reactive protein and interleukin-6.
SAb Biotherapeutics (Sioux Falls, SD) has demonstrated early clinical success in the development of SAB-185, a fully human polyclonal antibody candidate that has been designed to offer passive immunity. In April, the first patient was dosed with SAB-185 in the NIAID-sponsored Phase II/III ACTIV-2 study (NCT04518410), after earlier trials showed the antibody to be safe, with a half-life of 25–28 days.
SAb has received $143 million from the Biomedical Advanced Research and Development Authority (BARDA) and the U.S. Department of Defense toward SAB-185’s development, which is being carried out through SAb’s DiversitAb Rapid Response Antibody Program. The company develops genetically engineered cows, turns off the genes that produce bovine antibodies, and replaces the bovine genes with human antibody genes transferred into the animals. Cattle are injected with an antigen to generate an immune response, while human polyclonal antibodies are collected in the cow’s plasma. Human antibodies are then isolated through purification, after which a custom, high-potency immunotherapy is produced.
Cows produce more antibodies than humans and other monogastric animals, and they have more robust immune systems.
“One of the other reasons for choosing a large animal is that you can collect a lot of plasma,” says Eddie J. Sullivan, PhD, SAb’s co-founder, president, and CEO. “We can collect between 30 and 45 L of plasma from each animal every month.”
Synairgen (Southampton, United Kingdom) recently reported positive data from early studies of its SNG001 (inhaled nebulized interferon-beta-1a) for direct delivery to patients’ lungs.
Combined data from hospital and home cohorts totaling 221 patients in the Phase II SG016 trial (NCT04385095) showed 33 markedly or severely breathless patients treated with SNG001 were 3.41 times likelier to recover than placebo patients. Synairgen said the results reinforced confidence in its ongoing Phase III SG018 trial (NCT04732949) in hospitalized patients. The trial is expected to release data in the second half of 2021.
In May, SNG001 announced in vitro results in which SNG001 showed antiviral activity against two COVID-19 variants, B.1.1.7 (Alpha/United Kingdom) and B.1.351 (Beta/South Africa).
“Most people are going for early or very late treatment,” noted Richard Marsden, Synairgen’s CEO. “We’re kind of in the middle—with very strong effect sizes. We’re not interested in treating everybody in the home environment. In addition to treating breathless patients in the hospital, what we want to do is find the breathless people at home, which is probably only about 10% of the non-hospitalized population.”
The FDA has granted EUA to Vir Biotechnology (San Francisco, CA) and GlaxoSmithKline (London, United Kingdom) for sotrovimab (VIR-7831) to treat mild-to-moderate COVID-19 in patients who are 12 years of age or older, weigh at least 40 kg (88 lb), have positive SARS-CoV-2 viral testing results, and are at high risk for progression to severe COVID-19.
The EUA followed an early halt in March to the COMET-ICE trial (NCT04545060) in high-risk adult outpatients, after data from 583 randomized patients showed an 85% reduction in hospitalization over 24 hours or deaths in those receiving sotrovimab vs. placebo. Sotrovimab has also shown efficacy against variant lineages B.1.1.7 (Alpha/United Kingdom), B.1.351 (Beta/South Africa), P.1 (Gamma/Brazil), B.1.617 (Delta/India), B.1.427/B.1.429 (Epsilon/California), and B.1.526 (Iota/New York).
“We are still analyzing data for some additional secondary endpoints like virology sequencing resistance, as well as secondary clinical endpoints such as patient reported outcomes and also severity of hospitalization,” Phil Pang, MD, PhD, Vir’s chief medical officer, told GEN.
Preclinical data suggest it could both block viral entry into healthy cells and clear infected cells by binding to an epitope on SARS-CoV-2 that is shared with SARS-CoV-1. A biologics license application is expected to be submitted to the FDA in the second half of 2021.