Urgency to meet the world's worsening load of COVID-19 cases appeared unflagging Thursday, with four new trials kicking off to evaluate treatments aimed at keeping people from progressing to worsened disease and reports on two new variant-focused efforts yielding signs of preclinical promise. Amid the progress, a long-running evaluation of AbbVie's cenicriviroc in critically ill COVID-19 patients was dropped due to futility, the trial's sponsor said (BioWorld Science, April 29, 2021).
Chief among the advancing clinical efforts announced April 29 were a phase III study testing a pair of SARS-CoV-2 neutralizing antibodies developed by Brii Biosciences and a direct-acting antiviral from Atea Pharmaceuticals. A phase II study of Partner Therapeutics' Leukine (sargramostim) also got started, as did a phase I/II Reven's Rejuveinix.
The programs are part of a global undertaking that has, according to BioWorld Snapshots, so far involved nearly 700 therapies in various states of advancement, 4 of which have gained regulatory approvals, alongside a growing roster of assets approved for emergency or other provisional use permits.
Beijing-based Brii's monoclonal antibodies (MAbs), which got a green light to proceed after a prespecified analysis of phase II data by an independent data safety monitoring board, are under evaluation as part of the National Institute of Allergy and Infectious Diseases-sponsored ACTIV-2 trial. The overall study is focused on people who have tested positive for COVID-19 but who do not currently need hospitalization.
Now BRII-196 and BRII-198, non-competing SARS-CoV-2 neutralizing antibodies derived from convalesced COVID-19 patients, are being tested at sites across the globe to see how well they prevent either hospitalization or death through study day 28, the trial's composite endpoint.
As the candidates progress, "we look forward to adding international trial sites to this study, which is especially critical for regions experiencing a surge in COVID-19 cases and new variants," said Brii Bio CEO Zhi Hong.
Another phase III trial ramping up will test AT-527, an orally administered, direct-acting antiviral agent derived from Atea's nucleotide prodrug platform. It's partnered with Chugai Pharmaceutical, a subsidiary of Roche that now has development and marketing rights to the program in Japan. The candidate targets SARS-CoV-2 RNA polymerase (nsp12), a highly conserved gene that the company said is responsible for both viral RNA replication and transcription.
Boston-based Atea said Thursday it has dosed the first patient in the study, called MORNINGSKY, out of the eventual 1,400 nonhospitalized adults and adolescents with mild to moderate COVID-19 it plans to enroll. The primary endpoint of the study will evaluate the efficacy of AT-527 vs. placebo as measured by time to alleviation or improvement of COVID-19 symptoms (BioWorld Science, April 29, 2021).
Intended for broad use early in the course of disease, the trial moved the company "one step closer to achieving our goal of providing an easily administered oral, direct-acting antiviral in the fight against this global pandemic," said Atea founder and CEO Jean-Pierre Sommadossi.
Partner, of Lexington, Mass., is another company with the nonhospitalized COVID-19 patient population in its sights. In its randomized, placebo-controlled, double-blind phase II study, the company is evaluating a potential role for the hematopoietic growth factor sargramostim -- marketed for a variety of indications under the brand name Leukine -- in reducing progression and need for hospitalization.
Primary endpoints of its study, called Scope, are COVID-19-related emergency room visits, COVID-19-related hospitalization or death. Trial sites in the U.S., Latin and South America are expected to join the study with expansion to additional countries under consideration, it said.
The trial got its start following a positive topline readout from Sarpac, a phase IV study sponsored by Ghent University Hospital in Belgium, that showed administration of inhaled Leukine significantly improved lung function, as measured by oxygenation, in hospitalized COVID-19 patients receiving oxygen.
Another study getting its start is Westminster, Colo-based Reven's phase I/II evaluation of Rejuveinix, an intravenous formulation of physiologically compatible compounds that is being developed for more effective treatment of patients with sepsis, including COVID-19 patients with viral sepsis and acute respiratory distress syndrome.
Since RJX is a potent antioxidant and anti-inflammatory agent that has shown benefits in animal models relevant to COVID-19 symptoms, the company's team is "hopeful that it will contribute to prevention of progression of COVID-19 and its faster resolution in high-risk patients," said Fatih Uckun, the company's chief medical and scientific officer.
At least initially that hope appears founded. After a COVID-19 patient with hypoxemia, pneumonia and abnormally elevated inflammation markers in the blood became the first participant dosed with Rejuveinix in the randomized study, he experienced a rapid response, with normalization of inflammation markers and resolution of his hypoxemia, the company said. Data on the remaining 236 participants the company expects to enroll in the study will help illuminate how well the therapy separates from placebo.
Among the early-stage additions to the pipeline, researchers from the Walter and Eliza Hall Institute of Medical Research reported in the April 26, 2021, issue of the Proceedings of the National Academy of Sciences that they have identified a two-component cocktail of nanobodies that was able to "block ACE2 engagement with [receptor binding domain] variants present in human populations and potently neutralize both wild-type SARS-CoV-2 and the N501Y D614G variant at low concentrations." Nanobodies are small antigen recognition domains that occur in camels, llamas and alpacas. They are stable enough to be potentially useful as inhaled therapeutics against respiratory diseases. The team showed that when fused to Fc domains, "prophylactic administration of either single nanobody-Fc or as mixtures reduced viral loads by up to 10(4)-fold in mice infected with the N501Y D614G SARS-CoV-2 virus. These results suggest a role for nanobody-Fc fusions as prophylactic agents against SARS-CoV-2."