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 Abbvie Inc.'s cenicriviroc in critically ill COVID-19 patients was dropped due to futility, the trial's sponsor said.
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 Ltd. and a direct-acting antiviral from Atea Pharmaceuticals Inc. A phase II study of Partner Therapeutics Inc.'s Leukine (sargramostim) also got started, as did a phase I/II Reven Holdings Inc.'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, four 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 Co. Ltd., a subsidiary of Roche Holding AG 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 non-hospitalized 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.
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 non-hospitalized 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 top-line 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 I.V. 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.
Taking on the variants
As global awareness of SARS-CoV-2 variants of concern grows alongside better monitoring by public health officials, research on that issue is keeping pace, too. Progress on April 29 was announced on the vaccines front by Copenhagen-based Bavarian Nordic A/S and on the therapeutics side by Incheon, South Korea-based Celltrion Inc.
Bavarian Nordic reported additional preclinical data for its capsid virus-like particle COVID-19 vaccine candidate, ABNCoV2, confirming its ability to induce neutralizing antibodies against SARS-CoV-2 variants. Though the company had already published preclinical data on the candidate's ability to stimulate high titers of neutralizing antibodies against the wild-type (Wuhan) virus, new data demonstrated the generation of similarly high levels of neutralizing antibodies against the SARS-CoV2 variants B.1.1.7 (British) and B.1.351 (South African).
In light of the new data, the company said it will soon start a phase II study to investigate the ability of ABNCoV2 to boost existing immunity through prior vaccination. In parallel, it's seeking funding to support the program's advancement through phase III, it said.
Celltrion's monoclonal antibody treatment, regdanvimab (CT-P59), also put in a good preclinical showing, providing what the company described as a "significant reduction in viral load of SARS-CoV-2," with no significant difference between the neutralization titers stimulated against wild-type SARS-CoV-2 and those against the South African variant in an in vivo model.
Encourage by the data, the company has begun developing a neutralizing antibody cocktail with CT-P59 against new emerging strains in the U.K. and South Africa, it said.
As would be expected amid the huge number of efforts started this year and last to establish new therapies for COVID-19, not all turn out to be effective. Exemplifying the point on Thursday, Quantum Leap Healthcare Collaborative (QLHC), the sponsor of the I-SPY COVID Trial, said that Abbvie's cenicriviroc (CVC), an orally active dual CCR5/CCR2 antagonist, has been dropped from the trial due to futility, based on the low likelihood of success.
Testing was discontinued because, after 94 patients enrolled, the agent met the predefined futility criterion, defined as at least 90% probability that the hazard ratio for time to recovery is less than 1.5 compared to the control arm, QLHC said. The data from CVC patients were compared to those from 220 patients concurrently randomized to the control, which included backbone therapy, consisting of dexamethasone and Veklury (remdesivir, Gilead Sciences Inc.). The study did not identify new safety signals for CVC among critically ill patients.
The larger program of I-SPY trials, run by a wide-reaching consortium that includes the FDA, industry, patient advocates, philanthropic sponsors and clinicians from 20 major U.S. medical research centers, continues.
"Finding effective agents for people who become critically ill from COVID-19 remains an urgent priority," said Kathleen Liu, a professor of medicine at the University of California San Francisco and co-principal investigator for the trial.