LONDON – The U.K. has started a fast track national trial of experimental drugs in COVID-19 patients, with Bergenbio ASA’s phase II cancer immunotherapy, bemcentinib, the first of six products that are due to join the study.
The drugs to be tested in the government funded Accord (Accelerated COVID-19 research and development) program were chosen by the COVID-19 Therapeutics Taskforce of experts from the Medical Research Council and the National Institute of Health Research. Any that show positive effects in phase II will be fed into the national phase III Recovery trial.
Two other drugs to be named as part of the study are Astrazeneca plc’s anti-interleukin-33 inhibitor, MEDI-3506, which is in phase II development in the treatment of diabetic kidney disease, and the company’s Calquence (acalabrutinib), a selective Bruton’s tyrosine kinase inhibitor, which has U.S. FDA approval for treating chronic lymphocytic leukemia.
Richard Godfrey, CEO of Bergenbio, said he expects the first of the 120 patients in the phase II, comparing bemcentinib with standard of care, to be recruited this week. If there are positive results in the primary endpoint of reducing severity of infection and length of hospital stay, the drug will move seamlessly to phase III.
Axl kinase expression is a key mechanism by which cancer evades the immune system and bemcentinib, a once-a-day, oral, highly selective inhibitor of Axl kinase, is currently in phase II development in a number of oncology indications, including melanoma, non-small-cell lung cancer and acute myeloid leukemia.
Godfrey said Bergenbio put the orally available drug forward to the Therapeutic Taskforce on the basis of preclinical data showing it blocks viral entry and enhances the antiviral type I interferon response, a key cellular defense mechanism against viral infection.
One study was carried out in a guinea pig model of Ebola virus infection at Public Health England’s Porton Down laboratory. “Axl kinase expression increases when you have a viral infection [causing] suppression in expression of interferon-1. That was the observation that prompted the initial preclinical research,” Godfrey told BioWorld.
Further preclinical research carried out by Wendy Maury, professor of microbiology and immunology at the University of Iowa, showed bemcentinib is active against Zika virus. She subsequently discovered the essential role of Axl kinase is hijacked by viruses such as Ebola and SARS-CoV-2, enhancing their infection rate and substantially improving their survival in host cells.
Since the outbreak of COVID-19, Maury has shown bemcentinib is a potent inhibitor of the virus in several cell types and now has an experiment in progress to dissect the molecular mechanism of how SARS-CoV-2 uses Axl kinase activation to invade host cells.
“This is very encouraging, so we were thinking about how to do a test in COVID-19. Public Health England saw this as a continuation of the research that was previously done,” Godfrey said. “The Therapeutics Task force was evaluating compounds and saw the potential value of bemcentinib in COVID-19 treatments.”
The U.K. trial, in six hospitals, will test bemcentinib in patients with confirmed COVID-19 infection who are not so severely ill they require mechanical ventilation. The primary endpoint will be time to improvement of symptoms. There are secondary endpoints, but those are not being disclosed.
Godfrey said with Accord testing a number of drugs there could be different dimensions of therapeutic value. “But the most important for patients is how quickly they get better,” he said.
The dose administered in the COVID-19 trial will be the same as in Bergen, Norway-based Bergenbio’s oncology trials, with the aim of achieving maximum inhibition of Axl kinase.
One reason bemcentinib could be fast tracked is the significant body of safety data, with around 300 patients having received the once-daily drug, some for as long as four years.
All the patients in ongoing bemcentinib oncology trials in the U.S. are being monitored to see if they are protected against COVID-19 infection, after one elderly woman being treated for non-small-cell lung cancer developed the infection.
Despite multiple co-morbidities, including diabetes, emphysema and hypertension, which would indicate likely severe disease, she was ill for just two days. In Wuhan, China, the initial center of the epidemic, the overall mortality rate of cancer patients who contracted COVID-19 was 70%.
“This is just one case,” Godfrey said, “But she was on a host of medication and would be expected to react badly. It’s truly remarkable.”
Rapid recruitment to Recovery
The three other therapies to be tested in the Accord trial have not been named as yet. The Taskforce also is continuing to assess other early stage drugs to be included in the trial.
The value of running COVID-19 trials in the U.K. National Health Service – the largest health care system in the world – is underlined by the rapid recruitment to the Recovery trial, which is testing approved drugs as potential treatments.
Since starting 26 days ago, the study has enrolled 8,070 patients in 173 hospitals. Initially patients are randomized to one of four arms, but the adaptive design makes it possible to add other drugs. On April 23, the protocol was amended, allowing patients whose conditions are worsening to be randomized for a second time, to receive either Roche Holding AG’s IL-6 receptor agonist, Actemra (tocilizumab), or control, in addition to the treatment assigned at the first randomization.
Although the number of patients admitted to the hospital in the U.K. with COVID-19 is thought to have passed its peak on April 9, there is still a significant level of infection, with 360 deaths in hospital on April 27.
Given that, Godfrey said he expects the bemcentinib trial to be fully recruited and initial results available in one to two months.
Bergenbio’s [Oslo:BGBIO] share price rose by NOK17.80 (US$1.72) to NOK38.75 when news of the trial was announced on April 29.