LONDON – The search for modulators of the immune cascade that is the cause of the most severe respiratory symptoms of COVID-19 is intensifying, with Cyclacel Pharmaceuticals Inc. and Pharming Group NV adding their drugs to the list of repurposing projects.

Leiden, Netherlands-based Pharming is planning a 150-patient trial of its C1 inhibitor Ruconest after seeing encouraging results in a compassionate use program, while Cyclacel’s cyclin-dependent kinase (CDK) inhibitors, which are in development as cancer therapies, are to be evaluated as part of the Stopcovid research program at Edinburgh University’s Center for Inflammation Research.

Five patients with confirmed COVID-19 infection who had failed to respond to treatment with both the rheumatology drug hydroxychloroquine and the HIV combination therapy Kaletra (lopinivir/ritonavir), were given Ruconest (conestat alfa) at the University Hospital Basel, Switzerland.

All were suffering from severe pneumonia. Following treatment with Ruconest, fever resolved in four of the five within 48 hours. Levels of C-reactive protein and interleukin-6, markers of inflammation, fell significantly and the patients were discharged, fully recovered.

The fifth patient progressed and was moved to intensive care for intubation, but also recovered subsequently.

Ruconest, which is approved in the treatment of acute hereditary angioedema attacks, acts as an inhibitor of the complement and contact activation systems, which are both thought to be involved in the hyperinflammatory syndrome seen in COVID-19 patients.

“Compassionate treatment in a few patients suffering from COVID-19 pneumonia was therefore scientifically sound and these preliminary results are very encouraging,” said Bruno Giannetti, CMO of Pharming.

“The results demonstrate the potential effectiveness of using Ruconest as an anti-inflammatory approach to inhibit the complement and contact systems after SARS-CoV-2 infection,” said Michael Osthoff, treating physician, who will lead the 150-patient multinational randomized controlled trial now being planned.

Cyclacel’s CDK inhibitors fadraciclib (CYC-065) and seliciclib (CYC-202, R-roscovitine) initially are to be tested for their ability to promote apoptosis of inflammatory neutrophils in samples from COVID-19 patients.

As far back as 2006, Adriano Rossi, professor of respiratory and inflammation pharmacology and deputy director of the Edinburgh Center for Inflammation Research, published data showing that seliciclib resolves inflammation in mouse models of pleurisy and lung inflammation.

Rossi and colleagues subsequently demonstrated that seliciclib acts by suppressing levels of the apoptosis inhibitor Mcl-1 (myeloid leukemia cell differentiation protein-1), preventing it from promoting neutrophil survival. Dead neutrophils can then be cleared by macrophages.

In addition, CDK inhibitors have been shown to inhibit transcription of IL-6, another driver of the acute immune response seen in COVID-19 patients.

Kev Dhaliwal, consultant in respiratory medicine and lead of Stopcovid, said the project wanted to evaluate the use of Cyclacel’s CDK inhibitors as promoters of apoptosis in inflammatory neutrophils, because clinical data suggest early peripheral blood neutrophil response is associated with a poor outcome in COVID-19.

“If we can stop the inflammatory cascade early, we may be able to prevent or delay the severity of COVID-19 induced inflammation and the need for assisted ventilation in affected patients,” Dhaliwal said.

The Edinburgh center has been a world leader in investigating the role of inflammatory neutrophils in lung disease, said Spiro Rombotis, CEO of Cyclacel. “Because of our long-standing discussions in this area we became aware they were looking for molecules [for Stopcovid],” he told BioWorld.

“While they have experience of using seliciclib for over a decade, we are keen to let them access fadraciclib, which is 40 times more potent,” Rombotis said. Berkeley Heights, N.J.-based Cyclacel is donating the drugs for the Stopcovid project, which has £2 million in funding to assess the use of existing drugs as mediators of the acute lung inflammation caused by the virus.

Rombotis expects the results of the evaluation in patient samples to be available within a week or two. “They will then take the decision on whether to take into the clinic,” he said.

Both of Cyclacel’s CDK inhibitors have existing safety data from cancer trials. Rombotis said the ability to monitor Mcl-1 levels as a biomarker of response also will smooth translation to the clinic.

Among the tools available to the researchers in Edinburgh are optical sensor probes that can be used to see inside patients’ lungs, in real time, using endomicroscopy techniques. That makes it possible to assess how inflammatory pathways are being affected by the disease process and by possible treatments.

If there is a positive response in initial patient trials at the Royal Infirmary of Edinburgh, a 1,000 bed hospital, now reconfigured into a COVID-19 hot site, the products could progress to the U.K.’s Recovery drug repurposing trial, which as of April 21 has recruited 6,533 COVID-19 patients at 170 sites across the National Health Service.

The randomized trial has an adaptive design so that new drugs can be included as the study goes on. One drug, Roche AG’s Actemra (tocilizumab), an anti-IL-6 antibody has been added since Recovery started on April 3. There will be regular reviews so any ineffective or effective drugs can be identified quickly.

Rombotis said a critical issue with using any anti-inflammatory drug to treat respiratory symptoms of COVID-19 is at what point in disease progression they should be administered.

“There are five categories of patients, from presumed infected, to acute respiratory distress syndrome, when it’s too late. For the 1-4 group, you need to know when to go” he said. Mcl-1 levels could be a good indicator in the case of CDK inhibitors.

For Rombotis, unrealistic expectations have been raised by the rush to test multiple drugs in what he called a “throwing darts” fashion, in such a heterogeneous patient group.

“It’s so hard for the public to have hope, and then have hopes dashed, because we didn’t do proper science,” he said.

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