Reformulating Cancer Blockbuster For ARDS

by Kevin Grogan | Scrip

The UK firm has tapped into EU funds through an Irish subsidiary to advance its treatment for acute respiratory distress syndrome based on a reformulation of Novartis's Gleevec.

Having secured funding from the European Union, UK biopharma Exvastat is testing a reformulated version of imatinib, the active ingredient in Novartis AG’s cancer blockbuster Gleevec, to treat COVID-19-associated acute respiratory distress syndrome (ARDS).

The company has been awarded a €3.6m grant from the European Commission’s Innovative Medicines Initiative to fund a clinical trial of Impentri, an intravenous formulation of imatinib, to treat critically-ill COVID-19 patients. CEO David Cavalla told Scrip that Exvastat is collaborating with Vrije Universiteit Amsterdam, the Amsterdam Medical Center, KABS Pharmaceutical Services of Canada and the clinical research organization Simbec-Orion to produce a reformulated version of Gleevec which should take around four to six months. After that, the trial will enrol 110 COVID-19 patients, "which we think is necessary to get statistically significant results, at two sites in Amsterdam, he said. 

Banking the IMI grant is quite an achievement given that Exvastat’s project was one of just eight selected from 144 applications for funding and the only one focusing on a particular therapeutic.

 

Getting hold of the EU cash has been helped by the fact that Cambridge-based Exvastat has an Irish subsidiary, a useful add-on given the uncertainty about European funding for UK projects, with the transition period for Brexit due to end on 31 December 2020. Cavalla said that "the latest information is the European Commission is happy to provide money to UK companies but the IMI money going to the Irish subsidiary simplifies the process. "We'll do what's necessary, our main focus is actually on doing the work, getting the results and hopefully proving benefits to patients.

Cavalla has worked as an entrepreneur in the pharmaceutical industry for the past 20 years with a focus on drug repurposing and co-founded Exvastat in 2016 with investment from Cambridge Innovation Capital. He got hold of the Impentri project through a technology transfer office in Amsterdam "which had discovered serendipitously that imatinib might have effects in the alleviation of pulmonary edema after a patient walked into one of the hospitals there with what was thought to be pulmonary hypertension." The patient was refractory to existing agents, he noted, "so they tried her on imatinib and they found, surprisingly, a much more rapid effect than they had expected. It reduced the edema on the lungs within 24 hours."

This prompted Cavalla and his team to begin a clinical pharmacology trial in healthy volunteers in 2017 to evaluate the use of repurposed imatinib for ARDS, a life-threatening condition characterized by widespread inflammation in the lungs for which there is no approved treatment. He told Scrip that while ARDS is classed as a rare disease, "it is one of the more common ones," affecting 300-400,000 patients in the western world" and "the number of people who die from ARDS annually is more than those who die of prostate or breast cancer, an astonishing statistic."
ARDS is very much in the news as it is one of most serious consequences of COVID-19 and Cavalla noted that "because there are a lot of patients around, clinical trials can be done much more rapidly." Now there are "hundreds of patients a month at individual centers rather than perhaps one suitable for a trial per center per month."

Exvastat will be looking to treat patients at the late stage of the condition in contrast to the antiviral approaches for COVID-19 "where you've probably got to give those drugs early. People die when the virus is not really the problem, the problem is at the late stages of severe degree of inflammation and hypoxia," Cavalla added.

After the reformulation, "we'll start the intravenous work in the late third quarter or early fourth quarter and in addition to the Amsterdam centers, there could be other places around Europe that we could incorporate," he said.

As for potential partnerships, Cavalla said that "we can do this bit on our own but going forward, we're going to be thinking about partnering perhaps in Phase III. However, as a condition, it's quite easy for a small company to have a reasonable footprint because you would market a product to intensive care units."

There are not that many ICUs, he pointed out, "and you could probably accomplish that with a relatively small field force so it's not beyond the realms of possibility that we could commercialize this. We're not quite there in our current state, though."

As well as ARDS, Exvastat sees potential for Impentri in other different conditions. Cavalla noted that "sepsis is obviously a major possibility, there are similar processes involved, perhaps with different organs but with the same principle of leaky blood vessels." He said it is estimated that "between one in two or one in three patients who are in hospital when they die have sepsis as a component of the reason for them dying."

Exvastat has patents granted both in Europe and the US for intravenous imatinib – Gleevec is an oral formulation – and Cavalla stressed that "we have not only orphan drug designation but also differentiation relative to the generic product. That differentiation is clinically driven, it's not just a fancy sidestep to avoid generic competition."

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