Exvastat: The remarkable potential of re-profiled drugs 

Exvastat is a clinical stage company that is developing a new treatment for Acute Respiratory Distress Syndrome (ARDS) – and CIC is a proud investor. Through its action on Abl-related gene kinases, imatinib has been shown to be effective against pulmonary oedema associated with ARDS and has recently shown dramatic effectiveness in reducing mortality in the treatment of Covid-19.

Each year, approximately 200,000 people are diagnosed with moderate to severe ARDS in the US, with a similar number in Europe. The condition has a wide range of triggers including sepsis, pneumonia, drowning, trauma, blood transfusions and, as have been highly prominent during the Covid-19 pandemic, viral infections. One of the key features of ARDS is the build-up of fluid in the lungs – pulmonary oedema – causing acute shortness of breath and dangerous reductions in the body’s oxygen saturation.

The results can be devastating, with about one in 10 patient admissions to Intensive Care resulting from ARDS and approximately 40% of ARDS patients dying from its complications. For those who survive, the personal long-term impact of ARDS is enormous, as too are the public health implications.

At present, there are no licensed pharmacotherapies for ARDS – making Exvastat’s promising results with imatinib’s even more significant.

So how did it all begin?

In 2008, a 56-year-old woman was referred to VU University Medical Center (VUmc), Amsterdam with severe respiratory symptoms consistent with pulmonary oedema. A provisional diagnosis of pulmonary veno-occlusive disease (PVOD), a rare form of pulmonary arterial hypertension was made. Despite intensive interventions her symptoms deteriorated, and her condition became life-threatening. The clinicians decided to treat her experimentally with imatinib (Gleevec®). Within 24 hours her symptoms improved, and she returned to 100% oxygen saturation within 3 days. Most importantly, she was safely discharged.

The clinicians speculated that imatinib was diminishing pulmonary oedema by improving the integrity of the walls of the blood vessels, a mechanism of action that had not previously been described. To better understand their hypothesis, they recruited the help of Dr Jurjan Aman and his colleagues at the VUmc. Through rigorous scientific study, Dr Aman and his colleagues were able to demonstrate that imatinib addresses the dysfunction in the blood vessel walls through the inhibition of Abl-related gene kinase (Arg/Abl2), a previously unknown mediator of blood vessel wall dysfunction which causes the cells to stick together and for the blood vessels to become less leaky.

Based on this ground-breaking discovery, the VUmc team knew they were onto something. They filed patents around the use of Abl-related gene kinases in ARDS and related syndromes; sought ways to investigate imatinib’s clinical efficacy and safety; set about developing a suitable formulation for intubated patients; and explored how to bring this potentially life-saving treatment to patients. Lacking the experience in drug development, Dr Aman and colleagues identified Cambridge-based Dr David Cavalla, an expert in the development of re-profiled products. They formed the company Exvastat with the sole aim of developing intravenous imatinib for the treatment of ARDS.

The remarkable potential of re-profiled drugs

I have worked in drug development for over 25 years, across a wide range of therapeutic modalities and treatment types – but I have a particular fondness for the efficiency and de-risked nature of developing re-profiled and pro-drug opportunities. While the IP strategies around these products need to be carefully worked through, they provide substantial opportunity.

I have been fortunate to work on a number of re-profiling and pro-drug programs. At Roche, I was the Clinical Science Leader for the valganciclovir program (a pro-drug of ganciclovir) which became the standard of care for the treatment of cytomegalovirus (CMV) infection; as Medical Director at Arakis, I was involved in the clinical development of an inhaled version of the anti-muscarinic glycopyrronium which is now a component of Novartis’ successful COPD products Ultibro Breezhaler and Seebri® Breezhaler®; and I was founder and CEO of Treague, a company I set up to develop a re-profiled product for malaria (which sadly did not have a successful outcome). Despite the failure of this last programme, the development risks of re-profiled products is substantially lower. Compared with novel products, established drugs have the benefit of a huge body of toxicology, Chemistry, Manufacturing, and Control (CMC), and most importantly human safety data to support them. This significantly reduces the cost and risk of development and allows the rapid development of well-described products in areas of unmet medical need.

Vital investments

Cambridge Innovation Capital first invested in Exvastat to support the development of Impentri® for the treatment of ARDS in 2016 and we remain committed to the vision of providing a novel treatment for this devastating condition. The Covid-19 pandemic has raised the profile of ARDS and the impact of pulmonary oedema. It has also accelerated the investigation of the clinical utility of multiple drugs. Some of these anti-viral and anti-inflammatory drugs have demonstrated benefit in reducing morbidity and mortality and have the potential to be complementary to the effect of imatinib on the pulmonary blood vessel integrity.

Overcoming the commercial challenges

From a commercial perspective, the challenge for re-profiled products is around securing robust intellectual property. For intravenous imatinib (Impentri®), the scientists at VUmc had discovered a previously undescribed mechanism of action for imatinib that was unconnected to its original indication; this novel finding and its described use in ARDS and ARDS-like syndromes form the basis of the granted patents. In addition, patients with ARDS receiving mechanical ventilation do not typically receive oral medication due to the need for invasive naso-gastric tubes, and the unpredictable absorption in severely ill patients. Therefore, Exvastat has developed a novel intravenous formulation – whereas Gleevec and its generics are only available in oral form.

The Impentri program has benefited from the support of the Innovative Medicines Initiative and the work of academics and clinicians at VUmc and their collaborators at hospitals across the Netherlands. The demonstration of a dramatic reduction in the mortality of patients with severe respiratory symptoms associated with Covid-19 reported in the CounterCOVID study (n=385) (see further details here) provides high quality proof of clinical concept and justifies the further investigation of imatinib in pivotal all-cause ARDS.

Five years on since our first investment, we remain excited by the prospects for the company and supportive of its aim of bringing a life-changing treatment for a too often fatal condition and remain strong supporters of the potential of investigating old drugs for new therapeutic indications.