RESPIRATORY DISEASES

Dr Jane Robertson, CMO of Redx, sheds light on idiopathic pulmonary fibrosis (IPF), the side effects of current availabile treatments, and why the future of IPF treatment might lie in ROCK2 inhibition

Pharmafile: Can you tell us a little about idiopathic pulmonary fibrosis (IPF) and its currently available therapeutics?

Dr Jane Robertson: IPF is a fibrotic disease. Essentially, it’s a disease caused by an internal scarring process. This scarring process leads to the progressive replacement of normal lung tissue with collagen and connective tissues, which ultimately reduces lung function. It’s a lifethreatening illness: we know that there’s no cure for this disease, and that patients generally only survive for three to five years after their diagnosis. They have a progressively poorer quality of life as their lung function deteriorates, and often suffer from repeated infective episodes and disease exacerbations.

Unfortunately, there aren’t any effective treatments to reverse the lung fibrosis, but there are some treatments which can slow it down. There’s a clear unmet need, then, to find treatments that can modify this disease more effectively, and improve the quality of life for patients, as well as overall survival.

How can novel approaches potentially modify fibrotic disease processes and improve patient outcomes?

There are only two approved treatments for IPF, and both of those slow the progression of the disease, rather than halt or reverse it. One of these is pirfenidone, which acts in several ways, targeting primarily the TNF alpha and TGF beta pathways. The other one is nintedanib, which is a multi-kinase inhibitor also targeting several fibrotic pathways. Both drugs have been shown to be effective in trials, and were better than placebo in terms of slowing the progression of the disease. This in turn leads to an improvement in survival. However, they don’t reverse the fibrosis, Both of these drugs have side effects too, especially in the gastrointestinal system. These side effect profiles can limit usage of the treatments.

With only these two approved drugs, there’s a big unmet need for further treatments that will target different aspects of the fibrosis pathways to halt or reverse the process.

What is ROCK2 inhibition, and what is its potential in IPF treatment?

ROCK2 is an enzyme that sits at a nodal point of multiple fibrotic signalling pathways. Fibrosis is a very complicated process, involving many signalling pathways. By inhibiting ROCK2, we aim to inhibit several downstream pathways, and ultimately reduce and reverse that build-up of collagen and scar tissue. So we’re very excited about the potential of inhibiting ROCK2 to really modify this disease and improve quality of life and survival outcomes ofr patients.

ROCK2 is also upregulated in other fibrotic diseases, not just IPF, because the same sort of fibrotic process occur in several other diseases in the lungs, kidney, and liver, and in the gut as well. If we think of, for example, the fibro-stenotic strictures of Crohn’s disease. ROCK2 is a really important target to focus on, with several potential applications.

Why do you think previous therapies haven’t gone down this route?

ROCK2 has been quite hard to selectively target. There’s another enzyme called ROCK1, which is very closely related to ROCK2. The problem with inhibitors of both ROCK1 and ROCK2, is that they cause quite severe systemic hypotension and vasodilation, so they’re not suitable to be used as a treatment option. It’s been challenging to design compounds which are very highly selective against ROCK2.

What is the importance of ‘de-risking’ programmes within IPF?

IPF is a serious and complex disease that is difficult to treat, and has no cure, so we need to be sure we have a validated, relevant target when we are trying to develop novel drugs for this area of unmet need in a timely manner. With ROCK2 inhibition, we are taking a de-risked approached, as we know ROCK2 is highly up-regulated in IPF, so it is biologically validated, and the target has also been clinically validated in graft-versus host disease, a disease that sometimes occurs after bone marrow transplantation that causes fibrosis in several organs including the lungs, skin, liver, and gut. A ROCK2 inhibitor is approved in that setting, so we can be confident that ROCK2 is a validated and relevant target.

What are your hopes for potential future management and treatment of the condition?

IPF is a devastating disease that shortens life expectancy, and causes a progressive worsening of quality of life. As the lung function deteriorates, patients become less able to carry out the normal activities of daily life, and more prone to disabling lung infections. Currently, no cure is available for IPF, with patients having an estimated life expectency of three to five years after diagnosis.

I think patients need medicines that can halt or reverse that fibrosis, and actually restore lung function and improve respiratory symptoms, rather than just slowing the decline, as the symptoms worsen and the lung function deteriorates.