IPF: Could we reverse the progression?

Idiopathic Pulmonary Fibrosis (IPF) is a frightening, incurable disease where the lungs become increasingly damaged by scar tissue, resulting in breathing getting progressively more difficult. To date, it has been considered a terminal illness.

As its name suggests, the trigger for IPF remains unclear, though, it has been linked to certain types of dust, viral infections, gastro-oesophageal reflux disease, and smoking.

A challenging treatment landscape

Although drugs such as Roche’s Esbriet (pirfenidone) and Boehringer Ingelheim’s Ofev (nintedanib) are licensed in major markets, they can only slow progression, and do not necessarily improve patients’ symptoms, nor their quality of life. Despite these antifibrotic treatments being available for a decade, mortality remains high, with an average survival time of only three to five years from diagnosis. 

There are also several side effects with approved IPF drugs, including commonly reported symptoms such as diarrhoea, nausea, and stomach pain, which affect around two thirds of patients taking Ofev. A recent publication on the real-world treatment in the US shows that only 26.5% of patients diagnosed with IPF started on antifibrotic treatment, with 43% discontinuing the medication. On average, patients remained on the drug for only 10 months.¹

Professor Philip Molyneaux, consultant in interstitial lung disease at the Royal Brompton Hospital, London, said: “While current therapies have been successful in slowing the progression of the disease, they provide no symptomatic benefit to patients from a day-to-day perspective. They also both have a significant side effect profile, which means not everyone can tolerate them in the long term.”

The difficult search for new therapies

Unfortunately, there have been some notable setbacks in the search for new therapies. In August, Galecto’s stock slumped after the Copenhagen based biotech reported dismal results from a phase 2b trial of its inhaled galectin-3 inhibitor GB-0139. The drug performed worse than placebo in the 52-week study, which used annualised rate of decline of forced vital capacity (FVC) as a primary endpoint. FVC is a standard measure of lung volume and function commonly accepted by regulators.

This followed disappointment from San Francisco-based Fibrogen, which saw its monoclonal antibody pamrevlumab fail in the phase 3 Zephyrus-1 study. The top-line results revealed that pamrevlumab, which targets connective tissue growth factor, failed to produce an improvement compared with placebo, measured against an endpoint of change from baseline in FVC.

Roche also discontinued its zinpentraxin alfa in February this year, after the pivotal phase 3 STARSCAPE trial was stopped for futility.

This came following a failure in 2021 from Galapagos and Gilead’s autotaxin inhibitor ziritaxestat, which was a front-runner in clinical development until an Independent Data Monitoring Committee concluded that the risk-benefit profile on the phase 3 ISABELLA trial no longer supported development. This led the companies to discontinue development.

Hope on the horizon

But there is still hope in the pharma pipeline – Boehringer Ingelheim has made significant progress with their experimental drug BI 1015550, a phosphodiesterase 4B (PDE4B) inhibitor, which entered phase 3 development in October last year. 

United Therapeutics is also in search of an effective medicine with trepostinil, a prostacyclin mimetic, currently in phase 3 development for IPF. As is Bristol-Myers Squibb, recently announcing promising results from the phase 2 trial of their drug candidate BMS-986278 and now initiating a phase 3 trial in IPF. 

Vicore Pharma is currently developing a medicine which brings hope for patients, too. The progress is being made with C21, an oral, highly selective angiotensin II type 2 receptor agonist (ATRAG), that is currently in phase 2 development and has posted encouraging mid-stage data earlier this year that suggests stabilisation of disease and an improvement in lung capacity over 9 months, albeit from a smaller mid-stage trial. This has prompted the Stockholm-based pharma to start planning a late-stage phase 2b trial.

IPF and other fibrotic diseases

Although IPF is considered a rare disease, there are still around 100,000 people with the condition in the US alone, with up to 20 people per 100,000 affected globally. Meanwhile, the market for IPF drugs was valued at more than $4 billion in 2020, but this is expected to double by the end of the decade.

A cure for IPF seems closer than ever – but in the notoriously unpredictable world of clinical research, only time will tell which of these approaches, if any, are correct. There’s also academic research that could join the dots and give a clearer indication about which drugs, or drug combinations could eventually stop the disease.

At the same time, the research into IPF and other fibrotic diseases could also shed light on the long-term effects of COVID-19. Although the fibrosis that occurs through COVID may have a different mechanism, there have been calls for research into whether antifibrotic drugs could play a role in the management of long-term respiratory symptoms. The global tragedy of COVID drove funding into biotech and pharma, and respiratory diseases in particular, that could lead to new insights into a range of conditions.

The Royal Brompton’s Prof Molyneaux pointed out that, although the setbacks in the clinic have been a “massive disappointment” for patients with IPF, the recruitment of patients to large scale trials highlights the motivation of both patients and clinicians to improve treatment options. 

Prof Molyneaux concluded: “In the long term, we must look to the cancer field for inspiration, where therapies are targeted based on underlying drivers of disease. The ability to identify patients who will respond to specific therapies, halt fibrosis in its tracks, and provide symptomatic benefit without side effects should be our goal. And, until we have the ability to reverse the fibrotic process, we must focus on the early identification and diagnosis of patients to maximise the therapeutic benefit they can receive.”