Q&A: Dr. Toby Maher, MD, MSc, PhD, FRCP

Dr. Maher is the Professor of Medicine and Director of Interstitial Lung Disease at the Keck School of Medicine of USC University of Southern California

Dr. Maher has spent over 20 years specialising in the management of interstitial lung disease. Since June 2020 he has been Director of ILD at Keck Medicine of University of Southern California. He previously ran the ILD unit at Royal Brompton Hospital, London and was a Professor of ILD at Imperial College, London. His research interests include; biomarker discovery, cellular senescence in the pathogenesis of IPF and clinical trials.

He has been involved in >100 trials in fibrotic lung disease from phase 1b through to phase 4 and including those assessing IPF, sarcoidosis, scleroderma, rheumatoid arthritis and inflammatory myositis. He is an associate editor for American Journal of Respiratory and Critical Care Medicine. He has authored over 420 papers on pulmonary fibrosis.

The following questions were submitted from Three Lakes 12-20 subscribers and followers as a part of our Ask the Expert series, where we provide a forum to industry professionals to widen access and education from those who are actively working towards the treatment and future of pulmonary fibrosis.

It seems like most trials for Pulmonary Fibrosis have failed. What do you think are the most common reasons for failure?

Developing new drugs is challenging and frequent trial failure is true for all diseases and not just PF. In general, more than 80% of drugs that enter human trials can be expected to fail. What we see in PF is consistent with what is seen in other disease areas. There are several reasons for trial failures. The first is badly designed trials. This was an issue in the early days of IPF trials 20 – 30 years ago, but we learned a lot from these failures and now have a much more consistent approach to designing and delivering studies. The second reason is that the drug simply does not work. Although our understanding of the causes of PF has improved, there are still gaps in our knowledge of the key biological processes responsible for the development and progression of fibrosis. Despite data from extensive laboratory-based experiments run prior to clinical trials, it is still common for drugs to fail. This is simply a reflection of how complicated it is to understand human biology (hopefully this is something that will be improved by AI in the future). The third reason for trial failure is unexpected drug side effects. Unfortunately, a few recent trials have been stopped because the drugs had unanticipated harmful side effects.

Have you heard of the trial being run out of Boston Children’s Hospital using thymidine to extend telomeres for PF patients? Any thoughts on this?

The goal of extending telomeres makes a lot of sense given that we know people who develop pulmonary fibrosis are more likely to have short telomeres. It remains to be seen whether thymidine supplementation is sufficient to extend telomeres and whether, in turn, this improves outcomes.

What do you think about the Nicotinamide Riboside and Zinc trial being run at Cedars Sinai?

In mice, Zinc and Nicotinamide have been shown to slow down many of the processes related to aging. Similarly, in mouse models of fibrosis these two agents appear to be beneficial. It is less clear whether Zinc and nicotinamide are as important in human aging. They are, however, both very safe supplements and it will be interesting to see how they perform in the trial.

Which emerging therapies or clinical trials are you personally most excited about right now?

It has been an exciting last 18 months with positive phase 3 trials for nerandomilast and treprostinil. I am also excited for the results of the ALOFT studies of admilparant in IPF and PPF. Beyond that, we expect results from multiple phase 2 studies in the next 6 – 12 months and hopefully several of those molecules will move forward to Phase 3.

What should I know before enrolling in a clinical trial? What is the best way to find and join a trial?

There are several important things to keep in mind. First, the reason trials are run is to determine whether the drug is effective. Even in phase 3 studies there is no guarantee that the study drug will work to slow or prevent progression of fibrosis and, sometimes it might even be harmful. Second, almost all trials have a placebo arm. That means a proportion of participants (usually somewhere between 1 in 2 to 1 in 3) will be on a dummy treatment for the duration of the study. Because of the way studies are designed (so called double-blind) neither you nor the study team will know if you are on the placebo treatment until after the trial ends. Third, trials require a time commitment. The amount of time varies between studies, but you can expect a visit to the study hospital every 4 – 8 weeks (sometimes for up to 18 – 24 months) and you will undergo several tests at each visit. On the plus side, this means that your condition will be carefully monitored over the duration of the trial.

www.clinicaltrials.gov allows you to search for trials based on the disease being studied and by geography (and if you search individual trials, the site gives details on the study centers running the trial and this usually includes contact details). The Pulmonary Fibrosis Foundation newsletter also provides regular updates on active trials.

I was recently diagnosed with pulmonary fibrosis. When should I start treatment and which drug or drugs do you recommend?

I almost always recommend treatment at the time of diagnosis. Once fibrosis develops it cannot be reversed and symptoms cannot be improved. Given that the available drugs slow, but do not improve fibrosis I think it is important to start them as soon as possible to protect the lung from further scarring and damage.

At the moment there are three drugs; pirfenidone, nintedanib and nerandomilast. All of them seem to be equally effective. However, they do have different potential side effects and sometimes insurers will not immediately reimburse all of them. I would therefore discuss the final choice with your pulmonologist. But being on any one of them is much better than not being on any treatment.

What role do you think AI, genetics, and omics technologies will play in discovering new treatments for PF?

I am hopeful that they will help us better understand the causes of pulmonary fibrosis and to speed up the discovery of new treatments. However, it is important that prospective studies be run to collect blood samples from patients so that we have the data on which to train AI tools. I suspect that it may be several years before AI really makes a big difference to drug discovery in IPF.

How close are we to detecting pulmonary fibrosis before symptoms begin or before irreversible damage occurs?

We know that people who develop pulmonary fibrosis have abnormalities that are detectable on CT many years in advance of developing symptoms. There is research ongoing to work out who should be screened with CT and what should be done if early fibrosis is discovered. I hope that in the next 5 – 10 years we will be able to try and diagnose people before they have symptoms with the goal of preventing the development of PF.

If you could solve one unanswered question in pulmonary fibrosis tomorrow, what would it be?

How can we prevent or cure pulmonary fibrosis?!