Q&A: Naftali Kaminski, MD

Dr. Kaminski is the the Boehringer-Ingelheim Endowed Professor of Internal Medicine and Chief of Pulmonary, Critical Care and Sleep Medicine, at Yale School of Medicine

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.

The existing approved drugs seem to only act as anti-fibrotics and seem to only slow progression. The disease also seems to be a disease of aging, associated with mitochondrial dysfunction and short telomeres, leading to senescent alveolar stem cells, which may be initiating the fibrotic process. What are the most promising approaches being taken to try to help these alveolar cells get healthy again and therefore to avoid fibrosis at the start?

I am so glad that you asked this question.  This is an important question that is driving some of the most exciting research in the field right now. In recent years, we have increasingly come to understand IPF as a disease in which the breathing unit, the alveolus (air sac) is completely changed and that the alveolar epithelial cells that make up the lining of the air sac are failing.  We believe this is because type 2 alevolar epithelial cells (AT2) cells fail to do their job.  These cells are responsible for maintenance and replacing other cells.  Instead, some of them become what we call ‘aberrant basaloid cells.  These cells have features of senescent cells, can activate TGFB1, and express markers that can be found in the blood of patients with pulmonary fibrosis. It is unclear how to target these cells and the FDA-approved drugs do not affect them. Many of us are now assessing how to retain the health of the alveolar lining and whether we can reprogram these cells to make them normal again. There are many approaches but nearly all of them are still in the early development phase. Our lab and others have shown that thyroid hormone signaling plays a key role in maintaining healthy mitochondria in lung epithelial cells. Thyroid hormone analogs (thyromimetics) have been shown to have an antifibrotic effect in liver disease and are being developed, but there are issues with safety.  So, the honest answer is that this is a really important new concept, but we do not yet have an intervention to restore AT2 cell health and reverse fibrosis in patients that is ready for prime time. However, for the first time, we have a mechanistic roadmap, and the pace of discovery is accelerating.

Could you please provide a 20,000ft overview of the most recent significant findings in ILD research?

It is an exciting time in ILD research: science has never been better, drugs are being approved, it is a period of progression. Here are the developments I think matter most:

• We now understand what happens in the fibrotic lung. Using single-cell technologies and analysis of hundreds of thousands of individual cells from human lungs, we have generated an atlas of the fibrotic lung and discovered entirely new cell types, including the "aberrant basaloid cells" that I mentioned before, as well as specific types of macrophages, endothelial cells and fibroblasts that we did not know about just 6 years ago. Thus, you may say we now have a real blueprint of the disease - and with that and the new technologies of drug development, we should be able to develop much more precise drugs that target specific cell types and mechanisms with the aim of reversing pulmonary fibrosis.
  

• We now know what predisposes one to pulmonary fibrosis and we have good understanding of the genetics of sporadic and familial pulmonary fibrosis. The MUC5B promoter SNP is a key risk factor, and genetic alterations in the telomere pathway are also important. With the focus on better understanding early pulmonary fibrosis, I believe that in this decade we will have a better way to identify the disease earlier and potentially intervene. I believe that we will also see substantial progress in biomarker identification. We now have reproducible biomarkers to predict outcome: who will do better, and who will do worse, and we are getting closer to identifying the markers to tell if you are at risk of developing the disease and whether you will respond to a certain therapy.
  

• After 10 years with only 2 approved drugs, we suddenly have two more promising drugs with one was recently approved by FDA. In addition to providing more therapeutic options, having more drugs be successful and approved will encourage drug companies, investors and start-ups to invest more – it is simple. When trials fail people are reluctant to invest, but when they succeed money pours in. Which means many more discoveries will have a chance to be tested and potentially reach our patients.
  

• The AI revolution is accelerating everything. On the clinical dimension, applying AI to imaging and clinical information will allow better and earlier diagnosis and prediction of progression. On the research side, AI will accelerate drug discovery and design. Our group recently developed AI tools that can look at trajectories of cells and develop interventions that will reverse pulmonary fibrosis.  Even more exciting, there are tools available to design inhibitors and activators which could allow us to try and reprogram the lung to become normal again – and this is even more powerful because we have the cell atlases I mentioned before. 
  

I take Rituxan infusions with Ofev with all the new drugs in the pipeline. How many should I take? Ofev, Jascayd, etc . I mean is there such a thing as too many?

It is hard to answer clinical questions, and I should not even try. I will say that for any drug there may be ‘too much’ or ‘too little’.  This is why it is so important to be seen by a physician who is an expert in ILD, preferably in a recognized center, and be treated based on established guidelines.  It is also important to have access to clinical trials.

My husband diagnosed with ipf 2 years ago has no symptoms of the disease. His pulmonologist says that it's not necessary to start anti fibrotic drugs at this stage unless he wants to given the fact that once he starts he can't stop them and given the side effects as well. What do you think?

I cannot comment on any specific condition.  What we know about IPF is that the disease will progress, and we also know that people without symptoms may still have substantial disease.  What I always answer in such cases is that the patient be seen by a physician who is an expert in IPF,  preferably in an recognized center, be treated based on established guidelines, and consider participating in clinical trials. 

Any cures in the works?

We have 3 FDA approved drugs, and potentially a fourth one that have similar effects: they slow down disease, but we do not have any cures. We have a much better understanding of the disease now and we hope this will lead to therapies that not only slow down the disease but also result in improvement.

How can I find out about clinical trials and whether this is the right choice for me?

Clinical trials are one of the most important ways that patients with IPF can access new treatments and contribute to science that may help them as well as future patients. The best way is to ask your pulmonologist. I always recommend that patients be seen by pulmonologists who are experts in ILD/PF and preferably in an academic center that has an ILD program. This enures that you get access to approved therapies, clinical trials, other needed referrals and support groups. Beyond your physician, the best starting point is https://clinicaltrials.gov/ - the official U.S. government registry of all clinical trials. You can search by condition ("idiopathic pulmonary fibrosis"), location, and phase. It lists eligibility criteria, what the trial involves, and contact information. The Pulmonary Fibrosis Foundation (PFF) also maintains a trial finder specifically for IPF patients (https://trials.pulmonaryfibrosis.org/en-US). Their care center network can connect you with centers running trials near you.

How do you know if a trial for you? The team offering the trial will assess whether you fit the inclusion and exclusion criteria. But beyond the medical criteria, there are other considerations.  For instance, what phase is the trial? Phase 1 trials primarily test safety; chances for direct benefit for you are minimal – but you may benefit eventually if the drug progresses. Phase 2 trials look for early efficacy signals as an indicator that it is going to work and may also explore different doses, safety, and other factors so you may gain some benefit. Phase 3 trials that seek to validate that the drug works, sometimes includes a comparison to standard of care, and often offers the most potential benefit. Many trials compare a new drug to placebo, but in IPF this is usually done on top of standard anti-fibrotic treatment, meaning that you will not go without treatment. You may also want to look at the time and travel commitments.  The most important thing is to have this conversation with a physician who is an expert in the disease, knows you and the trial. Overall, besides medical considerations and personal preferences, for a disease with limited treatment options, participation, where appropriate, is both an opportunity for personal benefit as well as a contribution to the IPF community.

Are there biomarkers or imaging tools that could enable earlier diagnosis in routine clinical care? How close are we to identifying people at risk before fibrosis develops?

On the imaging side, high-resolution CT (HRCT) of the chest is already the cornerstone of IPF diagnosis, and it can detect early fibrotic changes, even before patients develop significant symptoms.  Indeed, early fibrotic changes are sometimes found incidentally, when people have lung cancer screening or coronary artery calcium scans. We also have peripheral blood biomarkers, and genetic markers. But the truth is that beyond research, we are not sure how to approach detection and management of early pulmonary fibrosis in the clinic. The NIH is investing 20 million dollars in a new program called   Pioneering Research for Early Evaluation and Mechanistic PreempTion of Pulmonary Fibrosis (PREEMPT-PF) which is a key NIH initiative aimed at shifting pulmonary fibrosis care from treating late-stage disease to early detection and interception. We hope that this project will lead to concrete and practical recommendations, but we need to ensure that the project is secure and that NIH funding is not disrupted, as it has been in recent months.

If someone has a family history of PF, what proactive steps should they take today?

I would like to start with a clear statement - having a family history does not mean you will necessarily develop Pulmonary Fibrosis. In fact, the likelihood is low. But it is higher than the general population. Thus, many of the recommendations are common sense - avoid other known risk factors aggressively. Smoking is the single most important modifiable risk factor; if you smoke, stopping is the highest-priority intervention. Certain occupational exposures (silica, metal dusts, agricultural dusts) also increase risk. If your work or hobbies carry risk for respiratory exposures, use proven protection or consider switching to lower risk activities.  It is important to follow all other public health guidance including vaccines, and do not postpone evaluation of respiratory symptoms. Based on your level of comfort and personal preferences, consider participating in research. There are now research protocols that assess at risk populations, and there will be more with the new NIH initiative. The Pulmonary Fibrosis Foundation (pulmonaryfibrosis.org) can help identify centers near you. These centers track at-risk family members over time, contribute to research, and are best positioned to monitor you appropriately. People also ask about the use of air purifiers, genetic testing, or establishing baseline pulmonary function. Regarding air purifiers, there is no clear data, but there is also no harm – I bought an air purifier during the pandemic and still have it at home.  Regarding being tested – the suggestion would be to do it only in the context of a clinical protocol or registry, led by experts in the field.