“Perhaps precision medicine will help us identify PAH patients who will beneﬁt from the 22 medications we have discussed,” the investigators concluded. For example, dichloroacetate would be indicated in patients with specific genetic profiles. “The use of genotyping and biomarker proﬁles are examples of a personalized approach that may enhance the success of translation from preclinical studies to human clinical trials.”
Pulmonology Advisor interviewed Dr Prins and the following experts regarding their views about repurposing medications for use in PAH treatment: Jeremy Mazurek, MD, assistant professor of clinical medicine in the division of cardiovascular medicine at the Perelman School of Medicine at the University of Pennsylvania in Philadelphia; and Adrian Tonelli, MD, a pulmonologist at Cleveland Clinic in Ohio.
Editor’s note: These interviews were lightly edited for length and clarity.
Pulmonology Advisor: What are your thoughts about the points made in the paper by Prins, et al and regarding the concept of repurposing medications for PAH treatment?
Dr Mazurek: This paper serves to highlight several aspects about the current treatment armamentarium for PAH and future potential therapeutic targets. More specifically, this paper underscores the relatively narrow mechanistic pathways of our current treatments, with the tremendous need for targeting many other pathways that have a direct impact on the cellular and metabolic profiles of the pulmonary vasculature and right ventricle.
The authors nicely delineated several currently available candidate therapies in PAH that have promising preclinical — and in some cases, limited clinical — data that can serve as the subject of future clinical trials. Last, and very importantly, the authors highlighted the role of a precision medicine approach based on a given patient’s genetic profile that may prove to dramatically improve response to therapies.
Dr Tonelli: Overall this is a great topic for discussion given that disease-modifying treatments are needed in PAH. Current therapies are mostly vasodilator agents that, although effective, do not provide a cure. Based on data from the most contemporary registries, the median survival of patients with PAH is about 7 years.1 Physicians treating patients with PAH commonly note that some patients experience pronounced improvement with current therapies, while other patients experience limited benefits. Repurposing currently FDA-approved drugs for indications other than PAH could simplify the process of getting other effective medications into the treatment repertoire for this disease.
This paper is mostly a description of therapies currently used for other indications that may be useful in PAH based on animal data. However, animal models of PAH are less than perfect since they are not capable of replicating all the aspects of human disease. Many therapies worked on animal models of PAH but failed when tested in humans. There are numerous limitations for successful repurposing of these medications beside the poor PAH models that the authors described at the end of the paper. This is, for me, the most important part.
Although there is a good rationale for the use of these medications, the road for repurposing them is not simple and the odds are against them being beneficial. Another factor to consider is that it is harder to show a benefit for a medication when patients are already receiving other PAH-specific therapies. Current PAH studies allow the use of 1 or 2 PAH-specific background therapies and then patients are randomly assigned to receive active medication or placebo. The active medication needs to prove its worth when used on top of the background PAH treatment.
Pulmonology Advisor: Dr Prins, what are the potential benefits and drawbacks to the proposed approach?
Dr Prins: The benefits: We should have a greater element of safety in repurposing medications for PAH, as these medications are already used in multiple conditions. We know what the side effects are and the potential drug-drug interactions that could occur. Therefore, clinical trials that would investigate these drugs would theoretically have a lower risk for adverse events. Furthermore, repurposing drugs is also a potentially inexpensive way to treat this orphan disease, as some of these drugs like metformin are cheap when used for other indications. Finally, we tried to highlight how these potentially repurposed drugs could combat other pathologic features of PAH that current treatments do not.