New “Old” Therapies in Pulmonary Arterial Hypertension: A Clinical Roundtable

The drawbacks: These drugs may not work with our current therapies. I say that because the preclinical data analyzing these drugs were from animals that were not treated with currently available therapies. Hopefully, this problem will be eliminated by targeting different aspects of PAH pathobiology, but it is an issue we have to consider. Second, because many of these drugs are cheap, there is not a lot of support from pharmaceutical companies for clinical trials, and thus we have to find other ways to fund these expensive trials. Finally, we may have drugs that do not work in all patients with PAH. For instance, immunomodulators may not work in all patients; if they cause too much immunosuppression that could increase the risk for infection, so we may need to be selective about which patients get which drugs moving forward.

Pulmonology Advisor: What are the treatment implications or other takeaways for clinicians?

Dr Prins: We tried to highlight the fact that there are many new potential therapeutic targets in patients with PAH, which offers hope for patients with a disease that has a median survival of only 5 to 7 years.¹ We hope that future clinical trials will identify which drugs we can repurpose for PAH and thus improve patient outcomes.

Dr Mazurek: There are several takeaways from this article. One is that not only is current PAH treatment not a cure but it is also not universally and equally effective across the patient population. In addition, it is important to recognize the tremendous progress that has been made in our understanding of the altered genetic, epigenetic, molecular, and metabolic pathways that result in the development and progression of PAH. Finally, the clinical audience should be reinvigorated by the potential for currently available medications that will perhaps prove effective in this still devastating condition. In this context, if one or more of these therapies is successful, it would allow for the use of a medication that is both well-known to the clinical community and one that is hopefully relatively lower in cost, which would be a win for the clinician and patient alike.

Dr Tonelli: One of the takeaway points is that these medications for PAH should only be used in the context of a research study, since they may create false hope and unnecessary side effects and expense. Fortunately, a good number of these medications are currently being tested in clinical studies, most of which are proof-of-concept investigations done at a single center with great effort. If current studies show a benefit, this will have to be reproduced in larger, randomized, placebo-controlled, multicenter investigations, ideally including a long-term study using contemporary end points such as morbimortality. As expected, this type of study would be expensive, and depending on the specific medication (eg, a generic drug) there may not be a funding source to support it.

Pulmonology Advisor: How likely is it that some of these drugs may ultimately be successfully repurposed for use in PAH, and what are the next steps needed toward this goal?

Dr Mazurek: As the authors pointed out, while excitement is warranted for many of these agents, caution must also be employed. Medical research is replete with examples of therapies that were quite successful in preclinical experiments that fail when carried out in human trials. There are many reasons for this as the authors described, but this should not deter us from pursuing some of these therapies. That said, there are several candidate drugs proposed in this article that seem truly exciting, and some that are already being used clinically in PAH, such as aldosterone inhibition.

In order to assess these agents, cooperation between the various stakeholders — including scientists, clinicians, pharmaceutical companies, funding agencies, and patients — must exist for well-designed clinical trials to be carried out. This includes carefully choosing candidate drugs and appropriate and clinically-driven end points in order to ensure that we are identifying therapies with true benefit, while not dismissing therapies due to poorly designed trials.

Dr Prins: The likelihood of translational success is generally low, which is demonstrated by the fact that previous attempts to repurpose PAH drugs have failed. I doubt that all the medications we mentioned will work in patients with PAH, but hopefully some will. We think that if we really deeply characterize our patients, we may be able to identify which patients have a higher likelihood of benefiting from different drugs. For instance, maybe patients with right ventricular dysfunction would benefit from ranolazine as opposed to all patients with PAH.¹ Likewise, patients with elevated interleukin-6 (IL6) may benefit from tocilizumab treatment rather than patients with normal IL-6 levels.

We need to perform clinical trials in personalized medicine. We are hoping to implement personalized medicine in PAH so we can better treat our patients and help them feel better and live longer.

Dr Tonelli: There is certainly hope that some of the medications will ultimately be repurposed for use in PAH, but the odds are low. As shown in the conclusion of the paper, there are a lot of hurdles to overcome before the proposed medications receive FDA approval for PAH. There are several examples of medications that had a great rationale for working in PAH but ended up not being effective (eg, simvastatin and aspirin) or caused serious side effects (eg, imatinib).¹ ​

References

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6. US National Library of Medicine. ClinicalTrials.gov. Hormonal, metabolic, and signaling interactions in PAH. https://clinicaltrials.gov/ct2/show/NCT01884051. First posted June 21, 2013. Last updated January 11, 2019. Accessed February 8, 2019.
7. Hansmann G, Wagner RA, Schellong S, et al. Pulmonary arterial hypertension is linked to insulin resistance and reversed by peroxisome proliferator-activated receptor-gamma activation. Circulation. 2007;115:1275-1284.
8. Kim EK, Lee JH, Oh YM, Lee YS, Lee SD. Rosiglitazone attenuates hypoxiainduced pulmonary arterial hypertension in rats. Respirology. 2010;15:659-668.
9. Legchenko E, Chouvarine P, Borchert P, et al. PPAR agonist pioglitazone reverses pulmonary hypertension and prevents right heart failure via fatty acid oxidation. Sci Transl Med. 2018;10:eaao0303.

This article originally appeared on Pulmonology Advisor