As a former chemist, I spent years making a series of drugs that I hoped would be effective in treating breast cancer, only to learn when they were tested in cultured cells that they did not have a substantial effect. The disappointment was palpable; yet continuing with more advanced testing should be limited to those drugs that hold the most promise by demonstrating early, successful results in the setting of rigorous testing. It is estimated that up to 12 years or more can be spent performing preclinical and clinical testing to bring an effective drug from the laboratory to patients. It sometimes seems impossible that this extensive process is ever successfully completed with positive results. In the special situation of a rare disease such as pulmonary hypertension (PH), it also requires that there be a high level of commitment to treating an orphan disease for the development process to proceed in the first place. In the last year, the PH community has seen the culmination of a great deal of effort as 3 new treatments for PH became available to patients. In this issue of Advances, we are delighted to discuss these new options in PH care.
Drs Caccamo and Lahm introduce us to 3 new agents: riociguat, macitentan, and oral treprostinil. In a competitive market, many “me too” medications are developed where a simple change is made to a molecular structure and a “new” drug is created. Riociguat excitingly has both a novel design and a novel mechanism of action. It provides a therapeutic option for patients with pulmonary arterial hypertension (PAH) but the soluble guanylate cyclase stimulator has also gained approval for treatment of patients with chronic thromboembolic pulmonary hypertension (CTEPH), which to date has lacked an approved pharmacologic treatment after appropriate consideration/performance of a pulmonary thromboendarterectomy. Also finding itself on the forefront of PAH treatment is the endothelin-receptor antagonist, macitentan. The clinical trial of the medication produced exciting results, but macitentan will likely remain most notable for performing well in a study design driven by events and not changes in 6 minute walk distances. Finally, oral treprostinil with its unique extended release osmotic tablet will provide an option for prostanoid therapy that is not dependent on parenteral administration. Overall, these 3 new medications add to the field because of unique characteristics and they will undoubtedly each find a position on the PH treatment algorithm.
Pulmonary hypertension is a complicated disease with multi-pathway dysfunction such that the successful introduction of several medications in a relatively short period of time does not mean that research and development can be totally eclipsed by the enthusiasm behind the new agents. Additional novel molecules and treatment pathways are under study and Dr Preston provides a glimpse in this issue of Advances as to where the field of PH research is headed in the future.
Finally, as the PH community is welcoming new medications, the complexity that is caused by the availability of these same agents cannot be overlooked. How is a particular medication selected? Who should be involved in the decision making? Is the drug worth the cost? How do we monitor response to therapy? These are all questions that are discussed by the roundtable participants, Dr Studer in the “Ask the Expert” column, and by Drs Raina and Benza in their article.
Although my first foray into drug development was less than successful, it taught me the importance of tenacity. Study the pathway, find the molecule, make the medication, treat the patient, and cure the disease.