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20 Years of Prostacyclin Therapy in PAH: Slow and Steady Progress, but Still Not at the Finish Line


Kathy Tang, PharmD
KTang@rx.umaryland.edu

Guatam V. Ramani, MD
GRamani@medicine.umaryland.edu
University of Maryland Medical Center
Baltimore, MD, USA



As we learned from the tale of the tortoise and the hare, slow and steady wins the race. Patience, hard work, and tireless commitment to innovation and progress are the keys to success. Are we winning the race when it comes to the management of pulmonary arterial hypertension (PAH)? From one perspective, the management of PAH has come a long way since the development of prostacyclin therapy in the mid-1990s. We now have14 FDA approved therapies, utilizing multiple delivery routes and targeting different molecular pathways. Yet, progress has been slow compared to other chronic conditions. For example, treatment for hepatitis C (HCV) and human immunodeficiency virus (HIV) have leapt ahead over the past few decades as a result of several breakthrough therapies. Today, HCV can be cured in most patients, and those with HIV are living for decades following their diagnosis. By comparison, the management of PAH seems to be at 3 kilometers into a 5K race.

Before exploring what we need to do to reach the finish line, let us first reflect on how far we have actually come. In 1995, PAH was a rapidly fatal disease, with calcium channel blockers, and anticoagulation forming the mainstays of therapy, and only a minority of patients satisfactorily responding. The dawn of prostacyclin therapy began with the approval of epoprostenol as a continuous intravenous (IV) infusion. For the first time, our patients had hope, and the race was on! It was not without limitations however, as the drug not only had to be kept cold due to its heat instability, but its short half-life also required that it be administered as continuous infusion via central venous catheter and infusion pump [1].

Seven years later, a slightly more convenient prostacyclin came to market. Compared to epoprostenol, treprostinil had a longer half-life, reducing the risk of a life-threatening medical emergency in the event of a sudden interruption in therapy. Treprostinil was also stable at room temperature and could be administered via IV or subcutaneous infusion.

In 2003, a breakthrough in formulation led to the development of iloprost, an inhaled prostacyclin stable at room temperature. Iloprost overcame several of the initial obstacles of prostacyclin therapy, mainly the need for central venous access or subcutaneous access, and had a theoretical benefit of direct drug delivery to the lungs. However, the short half-life of iloprost made it a challenge for patients to take, requiring 10-15-minute inhalations six to nine times daily. Development of the longer-acting inhaled treprostinil followed suit in 2009, adding to the armamentarium of prostacyclin therapy choices. As the addition of inhaled treprostinil to a background oral therapy has been shown to be efficacious, the role of inhaled prostacyclin continues to evolve with the potential to transition patients from the intravenous or subcutaneous routes [2].

The pacesetter in PAH has always been development of an oral prostacyclin. An oral formulation would obviate many of the disadvantages of parenteral formulations, including risk of infection and pump failure, as well as improve convenience for the patient [3]. Road blocks to development included a high incidence of drug side effects and developing a tolerable dosing schedule. Clinicians remained optimistic about the possibility of oral prostacyclin therapy, which finally materialized in 2013, when an oral form of treprostinil was introduced. The efficacy in clinical trials was limited, especially when used in combination with PAH therapy, but the drug gave physicians something to work with and motivation for the tortoise to keep running the race.

Optimism of oral therapy continued with the recent results of selexipag, an oral selective prostacyclin IP receptor agonist, showing clinical benefits when used as a monotherapy or combination therapy with other oral PAH therapies [4]. However, the ultimate role of selexipag of in PAH management - whether selexipag can replace inhaled or parenteral prostacyclin therapy - remains to be seen.

How does the future look for prostacyclin therapy? Is a finish line in sight? The results of delivering subcutaneous treprostinil using a fully implantable programmable intravascular delivery system was recently published, showing reduced catheter-related complications and improved patient satisfaction [5].

The BEAT study, a Phase III trial, is currently recruiting participants to assess the efficacy and safety of adding the oral prostacyclin beraprost to inhaled treprostinil [6]. The combination of oral and inhaled prostacyclin has not been explored previously and may represent a more efficacious alternative to current management strategies.

Although prostacyclin formulations have improved in convenience over the past few decades, overall advancements in the management of PAH remain slow when compared to other disease states. However, we remain hopeful that novel agents in the pipeline, targeting novel pathways, will not only enhance the pace at which the care of patients with PAH will improve, but also ensure we reach the finish line. ■

Disclosure Statement: The authors have no conflicts of interest to disclose.


References:

  1. Frumkin LR. The pharmacological treatment of pulmonary arterial hypertension. Pharmacol Rev 2012;64(3):583-620.
  2. Channick RN, Voswinckel R, Rubin LJ. Inhaled treprostinil: a therapeutic review. Drug Des Devel Ther 2012; 6:19-28.
  3. Ruan CH, Dixon RAF, Willerson JT. Prostacyclin Therapy for Pulmonary Arterial Hypertension. Tex Heart Inst J 2010;37(4): 391-399.
  4. Sitbon O, Channick R, Chin KM et al. Selexipag for the Treatment of Pulmonary Arterial Hypertension. N Engl J Med 2015;373(26):2522-33.
  5. Bourge RC, Waxman AB, Gomberg-Maitland M, et al. Treprostinil Administered to Treat Pulmonary Arterial Hypertension Using a Fully Implantable Programmable Intravascular Delivery System: Results of the DelIVery for PAH Trial. Chest 2016;150(1):27-34.
  6. Lung Biotechnology PBC. A Multicenter, Double-blind, Randomized, Placebo-controlled, Phase 3 Study to Assess the Efficacy and Safety of Oral BPS-314d-MR added-on to Treprostinil, Inhaled (Tyvaso®) in Subjects with Pulmonary Arterial Hypertension. ClinicalTrials.gov NCT01908699.



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