Transcript Related Guidelines

Prostacyclin Analogs for the Treatment of PAH

Jeffrey S. Sager, MD, MSc · University of Southern California


May 12, 2021

Key Takeaways:

  • Several prostacyclin and prostaglandin IP receptor agonists have been approved by the US Food and Drug Administration (FDA) for pulmonary arterial hypertension (PAH). These analogs work by promoting direct arterial vasodilation and inhibiting platelet aggregation

  • Epoprostenol is a very potent and powerful treatment for patients with pulmonary arterial hypertension (PAH), with potential mortality benefit. Drawbacks include infusion requirements, short half-life, and risk of serious complications

  • Treprostinil is available in multiple forms. It can be administered intravenously at lower infusion rates with smaller pumps because of its stability and longer half-life, and it can be administered subcutaneously, via inhalation, or as an oral formulation

  • Iloprost is available as an inhaled formulation. It has a short half-life, requiring 6 to 9 inhalations throughout the day

  • Selexipag, in one clinical trial, showed improvement in time to clinical worsening and functional capacity as add-on therapy to background therapy including endothelin receptor antagonists (ERAs) and phosphodiesterase inhibitors

This transcript has been edited for clarity.   

Pulmonary hypertension results from a diverse array of complex clinical conditions resulting in elevated pulmonary pressures found in the pulmonary vasculature. Group 1, or PAH, occurs when damage to the pulmonary vasculature occurs, and this leads to the condition of pulmonary arterial hypertension. PAH was first described as a clinical entity in 1891, but it was not until 1995 that the first disease-specific therapy for PAH became available. 

The current available agents approved by the FDA encompass three classes of therapy: Prostanoids, or prostacyclin therapy; endothelin receptor antagonists; and those that affect the nitric oxide pathway. Prostacyclin is a naturally occurring prostaglandin that’s synthesized from arachidonic acid. It is a potent vasodilator with antiplatelet and antiproliferative effects, and increases intracellular cyclic AMP. 

Prostacyclin synthase is the enzyme responsible for the formation of prostacyclin. The enzyme may be deficient in patients who have underlying pulmonary hypertension because of damage or injury to the pulmonary endothelin. Prostacyclin analogs and prostacyclin receptor agonists act by exerting their effects by promoting direct arterial vasodilatation and inhibiting platelet aggregation. 

Prostacyclin or prostanoids have historically been added as sequential therapy in combination with oral medication in patients with poor response or severe PAH. This approach has largely been based on the complexity of administration of prostanoids. However, the availability of oral prostanoid preparations introduces the possibility that these agents may be added earlier in the treatment course, as evidence mounts that combination therapy significantly reduces PAH mortality. 

A pivotal point in the development of treatments for the disease was the approval of the first PAH-specific therapy, intravenous epoprostenol. Although intravenous epoprostenol was first used for the treatment of PAH in 1984, it was not available commercially until 1995. In 1984, Higenbottam[1] and colleagues used intravenous epoprostenol in a young woman [with] severe WHO functional class IV idiopathic pulmonary arterial hypertension who had been bedridden for more than a year. 

Epoprostenol was originally intended as a bridge therapy while the patient awaited a lung transplant. However, the treatment resulted in clinical improvement beyond expectations. That experience was an important beginning in support of clinical trial development for epoprostenol. After the 1995 approval of epoprostenol for PAH, other prostanoids were introduced, including treprostinil for continuous subcutaneous infusion in 2002 and for continuous intravenous infusion in 2004. 

Also in 2004, inhaled iloprost became the first prostacyclin analog approved for inhalation. A second agent delivered by this route, the inhaled form of treprostinil, was approved in 2009. The oral form of treprostinil was approved in 2013. In December of 2015, the FDA approved a novel agent, a selective oral IP prostacyclin receptor agonist called selexipag. 

Treprostinil is a parenterally administered prostacyclin analog that has been chemically modified. Treprostinil is stable at room temperature. It has an extended terminal elimination half-life of approximately 4 hours. Epoprostenol is a synthetic form of a naturally occurring prostaglandin derivative and is chemically identical to endogenous prostacyclin. Traditionally, epoprostenol, as first-line therapy, has been reserved for patients with severe pulmonary arterial hypertension, namely those who have functional class IV symptoms. 

Additionally, some data indicate the possible benefit of epoprostenol in the long-term prognosis of patients with disease regression and clinical improvement from functional [class] III and functional class IV to functional class I or functional class II after they have received prostacyclin therapy. This suggests that prostacyclin used in earlier stages of PAH may improve outcomes in some patients. 

Due to the extremely short half-life of epoprostenol, estimated at around 6 minutes, treatment must be administered continuously through an ambulatory infusion pump connected to a permanent central venous access system. Emergency medical attention is required in cases of pump failure or loss of central venous access due to rapid drug elimination and possible life-threatening rebound pulmonary hypertension that can occur. The first epoprostenol formulation, known as Flolan (GlaxoSmithKline), is rapidly hydrolyzed and rendered inactive when administered orally and is unstable at physiological pH. 

To ensure stability, ice packs are needed after constitution for any infusion longer than 80 hours. Home infusion of epoprostenol is administered with a CADD infusion pump. However, due to the pump limitations, it is recommended that the drug solution be prepared and administered for 24 hours—hence, requiring ice packs. 

In April of 2010, a formulation of epoprostenol with improved thermal stability became available in the United States under the trade name Veletri (Janssen). This product is stable, without needing cooling packs, for 48 or 72 hours, depending on the concentration. Unlike Flolan, the buffer and osmotic agents that confer room temperature stability characteristics of Veletri are contained within the drug vial. Veletri can therefore be prepared with readily available sterile water for injection, or normal saline, which provides a cost advantage. 

Treprostinil, under the trade name Remodulin (United Therapeutics), is a parenterally administered prostacyclin analog that has been chemically modified. Treprostinil is stable at room temperature. It has an extended terminal elimination half-life of approximately 4 hours. Subcutaneous formulations can be administered for up to 72 hours at temperatures up to 37 degrees. 

Two inhaled formulations of prostacyclin are available in the United States. With inhaled iloprost, available since 2005, treatment requires 6 to 9 administrations, no more than every 2 hours during the day, through an I-neb adaptive aerosol delivery system. The other inhaled prostacyclin, inhaled treprostinil, available since 2009 under the trade name Tyvaso (United Therapeutics), requires four separate sessions spaced equally throughout the day, with inhalation through a TD-100 ultrasonic pulmonary delivery device. Each of these sessions requires 9 inhalations, with dosage titration based on tolerability

What are the challenges with prostacyclin therapy? The adverse event profiles, the complexity of administration and modalities, and potential complications of these therapies must be considered when administering prostacyclin therapy. The most common side effects of prostacyclins, specifically parenteral prostacyclins, include dizziness, jaw pain, headache, musculoskeletal pain, nausea, vomiting, flu-like illnesses, and—sometimes—anxiety. 

Some adverse events, such as flushing, hypertension, chest pain, and tachycardia, may occur more frequently during initiation of treatment or after dose adjustments. Health care providers must manage these adverse events to reduce the risk of treatment discontinuation. Due to the complications associated with the mode of administration, initiation of intravenous prostacyclin therapy may incur the additional cost of hospitalization for the placement of a central line, an infusion initiation system, and close monitoring during initiation of and dose titration. 

The patient and the caregiver require extensive education and practice to properly prepare, store, and administer the medications. Maintenance of proper administration techniques with intravenous prostacyclin assumes that patients and caregivers have access to a reliable refrigerator or other controlled storage area, are capable of learning to mix and administer medication at home, and do not have deficits of manual dexterity that can often occur with patients—for example, with scleroderma or elderly folks. 

They also need to be able to maintain central line hygiene to prevent local and systemic infections. With any form of long-standing central venous access, a potential for bloodstream infections exists with intravenous prostacyclin therapy. With epoprostenol, bloodstream infections due to sepsis have been estimated to occur at a rate of 0.3 events per patient, per year. Likewise, with intravenous treprostinil, the risk of bloodstream infections has been estimated to average one event per 3 to 5 years of use. 

To minimize the risk of infection, health care professionals must educate patients and caregivers on the proper aseptic technique during preparation. Patients and caregivers must also be prepared for failures of the central line or the infusion pump or inadequate medication supplies, because even transient interruption of continuously infused prostacyclin therapy may lead to complications requiring urgent hospitalization. 

Although continuous subcutaneous infusion of treprostinil may be preferable in some clinical situations because central venous access is therefore not required, infusion site pain can be an important treatment-limiting side effect. Up to 85% of patients receiving subcutaneous infusion of treprostinil may experience serious infusion site pain, leading to treatment discontinuation in up to 23% of these patients. 

In pivotal clinical trials of subcutaneous treprostinil, nearly 32% of patients received prescriptions for narcotic pain relievers, and 40% experienced severe infusion site pain, resulting in treatment discontinuation for 7% of all trial participants.[2,3] Because of these effects, treatment with subcutaneous treprostinil is generally not recommended for patients with a low pain threshold.

The potential for administration errors: Prostacyclin delivered via inhalation offers its own challenges and complications, including multiple treatments per day, as well as a cough, which was a commonly reported side effect noted in inhaled prostacyclin clinical trials. Common errors with prostacyclin infusion occur as a result of accidental insertion of the wrong medication set at the time of administration. Other areas include improper programming of the pump and errors in dosage calculations that can lead to possible administration of a prostacyclin bolus, resulting in hypotension and, in severe cases, cardiopulmonary arrest. 

Addressing the need for oral agents: Although prostacyclins are well regarded as the gold standard treatment of patients with severe forms of pulmonary arterial hypertension, prostacyclin therapy, overall, is grossly underutilized, even in the late stages of the disease. In the REVEAL registry, a substantial percentage of patients were not being treated with the recommended options of intravenous prostacyclin and/or a combination therapy at the time of the death or after being assessed as worsening to functional class IV. 

Only 43% of patients were receiving parenteral prostacyclin at the time of the PAH-related death,[4] and 8% of patients did not receive any PH-specific therapy.[5] Many postulate that some explanations for the underutilization include patients’ or clinicians’ unwillingness or inability to apply complex therapy or lack of belief in it as more efficacious than other drugs, as well as lack of acceptance, lack of referral to experienced PH centers, and some physician bias. 

Oral treprostinil: Traditional modes of administration, with potential challenges and complications, may have contributed to an important unmet need—prostacyclin in an oral formulation. The first oral prostacyclin sustained-release formulation of oral treprostinil was approved in 2013. It is limited, however, by poor bioavailability and efficacy data, based on a modest improvement in exercise capacity. 

Oral treprostinil was approved based on the results of one clinical trial in which the drug was used initially as monotherapy. It failed to show a benefit on the primary end point of exercise capacity when used in combination with an ERA or PDE-5 inhibitor. Oral treprostinil must be taken with food 2 to 3 times daily, with doses based on clinical response. 

Selexipag is an oral bioavailable selective IP prostacyclin receptor agonist. It was recently approved by the FDA. The structure of selexipag lacks the characteristic cyclopentane ring of prostacyclin and its analogs. Unlike existing prostacyclin therapies, selexipag and its active metabolite are a selective agonist of the prostacyclin receptor, also called the IP receptor, with very low binding affinity for other prostacyclin receptors. 

In addition to these pharmacologic differences from existing prostacyclins, it is important to note that selexipag demonstrated no tendency for tachyphylaxis than traditional infused prostanoids in animal models. Selexipag was studied in the largest long-term, event-driven, phase 3, randomized controlled trial conducted to date in pulmonary arterial hypertension, the GRIPHON study. 

The results, first reported at the American College of Cardiology [Scientific Sessions] in 2015, showed a long-term benefit of selexipag therapy on the combined end point of morbidity and mortality. Eighty percent of all enrolled patients were on a baseline PH-specific therapy, either ERA [or] PDE-5 inhibitor or ERA and PDE-5 inhibitor. Patients received treatment with oral selexipag titrated for over 12 weeks. Over the course of the event-driven trial, 7.1% of patients taking placebo and 14% of patients taking selexipag discontinued treatment due to adverse events.[6] 

Morbidity and mortality comprising the primary end point included all-cause death, hospitalization for worsening of PAH, worsening of PH necessitating lung transplant, balloon atrial septostomy, or initiation of chronic oxygen therapy or parenteral prostacyclin therapy. After a mean follow-up of 76 weeks and 71 weeks in the placebo with selexipag, there was a 40% reduction in the risk of experiencing an adverse event on the composite primary end point vs the placebo, which was highly statistically significant, resulting in the drug, ultimately, being approved for use.[7] 

So, key insight and summary: Several prostacyclin and prostaglandin IP receptor agonists have been approved by the FDA for pulmonary arterial hypertension. These analogs work by promoting direct arterial vasodilation and inhibiting platelet aggregation. The available agents include epoprostenol, treprostinil, inhaled iloprost, and oral selexipag. Epoprostenol is a very potent and powerful treatment for patients with PH, with potential mortality benefit. Drawbacks include infusion requirement, short half-life, and risk of serious complications. Treprostinil is available in multiple forms. It can be administered intravenously at a lower infusion rate with smaller pumps because of its stability and longer half-life. And it can be administered subcutaneously, [via] inhalation, or as an oral formulation. Iloprost is available as an inhaled formulation. It has a short half-life, requiring 6 to 9 inhalations throughout the day. Selexipag, in one clinical trial, showed improvement in time to clinical worsening and functional capacity as add-on therapy to background therapy, including endothelin receptor agonists and phosphodiesterase inhibitors. 


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