Evolution of PH Treatment in Canada

The landscape of PH treatment in Canada has evolved greatly over the last 30 years, with the result that patients have access to more treatment options and better care than ever before. Since the founding of the first PH clinic in Montreal, Quebec in 1986, our community has witnessed the expansion of a network of specialized treatment centres from coast to coast and the development of 10 new PH-specific drugs. While being diagnosed with PH today is still scary, life-changing news, patients and their families can take comfort in the fact that, thanks to the progress made in the last decades, PHighters are living longer and healthier lives.

Evolution of PH-Specific Drugs and Treatment Pathways

There are currently 10 PH-specific treatments approved in Canada. Taken individually (mono-therapy) or in combination (combination therapy), these drugs help alleviate symptoms and slow disease progression, allowing PHighters to live as normally as possible. If PH specialists are now well-equipped to provide their patients with optimal treatment, it was not the case 20 years ago, before Health Canada approved the first drug for the treatment of pulmonary arterial hypertension (PAH). Available therapies in Canada are now administered orally, intravenously, or subcutaneously, and target three different biological functions that play a role in pulmonary hypertension (therapeutic pathways).

Development of Drugs Targeting the Prostacyclin Pathway

After clinical trials were conducted in Canada on intravenous epoprostenol (Flolan®), Health Canada approved this drug for the treatment of PAH in 1997. This therapy delivers prostacyclin through a molecule called epoprostenol, which leads to the relaxation of the pulmonary arteries. The approval of Flolan® radically changed the landscape of PH care in the country as it gave patients access to a specialized drug to manage their symptoms. This treatment, however, had its drawbacks, as it needed to be delivered intravenously 24/7 through a permanent chest line and its temperature needed to be controlled in order to be effective. It was only in 2013, with the approval of room-temperature-stable epoprostenol (Caripul®), that IV epoprostenol therapy became much easier to manage. Caripul® allowed patients to pre-mix medication and carry their pump without worrying about keeping it cool. Meanwhile, Health Canada approved another treatment targeting the prostacyclin pathway for the management of PAH: Remodulin®. Unlike Flolan® and Caripul®, this medication delivers synthetic prostacyclin through a molecule called treprostinil to help dilate blood vessels. This therapy can be administered subcutaneously or intravenously through a portable infusion pump. More recently, Health Canada approved the first oral therapy targeting the prostacyclin pathway: selexipag (Uptravi®). This drug, which is classified as a prostacyclin receptor agonist, works differently than others targeting the prostacyclin pathway. Uptravi® stimulates the IP prostacyclin receptor in the pulmonary arteries to cause vasodilation (relaxation of the blood vessels) as opposed to delivering pure or synthetic prostacyclin.

Development of Drugs Targeting the Endothelin Pathway

The first oral medication for the treatment of PAH, bosentan (Tracleer®), was approved by Health Canada in 2001. Classified as an endothelin receptor antagonist (ERA), this medication helps prevent blood vessels from narrowing by blocking the reception of endothelin-1, a protein that causes vasoconstriction (tightening of blood vessels) in the pulmonary arteries. The approval of bosentan (Tracleer®) represented breakthroughs in terms of both medication delivery and therapeutic pathways; with the arrival of this new drug, patients gained access to increased options to manage their disease. Two other oral drugs, which are also classified as endothelin receptor antagonists (ERAs), have since been approved for the treatment of PAH: ambrisentan (Volibris®) and macitentan (Opsumit®).

Development of Drugs Targeting the Nitric Oxyde Pathway

In 2006, the approval of sildenafil (Revatio®, Viagra®) added another tool to PH physicians’ toolboxes as this new drug provided the option to target a third therapeutic pathway. Classified as a phosphodiesteras inhibitor (PDE-5 inhibitor), this oral medication prevents PDE-5 enzymes from degrading nitric oxide in the pulmonary arteries, which helps dilate the blood vessels. A similar drug, tadalafil (AdCirca®, Cialis®), came on the market in 2010. In 2013, an important breakthrough was made for the treatment of chronic thromboembolic pulmonary hypertension (CTEPH) when Health Canada approved riociguat (Adempas®), the first (and currently only) medication for the treatment of non-operative or residual CTEPH. Unlike other drugs targeting the nitric oxide pathway, this medication is classified as a soluble guanylate cyclase stimulator (sCG stimulator) and helps increase sensitivity to nitric oxide in order to stimulate dilation of the pulmonary arteries. In 2014, Adempas® was also approved for the treatment of pulmonary arterial hypertension (PAH).

Current Research Into PH Therapies

PH clinics across the country are involved in multiple research trials with the goal of developing new therapies, assessing the efficacy of existing drugs, and testing the use of approved treatments in patients with different types of PH or in children with PH. Currently, new molecules are being tested for the treatment of PAH, which could lead to the approval of treatments targeting new therapeutic pathways. Innovative research is also being done on the use of stem cell therapies for the treatment of PAH (see our interview with Dr. Duncan J. Stewart on pages 27–28 for more information). A number of research trials are also monitoring the efficacy of the long-term use of treatments and evaluating their action in combination with other therapies (combination therapies). Research is also being accomplished in the treatment of pediatric pulmonary hypertension, which is vital given that the drugs currently available in Canada have only been approved for use in adults. Trials are ongoing to study the use of tadalafil (AdCirca®, Cialis®) in children with PAH and sildenafil (Revatio®, Viagra®) in newborns. Observational studies are also in progress to track outcomes and practice in pediatric PH. Recently, the U.S. Food and Drug Administration approved bosentan (Tracleer®) for use in pediatric patients, which makes us hopeful to see PH treatments approved for pediatric use in Canada in the near future.

Looking back at the last 20 years, our community has witnessed PHenomenal progress in the evolution of the PH treatment landscape in Canada. The development of 10 new drugs and three therapeutic pathways is progress worth celebrating, as these advances have had tangible impacts on the lives of patients and their families across the country. It is also worth noting that a strong network of Canadian PH clinics has evolved in parallel to the development of PH treatments. In the last three decades, a total of 21 specialized PH treatment centres have opened across the country, two of which offer specialized care for CTEPH and four of which provide treatment to children living with PH. We look forward to seeing the materialization of new treatment innovations in the years to come, as the scientific community works towards improving therapeutic options for the management of PH, and the discovery of a cure for the disease.

References:

Clinical Trials.gov, https://clinicaltrials.gov.

Mohamad Taha, “Research Corner: The Role of Endothelin-1 in PAH and Drugs Used for Blocking Its Function,” Pulmonary Hypertension Association of Canada, /en/news-and-events/newsfeed/reseach-corner-role-of-endothelin-1-in-pah-and-drugs-used-for-blocking-its-function/.

Mohamad Taha, “Research Corner: The Role of the Nitric Oxide Pathway in PAH and Drugs Targeting this Pathway,” Pulmonary Hypertension Association of Canada, /en/news-and-events/newsfeed/the-role-of-the-nitric-oxide-pathway-in-pah-and-drugs-targeting-this-pathway/.

Mohamad Taha, “Research Corner: The Role of the Prostacyclin Pathway in PAH and the Drugs Targeting this Pathway,” Pulmonary Hypertension Association of Canada, /en/news-and-events/newsfeed/research-corner-the-role-of-the-prostacyclin-pathway-in-pah-and-the-drugs-targeting-this-pathway/.

Pulmonary Hypertension Association of Canada, “About PH,” http://www.phacanada.ca/en/about-ph/learn-more.

Pulmonary Hypertension Association of Canada. History of Pulmonary Hypertension Management in Canada. Edited by Todd Kasenberg and Jamie Myrah. Atwood: Guiding Star Communications and Consulting Inc., 2016.

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