Research Corner: New PH therapies, pathways and clinical trials

Research Corner: New PH therapies, pathways and clinical trials


In this issue of the Research Corner, some of the novel PH therapies under development are discussed. I will also explain the different target pathways for PH treatments, and the different research stages.

Currently approved PH treatments aim to increase levels of natural lung vasodilation, leading to opening (dilation) of blood vessels. Vasodilators work directly on the walls of your arteries, preventing the muscles from tightening and the walls from narrowing. PH drugs stimulate vasodilators (the prostacyclin or nitric oxide pathways) or inhibit vasoconstrictors (the endothelin pathway). Further information about these approved therapies is available at

As we understand more about the mechanisms behind pulmonary hypertension, we look at new targets and new pathways that may provide us with more treatment options.

Novel targets/pathways for therapies currently under investigation:

(1) Receptor tyrosine kinase (RTK) inhibitors: Drugs targeting this pathway aim to inhibit the binding of “growth factors”, the factors that signal the cell to divide and multiply, from binding the surface of the cells (the receptors). We are learning that in PAH, the normal cell cycle process is disrupted and cells divide more frequently than they should. Drugs targeting this pathway (RKT inhibitors) seek to decrease the levels of division of cells within the arteries of the lungs.

(2) Selective serotonin reuptake inhibitors (SSRIs): Drugs targeting this pathway aim to inhibit the reuptake of serotonin, a hormone that is associated with the development of PH. 

(3) Inflammation & immunity: Drugs targeting this pathway aim to decrease inflammation/ immune reaction. In some subtypes of PH, there is an increase in activity/numbers of immune cells, contributing to vasculature complications in the lungs.

(4) BMPR2 pathway: Targeting this pathway aims to increase signaling through the BMPR2 pathway in lung blood vessels. For more information, please review the April edition of the research corner.

(5) Stem cells: A novel therapeutic approach for PAH is the use of the EPCs, a stem cell population that can become mature endothelial cells, thus contributing to the repair of dysfunctional blood vessels in PAH.

(6) Metabolic imbalance: Targeting this pathway aims to decrease levels of division of lung vascular cells. The cells display an abnormal metabolic phenotype in PH, which can be reversed using drugs that target this pathway.

(7) MicroRNAs: MicroRNAs are small molecules that can change the levels of proteins by preventing their production. Drugs targeting this pathway aim to mimic or inhibit microRNAs, leading to reduced cell division. Some of these miRNAs have been observed to be high/low in PH patients.

Clinical trials

For a potential drug to go from concept to market it must go through 4 phases of research. First, a potential treatment will go through pre-clinical studies to confirm initial proof of concept/proof of efficacy of the treatment. This is usually performed on cells (in dishes) and animals. Once the treatment has shown efficacy on cells, it will enter a phase 1 trial. This is the first stage of testing of a treatment in humans. This type of trial has low enrolment (number of patients) and the primary point of it is to confirm if the treatment is safe for use in humans. If safety is established in phase 1, a drug will enter a phase 2 trial. This is a crucial phase where the drug is tested in a moderate number of patients to confirm whether or not the drug actually works for the disease for which it is being tested (the drug efficacy). If the drug proves to be effective in phase 2 trials, it will enter a phase 3 trial. This is the final phase of research before a drug is approved and available in the market. This is what most people think of when they hear “clinical trial”. These are trials in which a large number of patients are enrolled and which is focused on documenting side effects and testing the efficacy of the drug vs. a control group that is not taking the drug.

It is important to note that it can take many years for any one of these phases of testing to be completed and each often requires many millions of dollars in funding.

The table below shows some of the different trials currently ongoing with respect to research into new PH therapies. All of these trials have shown promise, and we look forward to new developments in this research. All registered clinical trials are available through use the number below for your search.

Name of drug

Phase of research, location & number

Pathway targeted


Phase 3 completed, Europe/Canada/USA, NCT00902174

Receptor tyrosine kinase inhibitor(1)

Selexipag (ACT-293987)

Phase 3 completed, Canada, NCT01106014

Prostacyclin pathway


Phase 2 completed, USA, NCT00942708

Selective serotonin reuptake inhibitors(2)

Bardoxolone methyl

Phase 2 recruiting, USA , NCT02036970


Rituximab (SSc-PAH)

Phase 2 recruiting, USA, NCT01086540

Inflammation & immunity(3)


Phase 2 recruiting, USA/Canada, NCT02234141


Tacrolimus (FK506)

Phase 2 re-starting, USA, NCT01647945

BMPR2 pathway(4)

EPCs (endothelial progenitor cells )

Phase 1 completed, Canada, NCT00469027

Stem cell therapies(5)

Dichloroacetate sodium

Phase 1 completed, Canada, NCT01083524

Metabolic imbalance(6)


Phase 1 completed, USA, NCT00452218

Receptor tyrosine kinase inhibitor

microRNA mimics or microRNA inhibitors

Pre-clinical studies


Please always keep in mind that while I can provide you with a small insight into PH research, you should always be able to get answers from your Pulmonary Hypertension Specialist, who is more familiar with your specific case and your treatment history. 


Contributed by: Mohamad Taha, Ph.D. candidate and pulmonary hypertension researcher in Dr. Duncan Stewart's laboratory at the University of Ottawa

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