Experimental PH Therapies Now Focusing on Treating Pathological Pulmonary Arterial Smooth Muscle Cells

As more scientific studies are conducted to understand pulmonary hypertension, it is becoming more apparent that pulmonary arterial smooth muscle cells (PASMCs) are important to the pathology of pulmonary hypertension. A group of researchers at the Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute recently reported on the advances in therapies that focus on modifying the pathological pathways of PASMCs in pulmonary hypertension.

Reported in the journal American Journal of Cardiovascular Drugs, the findings of the authors’ article, entitled “Novel Targets of Drug Treatment for Pulmonary Hypertension,” state that quite a few drug treatments are in early-to-mid stages (Phase 1 and 2 clinical trials) of development, while one particular treatment is in late stages (Phase 3 clinical trials) of development. This treatment, imatinib, is being developed by Novartis Pharmaceuticals and has completed a few Phase 3 clinical trials thus far.

Imatinib (Gleevec) acts to inhibit platelet-derived growth factor (PDGF), a growth factor that plays a role in pulmonary hypertension pathology. This drug has shown efficacy in inhibiting the proliferation of PASMCs in preclinical animal models and causes PASMC cell death in benchtop experiments.

One Phase 3 clinical trial, “Imatinib (QTI571) in Pulmonary Arterial Hypertension (IMPRES),” was conducted with 202 patients for 24 weeks. In this study, patients were treated with two or four tablets of imatinib mesylate or a placebo for a total of two weeks. Thereafter, patients were studied for improvements in six-minute walk distance (6MWD), right arterial pressure, and change in vascular resistance, among other parameters. Comparing the 6MWD results between imatinib and placebo, there was no benefit seen from imatinib treatment.

Two more clinical trials grew out of the IMPRES trial. Both were extensions to study the long-term safety, tolerability, and efficacy of imatinib, with one lasting for 96 weeks and the other lasting for 204 weeks. The shorter of the two, “Extension to CQTI571A2102 to Evaluate Long-term Safety, Tolerability and Efficacy of Imatinib in Severe Pulmonary Arterial Hypertension,” looked at 17 patients with pulmonary hypertension, while the longer, “Extension to QTI571A2301 to Evaluate the Long-term Safety, Tolerability and Efficacy of Imatinib in Severe Pulmonary Arterial Hypertension (IMPRES Extn),” followed 144 patients. The first study was completed, and the second study was terminated due to the discontinuation of developing imatinib for pulmonary arterial hypertension.

Results of the extension showed that there were fewer adverse events, serious adverse events, and deaths in patients treated with imatinib. With the exception of week 72, all weeks showed an improved 6MWD for patients treated with imatinib compared to placebo.

Although Novartis has withdrawn imatinib from its developmental pipeline, these results show potential for drugs that act to regulate PASMC activities. Future therapeutics may also focus on this pathway to add new treatments to the pulmonary hypertension pipeline.

Glossary of Terms:

[wikibox lang=”en”]Smooth muscle tissue[/wikibox]