Historic Treatment of Pulmonary Hypertension
For 30 years the focus of treating PAH has been finding medications that dilate (or relax) the pulmonary arteries. This approach has served patients well. The prognosis for patients diagnosed today with PAH is very different from 30 years ago. Today patients can expect to take usually two if not three different medications that work to relax the pulmonary arteries and allow blood to flow more easily. In the last decade, pills that deliver some of the benefits of the previously available pump-based medications are now in wide use. Medications like Uptravi (selexipag) and Orenitram (treprostinil) have allowed patients more options.
We have made great progress in improving the blood flow through the pulmonary arteries but clearly these therapies are not enough for most of our patients. Over time, we still see patients develop progressive problems with their right ventricle as it dilates (gets bigger) and functions less well.
New Studies and Treatments of PAH on the Horizon
A new category of medications is in clinical trials that seek to improve the way the right ventricle uses energy. The way that cells use energy is often referred to as bioenergetics. In PAH, cells stop using energy efficiently. This shift to less efficient energy usage is thought to be due to imbalances in certain proteins. NFKB is a protein that when present in too high amounts leads cells to function less efficiently. In contrast, NERF-2 is a protein that helps push cells to use energy more efficiently.
Two companies have drugs in studies that increase NERF-2 signaling and decrease NFKB signaling. Reata Pharmaceuticals is almost done with their phase 3 study of bardoxolone methyl in PAH. Complexa has just started a phase 2 study with their drug CXA-10. We eagerly await results from these studies.
Why Does Energy Efficiency for Cells Matter?
As PAH progresses, the right ventricle is not able to do the work needed to pump blood through the diseased pulmonary arteries. The thought is that if the right ventricle is able to be more efficient it may be able to continue pumping more effectively. We have some reason to be optimistic. Patients with congenital heart disease have right ventricles that pump blood at very high pressure for decades. This tells us that the ventricle does have the potential do such hard work but may need some molecular nudges to use energy more efficiently.