I’m Aware That I’m Rare: Vinicio de Jesus Perez, MD (444)

phaware global association®
8 min readNov 27, 2023

the phaware® interview

In this episode, Vinicio de Jesus Perez, MD discusses some of the most recent clinical developments in the field of pulmonary hypertension, highlighting new and ongoing clinical trials that are of great interest to the medical community as well as caregivers and patients looking forward to novel ways of treating their condition.

Good day to everybody. My name is Dr. Vinicio de Jesus Perez. I’m an associate professor and staff physician at the Pulmonary Hypertension Center of Excellence located at Stanford University Medical Center. I am a physician-scientist passionate about understanding the genetic and molecular mechanisms of pulmonary hypertension to identify new treatment strategies based on genetic and molecular targets.

Today, I want to tell you about some of the most recent clinical developments in the field of pulmonary hypertension, highlighting new and ongoing clinical trials that are of great interest to those who work in the community as well as caregivers and patients who are looking forward to novel ways of treating their condition.

I want to highlight a drug that has been in the public domain for a while, and many people, including patients and caregivers, have probably heard of it, called Sotatercept. Sotatercept is a new drug that has completed phase II and III studies. It is at the point of being evaluated by the FDA for approval, which means that this drug may be entering our treatment armamentarium over the next year or so.

What this drug does, which is quite different from the other 14 approved drugs we are currently prescribing to patients, is that while all the other drugs are vasodilators, these medications relax the blood vessels, allowing more blood flow, Sotatercept targets cell growth, the buildup of cells that ultimately closes the lumen through which blood needs to flow.

We believe in pulmonary hypertension that as the disease progresses, more and more of the cell-rich lesions build up inside the blood vessels. The vasodilators primarily target vessels that are still functional, and even though they may have some vascular changes, they can still be open enough so blood can be diverted through them and reach the areas involved in gas exchange. However, as the disease progresses, these vessels, too, become burdened by these lesions, and ultimately the number of vessels available to carry blood to the lung becomes less and less.

Sotatercept takes a new paradigm, which is rather than working on those vessels that can still be dilated, it’s targeting vessels that are already occluded with the idea that if we can melt away the cell growth inside the vessels, we can restore the patency and allow more blood to go in. That will work very well for the heart, because the right ventricle will not have to put so much effort into getting blood into the lungs to get oxygenated.

Sotatercept is an injectable drug given every three weeks, one injection that goes under the skin. It’s also different from other injectables like Remodulin or Veletri, which must be given continuously.

How does Sotatercept work? Its origins can be traced to the discovery around 23 years ago of the most common genetic mutations in pulmonary hypertension involving the bone morphogenic protein receptor two, or BMPR2. This gene is crucial to control the growth and viability of cells across the vessel wall. Mutations that result in loss or dysfunction of these receptors are associated with abnormal cell growth that leads to pulmonary hypertension.

This drug restores an imbalance in the cells, where activation through other alternative pathways overwhelms the lack of this BMPR2 signal. Sotatercept is a ligand trap that binds to the activin proteins and prevents them from triggering these abnormal or pro-PAH pathways, thus restoring balance.

We now have two clinical trials that have reported exciting results and have increased hope that we are entering a new age in how we treat the disease. What we have found is, to highlight the most relevant findings, number one, that even in patients that are being treated with three different therapies, the medication can add more significant benefit, both in reducing pulmonary pressures, increasing six-minute walk, reducing the risk predictors for mortality, reducing hospitalization, and allowing patients to be able to do more and expect more from their medications. I highlight that over 60% of patients in both trials already had triple therapy, including subcutaneous and intravenous.

This medication can be added to provide a benefit that’s in addition that can potentially allow patients to be able to carry out and have a better functional status beyond what can be offered for the current standard of care. This medication was also studied in patients who are on dual therapy and can be added as a third line agent, or triple therapy, indicating that it could be used as a third-line or a fourth-line agent. Now the big question is: How late or early can this drug be started? Two ongoing clinical trials are precisely exploring that.

Beyond pulmonary arterial hypertension, what other indications could Sotatercept help with? One of the unmet needs in the field is Group 2 pulmonary hypertension, the most common form of pulmonary hypertension, associated with left heart diseases such as left heart failure, valvulopathies, and pericardial restriction. We currently have no treatment for Group 2 PH.

There’s an ongoing clinical trial called CADENCE, which explores the use of Sotatercept to offset the impact of pulmonary hypertension in these patients. Having a medication that can help improve outcomes and quality of life in these patients will be revolutionary.

Another area where Sotatercept could be helpful is treating pediatric patients with pulmonary hypertension. As you all know, many of our drugs have been studied in adults, and only some are studied in children, creating many conflicts when figuring out the best dose and regime. Sotatercept is being studied in pediatric patients, which is a refreshing initiative, since we need studies to look at that unique patient population.

There’s a lot of excitement around this drug. As I said, the clinical trial data is quite compelling. The data is currently being evaluated to the best of my knowledge by the FDA for potential approval. We hope to see this drug in the clinic over the next year.

The other drug class that is currently being studied in clinical trials is what we call tyrosine kinase inhibitors or TKIs. The best-known is imatinib mesylate, which has been tested in Group 1 pulmonary hypertension. Unfortunately, the drug was plagued with significant side effects, including head bleeds, which ultimately resulted in not pursuing this drug further. However, the drug did meet its primary endpoint in the clinical trial (IMPRES trial). So how can we get all the benefits of imatinib while bypassing the toxicity, which will prevent our patients from getting the drug’s benefits?

Over the last five years, we have seen the development of imatinib and another drug within that class called seralutinib as inhaled agents that the patients can use to deliver the compound to the lungs, much akin to what we have now with Tyvaso. Recently, the results from a phase II study of seralutinib, the TORREY study, were reported. The primary endpoint for this trial was to determine whether the drug could reduce pulmonary vascular resistance, an important surrogate marker for phase II studies. In the data analysis, the drug did meet that primary endpoint, again in a patient population representative of our current PH standard of care.

With imatinib, we also have data now showing that, indeed, as seralutinib, these inhalable compounds seem to be safe, which bypasses a lot of the anxiety and concern rates due to the previous results that we had, including the phase III imatinib study that I referenced previously. These drugs are built on solid preclinical data and already robust clinical data showing clinical efficacy. These inhaled tyrosine kinase inhibitors could target cell growth and mechanisms leading to vessel obstruction. Now these two are the most advanced of the medications under investigation.

I want to close by pointing out other clinical studies that are either enrolling or are close to completion. The first study is the anastrozole study, also known as the PHANTOM study. This study is built on the premise that estrogen metabolites can contribute to pulmonary hypertension and may explain why females are more prone to develop pulmonary hypertension. The hypothesis is that anastrozole, an estrogen synthesis inhibitor, may reduce circulating estrogen in both men and women, thus allowing patients to gather benefits. Promising early clinical data supports this concept. We await the final results of the recently completed clinical study.

The other study uses a serotonin inhibitor called Rodatristat, also an oral agent. This agent can inhibit serotonin, one of the best-known and well-characterized triggers of muscularization and vessel remodeling. We have failed to be able to target this molecule because most compounds cross the blood-brain barrier. Serotonin is a neurotransmitter required for normal brain function. What Rodatristat does is that it shuts down serotonin selectively in the body while leaving the serotonin in the brain alone. Rodatristat is currently in a phase II study that is now active, and we are excited to see what the outcome is.

The last study I will point out is a stem cell study. It’s relevant because many patients ask me where stem cells are in treating pulmonary hypertension. There’s a study currently ongoing in Canada. This study is called the SAPPHIRE Study. It’s been going around for the last five years, where endothelial progenitor cells extracted from patients’ blood are genetically engineered to express nitric oxide synthase. In other words, the cells can produce a vasodilator allowing the vessels where the cells localize to vasodilate. Since these are endothelial progenitor cells, the idea is that these cells can differentiate into endothelial cells and potentially grow brand-new vessels, an important concept since one of the major pathological hallmarks in pulmonary arterial hypertension is a progressive loss of distal microvessels.

The trial is still ongoing. There’s data already, phase I data was published now almost 10 years ago, that showed that this approach was safe and beneficial. Still, given the small number of patients in that study, this particular study that’s currently ongoing, seeks to provide more solid definitive proof that this approach is not just practical but also safe.

We can talk about a lot, including other therapies currently in development, but I have concentrated on those at the most advanced stage of development.

Thank you all for listening. It’s always a pleasure to share my time with you all. Thank phaware, for giving me the opportunity and emphasizing that I’m aware that my patients are rare.

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phaware global association®

Are You #phaware? Pulmonary hypertension (PH) is a rare, life-threatening disease affecting the arteries of the lungs. www.phaware.global