Nov 29, 2019
Dr. Raymond Benza is a cardiologist in Pittsburgh, Pennsylvania and is affiliated with multiple hospitals in the area, including Alle-Kiski Medical Center and Allegheny General Hospital. He has been in practice for more than 20 years. In this episode, Dr. Benza discusses the importance of clinical trials in patients with pulmonary hypertension including a new molecule that's on the forefront of treatment for pulmonary arterial hypertension called PB1046.
My name is Dr. Raymond Benza. I'm a cardiologist who works at the Allegheny Health Network in Pittsburgh, Pennsylvania. The Allegheny Health Network is one of the largest health care centers in Pittsburgh and includes facilities throughout Central and Western Pennsylvania. I have a lot of responsibilities here, but the most important role I have is serving as the director for the system for advanced heart failure, which includes cardiac transplantation and mechanical circulatory support, as well as run the pulmonary hypertension programs for the system.
Today, I'm going to talk a little bit about some unmet needs in pulmonary arterial hypertension including giving a brief description about the disease and some of the current limitations of the current drugs that we have to treat the disease. Then, go into a little bit about a new molecule that's on the forefront of treatment for pulmonary arterial hypertension called VIP. Also, I'll talk a little bit about the PhaseBio clinical trial utilizing this new therapeutic. Then, tell a little bit about what we're doing in the trials and what variables we're measuring. Then, I will talk a little bit more about the long-term extension trial for this particular molecule.
As many people are familiar, pulmonary arterial hypertension is a rare disease. We see it in about 50 per million people. It involves a variety of different types of subsets. The main one that we're interested in is called Group I pulmonary hypertension. This form of pulmonary hypertension is where the disease modifications are directly related to changes in the arterials and capillary structures within the lung, so that there's not a secondary etiological cause for a problem with the left heart or problem with the lungs or blood clots obstructing these. These are intrinsic abnormalities with the pulmonary vessels themselves.
This disease affects a number of people, including those who have heritable components. So, patients can inherit certain mutations in genes that affect the way blood vessels remodel themselves. The most infamous are the defects in the bone morphogenetic protein receptor type II. There are also other disease entities like connective tissue diseases; patients with cirrhosis; those who have HIV; and very importantly in an ever-expanding a number of therapeutics, other drugs that can actually damage these arteries and cause a very life-threatening condition.
Now the problem with pulmonary hypertension is not only the remodeling that we see in the pulmonary vessels, it's what that remodeling does to the right side of the heart. That is essential in really trying to understand the prognosis in patients who have this disease. The right side of the heart as opposed to the left side of the heart is not built to be a very muscular chamber. So, it's not used to pumping against very high pressures. When these high pressures develop as a cause of the disease, the right ventricle starts to enlarge to try to counteract this pressure that it sees coming back at it from the lungs. Unfortunately, when the right heart expands and dilates, it loses its ability to contract. So, right heart failure is really the main leading cause of death in patients with this very terrible disease.
I am old enough to really have experienced the full spectrum of the treatments for this disease. When I started learning about pulmonary hypertension and treating patients with this disease, when I was a trainee many years ago, there was no treatment for pulmonary hypertension. [Patients] were all coming to the heart and lung transplant list. That's really where I first met these type of patients, because transplantation was really the only cure treatment for this terrible disease. Then luckily in the late 1990s, a drug started evolving and coming to the market. The first [drug] was intravenous epoprostenol, and that became a life-saving drug. Because now we had a treatment for the disease, there was intense interest from both the PH community and the pharmaceutical community to develop other drugs that can treat the disease.
So, learning a lot about the pathways and how the disease propagates, we were able to develop really now a full armamentarium of therapeutics that have really changed the course of this disease from a rapidly progressive, deadly disease to a more chronic and progressive disease. We've doubled the life expectancy of these patients. So, these therapeutics have really helped, but we have not found the magic bullet. We don't have the Holy Grail yet, and patients will continue to progress, and they will continue to die from this disease, because we have not found the right combination of molecules to really put the disease at bay.
The type of patients that we see with pulmonary arterial hypertension, I think, has also evolved over the last several decades. Typically, when I was a trainee and early faculty, the patients we were seeing were young women, and that was the classic phenotype that we would see. As we know, pulmonary arterial hypertension occurs in women five times as frequently as it does in men. When we started learning more about this disease, we recognize that other disease subsets could also develop this disease. We began seeing in patients with scleroderma, lupus, HIV and cirrhosis. We were seeing a whole mix of different clinical phenotypes now coming to us with this same deadly disease.
So now we're seeing, typically, people present in their 40s or 50s. The mean age of patients that we see has moved from the 20s and 30s to now the 40s and 50s, and in some cases in the 60s. So, it really has been an evolving landscape. As people present with the disease at an older age, we're seeing a whole mix of other comorbidities that come along with the disease; hypertension, diabetes, renal insufficiency. It really has been a dynamically changing landscape. That's very important, because that has helped us grow the drug therapies to tailor to this growing and changing population of patient.
There are very good guidelines that we've developed to teach clinicians how to both diagnose the disease, and once it's diagnosed, how to treat it. One of the most important things that we do in contemporary algorithms to treat pulmonary arterial hypertension is we risk stratify people. So, when someone is newly diagnosed with the disease, we want to know where they are in the spectrum of the disease. Are they in the early portion, the mid portion, or these very late presenters who are almost in the terminal portion of the disease? That initial risk stratification enables us to use the right combination medicines upfront to battle the disease as aggressively as we can.
There are a lot of contemporary tools now that we use to risk stratify people. One of the most well used and probably the one with the best discrimination is the REVEAL score. But there have also been very good scores developed in Europe, including from our colleagues in France, Germany and Sweden, that have also enabled us to profile these patients to match [a] patient with individual drugs such that a low-risk patient may be good with an oral drug - one, maybe two. But a high-risk patient should always be started on upfront combinational therapy including parenteral prostacyclin. Then the intermediate risk [patient], somewhere in between those. So, risk stratification and then marrying the appropriate risk with the appropriate drug or combinations of drugs including a parenteral drug is ultimately the most important thing that we do now.
Many of the medications we have now are not truly disease-modifying drugs. They mitigate the course of disease primarily by ensuing changes in their regulatory and vasodilatory status of the blood vessels. By doing so, they allow the right side of the heart to operate more efficiently, but they do not cure the disease. They don't stop the smooth muscle proliferation; they don't stop the unchecked endothelial proliferation or the adventitial remodeling in the blood vessels. So, the disease is still there. That's why new drugs that actually modify the disease, that actually can stop the pathological processes, that are causing the arteries to remodel, those are drugs that we're looking for now.
We have great Band-Aids, and these drugs do great things to patients. As I mentioned earlier, we have improved mortality with this disease, but it will continue to progress. So, we need disease-modifying drugs, and we need drugs that can push people back from the high-risk profiles to the low-risk profiles consistently and steadily. That's where the explosion in these new molecules come into a very important role.
Clinical trials really run at the heart of what we do in medicine. We can't use drugs on people until we prove that they are safe and effective. That's what clinical trials do for us. Enrolling patients in clinical trials, particularly those who have unmet needs - they're not cured from the disease, they're continuing to suffer from the ramifications of the disease, they're still short of breath. These are the patients that we need to enroll in clinical trials to test these new therapeutics to make sure that they drive this disease down, and they make people have a better quality of life. We want people to function and feel better about the way they carry on their daily activities of living.
Obviously, being a clinical trial investigator, I get to work on the forefront of seeing new molecules coming through the clinical trial arena. PB1046 is one of those molecules. It's interesting. This is a molecule that we have tested before, not in this specific chemical composition, but in other forms. We found that it was a very potent dilator [of] the pulmonary vasculature. Here's a new substance and a very unique molecule that we can give once a week, that can have long-lasting effects for the entirety of that week, and it will help with clinical efficacy in that manner. That affords the patient a lot of free time - [to] not carry pills with them, to set timers or take their drugs.
The important thing to remember is that it's a new kind of treatment for PH that targets the disease process itself rather than just opening blood vessels like some of the older drugs. The hope is that it can be a more effective drug than these older therapies that focus mainly on dilating the blood vessels. The real name for PB1046 is a vasoactive intestinal peptide analog or VIP analog. Even though it's called vasoactive intestinal peptide, it does work directly in the lungs and heart, but it was first discovered in the intestines of some animals, and that's why they call it that.
I think I was the first clinician to actually try this therapeutic, and I had three patients try it. In two of them, it made them feel better, but sometimes the patients want to feel better, so it's not really clear whether it worked or not. That's a very strong placebo effect. However, when I measured the pressure in their lungs during treatment, it seemed to have helped that. It's interesting, because we utilized this new compound in patients who had an indwelling hemodynamic monitor, and we saw very impressive changes in the pulmonary artery resistances and the way their right heart reacted to that drop in resistance by improving its stroke volume.
Now, the injection causes some redness on the skin. Patients need to be aware of that and not be startled by it. I think the company says that it's due to the blood vessels that are expanding in the skin that's caused by VIP and [it] doesn't usually bother the patients too much. My patients got used to it, and they were able to stay on the drug for six to 12 months. There definitely needs to be more research to test it in more patients.
The company that makes PB1046 is called PhaseBio. I work with the company as a paid member of their scientific advisory board, and they're currently conducting a larger clinical trial, to test whether PB1046 is safe and effective in slowing down or reversing the pulmonary arterial hypertension disease process. They need to test the drug in about 60 patients to see whether it works or not.
It's a randomized double-blind trial, which means that patients will either get a high dose of PB1046 or a low dose. The high dose is what the company thinks may be more effective. Patients won't know which dose they're getting, obviously, until the trial is over. The treatment periods are about 16 weeks long, so patients will get 16 doses, once a week. After the 16-week study period is finished, patients will get to join the extension trial, which means that the patients can all get the high dose until the overall study results are known. Patients will have their lung pressures checked during the study, they do multiple six-minute walk tests, and have a variety of other assessments that are basic in many of our clinical trials that we do now in this disease process.
We're involved in this study, and the company is opening study sites at multiple clinics around the United States and in Europe, also. They seem very committed to bring this new treatment to PAH patients around the world. To learn more about this study, you can visit www.clinicaltrials.gov, or www.phasebio.com, or even better, I would use the phaware global association® clinical trial matching tool at www.phaware.global/clinicaltrials.
I really thank you for letting me be part of this today. My name is Dr. Raymond Benza, and I'm aware that I'm rare.
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