Harold I. Palevsky, MD is a Professor of Medicine at the Perelman School of Medicine at the University of Pennsylvania and the Chief of Pulmonary, Allergy and Critical Care Medicine at the Penn Presbyterian Medical Center in Philadelphia. He also heads the Pulmonary Vascular Disease Program at that campus. For the past 25 years, he has been recognized as one of Philadelphia Magazine’s and America’s Top doctors. In this episode, Dr. Palevsky discusses the importance of clinical trials in patients with pulmonary arterial hypertension including a new molecule that's on the forefront of treatment for PAH called PB1046 and the positive effects it could have for the community.

My name is Harold Palevsky. I'm a pulmonary critical care physician, a professor of medicine at the University of Pennsylvania, where we have a large pulmonary hypertension associated comprehensive care center that has eight physicians working in it, as well as advanced practice nurses and research coordinators and research staff. We have a lot of people who are focusing their time and their academic careers on pulmonary hypertension and pulmonary vascular diseases.



I've been caring for patients with pulmonary hypertension since the time of the NIH Primary Pulmonary Hypertension Registry, which was in the mid 1980s. At the time of that registry, as a senior fellow, I was the individual taking care of the patients with primary pulmonary hypertension who were being seen at our center and entered into that registry. That was a very gratifying experience, although at that time we really didn't have any therapies for pulmonary vascular disease. We were trying to understand the disease and its natural history.



The particular interest in pulmonary vascular disease was as a consequence of an epidemic of primary pulmonary hypertension seen in Austria, Switzerland, and Germany; and ultimately determined to be the result of a diet medication that was sold in those three countries. That epidemic provided the impetus for the first World Health Organization Conference on Pulmonary Hypertension, which was actually held in 1973. That led to the NIH Primary Pulmonary Hypertension Registry.



I've been involved in the care of patients with pulmonary vascular disease since that time and have seen the landscape change to the point where we now have 14 approved medications, basically in three biologic families that we use for the treatment of pulmonary hypertension. So that's the good news. The disappointing component of our care of patients with pulmonary vascular disease is that we haven't had any medications in new families - medications working by different pathways - approved for the last 14 years. All of the current medications are in the same three families, the prostacyclin family, the nitric oxide pathway family, and the endothelin pathway. We have multiple medications in the three pathways and drugs that can be used in combination. And in least currently in the prostacyclin family, we have drugs that can be given orally, intravenously, subcutaneously, and by inhalation. All of these have allowed us to improve the effectiveness of our therapies over time, but we're not curing pulmonary hypertension. We are often arresting it, preventing it from progressing, but we'd like to have more options, so that we can use and choose the best drug or combination for an individual rather than our current approach, which is very homogeneous. We tend to treat patients in a very similar manner based on their functional class and functional capacity rather than on individual characterizations of their pulmonary hypertension and its causes and precipitants.



So, the fact that we now have a number of drugs in development, in early phase clinical trials, moving through the process by which we develop medications that represent new pathways and new mechanisms for us is very exciting. We can't predict which of these drugs are going to ultimately prove successful and come to regulatory approval, so that we have them at hand to treat patients. Having drugs that represent new methods of treating pulmonary hypertension, impacting on different biologic processes and biologic pathways, at least in some of these cases, using new mechanisms for drug administration represents a step forward and a very exciting time in our approach to pulmonary hypertension.



One of the directions of ongoing research is trying to determine how we assess each individual patient to be able to give them the best therapy for them and how we decide among the available choices - what that might be, trying to figure out how to individualize therapy within the options we have. Beyond that, there are exciting developments in the fact that there are several agents under development in various stages of clinical trials that represent totally new pathways for treatment and may be particularly important in a given individual. That's why part of what is being done in the current clinical trials are obtaining blood specimens, banking specimens. So, at the end of the period of study, when we can assess who responded very well to a specific agent, a new drug and who didn't respond as well,we can go back and look at their disease, how we assess it clinically, how we assess it functionally and how we assess it biologically by looking at some of the blood work and other things we may be able to monitor. So, that we can then try to distinguish who is likely to be a responder, who's not as likely to benefit, so that we can decide what order and when we try individual therapies in an individual patient is as informed and sensible a decision as we can make it.



Progress in understanding pulmonary hypertension and in developing more effective therapies relies on clinical trials. We have a basis in our understanding of biology and in what has been learned from animal models and animal experiments as to what pathways may be important in pulmonary hypertension. But when a medication is developed that appears to work in one of those pathways, we need to go through the sequence of studies that is usually done in the development of a medication to determine if it's going to be as useful as our hope based on the biology.



The three phases of study are basically, first, making sure that a proposed medication is safe. Then, trying to determine what the appropriate dose of a medication will be. Then, studying it in what's called a Phase III blinded study; blinded such that the clinician and the investigator doesn't know whether the individual is getting the active drug or placebo on top of their background therapy. So, that the assessments we're making in terms of interpreting symptoms, interpreting side effects, functional status, all of those sorts of things, that we are doing them in a manner where our hopes and preconceptions don't influence the results and therefore the data that we're generating from the clinical trial.



That's why Phase I trials are not really blinded. They're to prove that the medication is safe, and we generally use increasing doses in very carefully monitored settings to make sure it's safe. And then in the next phase of study, we know we're giving the active agent to individuals. We want to figure out what the appropriate dose may be to get the effect we want, not to give more than we need, but also not to give less than we need. Then comes the randomized, controlled, blinded studies [that] we're often asking our patients to participate in, so that we can really decide whether or not this proposed medication is really safe and effective. Does it really improve how our patients are doing? We can [then] determine whether or not this is really a realistic medication.



In terms of pulmonary hypertension, the first drugs were studied with an endpoint of the clinical trials being an improvement in the six-minute walk after three or four months of therapy. The more recent trials have used more important long-term outcomes as their endpoints, and in particular, whether or not we prevent the pulmonary hypertension from progressing, whether or not our therapy keeps people from needing hospitalization or needing additional therapies added to what they're taking. Those are called event-based trials. We're hoping that by identifying earlier changes that might be occurring in response to therapies, that we can shorten the duration of some of the event-based trials. So, that it just doesn't take as long to develop these new medications as sometimes has been happening.



There are clear challenges in the development of new medications. We currently know that we have effective medications. The clinical studies that are done, are done on top of a background of medication. So, it's not like when we did the studies of the first therapies for pulmonary hypertension where for a period of time patients either got the active drug or a placebo and nothing else. That's not appropriate. It's not ethical at this point in time, where we have approved therapies that we know benefit our patients. So, new agents are studied on top of standard-of-care background therapy. We then evaluate, in a blinded manner, whether those interventions, the new therapy, make a difference on top of our backgrounds and standard therapy. It's a little harder to evaluate, because hopefully individuals are responding to their background therapy. We really have to take a longer period of time or evaluate our patients to make sure that these new therapies are adding something to the approved agents that we currently have.



We are also involved as a field in improving the families of medications that we have, seeing if we can make them easier for the patients to take. If we can advance the drugs within the family, so we have fewer side effects and fewer problems. We'd like our therapies to be relatively convenient and very well tolerated and effective. I wouldn't like to take a medication four times a day, if we can develop a related and as effective medication that can be taken twice a day. So, there are quality-of-life benefits from improving the therapies we have now and making them more convenient and better tolerated. So, that's also an appropriate direction for our research to be taking. Not only developing and looking at new drugs and new pathways, but also seeing if we could make our current therapies more convenient and easier to tolerate and just as effective or more effective within the families that we have. So, having a drug within a family doesn't mean we're going to stop looking at how we can make therapy better. But we have somewhat different goals in terms of research within a pathway and family of drugs that we already have approved agents in, and when we're looking at novel pathways and the first drug within that family or that pathway.



One of the pathways that is currently under investigation as a potential new pathway for therapy in pulmonary arterial hypertension is the VIP pathway. VIP stands for vasoactive intestinal peptide. It was shown some time ago that patients with pulmonary hypertension have reduced levels of this compound, VIP, circulating in their body. Initial efforts to develop a therapy within this pathway involved inhaled dosing of the VIP. That didn't prove to be as successful as was hoped. What's now being studied, is a really fascinating investigational drug where VIP is bound to a polypeptide, a long protein. This peptide has the property of becoming a gel when it gets warmed to body temperature. So, this medication, which is a liquid, is injected subcutaneously. That means under the skin. It then forms a gel, and the VIP leeches out of this gel into the circulation.



We measure the biologic availability of drugs in something called the half-life. That's really how long the drug is lasting in an individual. When VIP was given by inhalation, one of the problems is that the half-life of the drug is really quite short. It's measured in minutes. When VIP is given by this new technology, as a subcutaneous injection, the half-life is on the order of two and a half days. That's dramatically different. It allows for this version of VIP to be administered by a subcutaneous injection once a week. Now, none of us really relishes the idea of giving ourselves subcutaneous injections, but it's something that's done frequently in medicine. It's done with a lot of hormones. It's clearly the method of administration for insulin. It's how we give some anticoagulants, blood thinners, so it's something that is easy to teach patients. It's something that we can all come to accept if we're giving ourselves a medication which is improving our outcome from pulmonary arterial hypertension. An injection once a week is really a minor inconvenience to allow us to add another family of medications, another pathway that we can impact in our treatment of pulmonary arterial hypertension.



This agent is now in clinical trials. The clinical trials, as I said before, go through the three phases. It's been proven to be safe. Now, we're trying to learn something about its efficacy, its effectiveness, and what the optimal dosing is for individuals. That Phase II study is currently ongoing. Until we get the results, we won't know more about whether or not this is going to prove to be effective for treatment in pulmonary arterial hypertension. But it's exciting because first, it represents a pathway which we know is of biologic relevance in pulmonary arterial hypertension, that patients have reduced levels of VIP circulating. Second of all, it represents a new mechanism for drug delivery with the once weekly administration of this polypeptide bound to the VIP, which allows it to be in the body and released in the body in a manner such that a drug which has a half-life of minutes is converted to a drug that has a half-life of days.



The compound under investigation has a corporate nomenclature until the drug is done with its clinical testing, is approved and is going to be available, at which time it actually gets a name. The compound I described is called PB1046. If you look at clinicaltrials.gov or somewhere else where you might want to get a little more information about a drug under development, many of the drugs that are being worked on and investigated for pulmonary hypertension have alphanumeric names rather than common names or brand names. In this case, the PB in PB1046 stands for the pharmaceutical company that is developing this agent. That's a biopharmaceutical company called PhaseBio.



I'll close by just saying that the field of pulmonary hypertension has evolved dramatically over my career, from starting at a time when we had no specific therapies for pulmonary hypertension to now when we have 14 approved drugs in the three families that we've talked about and many other new agents under development. If you are interested in finding out more information about the research that's ongoing, you can look for information at www.clinicaltrials.gov. You can look for information through phaware global association® . And importantly, you can talk to your PH physician, because they may have specific information on how any of these agents or any of these clinical trials is of specific relevance to the unique nature of your pulmonary hypertension and pulmonary vascular disease.



My name is Dr. Harold Palevsky, and I'm aware that I'm rare.

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