Dec 6, 2019
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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