Latest / Cardio Pod: Heart of the Matter / Implications of the Advisory Committee Meetings for the Heart Failure Community

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Implications of the Advisory Committee Meetings for the Heart Failure Community · Cardio Pod: Heart of the Matter

• 0:00
  Well, welcome to Heart of the Matter podcast.
• 0:08
  I'm Chris O'Connor, principal investigator of the Heart Failure Collaboratory, and we'll
• 0:12
  continue our series on looking on how we can improve the ecosystem of research in the heart
• 0:19
  failure arena.
• 0:20
  And today's topic is looking at some of the recent decisions that have been made by the
• 0:27
  FDA and the advisory committees that support advice to the FDA around three different programs.
• 0:37
  The TopCat Spirolactone and HEFPEF program, Paragon HF, which looked at succubitrol valsartan
• 0:45
  in patients with preserved ejection fraction, and the most recent advisory committee review
• 0:53
  of omicamp demicarbal, which a drug being developed for patients with heart failure
• 0:58
  and reduced ejection fraction.
• 1:01
  And we're going to start at the top with TopCat, but I first want to introduce our distinguished
• 1:04
  panel today and starting with Joanne Lindenfeld.
• 1:08
  Hi, I'm Joanne Lindenfeld.
• 1:10
  I'm a heart failure cardiologist at Vanderbilt University.
• 1:13
  Thank you, Joanne.
• 1:14
  Peter Carson.
• 1:15
  I have been a...
• 1:16
  I'm currently retired, but I've been a heart failure cardiologist at the Washington VA Medical
• 1:21
  Center and I am currently enrolled with Beach Delaware and I sometimes host our moderator
• 1:27
  at Chris O'Connor down here.
• 1:29
  That's all I'll say.
• 1:31
  That was benign this time.
• 1:32
  John Tierling.
• 1:33
  Thanks Chris.
• 1:34
  I'm John Tierling.
• 1:36
  I'm at the San Francisco VA Medical Center as a heart failure physician and also very
• 1:42
  honored to be the president of the Heart Failure Society of America this year.
• 1:45
  Thank you, John.
• 1:46
  Orly.
• 1:47
  Hi, I'm Orly Vardany and I'm a pharmacist and I'm located at the Minneapolis VA and
• 1:53
  University of Minnesota.
• 1:54
  And Bill Abraham.
• 1:55
  Yeah.
• 1:56
  Hi, Bill Abraham, professor of medicine at The Ohio State University, heart failure cardiologist
• 2:01
  and clinical trialist.
• 2:04
  Thank you, Bill.
• 2:05
  Well, in December 2020, we had two interesting reviews by the advisory committee to the FDA,
• 2:13
  to the CardioRenal panel and the first one was the TopCat trial, a trial with spiral
• 2:20
  lactone in patients with heart failure and preserved ejection fraction.
• 2:24
  And this was really an analysis of this trial and whether the label could be expanded for
• 2:32
  spiral lactone in patients with heart failure, indicated in patients with heart failure and
• 2:38
  reduced ejection fraction.
• 2:41
  And I may ask Peter to jump in and comment on, you know, the advisory committee voted
• 2:48
  in favor 8-4, but there was a lot of split feelings about whether the one trial was robust
• 2:57
  enough to change the indication.
• 3:01
  And was there enough supporting evidence and was that trial, did it have too many problems
• 3:08
  to be a standalone?
• 3:10
  So I'll start, Peter, with you and say, what are your thoughts?
• 3:14
  You've been involved in this space for a long time.
• 3:17
  Well, thank you, Chris.
• 3:19
  I was recused out of that meeting, unfortunately, but I would have voted against the indication
• 3:26
  and expanding the indication.
• 3:28
  And for a number of reasons, you know, one thing we often say is that trials get kind
• 3:34
  of points for style, so to speak.
• 3:36
  They're well done.
• 3:37
  They're well designed, et cetera.
• 3:38
  And for me, TopCat doesn't really fit that.
• 3:42
  And the particular protocol problem was in what was described as stratum one, which allowed
• 3:49
  patients to get in with what is described as a hospitalization within 12 months in which
• 3:57
  heart failure was a major component.
• 4:00
  It is not what we usually find in history of heart failure hospitalization as a criteria
• 4:07
  for entry where it is the primary reason for heart failure.
• 4:11
  So this opened the door, particularly in Eastern Europe, to the enrollment of patients who
• 4:18
  ended up having a remarkably low event rate and there was little benefit of spironolactone
• 4:26
  to be found.
• 4:27
  And that was half the trial.
• 4:30
  There was a lot of question about this, what was going on in Georgia and Russia with the
• 4:35
  enrollment of these patients came to the data monitoring board and they indicated that they
• 4:41
  end up thinking that a lot of these patients were ischemic heart disease because of the
• 4:44
  leniency of the definition for entry.
• 4:49
  So this markedly, this took away the ability of the trial to be favorable on its primary
• 4:54
  end point, if it would have been.
• 4:57
  And one is left then with this mixed up subgroups really where it's hard to tell where spironolactone
• 5:08
  works and where it doesn't and how you would label it.
• 5:12
  So for example, do you label it and say that it's for patients in whom natriuretic peptides
• 5:18
  were elevated but they do not have a previous hospitalization for heart failure where it
• 5:27
  is an important part of the admission or the management?
• 5:31
  How do you do that?
• 5:33
  And then finally at the end, with a whole bunch of conflicting signals regarding that
• 5:39
  group, including in the US, not just in Eastern Europe, you're then left with the issue that
• 5:45
  the drug is usable in the United States in patients.
• 5:48
  Patients won't be denied this therapy.
• 5:51
  And since most HEPF patients have hypertension, one could reasonably use this drug without
• 5:57
  expanding the indication.
• 5:59
  So I would have voted against it for the issues that I just elaborated on.
• 6:06
  Well, you're a tough guy.
• 6:08
  And I'd like to hear from other members of the panel because you do a large outcome study.
• 6:15
  You have a large subgroup that stands alone called North America.
• 6:21
  The interaction p-value is highly significant.
• 6:25
  There's enough events in that group to be a standalone trial.
• 6:30
  And yet you can't seem to move to find that that's enough evidence.
• 6:34
  Joanne?
• 6:35
  Well, I agree with Peter.
• 6:37
  I never know how to predict Joanne's responses.
• 6:40
  This has made my day.
• 6:42
  Nine years lesson as the senior associate editor at Jack, I never can predict Joanne's
• 6:47
  responses.
• 6:48
  Well, first, I think the Europeans say, if I'm correct, that the test of interaction
• 6:52
  for that, moving out of Georgia, moving those patients out was not positive.
• 6:59
  So while it seemed like a very good story, I believe the interaction test for the patients
• 7:03
  in Georgia versus others was not statistically significant.
• 7:07
  So that to me posed a problem, and I just think that while I'm sympathetic and I believe
• 7:13
  it probably works, this is one trial whose primary endpoint was negative.
• 7:18
  And so I would sort of side with Peter on this.
• 7:21
  Okay.
• 7:22
  Orly, you know a fair amount about this trial.
• 7:26
  Dr. Pfeffer and Dr. Solomon were heavily involved in this study.
• 7:32
  I think they would feel differently than Dr. Lindenfeld and Carson.
• 7:36
  Well, I think the issue is much more nuanced because while we have a neutral study with
• 7:44
  a non-sophisticated, non-statistically significant P value, we know that there were regional
• 7:50
  variations in study conduct.
• 7:53
  So I feel like it's difficult to dismiss and therefore thinking about the totality of evidence,
• 8:05
  especially when it comes to some of the secondary analyses of the groups or individuals with
• 8:13
  an EF that was closer to 40%.
• 8:16
  So in that mildly reduced ejection fraction.
• 8:20
  In addition to the, again, post-hoc, but still analyses showing that there was likely non-adherence
• 8:31
  to study medication, not just the wrong patients, but probably participants not actually taking
• 8:38
  the therapy.
• 8:39
  So that in combination with some of the post-hoc analyses makes me uneasy to dismiss it completely.
• 8:49
  So I would, I have a difficult time, but I would push back against both Joanne and Peter
• 8:54
  on this.
• 8:56
  So in this exercise, you have to vote yes or no or abstain.
• 9:01
  Yes or no for a...
• 9:03
  For an expanded indication of spartan.
• 9:06
  I would vote yes.
• 9:07
  Okay, good.
• 9:09
  Bill, you're hearing some of your colleagues here roll in.
• 9:14
  When we do the adcom, there's not a Bayesian influence of the previous votes.
• 9:20
  So we'll have to do this differently on round two.
• 9:25
  But what are your thoughts here?
• 9:28
  I mean, obviously, what I would say is if we had the right monitoring and surveillance
• 9:38
  structure, remember this was an NIH trial, these two countries may have been like how
• 9:44
  we treat sites that aren't adherent or violate inclusion exclusion criteria.
• 9:49
  We remove them from the analytical data set before the database is locked.
• 9:54
  Yeah, I think that's right, Chris.
• 9:55
  And I do think that this is one of the limitations of NIH funded studies, is that there are a
• 10:01
  lot of things that one can't do to really rigorously monitor sites during the conduct
• 10:07
  of the trial.
• 10:08
  And we generally only surface these issues after the trial is completed.
• 10:14
  And in many ways, it penalizes those studies.
• 10:20
  There've been a lot of discussion, as you're quite aware, at the NIH about the plethora
• 10:23
  of negative studies sponsored by NIH in the cardiovascular arena.
• 10:28
  There are a few positive ones, but there are more negative than positive ones.
• 10:31
  And I think part of it relates to some of these issues around execution.
• 10:37
  But coming back to TopCat, I think Orly has stated the position quite well.
• 10:42
  I think it is much more nuanced.
• 10:44
  I don't think that trials should live or die by their primary endpoint, but really a look
• 10:51
  at the totality of evidence, understanding the study, understanding its execution, looking
• 10:57
  at the evidence, looking in particular at, in this case, I think some of those secondary
• 11:03
  endpoints.
• 11:04
  There seems to be a robust signal for a reduction in heart failure hospitalization in these
• 11:11
  patients.
• 11:12
  And there are other studies of spironolactone used in the setting of HEPF-PES that have
• 11:19
  suggested improvements in exercise capacity and functional status and quality of life.
• 11:26
  And when I think about this from a risk-benefit standpoint in a population of patients for
• 11:31
  whom there is little GDMT available, now we've got emerging, secubitrol, Valsartan, and certainly
• 11:39
  the SGLT2 inhibitors, but we don't have the same treatment options for HEPF-PES that we
• 11:43
  have for HEPF-REF.
• 11:46
  To me, I think making this available to our HEPF-PES patients with, let's say for lack
• 11:53
  of a better term, the endorsement of the FDA by expanding its label makes sense.
• 11:59
  Really well said, Bill.
• 12:01
  John, and so your vote is yes, I assume, Bill.
• 12:05
  Yes.
• 12:06
  Oh, that puts John in a very difficult position.
• 12:10
  It's a position that I am more than happy to accept in this case.
• 12:14
  So I will vote yes.
• 12:17
  And I vote yes for the reasons that both Orly and Bill gave, and also to add that especially
• 12:24
  in the context that this is a label extension.
• 12:28
  This is not a new clinical drug entity that we don't know its safety profile and we don't
• 12:33
  know the other aspects of this drug.
• 12:35
  So what we're really looking at is, is there a potential for benefit in this label extension?
• 12:43
  And I certainly, even though the interaction effect, the interaction effect was not positive
• 12:47
  for the primary endpoint.
• 12:48
  You're right.
• 12:49
  It's 0.12.
• 12:50
  But the cardiovascular mortality interaction effect was significant.
• 12:57
  And so here we have that kind of signal.
• 12:59
  We have such a marked change between the two programs in terms of their event rates and
• 13:05
  other things such that the patient population in Russia, Georgia, as you alluded to, Chris,
• 13:10
  I think these countries would have been shut down in any other types of monitored program.
• 13:17
  You didn't see changes in potassium.
• 13:19
  You didn't see changes in blood pressure.
• 13:21
  These patients were effectively not getting therapy.
• 13:25
  And so when you looked at the patients who were getting in a randomized manner within
• 13:29
  an area in a healthcare systems that we understand, they showed a definitive benefit.
• 13:34
  So I would have voted yes.
• 13:36
  And I know Peter will never speak to me again, yet again.
• 13:39
  The things you have to discount, again, I see both sides here, but the things you have
• 13:44
  to discount in the study are not just the effect of the area of Georgia.
• 13:49
  You have to discount that the benefit is less and less as you get up into what we might
• 13:52
  call real HEPF test.
• 13:56
  And that's a great thing.
• 13:58
  Well, that's one thing that you have to discount to say this is a treatment for all HEPF patients.
• 14:02
  Well, that's a great theme we're going to talk about in our next round.
• 14:05
  Let me just, Chris, can I just bring one more point in?
• 14:10
  And Orly pointed this out.
• 14:13
  It's not just the design of the trial had an issue that allowed for inappropriate patients
• 14:19
  to be easily entered, but there was the conduct of the trial.
• 14:24
  And that was known during the study that these patients had a very low event rate.
• 14:32
  And I preserve when we thought the Russian patients were being enrolled too easily and
• 14:37
  we were worried about it, we capped their enrollment, we stopped it.
• 14:40
  And as it turned out, we didn't have an issue in terms of event rate.
• 14:44
  So I'm not sure how to look at the notion of saying that the trial conduct, unfortunately,
• 14:53
  because of some issues relating to the NIH, really damaged the ability to see what the
• 15:01
  effect of this drug really was.
• 15:03
  So I'm not sure that that pulls along the idea of approval, at least it doesn't for
• 15:10
  me.
• 15:11
  Well, as they say, it is what it is.
• 15:16
  I don't think the trial would have ever gone to Georgia and Russia if enrollment in the
• 15:20
  United States was robust.
• 15:22
  And that's one of the big problems that we're trying to address in the Collaboratory.
• 15:28
  And the other thing is that the monitoring strategy in NIH trials is allowed to be less
• 15:36
  robust.
• 15:37
  And so the data the Data Safety Monitoring Board got was late.
• 15:41
  The patients were already in and randomized before they could start figuring out that
• 15:46
  these were low event rate patients and likely didn't have heart failure that were entered
• 15:51
  into the trial.
• 15:53
  But let's move on to Paragon HF.
• 15:56
  This was a program, really important program that came to the advisory committee, did not
• 16:04
  meet its primary endpoint nominally with a p-value of 0.6, but yet received a overwhelming
• 16:11
  endorsement from the committee, 11 to 1, and a label expansion did occur with this drug.
• 16:22
  What do you think was different?
• 16:24
  We'll go in the same order.
• 16:25
  Why a label expansion?
• 16:31
  Why were people able to take one trial with a p-value of 0.6 and say, that's enough evidence?
• 16:40
  Well, this one I'll say I would have voted yes.
• 16:46
  But the reasons why, first off, it came close.
• 16:52
  It was a big well-done trial.
• 16:54
  They learned from iPreserve and from TopCap important lessons about enrolling an appropriate
• 17:03
  population.
• 17:05
  They were very cautious about what they got.
• 17:08
  They then did their follow-up and came very close to the primary outcome.
• 17:16
  Interestingly enough, this WETO6 did involve the use of adjudicated data for heart failure,
• 17:26
  hospitalizations, and cardiovascular deaths.
• 17:29
  What became remarkable was the data that showed that about 500 events were not accepted by
• 17:39
  the adjudication committee as being worsening heart failure in one form.
• 17:46
  The committee used a granular definition, series of definitions, required specific criteria.
• 17:55
  Dr. Kierlik will talk more about that later, I'm sure.
• 17:59
  But the investigators were not required to do that.
• 18:04
  So therefore, perhaps they had a broader view of worsening heart failure than what the committee
• 18:11
  did.
• 18:12
  When you then take the investigator-reported events, you now cross statistical significance
• 18:20
  and you get very close to what the original agreement with the FDA was.
• 18:25
  It's interesting.
• 18:26
  There was a one-tailed P value that was also part of, I think, the initial agreement.
• 18:30
  But even with the two-tailed P value, when you look at the investigator-reported events,
• 18:37
  you then cross into statistical significance.
• 18:41
  If you then expand the endpoint a little bit with the outpatient events, then maybe it
• 18:47
  gets a little stronger.
• 18:48
  But you would reach statistical significance by using the investigator-reported events.
• 18:54
  And there was also, of course, you may want to go after this later, the book that the
• 19:01
  FDA suggested as a proportional contribution of heart failure to an event that was not
• 19:08
  considered to be heart failure.
• 19:10
  And this involved a re-adjudication by some heart failure endpoint.
• 19:16
  Mavens and once again, a series of findings were shown that again, moved in the direction
• 19:24
  of support for succubitrile balsartan.
• 19:27
  The last thing I think is that, and you indicated this going into it, that this really ended
• 19:34
  up being an expansion of the indication of succubitrile balsartan, that the FDA was comfortable
• 19:41
  with, and that then moved out of having a strict ES cutoff at 35% to be higher.
• 19:50
  So I think for all those reasons, I thought there, when you look at the totality of the
• 19:54
  data, there was a lot there and I thought it was benefit.
• 19:59
  Joanne, you never agree with Peter twice.
• 20:02
  No, I can't.
• 20:03
  But today I do.
• 20:04
  I think, you know, again, I think that while patients with HEP-PEP don't have a lot of
• 20:10
  treatments, I'm not sure that means we want to approve something if we're not certain,
• 20:15
  because other treatments come up like the SGLT-2 inhibitors and maybe something else
• 20:18
  will come up.
• 20:20
  But you don't ever take them away unless some unsuspected safety issue comes out.
• 20:25
  But I agree with Peter.
• 20:26
  Also the point that he made, I think, is that, is how are endpoints adjudicated?
• 20:32
  You know, are they face-to-face committees?
• 20:33
  Are they online committees?
• 20:35
  And I'm biased by the face-to-face committees, but I think they sometimes do a better job
• 20:40
  than online going in where things just go happen very rapidly.
• 20:43
  So this issue of changing, you know, this was a very large number of endpoints that
• 20:48
  were changed and changed the endpoint from investigator.
• 20:53
  And usually, I don't remember the exact percentage, Peter, you made, but usually nowhere near
• 20:58
  this many of the endpoints are changed from the investigator adjudicated endpoints.
• 21:03
  This was a very large number.
• 21:04
  That was 25%, I think.
• 21:05
  Yeah, that's a huge number compared to what is usually done.
• 21:08
  So that's what influences me a little bit here for a slightly different reason.
• 21:14
  So I think probably there was enough data here to really think about this.
• 21:19
  But I would argue with one point that Peter made and someone else made on the previous
• 21:22
  discussion is I think just because something is an extension doesn't mean we should have,
• 21:28
  I think, less criteria.
• 21:30
  The safety issue aside, and safety is important, we have data about safety.
• 21:34
  But is it effective or not?
• 21:37
  You know, I think that should be the primary thing.
• 21:40
  And so you leave on I think on both of these discussions, there is uncertainty.
• 21:45
  But I would have probably I think the data is better enough here that I would have said
• 21:49
  yes.
• 21:50
  Fantastic.
• 21:51
  Orly?
• 21:52
  I am two out of two voting yes.
• 21:56
  So I'm going to agree with what's been stated so far and exactly for the reasons that have
• 22:01
  already been stated.
• 22:02
  And not much to add except that in addition to spironolactone, succubitrival sartin also
• 22:10
  has data to suggest that the benefit is more pronounced in individuals with an EF that
• 22:19
  is below normal.
• 22:23
  So from that standpoint, I think a story emerges that at least for neurohormonal agents that
• 22:32
  systolic dysfunction does appear to matter and may be an element that could be amenable
• 22:42
  to treatment, at least with succubitrival sartin and with spironolactone.
• 22:47
  So while there's not an efficacy cliff as you go from low EF to high EF, there does
• 22:53
  appear to be a cliff on the mortality signal.
• 22:56
  Bill?
• 22:57
  Yeah, no, I would vote yes as well.
• 23:01
  You know, I'll make a couple of points.
• 23:03
  One, you know, I think we have to not be so focused on a fixed p-value of 0.05.
• 23:11
  You know, this has become sort of the coin of the realm for success or failure in a clinical
• 23:17
  trial, but it really is all about uncertainty, right?
• 23:21
  And a p-value of 0.06 versus 0.05 means that I'm just 1% less certain than I would otherwise
• 23:30
  be if that p-value were 0.05.
• 23:33
  It's a very small incremental difference.
• 23:36
  And when one looks at the totality of data and balances risks versus benefits, and then
• 23:42
  needs to balance the degree to which one is willing to live with some uncertainty, I've
• 23:48
  seen very few clinical trials that are certain, right?
• 23:52
  There's always some degree of uncertainty, you know, more or less.
• 23:57
  So you know, here I thought the degree of uncertainty was relatively small.
• 24:03
  We quibble about a p-value of 0.05 versus 0.06.
• 24:07
  You know, if that's what we have to quibble about, you know, we're probably losing the,
• 24:13
  you know, what do they say, the forest for the trees.
• 24:16
  So you know, that's one point that I would make.
• 24:19
  The other thing that I do agree with Orly, you know, it appears that nor hormonal inhibitors
• 24:24
  and antagonists exert a greater treatment effect in patients with reduced ejection fractions.
• 24:31
  And perhaps our definition of a reduced ejection fraction needs to change.
• 24:35
  We use cutoffs of 35 or 40 percent, maybe it should be 50 or 55 percent, you know, as
• 24:41
  a cutoff.
• 24:42
  And the more one gets to a normal or toward a supernormal LVEF, you know, the treatment
• 24:49
  effect of nor hormonal inhibitors and antagonists seems to diminish.
• 24:53
  And I will just contrast that with what I think is the case with hemodynamically active
• 25:00
  therapies for heart failure, such as pulmonary artery pressure guided heart failure care.
• 25:07
  Joanne's done a lot of work in that area, you know, which seems to be as effective in
• 25:13
  true HEPF populations as it is in patients with any degree of reduction of LVEF ejection
• 25:22
  fraction as well.
• 25:24
  So you know, I think that EF might matter here a bit.
• 25:28
  And maybe there is also an upper limit, like you're suggesting.
• 25:31
  I think all of you suggested that something above 55, maybe there's attenuation.
• 25:38
  We've talked about cardiac amyloid and things like that.
• 25:40
  John, what's your, you're going to be the consensus or no?
• 25:45
  We're going to make it unanimous, buddy.
• 25:47
  Wow.
• 25:48
  Okay.
• 25:49
  So I'm going to go yes on this one as well.
• 25:51
  And as Peter alluded to, I think, you know, this trial is a bit of an outlier in terms
• 25:57
  of its adjudicator, the endpoints in the adjudication process.
• 26:00
  And it was rather striking how many investigator reported events were thrown out.
• 26:07
  But that being said, when you look at the investigator reported, the adjudicated, the
• 26:12
  probabilistic analysis and the sensitivity analysis, all of those rate ratios in terms
• 26:17
  of the beneficial effect, all centered around being between.84 and.87.
• 26:23
  So regardless of how you looked at it, the observed treatment effect was similar.
• 26:29
  Whether it hit, whether it was.014, which it was with the investigator reported all
• 26:34
  the way up to.059, depended on how many events you had, not necessarily, you know, the distribution
• 26:41
  per se.
• 26:42
  So that's actually fairly compelling for me to say this is a real benefit.
• 26:47
  And in the context of agreeing with what Joanne said in terms of we shouldn't change necessarily
• 26:51
  our efficacy requirements when we're doing expansion of label.
• 26:55
  But it does liberate us a little when we're looking at the benefit to risk, because we
• 27:00
  already have a good estimate of what the risk is in general.
• 27:06
  Obviously have PEP patients may have different comorbidities and different balance of comorbidities
• 27:10
  than have REF.
• 27:11
  But nonetheless, we already had the largest heart failure trial ever done in paradigm
• 27:16
  where we saw a very good safety profile with succubitrile L-sartan.
• 27:21
  So anyway, so I vote yes and am happy to give this agent to my HEPPF patients without supernormal
• 27:30
  EF.
• 27:31
  Well, this.
• 27:32
  Can I make one more comment on this?
• 27:34
  One of the concerns about data which isn't certain is that in HEPPF, we've built one
• 27:39
  therapy on top of another.
• 27:40
  And when one is therapies approved with a strong recommendation, then it's required
• 27:45
  if tolerated for subsequent studies.
• 27:48
  We do have some data in HEPPF, but we don't have the same, okay, this is strong data,
• 27:51
  so everybody needs to be on this before you start this.
• 27:54
  So we don't have the same idea about building therapies like we do in HEPPF.
• 27:58
  And that's one concern, I think.
• 28:01
  That's a really good point, because they're all sort of coming out late in our development
• 28:08
  experiences and they're coming out with some wins, but haven't had time to use them as
• 28:14
  background therapy.
• 28:16
  Chris, you know, my dad, I mean, this is a great role for our guideline writers, right,
• 28:24
  to try to help order these and make some recommendations perhaps based on the strength of the data
• 28:30
  about what to use first, right?
• 28:32
  So if we think there's more uncertainty with spironolactone than we do with an SGLT2 inhibitor,
• 28:38
  you know, the SGLT2 inhibitor might be used first, right?
• 28:43
  So I agree with Joanne, we do have to think about levels of evidence very carefully and
• 28:49
  make sure that we're making, I think, rational recommendations to ourselves and to other
• 28:55
  clinicians about, you know, what the, you know, sort of ordering of these therapies
• 29:00
  and what, you know, represents, you know, optimal guideline-directed medical therapy
• 29:05
  in this population today.
• 29:08
  Very well said.
• 29:09
  Chris, just one other point just percolated through a couple of the statements that people
• 29:15
  made and that is what about this higher EFs group, where the signal seems to certainly
• 29:21
  attenuated and the benefit that we saw with spironolactone in this trial also with secubitrolval
• 29:29
  sartin.
• 29:30
  It's true to some extent with empipoflose and maybe a little less so with GAPA, but
• 29:36
  it still remains an area in that higher EF, that really normal group, who those patients
• 29:42
  are in my mind, do they really have heart failure or do they have some other abnormality?
• 29:48
  You alluded to amyloid as being possible and that certainly is true.
• 29:53
  Some trials are now going to a lot of effort to make sure amyloid is excluded in this population,
• 29:59
  but that is a bit of a frontier that we still have.
• 30:02
  Yeah, maybe the trials that are trying to maximize singles will take a high level cutoff
• 30:09
  on EF so that it could drop into a label.
• 30:14
  I think there's been a struggle about EF cutoffs in labeling.
• 30:19
  I was actually in favor of an EF less than 55 for this indication, but it wasn't studied
• 30:27
  that way nor was the split was at 57, so that's what clinicians are going to measure 57.
• 30:35
  Let's go to the last adcom that we had.
• 30:38
  This one is fresh in many of our minds, perhaps more controversial.
• 30:44
  With Omakam to McCorbel indicated for patients with heart failure and reduced ejection fraction
• 30:49
  coming to the advisory committee, which in and of itself is a decision that's made by
• 30:55
  the regulatory agency, whether something comes to the advisory committee or not means that
• 31:00
  there probably is some need or want for some external opinions and advice.
• 31:12
  This presentation done by the sponsors and the FDA, the vote was unfavorable three to
• 31:21
  eight and a lot of issues came up though about the development.
• 31:26
  There were just an amazing number of issues, whether a large subgroup could stand by itself,
• 31:33
  whether a phase two is an independent trial as a confirmatory trial for phase three, whether
• 31:41
  the intermediate endpoints in heart failure are good enough to stand as a second confirmatory
• 31:48
  trial and some, I think, general misunderstandings about the data in general when it came around
• 31:56
  to the heart failure events and safety.
• 31:59
  Lots on the table here and we'll start with Peter who is sitting in Rehoboth and I don't
• 32:05
  know which way, what he's going to say.
• 32:07
  Well, Chris, you sometimes see the congressional committees and they say, I see my time and
• 32:14
  then they designate someone.
• 32:17
  In this particular circumstance, I'm going to see, if you don't mind, I'm going to see
• 32:21
  my poll positions here to Dr. Teerlink because I am worried that the atmospheric river is
• 32:28
  going to wash him out before he gets a chance to speak.
• 32:32
  Can I save my time initially to Dr. Teerlink and then come back a little bit later?
• 32:37
  Yes, but if he takes all your time, you're done.
• 32:41
  John, go ahead.
• 32:43
  John has a lot invested here, so I wanted to-
• 32:45
  Well, yeah, and I think, you know, as full disclosure, obviously, you know, I've been
• 32:49
  involved with this development program for 20 years and was primary author on multiple
• 32:54
  papers in this regard.
• 32:57
  I think there were a number of general issues that came up from this ad com that have kind
• 33:01
  of brought to the fair, one of which is, you know, I think it made very evident that there
• 33:07
  needs to be representation of the heart failure community on ad coms dealing with heart failure
• 33:12
  agents.
• 33:14
  It also revealed some of the limitations of the Zoom format.
• 33:19
  You know, there was clearly less discussion or interaction of members.
• 33:24
  There was no time for sponsor responses to questions, even when additional analyses were
• 33:29
  requested.
• 33:30
  There was no time allocated to that being given.
• 33:33
  And then there were patently false statements that were repeated and then became truth during
• 33:37
  the course of the ad coms.
• 33:41
  So those were some of the general things.
• 33:44
  Also, while the vote was three, eight, it was, you know, three, four, and then among
• 33:50
  the eight, three of those eight said, well, if the question had been a little different,
• 33:54
  I would have voted for it.
• 33:57
  So there was also some challenge with in this setting how the FDA frames some of the questions
• 34:02
  as being absolutes as opposed to allowing some of the nuance that actually the sponsor
• 34:07
  tried to present.
• 34:08
  As many of you know, the trial was overall had a positive primary endpoint, and so it
• 34:13
  met its primary endpoint with a p-valid 0.025 and 8% reduction.
• 34:19
  The sponsor went to the FDA and said, you know, it's an overall positive trial, but
• 34:24
  we actually think it's even better in lower EF patients.
• 34:27
  So we'd consider just having it in lower EF patients.
• 34:32
  That discussion, despite the sponsor saying that's where we wanted to go, where they wanted
• 34:37
  to go, was not really embarked upon during the meeting.
• 34:41
  So there were a number of things that emerged from this that I think were challenging.
• 34:47
  And you know, there were also requests by the FDA to have the committee members deal
• 34:55
  with regulatory issues that I don't believe any of us would have been qualified or educated
• 35:01
  enough to deal with.
• 35:02
  So you know, I certainly, even though I studied it and not up to speed on what kind of therapies
• 35:08
  would require companion diagnostic device.
• 35:13
  And in terms of what is considered substantial and sufficient evidence, the FDA outlined
• 35:19
  their own draft document that I'm not sure everybody on the committee had time to read
• 35:25
  or take into consideration.
• 35:26
  So there were many aspects to this ad com that I think did this particular proposal
• 35:32
  a great injustice, especially since this agent has the potential to really help and address
• 35:37
  a major on that need in the heart failure community.
• 35:41
  I think what you got most of it well said.
• 35:46
  And I think what John is saying is opportunities here for maybe making things better, looking
• 35:52
  at things differently.
• 35:53
  Joanne, you've been involved in this process for a long time.
• 35:57
  I haven't had a chance to read.
• 35:58
  This was very complex deliberation, as John said, and I haven't had the chance to read
• 36:01
  the transcripts yet.
• 36:02
  So I also have done a very minor amount of consulting for cytokinetics, I should disclose
• 36:08
  that.
• 36:09
  But to me, it was a positive trial.
• 36:13
  The effect size was very small, but it was a positive trial.
• 36:17
  And I'm not sure, John, if they asked for a separate conclusion, but to me, it's the
• 36:21
  job of the FDA.
• 36:22
  And that's what I said.
• 36:23
  We will approve you if you have a positive trial and we don't see any glitches in that.
• 36:27
  We will approve you for what your primary endpoint was.
• 36:31
  And then to me, sort of a corollary with what Bill said earlier, it's the job of the guidelines
• 36:35
  committee to say, should you use it or when would you use it?
• 36:38
  But to me, this was a positive trial.
• 36:41
  And so, again, I haven't had a chance to go through all the weeds, but on the surface
• 36:45
  of it, I would have proved it, saying you had a very large trial.
• 36:49
  There were no safety issues in this specific trial.
• 36:51
  There is some supportive data and it was a positive trial.
• 36:56
  And I think something that John mentioned is absolutely key, which is an unmet need.
• 37:05
  So while, yes, we have a positive trial period that should have us all at hello, right?
• 37:15
  The fact that in addition to that, we don't have a lot of options for severely ill patients
• 37:24
  with heart failure on the lower EF spectrum, whose therapies may be really limited to things
• 37:31
  that are anecdotally used, such as milrinone or advanced therapies for which a lot of patients
• 37:39
  may not qualify, such as invasive therapies, ventricular assist device or cardiac transplant.
• 37:46
  So short of those, there are not a lot of options for this particular group of heart
• 37:52
  failure patients.
• 37:54
  And this is where the importance lies in providing something, an option besides ones that have
• 38:05
  either not been studied appropriately or ones that may be limited in terms of access.
• 38:13
  And so Orly, you would be in favor of, while the trial was overall positive, I think people
• 38:21
  were concerned that that signal, while significant, that strength of that signal was more maximal
• 38:31
  in the low EF.
• 38:32
  But would you be in favor of a restricted indication in that low EF subgroup of the
• 38:41
  trial?
• 38:42
  I don't think the indication should restrict it.
• 38:46
  I think the clinicians and again, guidelines should weigh in and provide more input on
• 38:54
  specific clinical scenarios that would lend themselves well to the use of this drug.
• 38:59
  So I would hesitate to put a limit on the label itself.
• 39:06
  Thank you.
• 39:07
  Bill?
• 39:08
  Well, first of all, I have no conflict of interest here and I want to commend the study
• 39:12
  sponsor for actually going into these discussions with FDA and an advisory panel looking for
• 39:20
  a, let's call it a high responder group or a higher responder group.
• 39:27
  Because while I agree with the comments that Joanne and Orly have made about P values and
• 39:32
  the positivity of studies, I do think it's important, again, in looking at the totality
• 39:38
  of data to consider the clinical meaningfulness of the effect as well.
• 39:42
  And whether that be taken on by an advisory panel or a guideline writing committee, it's
• 39:46
  something we have to think about here.
• 39:48
  So the fact that this study sponsor looked at subgroups, particularly this sort of higher
• 39:56
  risk subgroup with fewer options for treatment, I think was a terrific thing to do.
• 40:02
  So whether the label speaks only to that subgroup or to the whole population and the
• 40:08
  guidelines help recommend which patients might benefit most from it, there does seem to be
• 40:16
  a potential role for this agent in the treatment of heart failure patients.
• 40:20
  That's really well said.
• 40:21
  I mean, I think we pre-specify subgroups and then we test for interactions.
• 40:28
  And the overwhelming majority of the interactions don't meet our criteria of what is statistically
• 40:34
  significant.
• 40:36
  In this case, this was a very robust interaction.
• 40:39
  And I think if we're going to test for interactions and you get something really robust, not like
• 40:45
  a P value of 0.1, then it does have meaning.
• 40:52
  And I think it can help amplify and understand a signal.
• 40:56
  Well, we've got Peter, we get a little time.
• 40:59
  You get a little time.
• 41:00
  Okay.
• 41:02
  So moderator, I mean, O'Connor, so I'm going to be the outlier again here.
• 41:12
  I guess I have to be.
• 41:14
  But within the briefing document, I think the comment was made, I just can't quite find
• 41:18
  it looking through here, that at an earlier meeting with the FDA, cytokinetics was told
• 41:25
  that the trial would have to reach, sorry, Bill, to get onto a P value again, but it
• 41:31
  would have to reach a statutory stated approvable value, which would be, I think it was 0025.
• 41:40
  And so this was one of the statements in the briefing document that sort of led off what
• 41:47
  was a pretty harsh briefing document.
• 41:51
  And I guess what I would ask people is, what about that?
• 41:57
  Because we used to hear that for many years about you're required to have two clinical
• 42:04
  trials at a statistically positive level or one that was very, very statistically positive.
• 42:13
  And the FDA's contention then was that this trial did not reach that statutory limit.
• 42:18
  And I think they then said, well, the key secondary, I think the first secondary was
• 42:25
  cardiovascular mortality and there was no benefit really there.
• 42:29
  And then that could put a blocker on looking beyond that.
• 42:33
  So I tried to come to terms on this particular study when asked in a sort of minor consulting
• 42:43
  role earlier before the advisory panel, I said I thought the drug would go through in
• 42:50
  part because of the experience or sequence.
• 42:54
  So let me just bring up then those two issues and ask my distinguished colleagues what they
• 43:00
  think.
• 43:02
  This statutory requirement that the FDA has said a trial should meet.
• 43:07
  And I think all of us may have been in those meetings where we were told this is what it's
• 43:11
  going to be.
• 43:13
  And if your trial is not going to reach that level, well, that will be a problem.
• 43:20
  We'll look at the totality data is the fallback.
• 43:23
  That became limited a little bit by the cardiovascular mortality signal.
• 43:27
  But then that is the first issue that I would ask.
• 43:31
  I'm wondering what people think about that in terms of going forward.
• 43:36
  John?
• 43:37
  Yeah.
• 43:38
  So if I may clarify what the FDA had said was that if there was the single trial and
• 43:44
  that if you hit 0.0025, absolutely, then it would get there.
• 43:49
  If you went less than 0.05 and your cardiovascular mortality was not bad and trending toward
• 43:57
  positive, then that would count.
• 44:00
  And so your analogy to variciguat is very salient here because p-value of galactic HF
• 44:10
  was 0.025 with an 8% reduction.
• 44:15
  And Chris, you can correct me on this, but I think Victoria was 0.02 something as well
• 44:22
  with a 10% reduction in their treatment effects.
• 44:24
  So very similar treatment trials.
• 44:28
  And so it's strange that in the committee that the trial was penalized a bit because
• 44:39
  it showed that actually this agent that improves cardiac performance didn't change cardiovascular
• 44:45
  death.
• 44:46
  And it showed that it was very safe in terms of its mortality signal.
• 44:51
  And yet that seemed to not work in its favor.
• 44:55
  And I think Joanne had a comment.
• 44:56
  No, not to take the focus off on the cancer, but you can ask yourself if we need one trial
• 45:02
  that has a trend toward positive cardiovascular mortality, that's significant, or two trials
• 45:06
  if it doesn't, then how many do we need if we're going to do retrospective evaluations
• 45:10
  of initially negative trials?
• 45:12
  Is one retrospective evaluation of a negative trial adequate, which is what we've said,
• 45:17
  right, twice here?
• 45:18
  I think we have to be careful about how we think of these things.
• 45:21
  Sorry, I couldn't read this.
• 45:23
  Yeah, you couldn't resist, Joanne.
• 45:25
  But I think what we didn't get on that track, I think, what John put is that a number of
• 45:34
  diabetic drugs were approved with guidance that the upper level of the confidence interval
• 45:43
  around mortality fell under a range, whether it was 1.3 or 1.1.
• 45:48
  And here the upper level of the confidence interval on mortality was less than 1.09,
• 45:54
  I think.
• 45:55
  And so I think reinforcing what John said is the safety of this drug.
• 46:01
  And tough decision.
• 46:05
  The advisory committee is only advisory.
• 46:07
  So I think the fact that there was healthy debate and there are still some dangling
• 46:13
  participles around some of these concepts that were allowed to stay in, as you highlighted
• 46:20
  with some of the limitations of the current format of the EDCOM committee, to stay in
• 46:25
  play will be sort of re-reviewed by the FDA, in my opinion.
• 46:32
  I know that a number of people are making communications to the FDA to do such.
• 46:39
  Peter?
• 46:41
  So I think the other issue that came up, and for TopCat and for SecureMetro, I don't think
• 46:51
  the FDA was finding that there might be a safety signal.
• 46:55
  But the FDA did become, Chris, you know this very well, very involved in the notion of
• 47:01
  whether there was a safety signal relating to all the captives.
• 47:06
  Now there is no safety signal that one saw regarding either adjudicated myocardial infarction
• 47:13
  or unstable engine events or those that were reported.
• 47:18
  But there was this concern about the drug accumulation and the adjustment for dosing.
• 47:27
  And that then I think presented another lens that they saw the drugs through.
• 47:33
  And it did seem like looking through the briefing document and then also some of the discussion
• 47:39
  that day, it was an issue that they would not let go of.
• 47:44
  So let me just bring that in because that is a little different than what we have in
• 47:47
  the other trials.
• 47:49
  Concern about the safety of the drug, even though you had an over 8,000 patient trial
• 47:53
  with no increase, no pre-trial increase in ischemic events of any kind.
• 47:58
  John?
• 47:59
  Yeah, I mean, I don't know how, yes, there was a lot of perseverance on that.
• 48:04
  There was also some discussion of how the sponsor was actually asked to present a no
• 48:12
  drug monitoring model, which they did.
• 48:15
  And then they were criticized for putting that forward.
• 48:20
  The intention was always to use some degree of initial therapeutic drug monitoring with
• 48:26
  the initiation of this, which is what was done in Galactic HF.
• 48:29
  And even despite the SIP variants and everything else that existed in that 8,000 patient trial,
• 48:35
  there was no bad signal.
• 48:37
  And when they did the final risk to benefit ratio, they forgot to include the fact that
• 48:43
  Omicam to McCarbel significantly reduced the stroke risk with over 190 events in the
• 48:50
  trial.
• 48:51
  So if you look at the overall mace, the extended mace, the heart failure mace, there is actually
• 48:57
  once again a 0.01 benefit in terms of Omicam to McCarbel.
• 49:02
  So I agree the briefing document and then the discussion was really driven by certain
• 49:07
  issues that I'm not sure were as constructively discussed or is relevant to the overall discussion.
• 49:17
  Well, let me just bring in the other point, John, that I mentioned and you were caught
• 49:24
  up on also.
• 49:26
  And that is the idea that Verisiquat, which would be another drug in more or less the
• 49:31
  same space of advanced heart failure patients, went through.
• 49:36
  So was it that there was not a detected safety signal that the FDA was concerned about?
• 49:44
  Because as we looked at the risk ratio, at least the primary outcome, p-value, et cetera,
• 49:51
  were pretty similar.
• 49:54
  So there have been multiple changes that have gone on at the FDA in terms of people involved
• 50:00
  in the different programs and things.
• 50:02
  There have been other things that have occurred, such as with the Alzheimer's drug.
• 50:06
  So there's a change in the environment there for one thing.
• 50:10
  The second thing was, and Dr. Stockbridge led the meeting off with us saying that, well,
• 50:16
  with Verisiquat, there was a non-significant 7% change in beneficial change in cardiovascular
• 50:23
  death, which is a p-value of 0.12.
• 50:27
  And Omicam to McCarbel did not have that.
• 50:30
  It was neutral.
• 50:31
  It didn't save lives.
• 50:33
  It didn't hurt people.
• 50:35
  So that was the distinguishing characteristic that Dr. Stockbridge started the meeting off
• 50:41
  with that kind of difference to try to actually take Verisiquat off the table as a comparator.
• 50:47
  Yeah.
• 50:48
  I think that's...
• 50:49
  Is that fair, Chris?
• 50:50
  I think that was accurately described.
• 50:53
  Well, or was the difference simply Chris O'Connor?
• 50:57
  No, I don't think it was Chris O'Connor.
• 51:01
  But look, we've brought up a lot of important issues today.
• 51:06
  I wasn't allowed to speak, folks.
• 51:08
  I was not allowed to speak at all.
• 51:11
  You're a government agent.
• 51:12
  I'm a government employee.
• 51:13
  I shouldn't do it.
• 51:15
  And maybe that's something we should look into too.
• 51:16
  I'm not sure why government employees in different branches can't speak.
• 51:20
  I meant for a Victorian, Chris.
• 51:22
  No, I know.
• 51:23
  Well, that's why I gave John my time.
• 51:27
  And John used it well.
• 51:29
  John used it well.
• 51:30
  You clarified a lot of good things, John.
• 51:32
  Thank you.
• 51:33
  But this panel has raised a lot of issues amongst all three ad comps.
• 51:38
  And we've come up with a few important, I think, suggestions, some ways that we can
• 51:44
  maybe improve the ecosystem.
• 51:46
  That's the goal of the Heart Failure Collaboratory.
• 51:48
  How can we improve the ecosystem?
• 51:49
  But I just want to personally thank each and every one of you for taking time out today.
• 51:53
  Joanne from sunny Florida there with the palm trees and making us all envious of where you
• 52:01
  are.
• 52:02
  But for this component of Heart of the Matter podcast and collaboratory, I want to say thank
• 52:07
  you.
• 52:08
  I've learned a lot and I think our audience has too.
• 52:10
  So have a great day and we'll talk again.
• 52:13
  Thank you.
• 52:14
  And have fun