Ep. 12 What does “No” mean to FDA?

Decoding the message of Intercept’s Complete Response Letter

Former FDA Director Brian Harvey joins the Surfers to discuss what obeticholic acid’s rejection might mean for other NASH medicines in development. Is this the end of accelerated approvals? Does it simply mean we need better drugs? Join the debate


Hey everybody. This is Dr. Brian Harvey, your in-the-trenches regulatory guy, and you’re listening to Surfing the NASH Tsunami.

Drug developers, investors, researchers, and corporate executives wrestle weekly to understand what is happening in commercial development of NASH medications. Join hepatology researcher and key opinion leader, Stephen Harrison, C-suite veteran, Peter Traber, and forecasting and pricing guru, Roger Green as they discuss the issues affecting the evolving NASH market from their own unique perspectives on this week’s edition of Surfing the NASH Tsunami.

Roger Green (00:39): For everyone with an interest in NASH or more broadly in fatty liver disease, surf’s up because episode 12 of Surfing the NASH Tsunami starts now.

Roger Green (00:46): When we started doing this podcast three months ago, one of the things that was important to us was that we could have timely and critical conversations as they arose about NASH drug and diagnostic development. Well, there hadn’t been many bigger stories in the past three weeks than what happened Friday afternoon when FDA released a complete response letter indicating that Intercept’s product, obeticholic acid would not be coming to market anytime in the near future.

Roger Green (01:10): We’ve thrown out the agenda that we had in mind for today and this is what we will be talking about. We have Peter here, we have Stephen here, and we’re being joined by Brian Harvey. Brian, tell us just a little bit about yourself and we’re glad to have you with us today.

Brian Harvey (01:22): Hi. Well, thanks so much for having me. My interest in NASH is long before it was called NASH. I got my PhD in Lipid Biochemistry back in the early ’80s, and then got out of the lab and went to medical school, did an internal medicine internship and residency up in Boston. Then a gastroenterology, hepatology fellowship at Johns Hopkins. Got wooed to the FDA where I was first in devices, then biologics, then drugs.

Brian Harvey (01:48): After my time as GI division director, 2005 to 2007, I went on to Sanofi-Aventis as FDA liaison, and then VP U.S. Regulatory Strategy at Pfizer. I have been an independent consultant since then, 2015, but also spent some time as a board member of the Global Liver Institute, and now an Entrepreneur-in-Residence at Yale.

Brian Harvey (02:12): But I’ve loved the NASH space for many years from the basic science side, the clinical side, and now the regulatory side, and glad to be here today.

Roger Green (02:22): Thank you. And Brian, we’re thrilled to have you. I anticipate eagerly some of your comments and how they will align with what others are saying. One more thing just before we get started. As I mentioned last week, we were getting ready to start a segment called Patient Week, which will have questions you raised with us, or coming on and talking to us, or other people talking about patient issues around the disease.

Roger Green (02:41): If you have a question about yourself, anyone you love or the disease in general, please be sure to either hit the button on the HepDynamics webpage, or to send a question directly, send a question to surfingnash.com. We will run it on the air. We might even bring you on with us if you’re interested.

Roger Green (02:55): All right, let’s get going. Best personal thing that happened to in the past week. Stephen, why don’t you go first?

Stephen Harrison (03:00): Despite COVID, my family is all coming to Texas for the 4th of July and we are going to be together for the first time in a long time. So we’re all going to try to stay socially distant, wear masks, do that sort of thing. They’re coming from a low prevalent disease State to one that is a little bit higher prevalent here in Texas, but we’re meeting out in the middle of nowhere. We’re in a county that actually has only eight confirmed cases. So I think we’re all good, but I’m looking forward to that time together with family, over the 4th.

Roger Green (03:32): Fantastic. Thanks Peter.

Peter Traber (03:34): Well, Stephen stole my personal anecdote, but given that it is Independence Day, we may all be doing similar things and we have the same situation. We have family coming from many parts of the country to be together on the 4th of July. I’m doing something that I’m really excited about, which is I’m roasting on a barbecue a whole pig weighing 100 pounds for our family on 4th of July.

Stephen Harrison (04:01): That sounds so Texan.

Roger Green (04:04): Brian, why don’t you go ahead. What’s your personal?

Brian Harvey (04:06): Okay. Well, I got to be up close and personal with the health care system. I was due for my periodic colonoscopy, and so I got tested for COVID-19 last Thursday with a nasal swab, tested negative. Then I got to quarantine over the weekend for my Monday morning colonoscopy. And as I was going in, I got the news about the Intercept complete response letter.

Brian Harvey (04:31): So when I was in recovery, I said, “I had the worst dream. I dreamt that Intercept didn’t get approved for NASH.” And they go, “Wasn’t a dream.” So that was my reintroduction to the news, but at least I’m negative, and so I’m trying to increase the denominator when it comes to COVID-19.

Roger Green (04:50): I guess my personal is, we lost my mother-in-law three months ago and she was very committed to the town she lived in, which is a town of working class people. And she’s also hoarder, a knee hoarder but a hoarder. So we did the first half of the estate sale last Saturday. Sold a whole bunch of stuff, not for much money, but watch people leave who were really excited because they could never afford what they were able to take out of the house.

Roger Green (05:14): And knowing what that was going to mean for them and their families was fantastic. A wonderful experience and great people. We’re going to spend the 4th of July weekend replicating this experience, and then really getting to know and love dumpsters.

Roger Green (05:24): To move on to the main topic, which we’ve all alluded to, on Friday afternoon, FDA issued a complete response letter on Intercept’s agent, obeticholic acid or OCA saying in part that the drugs, “Predicted benefit remains uncertain,” and not a sufficient one weighing against the drug safety issues. In the pre-conversation, we all made the point that nobody except FDA and Intercept has actually seen this letter. So we would be guessing what it said.

Roger Green (05:48): But what it implies is the very least is that Intercept will have to do some additional work before approval. Needless to say, the decision sent shock waves to stakeholder community that anticipated OCA would be our first launch. Some of us as we were standing up, some of us as we were coming out of anesthesia, I guess.

Roger Green (06:04): Interestingly enough, in the financial markets, there were speculation on what this would be for Intercept, even more speculation on what it would mean for future development on NASH drugs. Today, we intend to address both questions. I want to start by throwing simple question out to the group, which is, what does the FDA action and letter imply about obeticholic acid and extension about Intercept?

Roger Green (06:25): Do you think OCA will ever come to market in the U.S.? If so, when? What has to happen first? Whoever wants to start just dive in.

Brian Harvey (06:32): This is Brian. I can only answer one or two of your questions because the question is, when, I’m not sure about that. But I think the Intercept drug will be the first drug approved. First of all, I was heartbroken to hear about the complete response letter because I know how hard Mark and his team have worked at Intercept over 10 plus years to try to get this product to market.

Brian Harvey (06:54): But I think they’ve been caught in a change that’s come about because FDA, unlike anybody else, gets to see all the data. And that’s something I knew when I was GI division director years ago, not all data gets published, not all data get shared. And I don’t think the horse is quite out of the barn yet because FDA hasn’t approved anything, and I think that this action is more about the FDA division, the new hepatology division expressing their concerns over the concept of accelerated approval.

Brian Harvey (07:30): I don’t think any of the end points, whether they be histology, or biomarkers, or MRI, or fibroscan, I don’t think anything has come close to being a surrogate or an intermediate clinical end point is likely to predict clinical outcome. And there’s been so much focus on something getting its accelerated approval, our brain has forgotten that that comes then as a contract of having to succeed in a phase four trial where you actually are able to show real clinical outcomes, real clinical end points, having efficacy to then convert it to a traditional approval.

Brian Harvey (08:10): And in theory, at least based on the law, if you don’t meet that standard, FDA has the right to withdraw the approval like they did with the breast cancer indication with Avastin. So I think the nightmare scenario for any regulator is to accelerate approval, have that happen, and not be able to get it over the finish line. And although it’s not part of their purview, I don’t think payers will be that thrilled to be able to pay for a drug just because someone goes from an F3 to an F2.

Brian Harvey (08:47): And I don’t think patients’ quality of their lives would be necessarily improved by having that or decrease in their fat content. So, I mean, a little bit provocative, but I think in some respects, by not approving this under accelerated approval, they then don’t set that as a de facto standard. Everyone else now will have to actually study real clinical end points, whether it be all-cause mortality, or MACE 3, or MACE 4, or MACE 5, hospitalizations, et cetera.

Brian Harvey (09:20): And I think that ultimately Intercept will come on the market because since they’ve done such a good job with their seamless phase three to phase four, when I hear that FDA has asked for “Additional analyses,” I think they want to hear about the real clinical data. What have these patients done? And are there any things that can be gleaned from the database looking at traditional clinical end points in order to approve the Intercept drug as a traditional approval and not an accelerated approval?

Brian Harvey (09:55): So it was still going to be the first, but it’s just not going to be in the timeframe that some of us expected.

Stephen Harrison (10:01): Brian, this is Stephen. Let me just kind of… And I appreciate your thoughts on that, the color that you bring having been a director there and where you sit today is an interesting perspective. A perspective from somebody that’s “boots on ground,” living this day in and day out, enrolling patients, advising companies, and seeing, and meeting with the FDA on a regular routine basis, I have a couple serious concerns with what you said.

Stephen Harrison (10:29): Number one, the FDA gave Intercept breakthrough designation status. They met with them who knows how many countless times along the way, from they’re into phase two meeting through the development of their statistical analysis plan, protocol development, approval by the FDA. And they were told, “If you meet these end points, you will be granted Subpart H approval.” In other words, conditional approval to move forward into phase four.

Stephen Harrison (10:59): And nowhere along the way did a red flag go up to say, “Oh no, I think we’re rethinking our thoughts.” There was never an ad comm that was had to discuss this. It literally was a landmine that was stepped on in the middle of the night that said, “Whoa, we’re sending a CRL on this because of some nebulous reason of we just don’t think we have enough data to support the drug outweighing the potential risk of the drug and we need to analyze this further.”

Stephen Harrison (11:31): So if they’re going to do away with accelerated approval, I can tell you that this disease marches at a rate of about one State every seven years on average. Granted, uh, that, the rapid fibrosis progressions, we don’t fully understand who those are, but we know diabetes is part of that contingent.

Stephen Harrison (11:49): Having said that number one, killer cardiovascular disease, number two all-cause malignancy, number three, liver related death. We’re going after a liver related outcome, not a MACE outcome, not a CV outcome. Maybe that’s where we’ll ultimately going to have to pivot, but right now we’re working through the hepatology division, we’re going after a hepatology outcome. That takes a long, long, long time.

Stephen Harrison (12:12): In fact, even rolling a large contingent of F3 patients, which are the first to usually cross the finish line into cirrhosis, that’s going to take a while to show. And I think that one of the things that galvanized interest in the field of NASH, and I’ve studied this disease back when it wasn’t cool to study this disease.

Stephen Harrison (12:34): When I was a fellow in 1999, I looked at Vitamin E and Vitamin C, and then Orlistat. Then I looked at pioglitazone, and pioglitazone plus Losartan, all these repurposed medications. And the reason people were interested is because there was no defined endpoint that could be met in a realistic time point. And when the FDA came out with their new guidance, then you saw people jump on board.

Stephen Harrison (12:59): So I think it’s a bit of a travesty that we’re having to have this discussion today. And I think it’d be even more of a travesty if they remove accelerated approval from this process.

Brian Harvey (13:11): One of the things that I react to is first of all, it’s not as if the FDA granted accelerated approval and now removed it because accelerated approval is not a regulatory precedent until it’s been approved. Any sort of discussion, or meeting minutes, or guidance documents, it’s all just words to help guide a sponsor. It’s not until FDA ultimately approves something that it becomes a precedent.

Brian Harvey (13:41): I was shocked and this was unexpected. However, the bottom line is there are many companies who can’t even meet the bar that Intercept met. We’ve had discussions about other failures at Phase 2B and Phase 3 and FDA gets to see that data. FDA gets to see all those CRLs and perhaps there was more than we understand. Perhaps that FDA is giving us some tough love of everything they’ve seen that we don’t quite know yet.

Brian Harvey (14:12): But that’s the batter of faith on my part, and that’s when FDA actually accepts the accelerated approval pathway.

Peter Traber (14:21): I want to make a couple comments extending some of the things that Brian and Stephen have said. First of all, I think that this is a very inauspicious debut for the new hepatology section of the FDA. The process was not what I think investigators or the public should expect. There was PDUFA date and an advisory board date that were both delayed. Understandable because of COVID and so forth.

Peter Traber (14:51): Advisory board meeting that was postponed and a PDUFA date, which I think last week we talked about was likely going to be extended. And instead of having an advisory board meeting on the very first drug that’s coming forward for approval in NASH, they came out with a CRL. I think that that may be… It’s not unprecedented, but it certainly is irregular, and I think that is something that’s disturbing to the entire field.

Peter Traber (15:20): The other thing is that it’s very clear that the FDA is uncertain about the endpoint of a one stage reduction in fibrosis, and for the reasons both Brian and Stephen have mentioned. And I think that would have been a much better conversation with an advisory board than a complete response letter that nobody gets to read except the company and the FDA.

Peter Traber (15:47): The FDA has gone through this process with NASH cirrhosis where originally they said that they would agree except for an accelerated end point, a reversal of cirrhosis. Meaning going from stage four to stage three, which was also a one stage reduction in fibrosis, and then the full endpoint being outcome.

Peter Traber (16:10): They removed that and said, “Now there are no surrogate endpoints for NASH cirrhosis and you have to show outcomes.” So it appears to me, although we can’t be certain because we don’t have any of the primary information and there’s been no discussion, it appears that the FDA is moving in that direction with pre-cirrhotic NASH. I concur with Stephen that that would be a really big challenge for the industry.

Peter Traber (16:36): The only caveat I would put in there is whether they continue to accept as a clinical outcome progression to cirrhosis because that might be an endpoint that could be utilized because there is a significant rate of progression to cirrhosis with say, stage three disease. But if they back off on that as a clinical endpoint and go with actual clinical endpoints of how the patient feels, functions, and survives, then it’s going to be a big problem for the field.

Peter Traber (17:10): I’m a bit dismayed by the approach that the FDA has taken during this review and sending the CRL. And I am concerned about the future because of the uncertainty of what they meant by this CRL. I would also just end by saying, I mentioned this when we talked about this before at the end and so did Brian. The FDA gets to look at all the primary data and they do all kinds of analyses that you’re not going to see published by the company.

Peter Traber (17:44): So we don’t really know what they saw in the data set and that’s where an advisory board would have been advised in this situation.

Roger Green (17:54): Stephen, you have something you wanted to say next?

Stephen Harrison (17:56): I don’t know if you guys were able to listen to the Intercept conference call that happened in response to the CRL. Dr. Pruzanski did most of the speaking there. He did mention something that I want to clarify. He mentioned that Intercept believes that the efficacy goalpost at the FDA may be shifting and that’s not quote unquote, that’s just paraphrasing. I think it’s important to note that we have no guidance from the FDA that they’ve shifted the endpoints for Subpart H approval.

Stephen Harrison (18:27): That has not been made known to me and it’s not public as far as I’m concerned. I think as of today, we’re still operating under the standard guidance, it’s out there. That there are two ways to achieve Subpart H approval and things haven’t changed. I just want to make that clear just to clear up any confusion that might be out there.

Brian Harvey (18:48): I agree totally with Peter, but I think there will be an advisory committee. I think during the next cycle, I think you will see an advisory committee meeting with robust discussion on all sides. And I think that will be a better informed committee when Intercept comes back with some of these analyses, which I believe will show clinical data, and clinical outcomes, and whether it be hospitalizations, or progression deliver transplant, or all these other things that they can scrape together.

Brian Harvey (19:22): Although it’s in a post hoc or ad hoc manner, I think that’s going to be informative data on real clinical end points. And I think that’s going to be part of the discussion during the advisory committee during the next cycle, which will lay the foundation for the Intercept drug being approved under a traditional 505(b)(1) NDA approval.

Roger Green (19:45): If I can interject, whenever I find myself listening to conversations like this, I’m struck by the gap between how the world works outside the agency and how the world works in the agency. I had an experience a year-and-a-half ago with another client with an ultra-orphan drug where for a variety of reasons, it was going to be impossible to do a study in less than maybe 11 or 12 years, but the mortality rate for people with the disease was over 50% on first event.

Roger Green (20:10): In the end, despite the fact that the agency accepted the filing based on a study with this sample size and a secondary, in the end, the drug was not approved and then rejected again on appeal because the sample size wasn’t high enough. The p-values were only 0.7 or 0.8 and the agency decided not to look at the secondary supportive data. All this was known going in.

Roger Green (20:30): So I know in the interim it moved to a different group in FDA, but commercially, FDA has the right, I understand to change its mind, it doesn’t have to operate in full clarity. But Brian, one of the things I would have liked about seeing an advisory board now is that there are a whole bunch of other people out there developing a whole bunch of other drugs who are fundamentally left befuddled by this discussion in terms of knowing exactly what they need to do next.

Roger Green (20:52): Or whether what they think they have to do next is actually going to work, or what they’ve been told they have to do next is going to work. It’s always struck me that if you can get out of the agency and into the light a little bit, which is what advisory committees are supposed to do, it becomes a little clearer to everybody what happened. No one has seen the CRLs, no one knows exactly what the story is.

Brian Harvey (21:08): And I think your story is instructive, but also how you’ve described it. As you know, from the 1983 Orphan Drug Act, there is no such thing as ultra-orphan, which sponsors love to talk about. An orphan is an orphan, but also the level of evidence is not any less. It’s not as if you get a free pass. And when I was GI division director, we also had the inborn errors of metabolism and I was able to approve Myozyme for Pompe disease, and that was on a 20-patient study.

Brian Harvey (21:42): And it wasn’t accelerated approval, it was a full approval because all 20 patients survived out to two years, and based upon historical data, they should have all been dead by a year or so. The regulations allow it when there are motivated folks at the agency to do it, and then with ELAPRASE, which was around the same time for Hunter syndrome, which is an MPS disease, we required 100-patient study.

Brian Harvey (22:11): They said, “We’re ultra-orphan,” but we said, “If you want to get approved, you got to have enough power.” And they did the study, they got a significant p-value, they got approved. This was in 2006. All the other MPS developers whined and complained, and here we are now 15 years later and ELAPRASE is still one of the few that have been approved.

Brian Harvey (22:32): So if the sponsor is motivated, you can find the patients, you could do the study. 100 is not that many, but it just shows that whining and complaining is not a regulatory strategy because it hasn’t worked in the rare disease space, and it’s certainly not going to work in such a prevalent disease that’s epidemic, that is NASH.

Roger Green (22:52): I think I’m making a different point. I’m not talking about whining or complaining, I’m talking about consistency. Whether people whine or complain about inconsistency, well look, those are the breaks. Agency makes the rules, everybody has to figure out how to play. But inconsistency has a cost to patients and consistency has a huge financial cost-

Brian Harvey (23:09): Oh yeah.

Roger Green (23:10): … and it slows up progress. That’s what I’m talking about.

Brian Harvey (23:14): Yeah. But I can –

Roger Green (23:15): … inconsistencies don’t whine, it feels to me like it’s not answering the same question.

Brian Harvey (23:17): Yeah. Well, and I think FDA now is trying to be consistent and they don’t want anyone approved under accelerated approval. And I think the ultimate irony is that that original paradigm with histology came not out of FDA, but it came out of a publication from NIH from 2011, and that’s what was adopted in the initial guidance. And whereas the more recent guidance, where there was no entertaining of accelerated approval, I think was more informed.

Brian Harvey (23:50): And the ultimate irony is when I left the GI division in 2007, I was the last GI person there who trained in GI hepatology. Then it’s only been more recently that card-carrying hepatologists have joined the division. So what we’re seeing now is the result of having what Janet Woodcock envisioned, some centers of excellence, some expertise.

Brian Harvey (24:15): And it’s interesting that the outside world was happier when we didn’t actually have the GI experts, when the division was run by an oncologist. And now it’s being run by hepatologists and gastroenterologists, pediatric gastroenterologist, and we’re not happy with the outcome. So I’m not surprised they’re changing course because we actually have people from academics who have spent their careers in hepatology, and now they’re applying those perspectives to the regulatory process. There’s a touch of irony there.

Peter Traber (24:50): I’m not sure that the… You know, one of the things I would differ with you is that the agency is now showing consistency. I think that they have basically thrown everything up into the air with this CRL. Now, sure, they will have an ad comm, but it should have come before this CRL was put out there. Because now everybody is running around trying to figure out what the heck this means and they use the ubiquitous benefit-risk ratio.

Peter Traber (25:22): Well, there is no equation for a benefit-risk ratio, you’ve got to hear the data. Now let’s be clear, obeticholic acid has some warts. It increases cholesterol, LDL cholesterol. It has very quite severe pruritus in a high percentage of patients. It may cause gallstones, it may cause pancreatitis. But there are safety concerns and it may be that the safety concerns outweighed what they saw in the benefit.

Peter Traber (25:56): But we have no idea about that because there’s been no discussion about it. And I think that that’s not fair to an entire industry, and an entire group of patients and investigators who are out there trying to figure out how to bring drugs to the market. So that’s one of my points. We just don’t know, and frankly, it appears that Stephen may be right. They haven’t backed off an accelerated approval.

Peter Traber (26:27): We’re surmising that they have, but they may not have. We need to understand that. And I think it’s just a core approach.

Stephen Harrison (26:35): Based on what I’m hearing from Brian, let’s do a thought experiment. And this is having to do with whether we keep accelerated approval or we get rid of it. There’s nothing in what has come out yet that says that agency is still not considering accelerated approval, so I just want to make that point clear. Whether they do ultimately or they don’t, it hasn’t been made clear yet. So under that assumption, a thought experiment.

Stephen Harrison (26:59): Peter’s already talked about some of the quote, unquote “warts with the drug,” and there are certainly issues related to LDL, pruritus, gallstones, whatnot. However, I’m going to focus more on the efficacy side. There is no doubt that there are issues with placebo response. You saw a high, high placebo response with Genfit. You saw a low placebo response with selonsertib and obeticholic acid. It’s all over the map.

Stephen Harrison (27:25): There’s lots of inter- and intra-observer variability. We dropped a paper and JHep this week talking about liver biopsy heterogeneity and variability. We know the biopsy itself is very heterogeneous. We’re only taking 150,000 of the liver. All those things are important. Given that, then what about this? Let’s simplify the paradigm. Let’s make it easy.

Stephen Harrison (27:45): The first question I would ask the agency is, do you believe that fibrosis is linked to outcomes? There’s plenty of data, Taylor et al. just published a med analysis on hundreds of patients showing a link to both morbidity and mortality. And so if you believe that to be true, then delaying progression of disease or reversing disease should by default achieve that outcome. Doesn’t mean you don’t drive toward that outcome in Phase 4, but you should be able to approve on that outcome of a one-stage improvement in fibrosis without worsening of NASH.

Stephen Harrison (28:20): There’s not a lot of variability around fibrosis. There is some, but it’s not as much as what you see we’re trying to get at the components of NASH, the ballooning degeneration and the inflammatory component. Make it simple. Get rid of NASH as an end point. Focus on fibrosis improvement without worsening of NASH. And to add validity to that, you overlay it with artificial intelligence where you ask a computer to tell you about the fibrosis and the collagen deposition that’s present.

Stephen Harrison (28:55): We have very good studies now linking that AI to histo-pathology. So if you want to see data, that data exists. Now, you make it very simple. And the people that are studying drugs that predominantly affect mechanism of action related to metabolism, shouldn’t need to be concerned because there’s plenty of data out there now showing, if you get the fat and the inflammation out of the liver, and you give it enough time, fibrosis will improve.

Stephen Harrison (29:23): Simplifying this paradigm and making it easier, then allows everybody to have a level playing field. We take the eyeball of the pathologist out of the picture a little bit. One of the most famous pathologists on the planet in NASH basically made this comment. He said, People consider us to be like analytical chemists, that we should be able to differentiate down to the finite level.

Stephen Harrison (29:45): Unfortunately, pathology is an estimation, not a quantitation, similar to many fields in medicine, that observed variability like endoscopy and imaging and that sort of thing. If we can do that, I think it makes that part of the equation much more simple and allows us to maintain accelerated approval.

Brian Harvey (30:04): I have one more thought experiment. Let’s say that the past couple of days didn’t happen, FDA approves the Intercept product. They approve all the other products under accelerated approval. Then at the end of your career, you leave your current position and you become hepatology division director. Then the outcome studies, data comes and all of these drugs that were approved under accelerated approval, none of them show that there was any impact on any significant clinical outcome.

Brian Harvey (30:38): So now what do you do? Do you leave them on the market? Then how do you respond to criticism that billions of dollars have been spent on these drugs and didn’t help anybody, which Senator Grassley calls you up to the Capitol Hill for the hearings.

Roger Green (30:52): What’s the realistic probability that that happens by the way?

Brian Harvey (30:55): I think there’s a real possibility that you can show on histology and improvement, and patients still die because of CV or GI related events, not unsimilar… Remember the Helsinki Heart Study where they were able to lower cholesterol and they showed a reduction in CV-related mortality, but not all-cause related mortality.

Brian Harvey (31:24): I know Peter remembers that with the fibrates. That had people scratching their heads. So there was something that sure had a really positive effect on cholesterol, but it wasn’t able to show a reduction in all-cause mortality. So I don’t think it’s a stretch to think that it might be difficult for some of these drugs to actually have positive outcomes study done.

Roger Green (31:44): This is my thought experiment. I want simple answers from you guys. Yes, no, 1 to 5 word explanation, but if it goes over a sentence, it’s too much. If OCA had a significant impact on NASH and the same result on fibrosis, would this have happened? Peter.

Peter Traber (31:58): Yes.

Roger Green (31:58): Stephen, would this have happened?

Stephen Harrison (32:00): Yes, because of the magnitude of the effect relative to AE.

Roger Green (32:05): Okay. Come back to that in a second. Brian, would that have happened?

Brian Harvey (32:07): Yes, because it has nothing to do with OCA. It has to do with the disdain for the accelerated approval mechanism by FDA staff.

Roger Green (32:16): Okay. Let me step this up. Okay? If the effect on fibrosis occurred in 40% of patients instead of 23% of patients, and there were effect on NASH, would this have happened? Peter.

Peter Traber (32:28): Possibly, but probably not.

Roger Green (32:30): Stephen.

Stephen Harrison (32:31): No. It would not have happened.

Roger Green (32:33): Brian.

Brian Harvey (32:34): Yes because FDA still wants to see real clinical endpoint.

Roger Green (32:39): So that’ll take me to where I want to spend the rest of this conversation, which is, if I’m developing a drug right now, what do I do? I know, everyone I know is scratching their head with this question this week, so what do I do? What are the two or three guideposts I need to use going forward?

Brian Harvey (32:54): I say you go to the FDA website and you go over the transcripts of the advisory committees and diabetes where Steve Nissen and others talked about assessing cardiovascular risk for the diabetes agents. And you look at the endpoints that they use for those and you develop a clinical trial where you have easy-to-measure end points like MACE, classical-3 MACE or other end points and base it on that. Because you should measure what’s easy to measure.

Brian Harvey (33:25): It’s not unexpected that there were 100 drugs approved for blood pressure because millimeters of mercury were an easy end point to measure. And where things are more difficult to measure, FDA has a tougher time.

Stephen Harrison (33:37): If you went that route and there are companies in the NASH space that are doing exactly what you outlined, then you don’t need the hepatology GI division. You need to go to metabolism, you go to CV renal, Bob Temple, those guys because-

Brian Harvey (33:51): Yeah.

Stephen Harrison (33:51): … at the end of the day, you’re talking about a MACE outcome, not a liver related outcome. You could give two hoots in Hades about whether the patient develops cirrhosis, decompensation, transplant, liver cancer, death. All you’re focused on is cardio –

Brian Harvey (34:05): Is death, yeah.

Stephen Harrison (34:07): … is the outcome, which is an issue with fatty liver. But if you do that, you don’t need to make a diagnosis of NASH. All you need to do is a FibroScan, or MRI, or a CT, or an ultrasound that shows you have fatty liver, and then you’re in the game. The problem with that is if you want to show this in a reasonable number of patients in a reasonable amount of time, you have to do similar to what the other CV outcome trials had done.

Stephen Harrison (34:34): You’ve got to take people with renal disease, with prior CV disease. They’ve had an MRI, they’ve had a stroke, they’ve recovered, but their kidney function is poor. They’re diabetic and they have fatty liver. And that’s what’s going to get approval at the end of the day because the FDA approves claims, not drugs.

Stephen Harrison (34:51): So how are we going to ever get a drug into the hands of somebody that say my age, 51? I don’t have fatty liver, thank goodness, but let’s say I do have fatty liver. Let’s say I’m a pre-diabetic and I know ultimately that my dad died of cirrhosis, my sister died of cirrhosis. They don’t drink, they didn’t have viral hepatitis. They clearly had NASH that progressed rapidly. So I’m just left in the lurch because I don’t have a mechanism to get approval.

Stephen Harrison (35:19): So I think we have to be very pragmatic about it. Either we’re going down a CV outcome track, or we’re going down a GI outcome track. Right now, I don’t know what to do with that.

Roger Green (35:29): That’s of course, before you get to the data that’s says, that’s starting to suggest that it’s possible simple fatty liver has a relation to COVID, how do you go down that track? Peter, go ahead.

Peter Traber (35:37): To your question of what do you do if you’re developing NASH drugs? My tongue-in-cheek answer is, think about investing in bariatric surgery because we know that works in various stages of NASH. But the more serious way to look at this is when these type of events happen, we tend to lean towards the apocryphal. And what I would advise companies is to take the signals that we’re getting from the FDA.

Peter Traber (36:08): And hopefully we’ll get more clarity on their view of things and think a bit out of the box about how we can best link outcomes to earlier measures, and think about clinical trials that include outcomes. Now, what that means is that you’re going to have to have a pretty robust drug and you’re going to have to have a good financial support to be able to bring that about. But if that is the case, in other words, that the FDA is moving towards eliminating surrogate endpoints, it’s going to put up quite a pale on the industry, but it’s going to be those creative people that can see how to move things forward in that environment.

Peter Traber (36:52): But it is a very challenging issue, I think as Stephen has stated.

Brian Harvey (36:57): I’m looking at my crystal ball and I think that it’s going to take maybe three or four months for Intercept to resubmit. Then of course that means there’s a six month review on a resubmission. So we could be having an advisory committee meeting this fall, COVID-19 willing. And I think in the meantime, that draft guidance from 2018, which is still draft may either be revised or withdrawn, and then we’ll see what the advisory committee says. So that’s what my crystal ball is telling me.

Stephen Harrison (37:31): Well, I don’t have a crystal ball. I guess I’m just trying to be real about it. I have patients enrolled in all these trials and they’re ringing my phone all the time. “What’s the latest? Where are we at? What’s going on?” I think we need to know if we’re going to continue this trial or not continue the trial long before nine months from now. And so that’s like #realtalk. That’s something we need to know.

Stephen Harrison (37:55): The other thing I would say is the FDA needs to come around with some clear messaging real quick, like this month, July. “This is why we did what we did. This is our thoughts.” If they need guidance, if they’re requesting input, then myself and others that study this every day are more than happy to convene a working group to help resolve the issue so that we can get back to an accelerated approval platform. I’ll hammer that until this podcast is over, if we move away from that, we’re going to be in real trouble.

Stephen Harrison (38:30): The other thing I would say is you got other drugs in Phase 3 that are rapidly catching up. And we’re waiting nine months from now, you’re going to have Phase 3 trials that are going to be completed in other mechanisms of action likely, and we’re just waiting for them to wrap up. These guys are all hanging in the lurch now saying, “What do we do? Do we need to meet with the FDA? Do we need to go over our end points? Are they approved already and have another discussion?”

Stephen Harrison (38:57): So I think it really comes down to very pragmatic principle, is the FDA doing what they’re doing because they believe this risk-benefit ratio ultimately that the drug isn’t powerful enough to overcome the noise of the end point relative to its AE profile? If you have an end point that hits 40% fibrosis improvement with no worsening of NASH, or let’s say you hit 40% improvement in fibrosis and you resolve NASH.

Stephen Harrison (39:22): And you have a well-tolerated drug with minimal to no AEs. I think that’s a different discussion, a different discussion altogether. But ultimately that’s my final take on it.

Roger Green (39:32): Peter, go ahead. You were going to say.

Peter Traber (39:34): Stephen makes a very good point about patients and the doctors that are treating them, and what this means for them. I just want to give a C-suite perspective because there are a lot of companies looking to advance drugs into Phase 2B or into Phase 3 and they’re going out looking for funding to do that. And if it’s nine months or 12 months before we get some clarification of what the agency is thinking, those people, and those companies, and those programs are at severe risk and that’s going to be very hard.

Peter Traber (40:13): And also those large pharmaceutical companies that may be looking at acquiring assets and so forth are going to hit the pause button until they figure it out. So reverberations of this decision without further clarification go wide and far both in the industry, with physicians and with patients. And I think it is the duty of the FDA to clarify their position quickly.

Roger Green (40:42): That was great. Brian, go ahead.

Brian Harvey (40:44): Well, in some respects, this is just the next step because in the past year, we’ve talked about failures at Genfit, at Gilead, a number of other Phase 2Bs that have failed and why are they failing? And there’s a lot of speculation. And so in some respects, FDA’s decision is a partial response to that. Yes, it’s nice to have consistency, but if there’s consistency and it’s not going to lead to where you want to be, which is ultimately a drug that gets approved for the long term, it gets paid for in the long term, then perhaps this is the time, this is the inflection point.

Brian Harvey (41:28): And I’m hoping the sponsors will be contacting FDA, and given how important the information is, this would qualify as a Type A meeting, which is a much quicker meeting to get than Type C. And so there are mechanisms in place and I do hope that FDA withdraws that 2018 guidance document, and then that way it will be a clearer signal moving forward. But I think the subsequent guidance with a more advanced disease showed where we were heading.

Brian Harvey (42:00): We might not have realized it at the time, but I think that was the first in many steps. And I think ultimately, we’re going to be in a better place and I really do go to that example with the diabetes drug. And I think partly NASH is a failure of primary care docs or others to not adequately treat diabetes, hyperlipidemia, hypertension because as you watch the commercials on the SGLT2s, an A1C of 7, well, we should be going for six, we should be going for 5.5.

Brian Harvey (42:37): And it’s patients who are undertreated in their diabetes, undertreated with cholesterols and the high numbers, despite being on low-dose statin. Those are the ones that could show up with NASH, and so we failed every step of the way. And so NASH I see is a failure of the healthcare system, and it’s a much bigger issue than just Intercept, which just has gotten caught in the crossfire.

Roger Green (43:03): Okay. You said a couple of things I disagree with, and then I have a comment I want to make, and I’m doing all this with frank acknowledgment, which everyone hears every time they listen to this podcast that my last natural science course was high school biology. Issue number one is if a whole bunch of drugs fail in 2B, that doesn’t mean things aren’t working. That probably means in fact, things are working, particularly if better drugs that do well in 2B start coming up the pipeline, standing on the shoulders on the failures that came before them.

Roger Green (43:31): The way I understand it, that’s how this stuff is supposed to work. You take your first shot, you take a small shot, it doesn’t work, you learn something, you take a bigger shot. So we’re now starting to see some pretty good drugs coming through Phase 2B better than anything that we’ve seen in years past in terms of performance, and that’s kind of how I think, I understand it’s supposed to work and those are the drugs that get to go on to Phase 3, number one.

Roger Green (43:52): Number two, Brian, there’s a bias to bigness in a lot of what you’re talking about. The reality is, and I think Peter made this point from the perspective of C-suite in smaller companies, you have a bunch of smaller companies that really can’t afford to sit for 10 months waiting to figure out what comes out. And I know you said it might not be 10, but you know what? It might be 10.

Roger Green (44:10): Government has no particular impetus to react. I can’t believe that liver disease is going to be a major priority in the election year, and so it might be a while. Might not, but might. So the companies that benefit then are the big companies, but Big Pharma is a lot like Hollywood. They’d really rather than make Rocky 7 meets Godzilla 10 to make an independent film that’s got risk in it.

Roger Green (44:30): So when they stepped into NASH, people thought Gilead, they had to get it right, they know what they’re doing in liver. That hasn’t worked. In fact, Big Pharma in liver has not done well. The better drugs have tended not to come out of Big Pharma. So we could find ourselves in a situation where the innovators who are getting it right get squelched because they’re starving for money while they’re waiting and the big guys would pick them up don’t have particularly good judgment about what works.

Roger Green (44:51): And if you look at what we’ve seen over the past few years, I think that’s as realistic a scenario as any. Last point, if these small threads of data that are starting to emerge in different places about the relationship between fatty liver and COVID turn out to have a reality after there are more data sets, I don’t know how you do a perspective on that, but you’re going to wind up with enough metadata at some point to look.

Roger Green (45:12): Then it may actually be that liver undergirds a whole bunch of problems as compared to those problems are the real thing and we’re only treating NASH because we’re not getting at them. And that may be true for NASH, it may be true for NAFLD. I don’t know enough about the liver to say, I first want to say that. But I am pretty good with data and data suggests that we tend to do what we can measure and no one knows how to measure what’s going on with the liver yet.

Roger Green (45:35): It could be that nailing that measurement as efficiently as we can is the most important thing that we can do right now for this entire area of disease. I don’t I’m right, I don’t know I’m wrong. I haven’t seen anything that persuades me that’s not possible though. And if that were the case, laying a bet on outcomes using established measures created for other classes might not be the best way to deal with the underlying patterns of disease that we’re looking at.

Roger Green (45:59): Finally, just one editorial comment, as a guy with high cholesterol, Helsinki was a problem, but ultimately very, very large trial funded by the government resolved that issue. You’re not going to see that trial again. No one’s going to – the government’s not going to spend $150 million dollars on LRC-CPPT again. So how we get basic science advanced if we’re not doing it in increments, it becomes one more question I’m not smart enough to have the answer to.

Brian Harvey (46:23): My suggestion is a Framingham Heart Study for NASH or being more aggressive in getting the NASH-type end points and characteristics into the next generation of Framingham Massachusetts study. That’s how we were able to make advances in hyperlipidemia, was the underpinning of the epidemiology and not just individual sponsors doing trials.

Roger Green (46:47): Well, how long and how much time will it take to do that?

Brian Harvey (46:49): 20 years.

Roger Green (46:50): How much money will the health system spend on people with liver issues in the mean time?

Brian Harvey (46:56): Well, but you’re assuming that the treatments that we’ll come up with will actually have an impact.

Roger Green (47:02): I’m assuming that they’ll be sloppy, but they will head in the right –

Brian Harvey (47:05): Yeah. How many NASH patients are taking Vitamin E now? And that work was done 25 years ago. I did my GI fellowship ’92 to ’95 at Hopkins and animate deal was treating these patients that later became known as NASH patients. And there was so much focus on these elements and why has it… Very good research that was done and I think people should be on Vitamin E, but all of these things haven’t really translated into changes in primary care.

Brian Harvey (47:41): Vitamin E, talk about a positive benefit-risk, why aren’t more patients on Vitamin E? Why aren’t more patients on Metformin for thee… And everybody has their pet peeves and their view of the data, but it’s the translation from the clinical trial to the actual patient care, there’s been a problem. And like I said, we need more aggressive treatment of diabetes. There’s no reason why somebody should be walking around with an LDL of 150 with everything we have now, even physicians that I know will try diet and exercise for another five years and then they have their stroke.

Brian Harvey (48:23): A lot of people are on low-dose statins, they should be on higher-dose statins, PCSK9 are available. There are other options and that LDL, a goal of 70 should be the standard and not just a wish on the chart.

Roger Green (48:40): That’s too bad. We got mine down in ’87 with rovsuvastatin and I was pretty proud. Brian, this has been fantastic. This is actually what we needed.

Roger Green (48:47): Last question is really, what’s the one thing you heard in the last hour and 15 minutes that surprised you the most? Stephen?

Stephen Harrison (48:56): First of all, Brian, it’s great to have you on the podcast. Your perspective, it’s refreshing and it’s good to hear, but I would say what you said about accelerated approval is very surprising to me and concerning at the same time. You may be right, but I hope that’s not the direction that we’re headed in.

Roger Green (49:17): Peter then Brian.

Peter Traber (49:19): It doesn’t surprise me, but I think it worried me that I would hear from Brian the move away from accelerated end points at all in pre-cirrhotic NASH. I do think that that is a problem, even though there’s a lot of hoopla around litmus and other approaches to identify biomarkers that may link to outcomes.

Peter Traber (49:43): I think we’re still a good ways away from that. So I think that the surprising thing was more how much Brian from a regulatory standpoint reinforced my concern about where the FDA is going.

Roger Green (50:00): Okay. Brian, what’s the thing you heard that surprised you the most?

Brian Harvey (50:03): I guess I’m surprised that my, the colleagues on the podcast here, how they’re still optimistic about this old paradigm, despite the four or five, six failures of companies over the past year. And when I put these points together, I see a straight line away from accelerated approval. But hopefully they will have more clarity from FDA and I think that will happen in a relatively short timeframe knowing that FDA is a slow organization in the grand scheme of things.

Brian Harvey (50:38): Certainly it’s not known for being nimble, but when the recent failures were announced and discussed, that actually had a discouraging effect in the venture capital community, and this is just another step in that direction from my perspective.

Roger Green (50:54): I guess this isn’t a surprise, this is one of the things I believe, the degree to which there’s a dynamic between bigness, which tends to want to be safe and smallness, which is willing to take more risks, but also accept more incremental returns, I don’t know that very many people viewed OCA as a failure until Friday afternoon. Not a great success, but addition first step and a validation that if you did things right the way you were told, you’d get a result that was good enough to help you move forward. And I think that’s everybody’s shock.

Roger Green (51:24): I’m reminded that the kinds of errors that big organizations, whether private, or public, or not-for-profit accept tend to reduce risk, but reduce benefit and are likely to disproportionally reduce benefit at least as often or more often than not. So I think I heard that thought a couple of times today. It didn’t surprise me like I’ve never heard of it or thought of it before, but in the context of this conversation in liver disease, I kind of hope it isn’t that.

Roger Green (51:51): First, I want to thank Brian Harvey for being just a spectacular guest. As he noted before and during the conversation, he was expressing a point of view he understands well, some of which, but maybe not all of which are his own. And we’ll leave you a mystery up for that until the next time Brian comes back and then he could speak as Brian and we’ll see where all that goes.

Roger Green (52:07): I want to thank Peter, I want to thank Stephen and Eric Rounds who’s going to be in charge of making sure everybody hears about it. We will be back next Thursday, July 9th, with our next episode. I can’t tell you right now what it’s about because every time I tell you, it turns out I’m wrong. One more thing, please send questions. We will answer them, we will get them answered, we’ll create dialogues as we need to and we want you to be engaged and be part of what we’re doing here.

Roger Green (52:29): So until then, everybody have a great 4th of July, stay safe, be mindful of the environment we’re living in right now and surf on. Surf’s up, bye-bye.

Speaker 2 (52:41): You’ve been listening to Surfing the NASH Tsunami. Send in your questions to surfingnash.com and our panelists will spend the first five minutes of next week’s episode answering your questions. Visit us online today, surfingnash.com.