Reviewing press releases reporting preliminary findings from six recently announced Phase 2 trials

Stephen Harrison leads the Surfers, with guest Louise Campbell, through an examination of six Phase 2 clinical trials that put forth press releases over the last three months. In all, the discussion created an air of optimism based on better clinical outcomes than we have seen with earlier NASH drugs, all from medicines with distinct but potentially complementary modes of action.

[Listen to Part 1 – Episode 5 – WILD TIMES IN NASH-VILLE: PART 1]

This is Louise Campbell from Tawazun Health 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 (00:00:36): Hi, this is Roger Green and welcome to episode seven of Surfing the NASH tsunami. This week we have with us Steven Harrison and Peter Traber as always and Louise Campbell’s back in the fourth seat to join us. And we have I think a really fantastic program. So why don’t we just dive in right now with some quick personal groundbreakers and then we have lots of stuff to go over. Peter, how about a personal groundbreaker to get us started?

Peter Traber (00:00:57): I would say that personally I’ve enjoyed over the last week getting out in my yard starting to kind of come out of the COVID-19 hibernation and being outside as the summer breaks. And as we loosen up a little bit on hunkering down in place, and that’s been a real mood booster for me and the entire family.

Roger Green (00:01:17): That’s great. Thank you, Louise.

Louise Campbell (00:01:20): For me, it’s the fact that Australia is opening up and I’m resident in Australia and can work out there. That gives me the opportunity to maybe travel back later on in the year to do some more work.

Roger Green (00:01:31): Excellent. Stephen.

Stephen Harrison (00:01:32): The highlight for me was Memorial Day weekend and just reflecting back on all those who gave the ultimate sacrifice for our freedom. And personally, having known many of those soldiers that did that, it was a sobering time but also reflective time and one of being very grateful and humble for the opportunities that are offered for me to be successful in the United States and have the freedom that I enjoy today.

Roger Green (00:01:57): Similar theme, I was recalling… I haven’t thought about it this way in years, but I found myself yesterday thinking about the four high school classmates I lost in Vietnam. And that tells everybody how old I am or at least that I’m old, but those are powerful memories that never go away. You always envision people as they were and then they’re gone. So with that personal groundbreaker some just joyous and some I think sober but all important. I want to go back to Louise first two weeks ago, when we were talking about the clinical trial issues, Louise had a couple things that she wanted to comment on that didn’t get into the conversation. Louise, why don’t you kick us off with two questions that you had in that conversation, please.

Louise Campbell (00:02:33): Questions that I had that I wanted to come back on was when a clinical trial fails, like GenFit did, what is the effect on the patient community? And if so, what… the second question was, do patients consider the difference between phase two, a 2B, a three, when they choose to take part in clinical trials, or do you think this isn’t ever a concern?

Roger Green (00:02:59): From the patient advocate point of view, are these questions that you have experience with or should we just let Stephen and Peter dive in?

Louise Campbell (00:03:06): I think I’d like the guys to comment first, I’ve got some thoughts, feelings related to it. But I’d quite like to get a physicians point of view first.

Roger Green (00:03:16): Great. So first, and Steven is somebody who recruits people into trials in all different phases, what’s your sense about whether they consider the phase of the trial or what they consider actually, when deciding whether to participate?

Stephen Harrison (00:03:26): I don’t think there’s a mindset that’s unique or that is applicable to all of our patients. I think they’re all unique in how they approach clinical trials. Some are really agnostic to the phase of the trial. They’re trusting in their referring provider and they’re trusting in you as their clinical trial provider that you are going to give them an opportunity to take a pharmaceutical that may improve their overall health with a minimal adverse event profile. And then you have some that come in savvy, I call these kind of the Google savvy patients who basically have read a lot about what’s available. They kind of know the difference between early and late stage trials, and they’re very particular about the stage of the trial, the route of administration, the AE profile, the length of the study. Does the study involve a follow up liver biopsy? And if so, how many? How long ultimately, will they be required to be in the trial, particularly if it’s a phase three?

Stephen Harrison (00:04:29): You would think that people would jump all over the fact that it’s a phase three trial last study before going to the FDA for conditional approval, but some people are a little leery of committing to four or five or six year study, which is currently the way that phase threes are designed, you have conditional approval after 12 to 18 months, and then you have a long extension arm where you look for outcomes data, and so people are a little leery of that, particularly because they may wind up being on placebo for many years long after there’s an FDA approved pharmaco therapy agent out there. So I think it’s just really all over the map, we kind of offer a portfolio of studies that kind of fit each person’s unique perspective and personality. I would just close by saying I’m not sure there’s a one size fits all here.

Roger Green (00:05:15): Okay, Steven, thanks. Peter, would you like to tackle the first question about what you believe or have observed the effect of a clinical trial failure to be on the patient community?

Peter Traber (00:05:24): I find that patients are very savvy and prone to read a lot of the commentary on clinical trials. Of course, patient populations are heterogeneous, and you’ll find some that really are just going to speak to their physician about it, but others are going to have read a variety of things. And I do think that when a clinical trial fails, it will be a little bit more challenging to enroll people in the same class of the drug. And certainly if there were follow up studies with elafibranor. It’s just a matter of them reading a lot of the different commentaries, and of course, the first things that come up when you Google something is clinical trial failed. And I think that patients do take that into account, so I think it is harder to introduce patients in a class of drugs where there’s been a major failure.

Roger Green (00:06:17): Okay. Thanks, Peter. So, Louise, you had a couple comments you wanted to add.

Louise Campbell (00:06:21): Well, I was thinking at the last podcast we did for some patients, and I echo Stephen and Peter’s classification of the patients because you do find a huge mix in patients use clinical trials become experts in their field of disease and knowledge and they gain a lot from the nurses and the doctors that they are cared for by. But there is a level of disappointment and frustration within the community, and sometimes fear because depending on your level of disease, if a trial fails, and we’re talking long-term, like Stephen was saying, you may get a sense of where am I going to go next. And I think the important thing is just because a trial fails, it’s actually not the end there are other drugs coming up, there are other options. And I think there are lots of patients who within trials that fail, got a successful outcome, there will be endpoints that were met for some individuals maybe not enough to make the drugs successful and to get FDA approval.

Louise Campbell (00:07:18): But for a significant number of patients, those trials didn’t fail. And I think it’s important that they carry on, and we revisit and go to the next trials, because they get a lot of support and a lot of benefit from being within them. And I think we alluded to that in why the placebo arms of studies may well struggle, because they’re very behavioral trials, and they do like that constant contact the 24 hour phone number, and I think that’s a great reassurance to lots of patients and what are some of the reasons that they participate in trials. So they’re not always failures trials, there is something that comes out of a trial, even if it doesn’t successfully get to market. I think every patient has given a lot of time, effort and commitment to enable that information to make it the best opportunity. So that’s what I was going to say for those points really.

Roger Green (00:08:07): Thanks, Louise. That’s great. And with that, I would like to go on to today’s question of the week which comes in from Neil Harrison. Neil is a medical educator by profession, this is the second letter from him. The first one was several weeks ago to request that we devote a session to talking about the issue of what do you name the disease and to invite a European professor to join us we did last week. So Neil’s letter literally started by saying I don’t know whether it was a request from me a few weeks ago that made you cover MAFLED NAFLD or whether you’ve been planning it all along, but either way, thanks for the discussion, it was a great Listen. Neil, thanks for the suggestion and we had a blast taping it if you had half as much fun listening that’s a wonderful thing.

Roger Green (00:08:47): Neil also had two questions, which I want to share with the group. First, he noted that one of the arguments in the paper involved the effect on clinical trial recruitment. He described the paper and it’s a long quote, so I’m not going to quote, I’m going to summarize suggesting that if you make MAFLD as the term was in the paper, the sole criterion for trial inclusion, you would get more homogeneous trials, which would increase the probability of trials showing clinically meaningful advances. Now at this point, I would notice that we’ve touched on the issue of trial consistency in each of the last two weeks, may wind up doing so a little bit later today. But from there, we can comment on that. But now let’s just take a second and talk on that specific question, Peter, I know that you listen carefully and in fact, have some shift in your thinking over the course of the last week. This point, the one about if you call it all MAFLD, you end up getting homogeneous clinical trials and better chance of meaningful clinical results. Does that make sense to you?

Peter Traber (00:09:38): Well, I think it’s a very good point to consider. However, the name of NAFLD or MAFLD doesn’t really change the inclusion exclusion criteria of clinical trials. Simply what we call the syndrome is unlikely to shift the patient populations that would enter a clinical trial. I’m not sure that the name itself unless the name connotes some underlying difference between the recruited populations, whether we would really see a difference in the placebo response or the drug response. That’s just my initial impression of that.

Roger Green (00:10:21): Okay. Thanks, Stephen.

Stephen Harrison (00:10:22): Yeah, I completely agree with Peter on that one, as we talked about and alluded to in the previous podcast, where we talked about MAFLD versus NAFLD. One thing that Clinton and I really focused in on was this is a very heterogeneous disease, and as mentioned by the question, there’s an acceptance that it’s a heterogeneous disease. But it’s much more than a name as Peter alluded to, maybe with omics interpretation metabolomics, genomics, lipidomics, that sort of thing we’ll be able to refine our population down to a homogeneous group of patients that can then be defined by a particular name. Maybe it’s a subset of quote unquote MAFLED or maybe a completely different name. But I think only at that point will you have the visibility of a homogeneous enough group of patients to really have a name, make that happen for you. Right now, we’re just going from NAFLD to MAFLD and just taking the diagnosis of exclusion, meaning alcohol out of the picture. So I don’t think that a name change at this high level would give me any more homogeneous patient population in a clinical trial.

Louise Campbell (00:11:26): I agree with the guys but I’d also just throw I suppose another confounder in there, we always consider the NAFLD patients, particularly for clinical trials. And our inclusion exclusion criteria is usually based on things like BMI. There’s a significant number of patients with lean and non obese NAFLD who we’re not targeting particularly in some of the recruitment for these clinical studies. And I think there was a good article in The Lancet this week by [inaudible 00:11:55] discussing prevalence and incidence and one of their conclusions was maybe we should broaden clinical trial criteria to include all patients with NAFLD not just a select set of patients above the BMI of X, which may well again confound some of the placebo alarms, but would certainly get a broader range of NAFLD population.

Roger Green (00:12:17): Interesting thought. My snap reaction, having listened to all three of your comments, and also me thinking about what happened the last week here, where a lot of our conversation was about differences in placebo rates. It seems to me that having a broader, more homogeneous population isn’t inherently going to solve that problem. I guess what I’m hearing from all of us is that it’s an interesting point, but this is probably a more complex question than that solution is going to provide a big upside. Anybody disagrees, five seconds to say so? Okay, if not, his final point was that he didn’t want to open up a can of worms, but he noticed that there were no US KOLs who signed on to the paper, Stephen, you want to just take a couple of seconds and talk about that, and then we’ll cover that brief and then go on to the meat of the session.

Stephen Harrison (00:13:02): I mean, that’s very simple. The US KOLs, key opinion leaders basically met and decided that we were not ready for a name change, and we pulled our names off the paper.

Roger Green (00:13:13): Okay. I think that’s straightforward enough speaks to the idea that this will be an ongoing dialogue, because it’s an important thing to get right before anybody moves forward on it. I think I would like to dive into today’s results. As we discussed two weeks ago, the results of the RESOLVE-IT trial, shed a bit of a cloud over drug development in the area, because folks were hopeful that would succeed. The announcement on Friday that FDA has Intercept to reschedule its Advisory Committee for OCA, the later point in time has also I know what some people have used as being a little bit more cloudy. But the message of what we’re about to talk about is that if you go back into the phase two trials, there’s a lot of very, very promising and exciting work being done as we discussed two weeks ago, RESOLVE-IT results are exciting. And Stephen is going to walk us through first three phases 2B trials, and then comparable number phase 2A trials, and what we’ve learned and then the group will ask questions and comment on what it means. So Stephen, let’s take the 2Bs and start there, please.

Stephen Harrison (00:14:08): Yeah, and I think it’s important to keep all this in perspective, the pioneers of any field are blazing new trails. And these trails are fraught with complications with barriers with sometimes what seemed to be insurmountable odds and insurmountable obstacles. And so this is essentially Intercept and GenFit they started their phase three trials a long time ago. And a lot has changed, a lot of water has gone under the bridge, a lot of our understanding of the pathogenesis, the epidemiology, the natural history of disease, and even the heterogeneity of liver biopsy, and the intra and interobserver variability statistics were not fully appreciated at the start of these trials, so everybody’s learning. And we’re learning unfortunately, in some regards at the expense of these two companies. It’s ultimately exciting for the field. And so I look at these not necessarily as setbacks to the field granted, they’re potentially setbacks to the companies particularly resolve it because of the negative interim results of their phase three trial or the subpart H approvable endpoints.

Stephen Harrison (00:15:18): For Intercept, it’s hard to say why AdCom was delayed, some people speculated maybe a result of adverse event management and more data around adverse events and side effect profiles. Others think that maybe this liver biopsy issue that surfaced back with the series data, and maybe now looking at the RESOLVE-IT data and understanding that placebo responses in both those phase three trials were really the driver behind one meeting an endpoint and one not meeting an endpoint, particularly with fibrosis, because both essentially had the same fibrotic response for the drug group. But widely, vastly different placebo responses. So maybe there’s something to that right now it’s just speculation, it’s hard to say what we can say is that as we turn to the phase 2B and the phase 2A data, it looks really, really promising relative to those first two icons that have advanced the field.

Stephen Harrison (00:16:14): And it may be superficial and shallow to say this. But ultimately, while we have a very noisy endpoint, if you have drugs that are really knocking it out of the water, so to speak, on NASH resolution and fibrosis improvement, you overcome the noise. The signal becomes obvious, it becomes easy to see. That is one thing that maybe we’re able to also glean from some of this early data, and with that I’m going to tell you what the date is. We’ve been some amazing press releases recently, and we’re blessed with some really good top line results. We’re also hampered by some of the nuances of the data and that’s intentional. The companies want to really present this in an academic forum. They want to put it out in publication and peer reviewed data. So we’re not privy to all of the nuances of the trial. And so we’re limited in that regard. Having said that, I’d like to jump right in.

Stephen Harrison (00:17:06): So when I talk about these, I’m going to speak to the 2B’s first, these are paired liver biopsy data sets. Then we’ll go to the 2A’s and we’ll talk about the non invasive endpoints that were used as surrogates to maybe inform us what we’re likely to see on histology, so I have three 2B’s to report on three 2A’s. So the three 2B’s are NGM BioPharm, NGM Bio, and then Novo Nordisk and Semaglutide, and then I’m going to talk a little bit about CymaBay and the independent expert review panel looking at seladelpar as it pertains to the phase 2B NASH study. So just to jump right in NGM Bio press release back in February successful completion of a 24 week phase 2B study, where the primary endpoint was change in liver fat content, the secondary endpoint was clinically meaningful improvement at 24 weeks on fibrosis improvement and resolution of NASH and this was with a one milligram daily injectable dose.

Stephen Harrison (00:18:11): And just to set the stage a 12 week study, an uncontrolled study was done in approximately 20 patients already with paired liver biopsies showing at least with fibrosis improvement about a 25% overall improvement in fibrosis. Again, no placebo group there, so we don’t have a comparator so I can give you a Delta placebo response. But ultimately encouraging 12 week 25% improvement in fibrosis by at least one stage. So what did we find from the trial? Again, primary endpoint was changed in liver fat which was significantly reduced and in line with other studies looking at the FGF19 analog which is I’m sorry, I didn’t describe that NGM’s asset under development is an FGF19 analog, it’s a daily injectable and it works through Beta-Klotho FGFR1c as well as 4c and that has effects on both modulating fat as well as bile acids. And ultimately we know historically bile acids may have a positive impact on fibrosis. So we see primary endpoint met, liver fat content dropped dramatically. And then when we look at the secondary endpoints on histology, and we focus on NASH resolution, it was 24% for the one milligram dose versus nine percent for placebo.

Stephen Harrison (00:19:32): That nine percent for placebo is in line with other studies looking at histology in the placebo group on NASH resolution. When we shift to fibrosis 38% in the one milligram group had improvement by at least one stage versus 18% for placebo that 18% historically had been on the higher end for a placebo response, but we know now from resolve it of 22% that it’s kind of not too far off. We saw also Calmette having a 17% improvement in the placebo group for fibrosis. So that 18% yes, it’s higher than regenerate, it’s higher than stellar three and four for placebo. But it’s in line with some of the other studies that have reported out paired liver biopsy results for placebo as it pretends to fibrosis. Maybe the most compelling point from this entire press release was what we saw on fibrosis improvement by at least one stage plus NASH resolution. And there it was 22% for the one milligram versus zero percent for placebo. And that was statistically significant. Granted, it was a post hoc analysis and a secondary endpoint.

Stephen Harrison (00:20:37): But it set the stage to say no other drug has really raised the bar to the level of showing stat SIG for both fibrosis improvement and NASH resolution, and it makes us excited to see what the three milligram dose is going to do in the Alpine 2/3 study which is a 24 week, paired liver biopsy ongoing study. That looks at 0.3, one milligram and three milligram so we’ll get a look at that three milligram dose in a very similar type setting. So that’s NGM, moving on to Novo Nordisk. Unfortunately, we have even less data here, this press release was buried in a financial report for the company. But what we did here was that this study which was done in 320 biopsy proven NASH patients with F1 to three fibrosis treated for 18 months with several different doses of semaglutide was that on NASH resolution, the high dose the 0.4 milligram group 59% NASH resolution versus 17% for placebo. And approximately 10% or so had a one point improvement in fibrosis that wasn’t statistically significant.

Stephen Harrison (00:21:51): Again, the primary endpoint though was NASH resolution without worsening of fibrosis, and there we see the high dose group having 59% for the drug group, 17% for placebo, and that was statistically significant. Their comment on safety profiles consistent with observe profile and other trials and disease areas, scant data there on safety and tolerability, I think a lot of people had a question there. Now I would say that their data they reported out was really focusing on the 230 patients that had F2 and F3 fibrosis. And that was what was included in the primary analysis. And again, that primary endpoint was NASH resolution without worsening of fibrosis. Question marks for me or overall fibrosis benefit across the group more on not only tolerability of the drug but how many people had the dose reduced, how many people skipped doses that sort of thing. Again a lot more questions with Nova because they’re just scant on data in their press release.

Stephen Harrison (00:22:53): And then finally with CymaBay as you guys know, seladelpar is a PPAR-delta agonist. They had been studying PBC and decided to embark on a relatively large paired liver biopsy phase 2B trial in about 180 patients treated for one year with paired liver biopsy. Now their primary endpoint was similar to NGM, it was a change in liver fat content, they press that data already there was no difference between placebo and drug treatment group on liver fat content. I might add that the placebo response was inordinately high for the liver fat content drop, it may in fact play a role into why that wasn’t statistically significant. Having said that, ultimately, everybody knows the trial was stopped, the study was put on clinical hold because of some results from about 42 of the paired liver biopsies that came back as having some findings that were not normal for NASH, and there was some concern raised about the idea of drug induced liver injury. So the trial in an abundance of caution was put on clinical hold. The phase three trial for PBC was also put on clinical hold.

Stephen Harrison (00:24:06): But to CymaBay’s credit, I think they did a stellar job of assigning an independent expert panel to review the slides, not just the 42 that there was a question about but re-review all the slides and there were three pathologists. These pathologists in total have read about 4,000 study biopsies. So these aren’t just run of the mill pathologists these are liver pathologists that have spent really a lifetime focusing on fatty liver they were involved in prominent trials like RESOLVE-IT, regenerate, stellar, Flint, Golden 505. And ultimately, what they showed was that seladelpar was not associated with any clinical biochemical or histological injury in its phase 2B NASH study. I might also add that in addition to the three pathologists there were three clinical hepatologist that were experts in drug induced liver injury. This is Paul Watkins, Neo Kaplowitz and Willis Madrick. So ultimately, those three pathologists and three clinical hepatologist came to that conclusion.

Stephen Harrison (00:25:04): So I think moving forward, the plan is to reengage with the agency and to see if the clinical hold can be lifted. And re-engagement occur in both PBC and ideally, NASH. But I think it provides a lot of provocative discussion around additional lesions that may be here to for have not been well described in the setting of NASH that being interface hepatitis, plasma cells and bile duct injury, and even some vascular lesions that appear to be present on both baseline and follow up liver biopsies. But still, clearly the patient had NASH and really to the group’s conclusion without associated other liver diseases. So I think I’ll stop there. That’s my assessment of the phase 2B data published, and you guys can chime in on that.

Roger Green (00:25:52): So Peter, corporate client asks you to summarize what you take from those three studies in the aggregate and whether there’s any individually striking about any one of them?

Peter Traber (00:26:02): Yes, I won’t recount their review that Stephen has provided, which really was excellent. I’ll just make a couple of points on each of these studies. First of all, I was very impressed, as Stephen said, on the composite endpoint of improvement in fibrosis as well as NASH resolution and the NGM 282 study, because you see, the placebo response for both of those effects together is zero. And that’s a good placebo response when you’re… regardless of what response you’re looking at. But 22% versus zero is really quite impressive. And I will point out that back when the FDA and the EMA put out their regulations for endpoints in pre-psoriatic NASH, the EMA said that you had to have both an improvement in fibrosis and resolution in NASH. And the FDA had an or in there. So for instance, Intercept’s trial The primary endpoint was an improvement in fibrosis or resolution in NASH. And it’s still a little unclear how the EMA is going to come down on that, although they have shifted a little bit.

Peter Traber (00:27:11): But I think it is interesting that they had that as a composite endpoint, it makes me wonder with these results for NGM 282 if we’re not going to see people coming back to that. The other thing I would say about NGM is that it is a daily SUBQ injection. And I think that a lot of people are going to be looking for drugs that don’t have daily SUBQ injections for a chronic disease. But overall, it’s extraordinarily promising the results that NGM had. In terms of Novo Nordisk I agree with Stephen, we don’t have enough data, but certainly 59% NASH resolution in the subset that they reported is impressive. And if it follows that we see the significant weight loss that we anticipate With semaglutide this could be a very positive therapy, particularly since it’s already on the market for diabetes and weight loss. Regarding CymaBay, I agree with Stephen, that it’s a remarkable analysis and adds a tremendous amount to our understanding of clinical trials and daily in NASH trials, really extraordinarily strong analysis from a fantastic group of clinicians and pathologists.

Peter Traber (00:28:29): The only thing I would go back to is that they did not have a significant response in fat and we don’t have enough data to know how the other biopsy endpoints are going to end up. I’m sure that as they discuss this with the FDA and look to reopening their trial in both NASH and PBC, we’ll find out a lot more about the NASH response rate. But all three of these examples are really important for the field.

Roger Green (00:29:00): Louise, what would you tell patients who you see to take away from this story A, in the aggregate and then B, if there’s anything specific that jumps out at you?

Louise Campbell (00:29:10): I think having listened to Stephen and Peter, and what I’ve taken from that is that they’re both greatly encouraged by all three of these studies and the sort of results they’re getting, irrespective of some lack of data. And for me to take that home, it would be very encouraging moving into the phase three studies for recruitment and the need for patients to come into those studies. And I think we can take a lot of confidence with the CymaBay one having been so robustly reviewed if it moves into phase three, and also the other two. So I think we had one trial we discussed last time, didn’t do so well. There’s certainly encouraging signs from what I’m listening to Stephen and Peter here.

Roger Green (00:29:52): Thanks, Louise. So I guess my reaction and this would be a forecast or reaction is that the more shots you get that look promising, the more likely it is that something will stick. So the idea that each of these trials produce results that were impressive, and see how they certainly has been as well vetted as anything, we’re lucky to experience, Louise, I think the optimism in the midterm for the class and certainly in the long term. Peter, about a month back it suggested that we haven’t really nailed the case until we have a drug that’s got 50% improvement, both in terms of hepatitis and fibrosis. These might not be those, but certainly, it suggests that we have a lot to look forward to. And at the same time that we’re learning about multiple modes of action, which means as Stephen was talking about the different omics that might drive what goes on, or what we learned about genetics in targeting different parts of the liver, that this suggests that there are multiple paths that might have benefit, in combination, maybe even more so.

Roger Green (00:30:53): So as a forecaster, I would say this is pretty exciting stuff for the field in a five to seven year window maybe even three to five year window. Stephen do you have anything you want to add about the trials? And first of all, I’m reminiscent in saying that I’m tremendously impressed at how fast you were able to get through all of that data clearly and cogently. And likewise, Peter’s comments on it, Louise’s as well. Stephen, do you have anything you want to say, editorially or personally about the 2B’s studies before we go on to the 2A’s?

Stephen Harrison (00:31:18): Maybe just some thoughts to maybe crystallize this a bit more for the listener. So back to NGM Bio, this is a daily injectable and one of the positives with this, anytime I think of a route of administration that involves a daily injection, you really want to have what I call an Oh, wow effect, right, there really needs to be something that’s really moving the needle to get people to take this shot every day. Particularly in the setting of an asymptomatic disease and potentially taking this for a long period of time. So relative to an oral drug with no adverse events, the bar is maybe a little bit higher. So I would say just kind of first blush, they’re certainly jumping over that bar, and to that end, I’m anxious to see the three milligram doses I mentioned before.

Stephen Harrison (00:32:07): A couple things to think about, I didn’t mention the side effect profile. So this drug, the way it works is that it inhibits CYP7A1, which is the conversion of cholesterol to bile acid. So it’s going to raise LDL cholesterol. If the drug is working, it’s raising LDL cholesterol. And patients by default will have to go on a Statin. So there’s the whole LDL mitigation strategy, not totally different than what an FXR has to go through, although it’s a little bit more pronounced than what we see with just a general FXR agonist. Remember, this is not an FXR agonist, although it works through a very similar pathway to FGF19. So moving forward, into phase three, that’s going to be something that is going to be looked at very closely. And then another thing is, is this going to be used as induction therapy or is it going to be used for long term therapy and I think those are some issues with NGM that we need to still ask in our minds as we begin to think about how it might be utilized down the road, assuming that it makes it across the finish line.

Stephen Harrison (00:33:02): Peters comments with Novo Nordisk I like the GLP one class of meds, the big issues for me are gi tolerability, and how many people are going to take this thing for a long period of time. I heard somebody say the other day, I don’t know if it’s true or not, can’t validate this. But if you look at the prescription claims, for those people taking GLP ones for diabetes management, how many of those get renewed after six months, nine months a year? I heard it’s not as high as the company would like it to be. I mean, obviously, we’d like to have patients renew their medicines, continue to take them a vast majority of them for a longer period of time. And I’m hearing that maybe less than half of people actually renew their medicines after six months. And again, I’m not sure I can validate that this is not for NASH indication. This is obviously for diabetes indication, but if that’s true, that’s a little bit of a worrisome feature moving forward in the NASH field. Those are my additional comments I would make.

Roger Green (00:34:04): Okay, great. Then with those in place, why don’t we dive back to the 2A studies, please go ahead.

Stephen Harrison (00:34:08): Yeah, absolutely. So the 2A studies, there’s three companies that have put out press releases Acella, HighTide, and Akero. And I’m going to go in reverse order here. Akero first pressed on March the 31st some interesting data based off of their phase 2A trial and this phase 2A trial was called the Balance study and key inclusion criteria were patients with F1 to F3 NASH with an NAFLD activity score four more was at least 10% liver fat by MRI-PDFF and patients were randomized to three different dosing arms. 28 milligrams, 50 milligrams, 70 milligrams. This is a weekly injection as opposed to NGM which was a daily injection, this was weekly. There’s also a placebo arm so you had four arms of the study. They put about 20 patients in each arm treated them for 12 weeks, got some safety follow up at week 20 and then around week 22 to 24 in patients that achieved a 30% relative reduction in liver fat content at week 12 were eligible to have an end of study liver biopsy. Primary endpoint, absolute change in a paddock fat fraction, not relative change but absolute change at week 12.

Stephen Harrison (00:35:19): Key secondary efficacy endpoints were relative reduction in liver fat, ALT response and then key set exploratory endpoints for serum PRO-C3, fibrosis improvement in NASH resolution. So ultimately, what they pressed was that their absolute reduction in liver fat was significant for all dosing arms. All dosing arms met the primary endpoint that’s driven by two things. Yes, there was a significant effect on drug on liver fat but also the placebo response was essentially zero. There was a minus 0.3 absolute liver fat reduction in placebo group, you had 12.3% for 28, 13.4 for the 50 milligram and 14.1 for the 70 milligram weekly injection, and that was highly significant. Put that in perspective that’s better than any drug studied to date. When we look at normalization of liver fat, this is the proportion of subjects that had less than 5% absolute liver fat reduction in week 12. Placebo had 5%, 28 milligram had 21%, the 50 milligram group had 45%, and the 70 milligram group had 50% of their people at normalized liver fat 12 weeks, which again is pretty remarkable.

Stephen Harrison (00:36:38): And that translated into relative reductions in liver fat, I’m not going to go into the details there, but it was also pretty significant. We look at ALT reduction placebo response had a six, absolute reduction in ALT of six units per liter, whereas in the 28 milligram weekly injection it was 24 units per liter and the 50 milligram Q-week it was 30 units per liter. And in the 70 milligram weekly arm it was 32 units per liter. And just to put that in perspective, remember we’re looking at 17 unit per liter reduction, correlating with improvement in histology. So that gave it really two non invasive criteria as surrogates that point to a potential improvement in histology. That is the significant number of people who had a relative drop in liver fat and the significant number of people that had at least a 17 unit per liter drop in ALT. They went on to say that they had about 50 still eligible for end of study liver biopsy, and that they expect results from those liver biopsies to be reported before the end of Q2.

Stephen Harrison (00:37:42): So very encouraging news with Akero. What are we missing? Well, we’re missing safety and tolerability data. This is an ongoing blinded study so that data isn’t readily available. And obviously, everybody is cluing in on what the histology might be and at this point we just don’t have those numbers, although we have very positive the non invasive testing to date. PRO-C3 is a variable that was exploratory, we don’t have data on that yet either. Moving on to HighTide BioPharm, so HighTide press released on May 7th, an 18 week study with about 100 patients with NASH and type two diabetes. This was a phase 2A study. The primary endpoint again very similar to Acella change in liver fat content, absolute change in liver fat content and several secondary endpoints include glycemic control and numbers associated with liver injury like ALT and Gamma-GT. So the data here is not incredibly robust. But what they do say is that the study met the primary endpoint again, which is absolute liver fat reduction and several important secondary endpoints to include glycemic control and markers associated with liver injury. And this was in a dose response manner.

Stephen Harrison (00:38:52): So in the study, patients were able to get two different doses of drug or placebo. They either got what they call HTD1801 500 milligrams, or 1,000 milligrams or placebo BID for 18 weeks. They do comment that HTD 1801 was generally well tolerated. There was no unexpected side effects, but that further details would be forthcoming at a scientific meeting and a peer review publication. Let me back up to say that HighTide or HTD1801 is a combination of Ursodiol and Berberine. Ursodiol is well known, been around for a long, long time. And actually Berberine is been around mainly China in the Asia Pacific region for a long, long time. And it’s been used in those situations to treat insulin resistance and diabetes. So I find it interesting that in addition to meeting a liver fat reduction end point that there was improvements in glycemic control as well. If that holds true, you potentially have an oral agent that moves liver fat and also moves glucose. And to date when we talk about any of the agents in phase three, that’s one of the issues where maybe there’s a gap, and that is insulin resistance and glycemic control.

Stephen Harrison (00:40:13): So I think this provides maybe a unique opportunity for HighTide if that data continues to be positive. Moving on to the last phase 2A to press recently, and that’s Acella. And they recently had a press release describing some exciting data related to their study. And ultimately, I think it’s worth mentioning, they reported their top line data for a study called AXA 1125-003, which is a phase 2A clinical study in NAFLD D patients 16 weeks in duration. I think just to give you a little bit of a background on what this drug is, it’s an endogenous metabolic modulator. And these include amino acids in a very specific pattern in combination as well as dose, and so just as an example, one of the drugs studied was AXA 1125. AXA 1125 is a combination of six different amino acids, these would be arginine, glutamine, glutathione, N-acetylcysteine, leucine, and isoleucine. I think I hit them all so those six amino acids ultimately have a multifactorial effect, at least in theory relative to what we see in NASH.

Stephen Harrison (00:41:37): And that is they would be purported to have positive impacts on reducing inflammation and injury, improving metabolism, and ultimately preventing fibrosis progression. And early studies have shown that when you take drug or amino acids such as leucine and… I’m trying to think of the others. Essentially, let me back up and just say that these amino acid combinations, this six amino acid combination that comprises AXA 1125 there’s a little bit of a prior history here. There was a single arm clinical study in about 32 patients with type two diabetes and NAFLD that’s been presented previously that kind of generated enthusiasm for this study where there was reduced liver fat content on MRI PDFF improvements in ALT as well as PRO-C3. So ultimately, this study AXA 1125-003 is a 16 week trial looking at AXA 1125 and then a two different combinations or one different combination called AXA 1957 in low dose, and then in a high dose arm and then placebo. So ultimately, there were four arms in this study, patients are randomized in a two to one randomization schema.

Stephen Harrison (00:42:54): Now the criteria to get in this trial were a little bit different. So this wasn’t a biopsy proven NASH trial, but it was a trial focusing on what I would call presume NASH. You had to have at least 10% liver fat by PDFF and then you had to have a multi parametric CT one score of greater than 830 milliseconds, which has been linked to a NASH population values greater than or equal to 830. So ultimately, what did the studies show that AXA 1125 generated clinically significant reductions in liver fat content insulin resistance in fibro inflammatory markers when compared to AXA 1957. And that AXA 1125 actually generated greater activity in these clinical biomarkers in type two diabetic patients. The drug was generally well tolerated I believe AEs were mild to moderate most frequent involve gi issues. These adverse events again were mild and transient, there was only one discontinuation due to adverse event for placebo and AXA 1125. There were two SAEs reported both assessed as unrelated to study product administration, there was no meaningful changes seen in lipids or weight in the active arms.

Stephen Harrison (00:44:13): And so the take home message was the company plans to engage with the FDA to discuss an IND application for AXA 1125. And it proposed phase 2B clinical trial in adults as well as moving forward into pediatric development program. So with that I’ll stop and see if there are additional comments by my colleagues.

Louise Campbell (00:44:34): I was going to basically echo, obviously, for me 2B studies that Stephen’s summary still goes for all the positivity for the clinical trials coming through. And I think that’s certainly what I’m getting a sense of, in all of these. They may not be perfect, but they’re showing some extremely good science and each wave is showing better positives than the wave before. So I think there’s a lot of hope there to be able to engage patients and communities to be able to look forward to a future in the trials world.

Peter Traber (00:45:05): I am quite impressed with Akero’s results as Stephen you described them, I think that the percentage of patients and the reduction in fat as well as the reduction in ALT is really quite impressive. There are a couple things about this the mechanism of FGF21 is a very appealing mechanism of action because it does have these strong effects on metabolism. It also reduces triglycerides, and it doesn’t increase LDL cholesterol like FGF19, or FXR agonists. So there’s a lot to be excited about with this mechanism of action and I was quite pleased to see such a robust difference. The other thing is that there are two other FGF21’s that will be reporting out sometime this year one from BMS, and the other from 89Bio. There are some differences between them, the Akero is a once weekly, as is 89Bio. The BMS drug is once daily, so there are some differences between these FGF21’s. But this is, I think, very exciting data and very encouraging for this mechanism of action. And for the potential result that we’re going to see from BMS and 89Bio.

Peter Traber (00:46:25): The other two HighTide and Acella are oral medications, which I think even mentioned could have an advantage over peripheral medications if they don’t have a lot of side effects and have good effects on the disease. The HighTide study is interesting because of the combination of effect on fat as well as glucose. I would point out that the drug is a salt of two drugs, one of course, which has been around decades ursodeoxycholic acid and berberine, which has actually been around centuries. So it’s interesting that they have a salt of two older drugs. I think one of the things that’s going to be interesting is whether there is a combinatorial effect of these two or whether one versus the other is causing most of the effect. That’ll be an issue that probably they’ll need to sort out as it goes down the line. The Acella approach is novel from a number of standpoints. It could almost be called a natural type of therapy where you’re taking amino acids and metabolites of amino acids.

Peter Traber (00:47:33): It’s not quite a nutraceutical, but close because of course, it’s just a proprietary mix of amino acids which are in all of our protein foods and it raises the issue that what we eat affects the liver quite a bit. And I think that this is an interesting approach whether it turns out to be robust enough to rival say an FGF21 that we’re seeing will need additional studies. But I think it brings up a very interesting defined nutritional approach.

Roger Green (00:48:08): Thanks, Peter. When I look at all this, I think here’s some things that struck me. First of all, I take Peter’s point about the FGF21’s that appears to be an exciting class of drugs. And one of the two exciting classes of drugs we talked about was a matter on… two weeks ago, two classes of drugs that appear to have promise in a way that can be reproduced in multiple molecules. So I think that’s exciting. I also think that there’s something vaguely comforting the idea that NGM is looking at FGF19, Akero FGF21’s these are not the same pathway exactly. But it just feels to me maybe simply because I’m shallow and I work with first names and decide that must mean something, but there must be something about the general pathway or the general approach that suggests that will be a fertile place to look for drug development, number one.

Roger Green (00:48:53): Number two, one of the things that struck me about NGM and Acella is the same technologies or approaches that they’re using in liver, they’re using in other areas as well. Acella’s portfolio was fairly broad, NGM has properties oncology also, all based from a common developmental platform. So it suggests to me that there might be more different ways over time to think about those molecules and their place in liver disease than we know. Finally, it’s the nature of phase two studies to be promising and then phase three studies to disappoint. But sheer probability of shots on goal, if you’ve got six of these things that are reported out in a two or three month period, all of which are promising, it would be logical to believe that we will find ourselves with at least a couple of paths forward coming out of phase three that people should be excited about. In that regard, I find myself meaningfully optimistic and I think this a pretty good antidote to the RESOLVE-IT results.

Roger Green (00:49:45): Stephen, editorial or other thoughts and then maybe one or two wrap up questions?

Stephen Harrison (00:49:50): First of all, Akero based on what we see non-invasively and some of the work that’s come out looking at what the magnitude of effect changes on both PDFF and ALT reduction relative to histology, this sets up for a really exciting time as we anticipate the readout of Akero’s liver biopsies. Now granted, this isn’t a standard phase 2B paired liver biopsy controlled study. This is a controlled study, but it’s a 2A study, and anybody and everybody who had a 30% relative reduction in liver fat and also met some ALT criteria, were eligible for liver biopsy. So it’s not your classic paired liver biopsy controlled trial. Having said that, I think one of the unique things about this trial design is that even though it’s a 2A, it’s giving us a glimpse at how the non-invasive test report out relative to the change in histology because some of us believe that the mechanism of action is really key to understanding the magnitude of effect change in these non-invasive tests relative to the MOA.

Stephen Harrison (00:50:53): An example would be CymaBay right where the PPAR-delta didn’t show any real change in PDFF. But yet at the end of the day, if you look at their preliminary result readout, in those people that had 52 week liver biopsies, there was a pretty positive impact on NASH resolution and fibrosis improvement, despite not having changes in PDFF. Again, there’s lots of reasons why that may be, but I think it gives us our first shot on goal on histopathology relative to an FGF21. As Peter alluded to, there’s a whole cornucopia of companies studying FGF21, where BMS was the first to report phase 2A data, and they have the very large 2B trials both in F3 patients and in F4 patients underway and set to read out in the near future. But as of today, we do not have histology in an FGF21 compound. And so here we are on the precipice of getting that data, exciting times for sure. And then when we look at the other two 2A’s, the glaring hole in drug development is finding an oral insulin sensitizer that could augment the drugs that work in other ways that have shown a positive impact.

Stephen Harrison (00:52:04): Resmetirom is a great example, right? It’s a thyroid hormone receptor beta agonists that really focuses on improving mitochondrial health and up regulating beta oxidation, but it has no impact on insulin resistance or free fatty acid flux from adipocytes. So if, for instance, you were able to show independently, a positive histopathologic benefit of either of those two compounds on NASH resolution, while at the same time improving insulin, Homa glucose, I can envision a potential combination study where ultimately we’re getting at all the different targets and pathways that could be implicated in NASH, ultimately making for a combination therapy that really kind of hits all the bases.

Roger Green (00:52:52): So Stephen, listening to you and listening to the discussion I’m mindful if I’ve already said this on the podcast, please forgive me of Bobby Fisher, the chess player who once when asked why he was the greatest chess player in the world, said, you see black squares and white squares, I see streams, promontory, forest. I think a lot of NASH drug development has felt like independent shots in search of something which to me would be black squares and white squares. The different ways these agents work and the way you’ve been able to weave together that last couple of minutes of conversation feels to me like it might be the beginning of an integrated strategy in terms of how to attack liver issues around fatty disease broadly. If you put the omics on top of that, it feels to me like a strategy that makes liver disease look more like a chessboard and less like a bunch of black and white squares.

Roger Green (00:53:43): So personally, I think that’s very encouraging. Louise, Peter, quick comments and then we’ll go to wrap up.

Louise Campbell (00:53:49): I think just for me, yes, I’d like to echo that and I think it’s interesting that when we talk about… and Stephen was quite clear that certainly Akero and Acella a little bit more holistic in what they’re targeting with insulin resistance and that. And I think that’s reassuring for patients because they don’t just come with one problem. And I think as they can gain more and more benefits, I think those drugs and the strategies to combine them or do different targeting is very, very useful for getting resolution, getting hope. And I think going back to the beginning of the evening, talking about that when one area fails, it’s not always a failure for everybody. But actually having the next waves coming along in this tsunami are always going to be beneficial.

Roger Green (00:54:35): Thanks Louise. Peter.

Peter Traber (00:54:36): I don’t think I could summarize any better than Stephen did with talking about how this all might fit together. And I love your chess analogy, Roger. I think that the picture is even bigger. We’ve talked about these six programs, but then of course, there are many compounds in large pharma at Pfizer and Novartis and other places that fit into this puzzle and show a chessboard that could be very rich over the next couple of years. So we are in the adolescence of NASH drug development. We’ve gone through the childhood and the toddler phase, and we’ve had our falls and missteps and negative studies. But I think we’re starting to see some real potential benefit that’s kind of coming out of all of this work. And so I think it’s encouraging and those that look at the failures and see it as discouraging should really look at this second generation and feel good about how things are moving forward.

Roger Green (00:55:41): So I want to thank, first of all, Stephen for fantastic presentations of the products and putting it all in context. Louise and Peter for two great metaphors in each of their last comments. I keep thinking Peter, about adolescence that adolescence are the people who try crazy stunts because they’re cool, and I can’t think of a much more interesting stunt to try to play chess on a surfboard which is kind of what we’ve been referring to in the last three or four comments. Thanks everybody, this has been great, wonderful discussion. I would like now to go to our closing question, which is the one thing you’ve heard on today’s episode that you find surprising? Louise, let me start with you.

Louise Campbell (00:56:14): It was the optimism I think that I get from Peter and Stephen as to where the next set of trials are coming. And I think as Peter is quite right, you said there were a lot more in the pipeline, the ones we’ve covered, so that gave me encouragement for recruitment, for patient access, and for the population out there who want to participate in clinical trials. So they’re up and coming and discussion with patients who want to access clinical trials, they’ve got something to look forward to.

Roger Green (00:56:43): Thanks, Louise. That’s great, Peter.

Peter Traber (00:56:44): I guess the one bit of a surprise to me is that Stephen and I come out a little bit separated on HighTide and Acella with him being a little more positive than I am. But having said that, I think the way Stephen weaved together the thinking about how they may work together is an important insight that I liked hearing.

Roger Green (00:57:08): Stephen, did you surprise yourself or did anybody else say anything that surprised you?

Stephen Harrison (00:57:13): Well, I was thinking about what I might have said that surprise myself. But I’m more surprised by the fact that Peter potentially disagrees with me, because normally we agree on most things. So that’s a little surprising, but I understand his viewpoint. I mean, it’s easy to look at oral agent and try to rank them against other mechanisms of action and see that maybe it’s got a higher bar declined, and I get that. I think my point is, at the end of the day, we’re going to have very few monotherapy drugs for this disease state. And I think if we’re able to put drugs together that get at the majority of the pathways that trigger the inflammation and the downstream fibrosis, in the liver, and the fat in the liver as well, then I think we’re going to have the best shot on goal. And it may be that some of the drugs we combine has minimal incremental benefit, but are absolutely critical to the synergy of what the outcome is for that patient.

Stephen Harrison (00:58:16): And I reflect back on hepatitis C therapy, for instance, we still don’t have a clue as to how ribavirin works. And when used alone, it didn’t do jack squat to overall SVR for patients with Hep C, but when you put it together with interferon, and even putting it together with some of the direct acting antiviral, it really helped reduce relapse rates. So some of these drugs that maybe have marginal benefit when used alone, or that have adverse event profiles that prevent you from dosing high enough to get maximum benefit, and I put the FXR class in that category, maybe just a whiff of them, or combining them in lower doses with other backbone therapies, you may be able to really jazz a drug for NASH that could have a dramatic impact on a broad swath of the population. So that’s how I guess I would provide my summary there.

Roger Green (00:59:17): First, I want to thank everybody for bringing unique perspectives and a lot of energy and individual thoughts. As we cover six clinical trials in various stages of development, each of which represents a different opportunity. I have a hard time processing all this stuff. I’m sure that in our audience, some people will get it all and some people won’t. Someone told me they listened to last week’s podcast five times. I don’t encourage you to do that. But if you have to, have fun with it. My surprise goes back to Bobby Fischer. That I believe that the key to solving the puzzle of liver disease will be drawing a map and getting this out of modes of action of black squares and white squares and getting it over to so what is the whole thing look like? Where are the hills, where are the valleys, where are the best opportunities, where are the points you have to win?

Roger Green (01:00:00): Listening to Stephen talking about combination therapies and some of Peter’s thoughts about the same issue say to me, not only do we have some drugs that are promising, but we might be starting to build that kind of understanding. And if we have that, I believe we will move very quickly, and it’s very powerful ways to look at liver in all kinds of contexts. It’s worth noting that next week’s conversation will wind up being about diagnostics, and what we need to do to bring diagnostics along as we move the drugs along kind of the analog to what we talked about today. That ends today’s episode, episode seven. We’ll be back on Thursday, June 4th, with the next episode of surfing the NASH tsunami focusing on diagnostics. Until then, stay safe. surf on. Bye bye.

Speaker 2 (01:00:41): You’ve been listening to surfing the NASH tsunami. Send in your questions to surfingmash.com and our panelists will spend the first five minutes of next week’s episode answering your questions. Visit us online today, surfingmash.com.


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