Genfit Thinks Intercept’s Lead In NASH Not As Wide As Perceived
Executive Summary
Genfit believes elafibranor’s clean tolerability and safety profile may help narrow the gap between it and Intercept’s OCA, with safety questions delaying OCA’s entry to market. Part two of Scrip’s interview with Genfit’s CEO and COO.
Genfit SA is positioned to bring the second drug to market in non-alcoholic steatohepatitis (NASH) behind Intercept Pharmaceuticals Inc.’s obeticholic acid (OCA), but some analysts have expressed little confidence in Genfit’s elafibranor because of initially poor data in a Phase II trial. New Genfit CEO Pascal Prigent and his team are fighting against that perception as they look forward to reporting data from the Phase III RESOLVE-IT trial early in 2020.
The Lille, France-based company has argued for years now that it will compete well with OCA in the unmet medical need based on a cleaner safety and tolerability profile than the Intercept drug, and also by offering the ability to resolve NASH by reducing inflammation and hepatic ballooning. (Also see "Genfit Hopes To Make Case For First-Line Treatment In NASH" - Scrip, 4 Apr, 2019.)
OCA, an FXR agonist filed for US approval in late September, is meant to help patients by reducing fibrosis, but there are safety questions due to pruritus and increased LDL levels in clinical trials. (Also see "Intercept’s NASH NDA Positions OCA For May 2020 Approval, Then Launch" - Scrip, 30 Sep, 2019.) Already on the market for primary biliary cholangitis (PBC) under the brand name Ocaliva, the drug also has a black box warning for potential liver damage in some patients. (Also see "Intercept Makes No Changes To Ocaliva NASH Study Despite PBC Safety Issues" - Scrip, 25 Sep, 2017.)
In a wide-ranging interview with Scrip, Prigent and chief operating officer Dean Hum explained why they believe elafibranor, a dual agonist of PPAR alpha and delta, showed better efficacy than commonly believed in Phase II and also talked about why they think a safety and tolerability advantage may help them erode Intercept’s perceived time-to-market edge.
[Editor’s note: See part one of the interview for details on Genfit’s commercial preparations and leadership changes. For further analysis of the NASH market, please register for our complimentary webinar on 31 October.]
Elafibranor looks likely to be the second NASH drug to market, but some analysts have questioned the magnitude of benefit the drug showed in its Phase II program. (Also see "NASH Pipeline Includes Six Candidates That Have Reached Phase III" - Pink Sheet, 30 Sep, 2019.) How does Genfit respond to that commentary?
Prigent: In terms of time to market, we will be probably a year after Intercept of terms of filing. Now, we’re not sure that will be a full year from a launch perspective. Assuming we have positive data and an approvable product, our perception is that the discussion with the FDA should be a simple discussion. With Intercept, we think there are several things about their filing that are likely to raise questions. It always takes time to answer FDA questions. The LDL increase, for example, and the fact that they have the black box in PBC, even the pruritus, all those things are likely to be discussed with the FDA. (Also see "Intercept's OCA Data Bolster NASH Efficacy, But Pruritus Worries Worsen" - Scrip, 11 Apr, 2019.)
For us, if we have a successful Phase III study, we know we are squeaky clean from a tolerability and safety standpoint, so we think the difference in launch could be much smaller. In our minds, we’ve always felt we’re going to be more or less simultaneous. We don’t necessarily see us as launching second-to-market, we’ve expected that we’ll launch with Intercept.
We think the products are very differentiated. To start with, Intercept is going to be approved, hopefully, based on their action in fibrosis, one of two acceptable primary endpoints. (Also see "Intercept’s Phase III Endpoints May Not Apply To Other Firms’ NASH Programs" - Pink Sheet, 25 May, 2015.) So, you have two products that, if they are approved, are going to be positioned very differently in the marketplace, and the product profile is very different.
What we’ve seen in our market research is that physicians say depending on which NASH patient you are talking about, different things are important. Earlier NASH patients with maybe F1 or F2 fibrosis, the most important thing in our mind is resolve NASH and [address] those other cardiometabolic parameters because what kills those patients is cardiovascular disease. In our market research, people were saying they much prefer the product profile of elafibranor because it works in NASH and it has that cardiometabolic benefit.
For the later-stage patients – those who are much closer to cirrhosis, have much more fibrosis – then we think it is important to have anti-fibrotic activity. Physicians may add an anti-fibrotic on top of our drug … because they want the anti-fibrotic activity and they still want the NASH activity. If you don’t have the NASH activity, you don’t act on the cause [of the disease.] You wouldn’t use an anti-fibrotic to treat someone with hepatitis C because you want something that acts on the virus; the same logic applies here.
We have seen Intercept as a potential competitor, but it looks like OCA could be a drug that is going to be used concomitantly, not necessarily instead of. So, the question of how you position the two together is taking a different shape.
For us, if we have a successful Phase III study, we know we are squeaky clean from a tolerability and safety standpoint, so we think the difference in launch could be much smaller. In our minds, we’ve always felt we’re going to be more or less simultaneous. We don’t necessarily see us as launching second-to-market, we’ve expected that we’ll launch with Intercept.
We think the products are very differentiated. To start with, Intercept is going to be approved, hopefully, based on their action in fibrosis, one of two acceptable primary endpoints. (Also see "Intercept’s Phase III Endpoints May Not Apply To Other Firms’ NASH Programs" - Pink Sheet, 25 May, 2015.) So, you have two products that, if they are approved, are going to be positioned very differently in the marketplace, and the product profile is very different.
What we’ve seen in our market research is that physicians say depending on which NASH patient you are talking about, different things are important. Earlier NASH patients with maybe F1 or F2 fibrosis, the most important thing in our mind is resolve NASH and [address] those other cardiometabolic parameters because what kills those patients is cardiovascular disease. In our market research, people were saying they much prefer the product profile of elafibranor because it works in NASH and it has that cardiometabolic benefit.
For the later-stage patients – those who are much closer to cirrhosis, have much more fibrosis – then we think it is important to have anti-fibrotic activity. Physicians may add an anti-fibrotic on top of our drug … because they want the anti-fibrotic activity and they still want the NASH activity. If you don’t have the NASH activity, you don’t act on the cause [of the disease.] You wouldn’t use an anti-fibrotic to treat someone with hepatitis C because you want something that acts on the virus; the same logic applies here.
We have seen Intercept as a potential competitor, but it looks like OCA could be a drug that is going to be used concomitantly, not necessarily instead of. So, the question of how you position the two together is taking a different shape.
So, you anticipate that some clinicians will use OCA and elafibranor as combination therapy? Both companies want to position their drugs as a backbone therapy down the road in combination therapy, so how do you see that getting resolved?
Prigent: What we’ve seen in all our research is that the backbone needs to be a drug that is well tolerated, by definition, because that’s the one the patient is going to take long-term. Tolerability is absolutely critical. We are talking about a disease that is asymptomatic, so when you have an asymptomatic disease, compliance is always an issue.
Back when I was with Eli Lilly & Co., we launched Evista (raloxifene) and it was a great drug but in an asymptomatic disease like osteoporosis, compliance was a huge issue. The threshold of patients to tolerate side effects is very low, because, obviously, when you feel fine why would you deal with side effects?
We think the first big advantage for elafibranor is that from a tolerability standpoint it’s much better than the alternative. Then, of the two approvable endpoints, ideally you want something that acts on both, but if you must make a choice between resolution of NASH and fibrosis for the backbone, our argument has always been that it has to be resolution of NASH. You want to eliminate the cause of your disease, not to work on the fibrosis. At least in our market research, the extra fibrosis action in F1 patients doesn’t really matter, so why would you have a backbone for all those patients that is an anti-fibrotic?
Back when I was with Eli Lilly & Co., we launched Evista (raloxifene) and it was a great drug but in an asymptomatic disease like osteoporosis, compliance was a huge issue. The threshold of patients to tolerate side effects is very low, because, obviously, when you feel fine why would you deal with side effects?
We think the first big advantage for elafibranor is that from a tolerability standpoint it’s much better than the alternative. Then, of the two approvable endpoints, ideally you want something that acts on both, but if you must make a choice between resolution of NASH and fibrosis for the backbone, our argument has always been that it has to be resolution of NASH. You want to eliminate the cause of your disease, not to work on the fibrosis. At least in our market research, the extra fibrosis action in F1 patients doesn’t really matter, so why would you have a backbone for all those patients that is an anti-fibrotic?
Hum: Another way to look at it is if you have a drug that truly works on fibrosis, you would have to combine that drug with something that is able to resolve NASH. If you look at the results from the Tobira Therapeutics Inc. trial, cenicriviroc supposedly works on fibrosis but they saw that effect only after one year when they did the first biopsy. (Also see "Tobira Says Secondary Endpoint In NASH Will Carry CVC Into Pivotal Study" - Pink Sheet, 25 Jul, 2016.) Then, they took another biopsy after two years of treatment and they expected they’d reproduce that benefit, but they lost that benefit after two years. (Also see "Allergan’s Two-Year NASH Data Fail To Show Fibrosis Benefit" - Scrip, 22 Sep, 2017.)
What’s probably happening there is that because the drug only works on fibrosis and was not able to resolve NASH, the NASH was still there and continuing to push the disease forward. This is why is we have the understanding that a drug that only works on fibrosis will have to be combined with a drug that will be able to resolve NASH.
What’s probably happening there is that because the drug only works on fibrosis and was not able to resolve NASH, the NASH was still there and continuing to push the disease forward. This is why is we have the understanding that a drug that only works on fibrosis will have to be combined with a drug that will be able to resolve NASH.
Prigent: I just wanted to go back to your question about our Phase II data because I think it’s an important point. From everything I’ve seen in market research, I feel very strongly that we do have a winning product profile. The remaining question, the true question is what confidence can we have in the Phase III study? Everybody would love to have a preview of efficacy, including us, but it’s just not possible because it’s a blinded trial, so like everybody else, we have to base our faith on the Phase II.
It’s true that some people have said that the Phase II [GOLDEN-505] is a failed study and therefore they have low confidence that we’re going to show efficacy with elafibranor. (Also see "Genfit Dives Into Uncertain Late-stage NASH Trial" - Scrip, 16 Nov, 2015.) The way we look at it is we have to put ourselves back in the context of the time and, at that time, there were only two programs in NASH, not like the 80 or so today. For all intents and purposes, Intercept and Genfit were paving the way in a market that really was super-fluid. What that meant for us is when we had to come up with a definition of what was resolution of NASH, there was no consensus. (Also see "NASH Drugs Soon May Have A Registrational Pathway, Finally" - Pink Sheet, 30 Mar, 2015.)
Therefore, we talked to some KOLs and came up with something that seemed to make sense at the time, which was basically the definition of a NASH patient as somebody who has at least one of the three [histological components of NASH – steatosis, lobular inflammation, hepatocyte ballooning]. If you get to zero in one of those three, you’re technically not a NASH patient. Therefore, we decided to call that NASH resolution. We shared that with the FDA and that was the per-protocol definition in the Phase II trial.
We found out later when we read out on that study that that probably was not the best definition, because it was not stringent enough, especially when combined with the fact that we had a patient population with fairly mild disease. For steatosis, dropping your score by one level is actually very easy to do, because if you take someone who’s not really paying attention to what they’re eating or how much they’re exercising and tell them they have NASH, if you include them in a clinical trial, the first thing they’ll do is watch what they eat and be a little bit more diligent in when they go to the gym, etc. Then, they can drop one level in steatosis score pretty fast and therefore in our trial, we had a huge placebo response. That’s why it was a failed study on a per-protocol basis.
Some people say we missed our primary endpoint and then did a bunch of adjunct analyses and found some that were working. Actually, what happened is the FDA came back and said they had a new definition of NASH resolution that it would going to use going forward, one that’s more stringent and on which all regulatory decisions are going to be based. That’s the one that they published at the end of 2018. (Also see "NASH Drug Development Guidance Encourages Sponsors To Adopt Innovative Trial Designs" - Pink Sheet, 4 Dec, 2018.)
Now that we had that new, accepted definition that the FDA was going to use going forward, we said ‘ok, what happened if we used that definition?’ What we saw was that the placebo response decreased, but not the active product response and now it was a successful trial on the intent-to-treat (ITT) basis. That’s the point that I think some people are missing. On an ITT basis, just changing to the new FDA definition of NASH resolution meant we were statistically significant on resolution of NASH.
It’s true that some people have said that the Phase II [GOLDEN-505] is a failed study and therefore they have low confidence that we’re going to show efficacy with elafibranor. (Also see "Genfit Dives Into Uncertain Late-stage NASH Trial" - Scrip, 16 Nov, 2015.) The way we look at it is we have to put ourselves back in the context of the time and, at that time, there were only two programs in NASH, not like the 80 or so today. For all intents and purposes, Intercept and Genfit were paving the way in a market that really was super-fluid. What that meant for us is when we had to come up with a definition of what was resolution of NASH, there was no consensus. (Also see "NASH Drugs Soon May Have A Registrational Pathway, Finally" - Pink Sheet, 30 Mar, 2015.)
Therefore, we talked to some KOLs and came up with something that seemed to make sense at the time, which was basically the definition of a NASH patient as somebody who has at least one of the three [histological components of NASH – steatosis, lobular inflammation, hepatocyte ballooning]. If you get to zero in one of those three, you’re technically not a NASH patient. Therefore, we decided to call that NASH resolution. We shared that with the FDA and that was the per-protocol definition in the Phase II trial.
We found out later when we read out on that study that that probably was not the best definition, because it was not stringent enough, especially when combined with the fact that we had a patient population with fairly mild disease. For steatosis, dropping your score by one level is actually very easy to do, because if you take someone who’s not really paying attention to what they’re eating or how much they’re exercising and tell them they have NASH, if you include them in a clinical trial, the first thing they’ll do is watch what they eat and be a little bit more diligent in when they go to the gym, etc. Then, they can drop one level in steatosis score pretty fast and therefore in our trial, we had a huge placebo response. That’s why it was a failed study on a per-protocol basis.
Some people say we missed our primary endpoint and then did a bunch of adjunct analyses and found some that were working. Actually, what happened is the FDA came back and said they had a new definition of NASH resolution that it would going to use going forward, one that’s more stringent and on which all regulatory decisions are going to be based. That’s the one that they published at the end of 2018. (Also see "NASH Drug Development Guidance Encourages Sponsors To Adopt Innovative Trial Designs" - Pink Sheet, 4 Dec, 2018.)
Now that we had that new, accepted definition that the FDA was going to use going forward, we said ‘ok, what happened if we used that definition?’ What we saw was that the placebo response decreased, but not the active product response and now it was a successful trial on the intent-to-treat (ITT) basis. That’s the point that I think some people are missing. On an ITT basis, just changing to the new FDA definition of NASH resolution meant we were statistically significant on resolution of NASH.