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Dr. Kris Kowdley: Hello, and welcome to this broadcast titled Unlocking Treatment Possibilities in PBC. I'm Dr. Kris Kowdley. I'm Director at Liver Institute Northwest and Professor at Elson S. Floyd College of Medicine, Washington State University. And joining me this evening are:

Dr. Steven Flamm: Thank you, Chris. I'm Dr. Steve Flamm from Rush University Medical School in Chicago. I'm the Director of the Liver Transplantation Service Line and the Director of Clinical Research in Hepatology.

Dr. Sonal Kumar: And I'm Dr. Sonal Kumar. I am a Hepatologist and Assistant Professor of Medicine at Weill Cornell Medicine in New York, New York. And I am the Director of Clinical Gastroenterology and Hepatology.

Dr. Kris Kowdley: So this presentation is a promotional program provided by Ipsen Pharmaceuticals. Faculty are speaking on behalf of Ipsen and being compensated for their time. This presentation is not a continuing medical education program.

Dr. Kris Kowdley: Steve, can you start discussing the fundamentals of PBC in terms of the course of the disease, the common symptom profile, and extrahepatic manifestations?

Dr. Steven Flamm: Sure, Chris. People in this audience are aware of PBC, but it always is instructive to serve as a foundation to discuss the disease state. PBC is a complex autoimmune disease characterized by progressive destruction of the biliary ducts. And because it's an autoimmune disease, we really don't understand the underpinnings of the process. Patients first get inflammation and cholestasis early on, and a fraction of those patients that have PBC develop hepatic fibrosis, not all. And of the patients who develop hepatic fibrosis, a fraction of them develop, in the end, cirrhosis. And then later on, they can get complications of end-stage liver disease, including encephalopathy, variceal bleeding, ascites, or even hepatocellular carcinoma. Now, it turns out that half, almost half, 46% of patients with biochemically early-stage PBC in one study progressed to moderately advanced liver disease within only five years, despite the vast majority being on UDCA. So, you cannot be lulled into a false sense of security in your patient with PBC just because at the beginning they might have early disease.

Dr. Steven Flamm: PBC, for reasons that remain unclear, disproportionately affects women. And it seems the incidence and prevalence are increasing in recent years. It turns out that over 90% of patients that have PBC are women, in fact, most commonly middle-aged women. And as I mentioned, the incidence and prevalence increasing. You see different numbers in different studies. But it seems like PBC, even on an anecdotal basis, if you talk to doctors like us who see a lot of patients with PBC, that the number of patients with it are increasing. Now, men do get it, and when men get PBC, they generally are diagnosed at a more advanced stage of disease, and it's likely due to delayed presentation. And they are, too, unfortunately, less likely to respond to UDCA.

Dr. Steven Flamm: You also cannot be lulled into a false sense of security when your patient with PBC has no symptoms, because many patients, up to 60% of patients with PBC are asymptomatic at the time of diagnosis. But patients can develop symptoms and can develop complications over time. And not only can they develop these symptoms over time, but the symptom severity, once they develop them, can also fluctuate over time. And what may be surprising to the audience is that symptoms do not always correlate with the severity of the underlying liver disease. Now, when patients do develop symptoms, generally the symptoms that are developed in PBC are fatigue and pruritus, and either or both can be very severe. And worsening symptoms, particularly fatigue and pruritus, of course, may affect the patient's quality of life in a very adverse way. PBC is also one of those liver diseases that you cannot forget other problems that occur in association with it. Patients can have sicca complex, abdominal discomfort, restless leg syndrome, sleeplessness, depression, and cognitive dysfunction. Also, not listed on the slide, patients frequently get osteopenia or osteoporosis and may also have hyperlipidemia. So PBC is associated with many other problems and the practitioner should be well aware of these issues.

Dr. Kris Kowdley: Thank you, Steve. We have several guidelines for management of PBC. One such guideline is from the AASLD. This is adapted from the 2018 guidelines. And it states, the goals of therapy in PBC are to prevent end-stage complications of liver disease and management of associated symptoms with a strong emphasis on first-risk stratification followed by treatment. The guidelines recommended that ursodeoxycholic acid, or UDCA, at a weight-based dose of 13 to 15 milligrams per kilogram per day should be started. And at one year, biochemical response should be assessed, with a goal of identifying patients into those that may be low-risk or high-risk after that one year of treatment. So patients would then be classified as low-risk patients who had responded to UDCA. And it's recommended those patients continue to be followed in an individualized basis, particularly with an emphasis on their symptoms and disease stage. Now, there are patients who have failed to respond to UDCA adequately. It's important to consider other possible confounding factors such as features of autoimmune hepatitis, and a recommendation was made to add second-line therapy. And in 2021, the guidelines were updated to add not just the licensed obeticholic acid but also consideration of off-label treatment with fibrates. And of course, clinical trials have remained important to try to find better therapies. The AASLD has recommended that it's important to continue to monitoring patients with regard to biochemical tests and signs of portal hypertension and liver stiffness.

Dr. Kris Kowdley: But it's important to remember that up to 50% of patients with PBC will have an inadequate biochemical response to this first-line UDCA therapy.

Dr. Kris Kowdley: And furthermore, existing therapies that are second-line therapies may have limitations because of potential side effects, efficacy, or other concerns. With that in mind, we want to be able to risk-stratify our patients. We want to be able to identify which patients may be in need of additional therapies. Can you tell us, Sonal, about the role of alkaline phosphatase and bilirubin and what we've learned in terms of risk stratification?

Dr. Sonal Kumar: Absolutely. So when managing patients with PBC and monitoring these patients, alkaline phosphatase and bilirubin levels have been the primary thing that we follow over time, and that's because they've become strong predictors of risk progression, need for liver transplant and death in patients with PBC. So you can see here on the graph on the left, high alk-phos levels are a persistent and early indicator of disease progression. And then on the flip side of it, lower alk-phos levels are associated with improved survival. So if you translate that into numbers, survival rates in patients with a normal alk-phos, so less than the upper limit of normal, were 8% higher than those with an alk-phos level of 1.67 to three times the upper limit of normal. So even small elevations in alkaline phosphatase can affect patient survival. And then when it comes to bilirubin, high bilirubin levels also are a predictor of poor outcomes. And elevation may occur as PBC progresses. So if you see a patient and their bilirubin is starting to trend up, especially if they have a significant elevation in their bilirubin, we worry about more advanced disease.

Dr. Kris Kowdley: So, this is really impactful, it's really important. This is work that I've had an opportunity to contribute to from the Global PBC Study Group. And it's really changed my way of thinking about what is our treatment goal? What's an optimal response to therapy? And when should we reassess patients as far as on treatment follow-up? Steve, what are your thoughts about monitoring patients on UDCA? And at what point do you think that second-line therapy may be something you might consider?

Dr. Steven Flamm: Well, I too, in my practice, I'm impressed with the fact that you can assess alkaline phosphatase as a responding metric earlier than a year despite the AASLD guidelines. And in my practice, I look at the six-month alkaline phosphatase level to identify patients that I think might be good candidates for second-line therapy. I think the data are emerging, they've started about five to 10 years ago, much of it through your work and the group, but I'm very impressed with it. I use it in my practice. Alkaline phosphatase decline on UDCA, the majority of it happens early on and you will get a very good sense, Chris, at six months whether or not a patient might benefit from second-line therapy.

Dr. Kris Kowdley: Your thoughts?

Dr. Sonal Kumar: I completely agree with both of you. We know by 6 months if someone is gonna be responding to UDCA or potentially needs second-line treatment. So I start having those discussions very early on with my patients, especially in the patients who have more fibrosis. Those are the patients that we really want to act as quickly as possible.

Dr. Kris Kowdley: I would agree. I think we can state with some confidence that transitioning to six-month assessments, especially early into the patient's journey for closer monitoring of response to treatment and risk stratification is the current best practice. And so after the initial six months of UDCA therapy, recent studies have advocated for second-line therapy in those who have an inadequate response. Since, as you mentioned, 90% of the improvement occurs in the first 6 to 9 months. There was a study from the Global PBC Study Group that showed that patients who had an alkaline phosphatase greater than 1.9 times upper limit of normal at 6 months, very unlikely to achieve our therapeutic goal at 12 months. So, a 6-month assessment period, we're all sort of converging on that, provides early insights into response to UDCA and sort of replacing the traditional 12-month framework, at least in my practice. So, the ongoing reassessment cadence that's been recommended is frequency of liver biochemistry assessments may be increased to every three to six months to closely monitor for patients at risk for complications. And also, this is important so that we're more aware of symptoms and the effect of symptoms on patient's quality of life. So, evaluating UDCA response at 6 months may offer early insights in treatment response and more frequent biochemical checks are vital as the disease progresses in the majority of patients, as you mentioned, or at least in a substantial proportion.

Dr. Kris Kowdley: So with that, let me now turn to Dr. Kumar to introduce a new treatment option for PBC.

Dr. Sonal Kumar: Yes. Thanks, Kris. So IQIRVO, or elafibranor, is FDA first-in-class oral therapy for PBC that contains elafibranor 80 milligrams. It is indicated for the treatment of primary biliary cholangitis in combination with ursodeoxycholic acid in adults who have an inadequate response to UDCA or in those patients who can't tolerate UDCA, and it can be used as monotherapy. The indication is approved under accelerated approval based on reduction of alkaline phosphatase, but improvement in survival or prevention of liver decompensating events have not yet been demonstrated. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. And limitations of use for IQIRVO, it's not recommended in patients who have or developed decompensated cirrhosis. So any evidence of ascites, variceal bleed, or hepatic encephalopathy.

Dr. Sonal Kumar: So now, we will talk a little bit about the important safety information. There's a lot of information here. But I think it's really important as providers that we are aware of all of these things. So starting with myalgias, myopathy, and rhabdomyolysis, so rhabdo did occur, resulting in acute injury in one patient who was treated with IQIRVO, who had cirrhosis at baseline and was also taking a stable dose of a statin. Outside of that, myalgia, or myopathy with or without CPK elevations occurred in patients who were treated with IQIRVO alone or treated also with a stable dose of a statin. So the recommendation is for us to assess for myalgia and myopathy prior to starting IQIRVO in our patients and then consider periodic assessment, clinical exams, CPK measurement, during treatment with IQIRVO, especially in those who have signs and symptoms of new onset or worsening of muscle pain or myopathy. And then if there's any evidence of worsening muscle pain, myopathy, or rhabdo, you want to interrupt IQIRVO treatment.

Then there are fractures. So fractures did occur in 6% of IQIRVO-treated patients compared to none in the placebo-treated patients. So, for this, we want to consider the risk of fracture in the care of patients who are treated with IQIRVO and monitor bone health according to the current standards of care. And then adverse effects on fetal and newborn development, so IQIRVO in animal studies was shown to cause fetal harm, so when administered during pregnancy. So for females of reproductive potential, we want to verify that the patient is not pregnant prior to starting the drug and then advise females of reproductive potential to use effective nonhormonal contraceptives or add a barrier method when using systemic hormonal contraceptives during the entire treatment with IQIRVO and for three weeks following the last dose.

Dr. Kris Kowdley: Thank you, Sonal. Can you walk us through some of the other safety information, Steve?

Dr. Steven Flamm: Yeah, Kris. Drug-induced liver injury is also an important consideration when giving any product. And in fact, drug-induced liver injury occurred in 1 patient who took IQIRVO at the recommended dose of 80 milligrams once daily and 2 patients who took IQIRVO at 1 and a half times the recommended dosage, of which one of those presented with an autoimmune-like hepatitis picture. The median time to onset of elevation in liver enzymes and liver tests was approximately three months, 85 days. So you should obtain baseline clinical and laboratory assessments at treatment initiation with IQIRVO and monitor thereafter, according to routine patient management. You should interrupt IQIRVO treatment if liver tests, including ALT, AST, total bilirubin, and/or alkaline phosphatase worsen, or if the patient develops signs and symptoms consistent with clinical hepatitis, including jaundice, right upper-quadrant pain, and even eosinophilia. Consider permanent discontinuation if liver tests worsen after restarting IQIRVO. As far as hypersensitivity reactions, hypersensitivity reactions have occurred in a clinical trial with IQIRVO at one and a half times the recommended dose. Three patients, 0.2%, had rash or unspecified allergic reactions that occurred early on, days 2 to 30 after initiation of IQIRVO. Hypersensitivity reactions did, in fact, resolve after discontinuation of IQIRVO and treatment with steroids and/or antihistamines. If severe hypersensitivity reactions occur, permanently discontinue IQIRVO. If a mild or moderate hypersensitivity reaction occurs, interrupt IQIRVO and treat promptly. Monitor the patient until signs and symptoms resolve. If a hypersensitivity reaction recurs after IQIRVO rechallenge, then permanently discontinue IQIRVO. And what about biliary obstruction? You should avoid use of IQIRVO in patients with complete biliary obstruction. And if biliary obstruction is suspected, interrupt IQIRVO and treat as clinically indicated.

Dr. Kris Kowdley: Thank you, Steve. So we have a lot of patients who take a lot of medications. So I think anyone taking care of patients needs to be aware of drug-drug interactions. IQIRVO may reduce the systemic exposure of progestin and ethinyl estradiol, CYP3A4 substrates, which may lead to contraceptive failure and/or an increase in breakthrough bleeding. So, it's important to switch to effective nonhormonal contraceptives or add a barrier method when using hormonal contraceptives during treatment with IQIRVO and for at least three weeks after the last dose. We've already talked about muscle, CPK elevation and/or myalgia occurred in patients on IQIRVO monotherapy. Co-administration of IQIRVO and HMG-CoA reductase inhibitors or statins can increase the risk of myopathy. So, it's important to monitor for signs and symptoms of muscle injury, consider periodic assessment using clinical exams, CPK during treatment, and important to interrupt IQIRVO treatment if there's new onset or worsening of muscle pain or myopathy. Co-administration of IQIRVO with rifampin, an inducer of metabolizing enzymes, may reduce the systemic exposure of elafibranor, resulting in delayed or suboptimal biochemical response. So, again, important to monitor the biochemical response, such as alkaline phosphatase and bilirubin when patients initiate rifampin during treatment with IQIRVO. And finally, bile acid sequestrants may interfere with IQIRVO absorption and systemic exposure, which may reduce efficacy. So important to administer IQIRVO at least 4 hours before or after a bile acid sequestrant or at as greater an interval as possible. Steve, can you finish up with special populations?

Dr. Steven Flamm: Yes. Special populations are very pertinent for any drug in which we treat patients, Kris. And as far as pregnancy goes, we've already discussed in the safety section the fact that during- data on animal reproduction studies show that IQIRVO may cause fetal harm when administered during pregnancy. There are insufficient data from human pregnancies exposed to IQIRVO to allow an assessment of a drug-associated risk of major birth defects or miscarriage or other adverse maternal or fetal outcomes. Report pregnancies if they occur to Ipsen Biopharmaceuticals. And you can use the adverse reporting line that is listed on this slide or the website that is listed on this slide. As far as lactation goes, there are no data available on the presence of IQIRVO or its metabolites in human milk or on effects of the drug on the breastfed infant or the effects on milk production. IQIRVO is not recommended during breastfeeding and for at least three weeks following the last weeks of IQIRVO because the risk to breastfed children cannot be excluded. Men and women of reproductive potential should be notified that IQIRVO may cause fetal harm when administered during pregnancy to women. You should verify the pregnancy status of women of reproductive potential prior to initiating IQIRVO and advise females of reproductive potential to use effective contraception during treatment with IQIRVO and for 3 weeks after the final dose. We're going to talk a little bit more about adverse events shortly. But to summarize, the most common adverse events occurring in at least 10% of patients in the IQIRVO arm of the trial that we will soon discuss were weight gains seen in 23%, and then abdominal pain, nausea, vomiting, and diarrhea, each in 11%. Side effects, also, you are encouraged to report to FDA at the number or website listed on this slide. Or you can report side effects, again, to Ipsen Pharmaceuticals and use the phone number listed on this slide.

Dr. Kris Kowdley: Thank you, Steve, and thank you, Sonal, for going through the important safety information. So IQIRVO, elafibranor, is the first-and-only treatment in PBC with PPAR alpha and delta activation. It has a novel mechanism of action, targeting key pathways in PBC. The clinical efficacy has demonstrated improvement in alkaline phosphatase, including normalization in some patients. Rapid reductions in alkaline phosphatase may be observed starting as early as week 4, which was sustained through 52 weeks. The safety and tolerability, which we've already discussed and will review again were established in the ELATIVE trial. And the treatment potential with IQIRVO is it offers a targeted therapeutic option for patients with an inadequate biochemical response or intolerance to their current PBC therapy. With that in mind, Steve, can you walk us a little bit more into a deeper dive into the mechanism of action?

Dr. Steven Flamm: Yeah. We're not going to dwell too much on mechanism of action. But I think it's very important to echo what you already said, Kris. This is a first-in-class product. And it does activate PPAR alpha and PPAR delta. And it turns out that both of those PPARs, alpha, and delta, seem to work in bile acid metabolism. And when you activate PPAR alpha, it seems to have effects on decreasing bile acid synthesis and modulating bile acid output. And when you activate PPAR delta, it seems to promote bile acid transport. The two, together, decrease bile toxicity, which we think is a major mechanism of toxicity in the liver to patients or in patients with PBC. And in addition, activating these- the PPAR alpha and delta also both seem to have anti-inflammatory effects. So when you use this product, which has this novel mechanism of action, it seems to benefit particularly patients with PBC in this way.

Dr. Kris Kowdley: Thank you. That was a great summary. So now, let's take a closer look at the ELATIVE clinical trial. Let's start with trial design and baseline characteristics. Sonal, can you take us through that?

Dr. Sonal Kumar: Sure. So, the ELATIVE trial is what led to the approval of IQIRVO. It enrolled 161 patients with PBC. It was a double-blind, randomized, placebo-controlled phase III trial that looked at efficacy and safety of elafibranor once daily in patients with PBC who had an inadequate response or intolerance to UDCA. So the key inclusion criteria were that they were adults between the age of 18 to 75. They had to be on UDCA for at least 12 months if they were tolerant of UDCA. They had to have an alkaline phosphatase of at least 1.67 times upper limit of normal and a total bilirubin that was less than or equal to two times the upper limit of normal. They were the 161 patients. And those patients were randomized 2 to 1 to either receive elafibranor 80 milligrams in conjunction with UDCA or placebo plus UDCA. And then there was a primary- the primary endpoint was actually a composite endpoint that looked at biochemical response at week 52. And that composite endpoint had three components. Alkaline phosphatase had to decrease to less than 1.67 times upper limit of normal. The alkaline phosphatase had to decrease by at least 15% from baseline. And the bilirubin had to be within normal limits. There were secondary endpoints as well. Things that were looked at: alk-phos normalization, reduction in the Worst Itch NRS score, the PBC-40 itch domain, 5D itch scale, and change in alkaline phosphatase. And that was the randomized placebo, double-blind, controlled part of the trial. Then after those 52 weeks, patients were offered enrollment into the open-label extension, which was a five-year- which is a five-year ongoing study. Some important things to note about the ELATIVE trial- one, that majority of the patients were on UDCA. So again, patients were offered enrollment if they had an inadequate response to UDCA or if they were intolerant to UDCA. But the majority were- just had the inadequate response. That was 95% of patients. And there were really strict criteria for defining the upper limit of normal for alkaline phosphatase. So it was 104 units per liter for women and 129 units per liter for men. And then, finally, no clinically relevant imbalances in baseline characteristics between treatment groups were seen.

Dr. Kris Kowdley: That's a lot of information. Tell us a little bit more about the patient characteristics.

Dr. Sonal Kumar: Sure. So, looking at the baseline patient characteristics, you can see the IQIRVO plus UDCA arm on the left, in purple, and then the UDCA-alone arm in gray on the right. The age, mainly, most patients were under the age of 65. And majority were female, kind of typical for what we see in our PBC population. Time since diagnosis, about eight years in both of the arms. And then, importantly, the mean alkaline phosphatase level at baseline was over 300 in both groups. And about 40% of patients had a baseline alkaline phosphatase that was greater than three times upper limit of normal. Then you can see the total bilirubin was normal for both groups. The mean total bilirubin, the mean PBC NRS score, you can see there. The mean liver stiffness was 9.9 in the IQIRVO arm and 10.7 in UDCA alone. But importantly, a liver stiffness greater than 10 kilopascals and/or bridging fibrosis or cirrhosis on histology was seen in over a third of patients in both groups. So a significant number of patients had more advanced disease.

Dr. Kris Kowdley: But more advanced disease and high alkaline phosphatase in high stage, so really, a population with a significant unmet need.

Dr. Kris Kowdley: Let's now look at the results. Significantly more patients achieved biochemical response compared to UDCA alone and 51% of patients treated with IQIRVO reached the primary composite endpoint of the biochemical response, significantly outperforming patients in the UDCA-alone group by 47% (so 51% to 4%). And what that translates to is 13-fold more patients- or 13 times more patients responded with IQIRVO compared to UDCA alone with a treatment difference of 47%. This was highly statistically significant. And just to remind everyone, biochemical response was defined as achieving an alkaline phosphatase less than 1.67 times upper limit of normal, at least a 15% reduction, and maintaining a normal bilirubin.

Dr. Kris Kowdley: So now that we have reviewed the primary endpoint data, Steve, can you discuss the data we have, looking at subgroup analysis from the study?

Dr. Steven Flamm: Yeah, Kris. I think this is very important. Some subgroup analyses are important because they help a practitioner convey to a patient what the likelihood of a response is. And when you look at patients that had alkaline phosphatase levels less than or equal to 3 times the upper limit of normal when they enrolled in the trial, and as Sonal just mentioned, that's about 60% of the patients, 71% of them actually achieved the biochemical response, 71%. And when you compare that to the urso-alone group, again, alkaline phosphatase less than or equal to three times the upper limit of normal, there was a 6% response. So, this was a fairly dramatic increase in response in the IQIRVO treatment arms. When you looked at people that had higher alkaline phosphatase, that's greater than three times the upper limit of normal, 21% still achieved the biochemical response, even with these much higher alkaline phosphatase levels, to begin with. So IQIRVO demonstrated significant clinical efficacy. And as far as achieving the biochemical endpoint, the biochemical response, lower alkaline phosphatase rates, the majority of patients achieved what we want them to achieve.

Dr. Kris Kowdley: That's a great summary. And it gives us something that we can use to stratify or counsel our patients in terms of their individual likelihood of achieving that response. So thank you for that. There were also secondary endpoints. Sonal, can you walk us through the reductions in alkaline phosphatase and what they mean?

Dr. Sonal Kumar: Yeah. So, I think there's a lot of information on this slide, actually. So, looking at the reduction in alkaline phosphatase, you can see that it happens really early. So as early as week 4, you can see that steep decline on the graph in alkaline phosphatase levels, which is really nice. It's encouraging for us as providers. I think it's encouraging to patients when they see their labs improve. And then you can see that it's sustained over the entire 52 weeks of the trial. And you can see the UDCA-alone line on the top of that graph. And what that translates to is that 22 times greater reduction in alk-phos in the IQIRVO-treated arm compared to UDCA alone, huge difference. The between-group difference was 40.6%.

Dr. Kris Kowdley: So we have a question coming in about this presentation. What was the average reduction in alkaline phosphatase for patients in the IQIRVO arm?

Dr. Sonal Kumar: Yes, so the average reduction in alkaline phosphatase from baseline in the IQIRVO treated arm was 117 units per liter. And that's really impressive because it happened rapidly, and it was sustained over 52 weeks and there was no dose titration, or anything required in the trial.

Dr. Kris Kowdley: Great. Very helpful. So, other secondary endpoints that we are interested in, especially now as we were talking earlier about driving that alkaline phosphatase as low as possible, including trying to achieve normal alkaline phosphatase. Can you talk us through some of these results?

Dr. Steven Flamm: Sure, Kris and I was going to emphasize that too. One of the, I would say, evolving ways we look at treating people with PBC in these recent years is that we really want to drive that alkaline phosphatase down. We wanna drive it down, and normal would be optimal. So, a key secondary endpoint in this trial too looked at how many patients achieved actual alkaline phosphatase normalization through week 52 with IQIRVO compared to UDCA alone. And throughout the 52-week treatment period, 15% of patients in the IQIRVO treatment arm actually achieved normalization of alkaline phosphatase. With these very aggressive normal parameters that Sonal mentioned earlier, how many achieved that in the UDCA only arm? Zero, zero. So we achieved 15% complete normalization. And the mean reduction to achieve that was 216 units per liter. So you had dramatic responses in patients that, again, we think optimize their clinical outcome.

Dr. Kris Kowdley: Yes, no, thank you. And this is particularly impressive given that the alkaline phosphatase levels for normal were set at 104 for women and 129 for men. So, achieving a normal alkaline phosphatase in this population is certainly not something that's easy to accomplish. And I think is quite meaningful clinically. The amount of reduction of alkaline phosphatase to achieve normalization was 216 units per liter. So a very substantial change. So with this new data, what are the criteria for considering IQIRVO as a second-line therapy for patients with PBC? What should we advise our audience in terms of how they should be considering incorporating IQIRVO into their practice? And then I'd like to hear your own thoughts given your experience.

Dr. Steven Flamm: Well, again, in my practice, Kris, I'm increasingly operating on two principles. One, that we should assess at 6 months rather than the standard 12, whether or not a patient would benefit from second-line therapy. And two, we should really try to aggressively lower alkaline phosphatase as close to baseline or normal, I should say, as close to normal as possible. So with those two tenets in mind, when I see a patient at 6 months that does not have an optimal response to UDCA in my practice, I am aggressive with second-line therapy and will use a product like IQIRVO, which I think will optimize outcomes.

Dr. Kris Kowdley: Your thoughts?

Dr. Sonal Kumar: Completely agree. I think as we're moving towards normalization, which I'm doing in my practice, seems like you guys are as well. I am very quick to think about second-line therapy in our patients. And I agree, not only the degree of elevation that matters, but how long patients stay out of that normal range matters in terms of long-term outcomes. So I would be, similarly to Steve, I would start thinking about IQIRVO or second-line therapy in patients at six months.

Dr. Kris Kowdley: Yes, I really like what you just said about how long, and I'm starting to think about this area under the curve concept, we measure at static intervals these tests and assume that nothing changes between those measurements, whereas in fact, that's not the case. So excellent points. Great discussion about efficacy.

Dr. Kris Kowdley: Another vexing symptom in PBC that has been very disturbing for patients is pruritus. I'll now provide an overview of the data on reduction pruritus with IQIRVO. So here are the data. There was a trend toward improving pruritus with IQIRVO as measured by the Worst Itch-NRS scale. And you can see the least squares mean change from baseline 1.93 versus 1.15 with UDCA alone. These results were not statistically significant, however, and should be considered descriptive. Other measurements of itch which I think are also important to consider are the PBC-40 and the 5D itch. The PBC-40 itch domain in particular is an important tool in my opinion, because the PBC-40 is a validated instrument to measure the impact of itch on health-related quality of life. And similarly, the 5D itch also has useful implications with regard to how it affects patients. And you can see that there was a numerical difference with IQIRVO in a favorable way compared to UDCA alone. Can you tell us about safety and tolerability that was demonstrated and established in the ELATIVE trial?

Dr. Sonal Kumar: Sure, absolutely. I think it's really important that we are aware of the adverse reactions or adverse events that were seen in the trial, because I always talk to my patients about these things before we're starting a drug so that they know what to expect and how we can potentially manage them. So if you look at the adverse reactions that were seen in the ELATIVE trial weight gain was at the top of the list, but I'd like to point out that it was seen in both the IQIRVO and UDCA arm and the UDCA alone arm at about very similar percentages, 21% in the UDCA alone and 23% in IQIRVO and UDCA. And then if you actually look all the way down on the bottom of the list, you can see weight loss also being seen in the IQIRVO plus UDCA arm at 5%. Outside of that, a lot of GI side effects, so diarrhea, abdominal pain, nausea, vomiting, constipation, reflux were commonly seen. And then other things that we've already spoken about in the safety data, muscle pain myopathy, we've talked about the fractures already and the hypersensitivity with rash.

Dr. Kris Kowdley: Thank you for walking us through all of that. One of the best testimonials about how a patient tolerates a medication is whether they're willing to go into an open-label extension trial. Can you tell us, Steve, about the open-label long-term extension study and what's happening with that?

Dr. Steven Flamm: Absolutely, Kris. It's very important when you're using a product over the long-term to look at efficacy and safety adverse events over the long-term. It's important for practitioners, it's important for us to be able to counsel our patients appropriately. So that's why this study is so important. And it turns out, first of all, that 92% of the patients completed the ELATIVE trial in the first place. And the vast majority of those patients agreed, at least from the active arm of the trial, to enter the ongoing open-label extension trial, 97%. So, the vast majority of patients are still on the drug open-label, and we will get very important information in the coming years to convey to our patients.

Dr. Kris Kowdley: Great. There's a question here pertaining to long-term exposure and long-term treatment with elafibranor IQIRVO. Are there any long-term data yet, Sonal?

Dr. Sonal Kumar: So the ELATIVE trial gave us a lot of information but really it focused on safety and efficacy at that one year-time point. And like Steve said, the open-label extension will provide us with a lot more information. It's ongoing. We have 97% of patients from the ELATIVE treatment arm in that open-label extension. So, we'll get a lot of information, but not yet.

Dr. Kris Kowdley: Great. Thank you. So now let's get into the nuts and bolts of how patients would be started on treatment and the details. So Steve, can you tell us about starting a patient with IQIRVO treatment?

Dr. Steven Flamm:  Yes. This of course, is important for practitioners and patients alike because once you decide you have an appropriate patient, you need to start them on the med. And IQIRVO is a once-daily, 80 milligram oral tablet that requires no dosage adjustments, and you can take the drug with or without food. Now, if you happen to be on cholestyramine or some bile acid sequestrant, keeping in mind some of the drug-drug interactions you discussed earlier, Kris, you should administer IQIRVO at least four hours before or after administering the bile acid sequestrant. So keep that in mind. And some of these patients will be on bile acid sequestering for pruritus, so dose the drug at the appropriate time.

Dr. Kris Kowdley: Yes, thank you. That's very clear. So, it's pretty exciting. We have had the first new therapy for PBC in close to 10 years before which it was decades before we had the first approved therapy for PBC. I think more options for patients are extremely welcome especially those that have different mechanisms of action and help us accomplish the goal of trying to really achieve what I like to call a deep remission or biochemical remission. Any thoughts from you Sonal, about how getting this new medication available in the clinic will change things both for you as a practitioner and for patients?

Dr. Sonal Kumar: Yes, I think it's a really exciting time for PBC. Like you said, we haven't had a new therapy in a long time, and I think even over the last few years or so, we've all talked about it here today, our mentality has really shifted. We want to get patients down, their alk-phos normal, we want to do it sooner. And this really offers another option of how we can do that in patients who are inadequately treated.

Dr. Steven Flamm: I think it's very important, Kris. I have quite a number of patients that have a higher alkaline phosphatase than I'm comfortable with PBC. I think they're gonna benefit with this drug. I'm impressed with its efficacy and safety profile, and I think it's gonna offer, really, something that's very important for the appropriate patient with PBC.

Dr. Kris Kowdley: Yes. And the appropriate patient is key, right? Because obviously every patient is slightly different. Some have one set of symptoms, some have other sets of symptoms, they have different expectations, they have different disease stage, they have different rates of progression. The younger patient with more aggressive disease is still very much in need of effective therapies. The average age of transplantation has not changed despite all of these therapies from my perspective and from the data. So, I think it's welcome that there are new therapies that we can now incorporate into our armamentarium. But of course, no discussion about therapies would be complete without figuring out access. And so this is something that we deal with every day.

Dr. Kris Kowdley: And so, Steve, you've been nominated to tell us how we can provide access to our patients.

Dr. Steven Flamm: Well, I'm happy to do it, Kris. And this is very important. After efficacy and safety and administration, of course, the next most important thing about any product is how do you get it? And fortunately, IPSEN does have a program, IPSEN CARES, that is a patient support program that helps patients get access to IQIRVO. And they also provide information and support they might need on their journey. The IPSEN CARES Patient Education Liaisons and Patient Access Managers are here to help patients that will benefit from IQIRVO. There's financial and insurance assistance, there's dedicated individualized support and educational materials and programs that are available for patients. And to learn about IPSEN CARES, you can visit ipsencares.com or call the number on this slide Monday through Friday at the times that are listed. And I'm sure the IPSEN reps will also have information about how to help appropriate patients that could benefit from IQIRVO have access to the product.

Dr. Kris Kowdley: Thank you both. Some key takeaways from this program, 13 times more patients achieved the biochemical response with IQIRVO and UDCA. Alkaline phosphatase normalization was achieved only in IQIRVO treated patients at 15 versus zero percent. Multiple scales were used to assess the impact of IQIRVO treatment on pruritus, and this is now an effective option with an established safety profile in a once-daily treatment. So we can see the safety profile is acceptable. I've described the impact on pruritus, alkaline phosphatase normalization, so adding IQIRVO, elafibranor, to UDCA can offer efficacy with an established safety profile in a once-daily oral treatment. Any other key takeaways that you want to share?

Dr. Sonal Kumar: I think this this is a great time. I think one of the things that we always talk about is that PBC may not be as rare as we have previously thought it was. So, it's always important that we as providers keep PBC in the back of our mind. And having IQIRVO now will bring the disease up to the forefront again. And it's a really great option for patients who are right for the therapy.

Dr. Kris Kowdley: Steve?

Dr. Steven Flamm:  Same, Kris. This disease I think is increasing in frequency when you talk to key opinion leaders around the country that care for these kinds of patients. This problem is not decreasing, it's increasing. And I think providers cannot be lulled into a false sense of security because a patient is asymptomatic. Many are, but that does not correlate with the degree of disease in the liver. So don't be tricked by that. And also, I think the take-home messages are what we've discussed in this talk tonight. And that is that we need to assess patients that are on UDCA earlier at month 6, at least in our practices, to see if they're appropriate for second-line therapy. And furthermore, drive the alkaline phosphatase down. It's becoming increasingly apparent that patients have better clinical outcomes when you do that. So those, I would say are the take-home messages from tonight.

Dr. Kris Kowdley: Yes, those are great comments and observations. And I would just add that, the research has never been more flourishing and productive in PBC. We now know that we can diagnose the disease in 97% of our patients using just disease specific ANA or AMA. We know now that there's robust data with elastography suggesting that it's a very useful tool for staging patients. And so we no longer really need liver biopsy. And as we have more therapeutic options for our patients, I think everybody wins, most of all our patients. So that completes our presentation. Dr. Kumar, Dr. Flamm, thank you for joining me on this panel and many thanks to the viewers for watching the broadcast.