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Don't believe us? Watch them on DancePlus5, Tonight at 8pm on Sujal shah ft. Manas prod. Vision deval prod. Jhola Nepali Movie ft. Sunlounger Dreamstate - DJ Shah feat. Yes, thank you for the question, Yasmeen.
We continue to make significant progress every day. All of this effectively is counted by country approvals, followed by site activation, screenings and randomization. We're still in that early part of the curve, where things continue to accelerate significantly as we get more sites activated.
I think we've discussed also, Yasmeen, that there's no question the global pandemic is a factor is a headwind as is greater competition for patients today than when we are in rolling ENHANCE. So fundamentally, our strategy remains for this global significant effort to offset those headwinds. And I think it will be important for us as we continue to see this progress we're making every day to reassess on a quarterly basis. As of now, it remains our goal, Yasmeen, to get this study completed by the end of the year.
And that would effectively put us in a position of having top line data by the end of or very early Thank you for highlighting that you guys were doing the hepatic impairment study as well as the data on the 2-year study of 50 patients that are compensated with efficacy and clean safety. I just want to understand, do you think that, that data as well as the results from the hepatic impairment would be sufficient that you - the ultimate label would allow you to dose-compensated patients with portal hypertension?
Or do you think the FDA stands at this moment is that no therapy at this point should be given to this patient population. If you could just drill down a little more, that would be helpful for us. Certainly, Yasmeen. I think as we've discussed previously, in our prior Phase II as well as the ENHANCE study, we have had patients that have been well compensated cirrhotics, some actually with portal hypertension. So this is an area in which we continue to further investigate.
It is an area that we expect to continue collecting both safety as well as efficacy data in the population. And I think this question will continue to be answered by the data sets themselves. And perhaps I'll invite Chuck to speak more specifically around what we've learned thus far and what's important for us to evaluate as we go forward. Yes, sure. And thank you for the question, Yasmeen. We did find patients that we enrolled that had clinically significant portal hypertension, which in a compensated cirrhotic patient reflects a higher risk for liver-related or decompensation events.
Just for background, these could be things like liver bleeds, ascites or encephalopathy. Their medical complications that themselves require invasive intervention and reflect increasing likelihood for poor prognosis. So the ability to deliver efficacy in that population, there is an unmet need there.
So evidence of - hypertension - measuring portal hypertension is an invasive procedure. And so evidence where it can come from a variety of ways using laboratory findings or noninvasive imaging. This could be things like low platelet counts or typical routine ultrasound can detect an enlarged spleen. And there are some other imaging methods that can detect evidence of portal hypertension without actually having to go through complicated procedures. So we do have some data there.
I think that's still available on our website. And we found that it was a reasonably comparable exposure. So there was not a real large difference just about a twofold increase in steady-state exposures. And as you can see in the baseline demographics, you can detect that many of these patients had evidence of portal hypertension. So we'll - as Sujal said, we'll continue to expand the study of this important population.
We so far feel like the experience has been favorable. And then one last question that we've been getting from clients is, in the past, we have spoken with strategic partnership on seladelpar in NASH. But maybe what would be helpful to understand is, are the strategic players who are interested in NASH, maybe the same players who are interested in and having a therapy such as seladelpar in PBC, if you could just comment on that to that to the extent you can, that would be helpful for us?
Happy to address that. In the one case, you have a highly prevalent disease for which there are no current treatments with respect to NASH. I think some growing level of questions around regulatory hurdles as well as profiles for agents that have been studied to date in that setting.
PBC is an area of high unmet need as well. And although there are 2 approved treatments, there are significant unmet needs for PBC patients. A very straightforward regulatory pathway, of course, in the setting of PBC in an area in which we have a significant data that we believe continues to derisk seladelpar. When you asked specifically about strategics, I think there are certainly some who are focused in the liver space in both large unmet need areas in highly prevalent diseases like NASH as well as an interest in areas like PBC.
Although there are also some that are more specifically focused on rare - in orphan diseases versus others that really are predominantly focused on a disease like NASH. So it's a bit of a bifurcation, Yas, but I think there are quite a few players that are solely focused in the area of NASH, and then there are some that have a more holistic approach to treating patients with liver disease. This is Timur Ivannikov on for Steve Seedhouse.
So I just wanted to clarify. It sounds like you haven't started dosing in your Phase III response study. So if you just can clarify that? So we see 11 sites are up in the U. Or is it more by competition? Because you think Janssen is trying to read out around the same time line as you are? Good question. So we are, in fact, screening and randomizing patients in that study. To address your question around the sites that are updated on clinicaltrials. They're not seamless in terms of time lines to getting that information uploaded.
That was a study for which we had actually activated sites in plus countries around the world. Of course, in the U. And then when we look at countries in Europe, these are things that we do really largely in parallel. So what you see is a reflection on clinical trials is simply where we've been able to accelerate the approval processes from IRBs and Ethics Committees.
In some cases, those take longer time lines, just depending on the country. But I simply say that the process internally here is one in which we try to parallel as many of those country and site activations as we possibly can. Of course, they don't all happen instantaneously. It is a process in which we expect these to continue to accelerate through the rest of this quarter and beyond. It's a good question. Once again, in that study, those patients would not have had a second biopsy until perhaps 2 to 3 years into the long-term study.
And so as we've discussed in the past, the change here with respect to RESPONSE, that patients that do volunteer to have a baseline biopsy will have a second biopsy at 52 weeks as an additional safety assessment. And although it's voluntary for patients as to whether or not they elect to get a biopsy in this study, it is required for us to have a subset of patients, of course, for an additional safety assessment at the time of NDA submission.
We've had a very open dialogue with the agency around this threshold. This was not prescriptive. It was a very constructive dialogue, I would simply say, and we're confident that we can meet the requirement that's set forth for us here. Just curious if you have any further physician KOLs plan to keep the community engaged during this time?
And I know it's early, considering you just brought on Lewis as Chief Commercial Officer, but what pre-commercialization efforts - I guess, when will those efforts begin to ramp? And what will those look like? Thank you for the question, Patrick. We're like-minded, by the way, with the suggestion in your question. We've actually already begun some of the work around market research and pre-commercial efforts. So Lewis has, of course, come on board this week and really hit the ground running.
It is absolutely our goal to continue to communicate our strategy and our pre-commercial planning and commercial plans, ultimately. And I would simply say this, Patrick, I think as Lewis gets integrated to the team here internally and the work that's already been done and continues to effectively help us think about the commercial strategy for seladelpar going forward, we will, in fact, look to have an Investor Day in the second half of the year, perhaps even 2.
One, that I would envision being centered around seladelpar for PBC, anchored around some of the opportunities, we think, with respect to commercial opportunity for seladelpar and perhaps even life cycle management going forward. And then potentially a second that's more centered around the earlier-stage pipeline with respect to MBX and CB Of course, our goal is to make sure that there's a meaningful amount of update and information for us to share.
But I would absolutely envision us doing that in the second half of this year. Got it. That's helpful. And I know you've talked about primary sclerosing cholangitis before. I would love to hear how you're currently thinking about the potential of seladelpar in this indication?
And kind of ultimately, just how you're thinking about a go or no-go decision in pursuing this indication at the moment? No, another good question, Patrick. Look, I think fundamentally, there's no question in our mind that the opportunity for seladelpar in PBC is a central focus, and one for which, as we've discussed. If we execute appropriately, we have an opportunity not just to be preferred second-line treatment alternative of choice, but potentially to collect data sets that really start to expand the overall addressable patient population potentially in a very significant way.
And so we continue to remain highly focused on that objective. We do believe based on the profile of seladelpar in PBC as a cholestatic disease, that there is, of course, promise potentially for the potential of seladelpar in the setting of PSC. There's no question patients with PSC are more heterogeneous, often with more advanced fibrosis, often with biliary strictures, complications also including comorbidity with inflammatory bowel disease.
So it is a more complex patient population. And our approach here, Patrick, is really to think about 2 things. One, just the early focus for us to make sure that we get RESPONSE enrolled as quickly as possible, the most near-term derisked opportunity; and then two, to really reconvene with a set of experts in the setting of PSC, where we're continuing to learn more and more about the disease and about treatment alternatives. And then really put together the right development program in a setting of PSC and communicate that when our plans are effectively set and we're ready to act behind it.
But it remains an area of focus. It is an area that we recognize as high unmet need. And when we step forward into PSC, we want to do so with a really meaningful and focused development program that's going to generate the kind of data set to really inform a path forward. It's William Wood [ph] on for Mayank Mamtani. I was curious, how does the kind of label update read through to seladelpar?
Well, I think - again, perhaps I'll invite Chuck to talk more specifically about what we know today. Of course, we only know what's been made publicly available by Intercept to date. And we don't yet have the revised label, of course, for medical [indiscernible] just yet. We recognize that very likely as Intercept has articulated that there could be further restrictions, particularly for patients with compensated cirrhosis and clinically significant perhaps portal hypertension. As we've discussed, this is a patient population for which we've collected some data.
In addition to having a sense of the efficacy, which is comparable in the subset of patients we've studied thus far with compensated cirrhosis as it is with those that are non-cirrhotics, we also see comparable safety to date in those subset of patients. We think that could be potentially a significant differentiator, but there's much more data for us to, of course, collect. But perhaps, again, here, I'll pause and see, Chuck, if you'd like to add any additional color?
I think that's a pretty good summary. Just to reiterate, it's really important that you study a broad population of PBC patients. You would typically expect that if you're safe and effective, that the population you study will be the label that you receive. But even beyond that, there's a potential for patients who are treated once a drug is marketed for those patients to progress. And if they progress into advanced disease that hasn't been studied, that's a problem.
So you do have to study those patients even if you're not seeking an indication. But for us, I think right now, the inclusion, the eligibility criteria really has been non-cirrhotic and compensated cirrhotic patients with PBC. We have included some patients with clinically significant portal hypertension. And if we can confirm the benefits for safety and efficacy, it's the potential path forward for us to have that to be the indicated population, but we'll have to see - wait and see what RESPONSE tells us.
And then one second question. Could you provide any update on how you are thinking of the next steps in NASH? Look, I think our strategy is really consistent with what we've outlined in prior calls. With our focus on PBC, the plan fundamentally, based on the data set in NASH, is to have conversations with other strategics who particularly have assets that can complement the effects we've seen with seladelpar.
Just as a reminder, we saw significant effects, in fact, on reducing fibrosis. In our Phase IIb study, although the study wasn't designed to show statistical significance there, we did see meaningful effects. The overall profile of seladelpar is an anti-inflammatory.
And now with these data showing the anti-fibrotic effects, we think could be quite complementary to target that otherwise can either cause weight loss or a more significant reduction in total liver fat. And so these are things that we've talked about. We continue to talk about with other strategics. Also very important that any path forward brings with it a partnership with significant resources.
Today, we do believe that the most fruitful and derisked opportunity for us is to continue to conserve our capital for what is a very near-term significant opportunity, we believe, in PBC, first and foremost. And so we've articulated that we will not carry forward once again in NASH solely on our own, again, without a partner with significant resources and the right complementary assets. So those conversations are ongoing. They continue. Of course, they're never done until they're fully completed.
But we do think seladelpar has a promising profile here, and we'll continue to carry on those conversations. This is Matt on for Jay. We were wondering if this compound has any CNS penetrability and if that's something you're looking at in the Phase I study?
And then also which potential indications, I know it's early, but at the moment, could you potentially envision pursuing ultimately with that asset? That would be great. Thank you for the question. This is Chuck.
Well, I would say fundamentally that we have not seen - we don't believe that this would be a drug that would potentially be targeted towards CNS indications. We do think this pathway, the NLRP3 pathway we recognize has got a lot of attention with respect to [indiscernible] generation, but that wouldn't be our focus. In terms of what we might focus on, I will say that we're very excited based upon the clinical validation of the target and a lot of emerging science in inflammatory driven diseases, including ones that drive fibrosis.
We're not really ready quite yet to give any specific guidance, but I think it would - suffice it to say that for us, it starts with the scientific rationale, the medical need, is there a medical need here? Do we believe that it would be differentiated? Development possibility is there a regulatory pathway? Is it feasible to accrue patients and do a trial in a capital-efficient way that gives a meaningful result? And then, of course, there's always the business case.
We have to understand the market, what the unmet need is, but the existing therapies, if any, and if there are any emerging therapies so that we have a full view of the landscape before we make a decision. So I think as we alluded to before, we think that once we have the Phase I data and we've completed some of our diligence around making a selection from honestly, quite a number of opportunities that fit what I've just described, we'll be able to communicate that in the latter half of this year.
And then we were just curious if you could please remind us actually the expected IP expiration on seladelpar? Really appreciate that. Yes, absolutely. So seladelpar has composition of mattered to , the lysine salt form, which is the only form that's being developed carries to And that's without the potential for an additional 5-year patent term extension. Importantly, in the setting of PBC. And then also, we have orphan drug designation in the U. So the exclusivity associated with orphan drug designation exists for seladelpar in the setting of PBC as well.
And congrats on the recent progress, including the filling of your executive team. Some of the questions I had already been asked and answered, but I did have a couple related to MBX You had mentioned that your goal is to enroll 30 subjects via the investigator who's doing this by the second half of this year. And the primary endpoint is maximum glucagon release. My two questions around this program are where does that endpoint fit in sort of the regulatory pathway?
How well-defined and validated? Is there a pathway for this specific indication? And then related to that is, what exactly does the landscape for this indication look like? And where would you potentially see it fitting in, if indeed there are others already in the market? Yes, I'd be happy to take that question, Ed. Thank you.
It's a very interesting and important question. Just to emphasize that the study that we've started is a proof of pharmacology study. So as what you've alluded to, it's not actually directed at what you would expect to be a regulatory endpoint. The first thing that we're trying to establish is that we can affect the increase in glucagon secretion in response to the hypoglycemic clamp. So low sugar - low blood sugar conditions.
That will be benchmarked. The study includes both type 1 diabetics and healthy volunteers. So we'll be able to benchmark the responses that we see in the diabetics versus what we see in the healthy volunteers. Now we also do include continuous glucose monitoring in the study. So we'll look - be able to examine the effects on restoring glucose levels as well. So that's an important aspect to it.
In terms of the product concept, there is no product on the market right now that's a preventative for hypoglycemia. And so the challenge for a type 1 diabetic who's using insulin to try to control their blood glucose, there are always concerns of potential risk inducing - insulin-induced hypoglycemia, especially, as you know, type 1 diabetes could be something that emerges in childhood or adolescence. So you have families that are concerned about their children.
Hypoglycemic episodes can happen nocturnally overnight while you sleep. So there wouldn't be anybody around to help deal with the situation. Now they're typically dealt with, for example, just by taking glucose by mouth. You can take glucose pills. And - but there are marketed rescue therapies, glucagons, sublingual glucagon.
There are glucagon pumps that are being developed as well. But these are all just rescues. They don't actually deal with the unmet need of having a preventative, really providing the patient and their families with the confidence that they no longer have to be concerned by low blood glucose. And that they basically can be more intentional about using their insulin appropriately to get better glucose control. I think in terms of regulatory endpoints, I'd just say that this would be a first.
So that would, of course, have to come through, first, developing the concept, conversations with experts, regulatory interactions. But in our mind, in early discussions, it would really be about preventing either moderate or severe episodes of hypoglycemia. And so those have clinical definitions with various levels of glucose concentrations that define those.
And you could use continuous glucose monitors as a way to make the measurements to evaluate the endpoints. That's very helpful. And so just as a follow-up, how would you envision moving forward, taking over from AdventHealth? Were you to see significantly positive effects here that would lead you to want to move forward with this asset? Well, I think we would take the approach that we always take, which is we engage with external experts and develop a deeper understanding of the indication, the patient need, the clinical development as well as what we would understand to be the regulatory environment.
So that would require specific regulatory interactions to help define it. And then of course, importantly, you're not going to make significant investments without doing a deeper dive, a full analysis on the business case, what is the commercial opportunity like? And then finally, we'd have to evaluate what's the strategic fit with CymaBay at the time? Where does - where our other assets lie? What are our aspirations? And does the company want to become and we make a decision assuming all of those things lined up, what's the best for the asset?
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