A First-in-Class Approach to Treating a Rare and Chronic Liver Disease

December 31, 2021

Primary biliary cholangitis is a rare, chronic, progressive, autoimmune disease of the liver. People with the condition suffer from inflammation, destruction of the intrahepatic bile ducts, and accumulate toxic bile acids that cause damage over time. The condition can lead to fibrosis, cirrhosis, and liver failure. CymaBay Therapeutics is developing an experimental therapy, Seladelpar, as a treatment for PBC. We spoke to Sujal Shah, president and CEO of CymaBay Therapeutics about PBC, Seladelpar, and why this first-in-class therapy has promise to address this condition with high unmet needs.

Daniel Levine: Sujal, thanks for joining us.

Sujal Shah: Thank you for having me.

Daniel Levine: We’re going talk about CymaBay, the rare liver disease, primary biliary cholangitis, or PBC, and your experimental therapy to treat it. Let’s start with PBC. For listeners, not familiar with the condition, what is it?

Sujal Shah: PBC, or primary biliary cholangitis, is a rare, progressive and chronic autoimmune liver disease. The disease is actually characterized by impaired bile flow, or cholastasis, and it leads to portal inflammation in the liver, and even a destruction of the intrahepatic, small bile ducts in the liver that are responsible for taking the bile acids produced in the liver and transporting them to the gallbladder and to your intestine for essential digestion. As that bile acid builds up, eventually it leads to an overall destruction of intrahepatic bile ducts. From that you get chronic inflammation, fibrosis, and eventually cirrhosis, which leads to the need for a liver transplant. Now, a couple of other quick things I’ll mentioned about PBC. The disease itself is marked by elevations in serum markers of cholastasis, including the enzymes alkaline phosphatase, or ALP, gamma GT, and total bilirubin. I’ll also mention that clinical symptoms of the disease include fatigue, an intense level of fatigue, and pruritis, or itching, which can severely impact quality of life for patients. PBC, as a rare disease, actually affects about one in 1000 women over the age of 40. There is a preponderance of this disease in women versus men, not well understood, but say 90 percent of the cases are in fact women. So, in the United States there’s approximately 130,000 people known to have PBC.

Daniel Levine: How is the condition generally diagnosed these days?

Sujal Shah: So, the diagnosis of PBC has evolved. Originally you would require a liver biopsy and an assessment by a liver pathologist. Biopsy is no longer required to positively diagnose PBC, in fact, it can be one of three measures used, but you can do so in the absence of biopsy with an elevation of alkaline phosphatase, or ALP, well above the upper limits of normal plus positive anti mitochondrial antibodies. As an autoimmune disease, a vast majority of patients, in fact, have autoimmune mitochondrial antibodies, auto mitochondrial antibodies. So, a positive AMA plus elevated alkaline phosphatase—those two criteria can positively diagnose PBC in the absence of the need for a liver biopsy. In fact, it’s not very common today to require a biopsy to diagnose PBC although it can be used as one of those three confirmatory measures to diagnose PBC.

Daniel Levine: So, would a doctor pick this up with a simple routine blood test or would they have to be looking for this?

Sujal Shah: Great question. It’s not uncommon for patients to be diagnosed sometime later in the disease because it’s not a routine measure to look at alkaline phosphatase. I think what you would typically find is a patient experiencing some significant level of fatigue. And I should be clear here. PBC related fatigue is not like many of us might experience when we think of fatigue—when we’re tired or haven’t gotten a lot of sleep. The type of fatigue patients experience includes things like overall brain fog or some patients will describe a feeling like they’re in quicksand. They just cannot get themselves to move. Many patients can’t get themselves to leave their home or their apartment, even just to go out is a significant challenge. So, it’s a chronic level of fatigue that’s quite debilitating. It’s often either this feeling of fatigue or pruritiis that would then lead a physician, or more often a gastroenterologist once a patient is referred, but even a primary care physician to then order a lab test to look at the serum markers of alkaline phosphatase. And so that’s typically when someone realizes that a patient is likely to have PBC and again, is confirmed with the positive AMA test.

Daniel Levine: You mentioned the itching, I think for most people that haven’t experienced a disease like this, itching doesn’t sound like a horrendous symptom, but when I hear patients who actually go through this it’s, this is not just normal itching. What’s it like to live with a condition like this?

Sujal Shah: Yeah, and another great question. Including myself, we have spent a significant amount of time with patient advocacy groups, a significant amount of time understanding the disease from patients themselves and the pruritis that patients describe. First of all, I’d like to at least articulate to the average person that this is not an itching like many experience on their skin, for example, where if you have a mild rash or some dry skin and you itch, then at the end of the day, you can scratch that part of your skin and get some relief, even if it’s only temporary or put some ointment. Cholastatic itch, as it relates to pruritis-related PBC, is almost internal, if you will, and therefore, when a patient has the sensation that their arm or their leg is itching, they’ll scratch to no avail. There’s no relief from scratching. In fact, the scratching is just a trigger mechanism to attempt to relieve that itch. But it doesn’t have an effect because this itch is almost generated internally, believed to be associated with a build-up of bile acids or a composition of specific bile acids, not overly well understood, but that’s the leading theory in terms of how this itch is generated. Patients will scratch to the point of breaking skin and bleeding. And it’s not just the itching in private, it’s being at a restaurant and having dinner and not being able to control yourself from scratching multiple body parts, and then the psychological effect of feeling as though people are looking at you, or just feeling like you’re standing out in public has a significant psychological detrimental effect. Once again, on overall quality of life, mental health, emotional health, that’s really what this cholastatic itch does to patients. And you’re absolutely right. It’s quite extraordinary versus how we think of common derm itch, and quite debilitating for these patients.

Daniel Levine: How is PBC treated today and what’s the prognosis for someone with a condition?

Sujal Shah: So, the disease, generally speaking, is a slowly progressing chronic condition. It’s not uncommon for patients with progression from inflammation to fibrosis, to cirrhosis, to the need for liver transplant, for that path to take anywhere from 10 to 15 years. There are certainly patients that progress much more quickly in that path, and in fact, when patients are diagnosed at a younger age, often the disease is much more progressive over its time course and progresses more quickly. That gives you a general backdrop of disease progression. Even in between that 10 to 15 years it may take for a patient to progress to cirrhosis and the need for liver transplant is significant suffering for patients and health challenges all throughout. So, it’s not that you live a healthy life for 10 to 15 years, and all of a sudden you have cirrhosis. It is a very challenging disease to even live through. Of course, in that timeframe, there are only two drugs approved for PBC patients today. The first drug is called ursodeoxycholic acid, or UDCA, is a that is first line therapy for patients with PBC. All patients once diagnosed will initiate a therapy with UDCA, and almost all patients have some benefit from UDCA. What is that benefit? I think largely that benefit is to reduce the level of alkaline phosphatase in the liver of patients and ultimately to help flush the bile ducts or reduce the level of cholastasis, and therefore effectively slow the progression of disease. It’s certainly not a cure.

We don’t have a cure for patients with PBC today, but UDCA has been shown over the years to actually improve outcomes for patients. Clinical studies that have been conducted to get ursodeoxycholic acid approved, this is now 30 years ago, have been shown to improve transplant-free survival for patients, and so that’s the therapy that’s initiated as a first line. It’s a generic treatment for patients today, although it’s not cheap. I would say in many ways it can cost several thousand dollars a year, but that is first line treatment. And as I mentioned, most patient have at least some benefit. There is small a percentage of patients, maybe around 5 percent that are intolerant to treatment. What does that mean? It generally means they have either some GI issues or some other challenges. As they would take UDCA daily and therefore are intolerant, the more significant proportion of patients that are not fully, or completely treated with UDCA maybe as large as 40 percent of those patients who we would describe as having really an incomplete response to UDCA. What does incomplete response mean? It means a patient’s alkaline phosphatase and level of cholastasis is quite advanced and they take UDCA and they have some improvement. Their alkaline phosphatase, for example, let’s say it’s three times the upper limit of normal at diagnosis and maybe that patient gets down to two times the upper limit of normal. So, there is a reduction, but they’re still highly elevated, double the upper end of normal limits. Therefore, although there’s some improvement and some reduction in disease progression, they’re still at an elevated level of risk of progressing disease. So, that’s a patient we would characterize as having an incomplete response or an inadequate response to UDCA today. And as recently as 2016, the first ever drug approved for second line treatment for those patients who are either inadequate responders to UDCA or intolerant is a drug called obetacholic acid. The brand name is Ocaliva. Ocaliva is an FXR agonist so it’s a different mechanism than UDCA, and in the phase 3 clinical studies, if you look at the label for Ocaliva, you will see that just under 50 percent of patients that took Ocaliva, either on top of UDCA, as inadequate responders, or as monotherapy for those that were intolerant, actually met the primary endpoint of having a reduction in alkaline phosphatase, bringing it below 1.67 times the upper limit of normal with at least a 15 percent drop in alkaline phosphatase and normal bilirubin measured at 12 months. So, there are patients that benefit from Ocaliva in terms of their level of cholastasis and alkaline phosphatase and will have some further improvement in reducing the risk of disease progression. But they’re still, according to their phase 3 data, another 50 percent of patients who remain as inadequate responders, their alkaline phosphatase doesn’t drop to the point of meeting that primary endpoint. They are deemed to be, again, incomplete responders or inadequate responders even to obetacholic acid, or Ocaliva, as second line treatment. There is one other challenge with the obetacholic acid in particular that I’ll highlight, but another challenge I’d like to point to first is that drug can actually cause or worsen pruritis in PBC patients. It’s believed that up to 70 percent of PBC patients have experienced pruritis at some point in time in their disease and those that take Ocaliva as second line treatment, if they already have some itch that itch can actually worsen, and if they don’t have itch, they can actually start experiencing itch. And so there’s a significant tolerability issue with obetacholic acid that patients experience. Finally, there have been some challenges around overall safety, particularly in more advanced PBC patients and those are reflected in black box warnings for Ocaliva that are also on the label. So, as I described to you, this picture of only two treatment alternatives for PBC patients today, hopefully you can appreciate that the unmet need today remains for treatment alternatives with greater efficacy, the ability to actually further reduce the risk of disease progression and in a greater proportion of patients and then a need for better tolerability. As I mentioned, Ocaliva can cause worsening itching; UDCA, although it’s not known to cause or worsen itching, it’s also not known to actually improve itching. In fact, there’s nothing approved for patients today that have PBC related pruritis, so there is also a need to address this clinical symptom burden that patients experience. Finally, given the black box warnings for Ocaliva and more advanced patients, I would say there is yet a third stool of need, which is a safer treatment alternative for patients.

Daniel Levine: What is PPARd (PPAR delta) and what role does it play with regards to PBC?

Sujal Shah: Great question. PPARd  is a nuclear receptor that actually drives metabolism, transport, storage of fatty acids. That’s a fundamental mechanism of PPARd. Now in the liver, there are pluripotent benefits of agonizing PPARd, and drugs that agonize PPARd  like Seladelpar, in fact, will upregulate various genes and downregulate various genes involved in these metabolic processes. Importantly, PPARd is expressed in all four major cell types of the liver. It’s expressed in the workhorse cell type in the liver called hepatocytes, which makes up much of your liver tissue. But it’s also expressed in Cooper cells in the liver, which are the resident macrophages, or inflammatory cell type, stellate cells, which are responsible for initiating collagen synthesis and the fibrotic process, as well as cholangiocytes, which line the inner wall of bile ducts. PPARd are expressed in all four of these major cell types, and in fact, we think is quite specifically suited for chronic inflammatory liver disease. I’ll give you just very quick highlight of why we think PPARd in particular is a great target for chronic inflammatory liver diseases. First of all, in hepatocytes, PPARd agonism actually decreases bile acid synthesis. In PBC, part of the challenge is bile acid builds up in the livers of PBC patients. Given the destruction of the intrahepatic bile ducts, which, are used to flush out bile acids, you have a buildup of bile acids in the liver in diseases like PBC. And so Seladelpar actually regulates PPARd by agonizing PPARd and inhibiting the synthesis of bile acids. Now bile acids are actually created from the precursor cholesterol, which are converted into bile acids and PPARd agonism also decreases cholesterol synthesis. So, you decrease the substrate and you also decrease the synthesis of bile acids themselves. Also, in the hepatocyte PPARd agonism drives fatty acid oxidation, you burn triglycerides and that reduces fatty acids. It also inhibits cholesterol synthesis. So you see this reduction in LDL cholesterol and PBC patients aren’t necessarily at a risk for cardiovascular disease, but they all often can have slightly elevated cholesterol. That is an added benefit to these patients with a drug that agonizes PPARd like Seladelpar that is in contrast to obetacholic acid, which actually increases LDL cholesterol that is not a major concern in PBC patients as it is in fatty liver diseases like NASH, for example, but those are two actions of PPARd in hepatocytes that are quite important. Another key element of the action of PPARd, particularly in the liver, is that it’s anti-inflammatory because it’s expressed in the resident macrophage cell type in the liver (Cooper cells) as well is in circulating macrophages outside the liver. It’s known to actually decrease NF Kappa B-dependent gene activation—so a very fancy way for me to say that it’s anti-inflammatory, it reduces inflammatory cytokines. And because PBC is a chronic inflammatory liver disease, this anti-inflammatory benefit we think is quite important to the longer term potential outcomes for patients. Finally, PPARd is expressed in these stellate cells of the liver, where it’s known to actually be anti-fibrotic. It effectively arrests these stellate cells in the quiescent state and actually decreases collagen synthesis and deposition. This anti-fibrotic effect—even PBC will progress from inflammation to fibrosis to cirrhosis–this effect we also believe has a potential to lead to better longer-term outcomes for PBC patients. So there’s a variety of different effects of PPARd, in particular, that we think is quite well suited for chronic inflammatory liver disease.

Daniel Levine: What’s known about the safety and efficacy of Seladelpar from studies that have been done to date?

Sujal Shah: We’ve actually been studying Seladelpar specifically in PBC patients since 2015. We have had Seladelpar in north of 300 patients with PBC where we’ve actually seen very good safety and efficacy. Just focusing for a moment on the safety review, it’s important for me to point out as a drug developer, it is our responsibility to measure and assess safety for the life of a drug through development, but also from commercialization through the life of commercialization for any drug, so we’re always learning more about the overall safety of any drug in any indication even after it’s approved. And I can tell you, at least to date, Seladelpar has been shown to be safe and well tolerated in PBC patients. We’ve studied Seladelpar as low as two milligrams and all the way up to hundred milligrams in patients with PBC. And we’re focused today on our current phase 3 study for registration of Seladelpar in PBC at 10 milligrams. At 10 milligrams, we see some of the things that I mentioned to you earlier as potentially meeting unmet needs for patients with PBC. We’re seeing greater efficacy than we’ve seen with the drugs that are already approved. I should point out, I’m not giving you that assessment from head to head data, as opposed to independent studies, largely in the same patient population, but we’re seeing this improved efficacy. We’re seeing a greater proportion of patients have improved efficacy. We are seeing an anti-inflammatory effect in patients, and we’re also seeing an anti-pruritic effect, and that’s one of the things that’s really exciting is our data is showing the ability for Seladelpar to actually reduce pruritis. Now we’ve got to confirm it once again in our ongoing phase 3 study. I know we’ll get to some of the data elements here shortly, but those are some of the promising things we’ve seen, and we’ve seen it in the backdrop of very good safety in patients. Overall, I’ll give you a couple of summaries here. We haven’t seen anything at the doses we’re studying today and the 10-milligram dose that we’re studying in phase 3 that would prevent us from completing this phase 3 and potentially registering Seladelpar, if successful, and launching this dose as a chronic treatment alternative for patients. And again, this would be chronic treatment. They would take Seladelpar, if approved, once a day through the rest of their life to help slow the progression of disease and hopefully not ever progress to a liver related outcome, including the need for liver transplant. So, we’ve not seen anything from a safety review perspective that would cause concern. PPARd, in particular, outside of the liver is expressed in muscle. So that’s a tissue in which you have to have some diligent assessment of either causing muscle pain or myalgias, we haven’t seen anything related there at these doses that would have any concern from us continuing to progress. So, I think those are the important, the other things we’ve seen in clinical studies are things that are not uncommon to see in general. So, the most common things are patients that still experience some pruritis, that’s a common adverse event that’s measured, or at least assessed in clinical studies, or abdominal pains, nausea, headache. These are some of the more standard things that are not atypical to see and nothing that we’ve seen of concern relative to Seladelpar versus placebo in a prior, truncated phase 3 study that we had conducted.

Daniel Levine: What’s the path forward to filing for an approval?

Sujal Shah: As I mentioned, we’ve conducted phase 2 studies with significant dose ranging. Those studies actually dosed patients out to a year, and 95 percent of those patients elected to stay on treatment into a long-term study. In fact, recently at the liver meeting, ASLD, in November of this year, we reported data for a little over 50 patients out to two years of treatment where we see the effects actually continue to improve from one year to two years. And we still see good safety overall in that population, some really exciting data, but even the one-year phase 2 data led us and supported us moving into phase 3. We currently are enrolling a global phase 3 registration study called RESPONSE, the details of which can be found on clintrials.gov, and PBCclinicalstudies.com. We’re enrolling right now this global phase 3 study that would, if successful, we believe allow us to register Seladelpar in the U.S., as well as in Europe. We continue to look for opportunities to bring Seladelpar more broadly globally outside of those two key regions. But currently we’re enrolling in this phase 3 study RESPONSE. We anticipate that study completing enrollment in the first half of next year. It is a 12 month dosing period, so 52 weeks of treatment. And so, if we’re successful at completing enrollment in the first half of next year, approximately 13 months from the last patient into the study, we would have top line results from that RESPONSE study, say Q2 or Q3 of 2023. And once again, if that data is positive, if it reflects the data we’ve amassed to date in a significant number of PBC patients, we would then look to file for approval, by the end of 2023 for a 2024 approval and launch.

Daniel Levine: This is a molecule that was originally licensed from Janssen Pharmaceuticals. Are they playing any role in the development or commercialization of Seladelpar?

Sujal Shah: Great question. You’re right. It’s actually quite an interesting story. CymaBay was developing another molecule to address some unmet needs in type 2 diabetes and that was a very promising model in phase 2 at the time—this is in the 2000s—that the company was looking to out-license. The rights to that drug—type 2 diabetes obviously is a very large disease and requires a significant amount of capital—so as they entertained licensing discussions, which were quite competitive, the company had the foresight to ask those interested to not only offer economics for that type 2 diabetes potential drug, but also offer in return another clinical asset that CymaBay could wholly own. And so CymaBay received Seladelpar, as you mentioned from Janssen in this prior transaction and effectively as a quit—there was no upfront payment, there are no trailing milestone obligations. We do owe Janssen a 5 to 8 percent royalty if the drug is approved. But outside of that, the drug is wholly owned by CymaBay and CymaBay is really conducting the entirety of the development program in PBC.

Daniel Levine: And is the expectation that you would commercialize this on your own, or are you going to be seeking a partner?

Sujal Shah: So, one of the great things aboutfocusing in rare disease is the ability for companies like CymaBay really to go end-to-end from development all the way through commercialization and ultimately achieve the objective that we all care about inside the walls of CymaBay, which is to put this drug in the hands of patients that can benefit and in the hands of as many patients with PBC that can benefit. And so, as a rare disease, at least in the U.S., it requires a relatively reasonably sized salesforce. Perhaps the salesforce is as small as 40 to 50 sales reps with perhaps another dozen medical science liaisons, these specialty individuals, and that is something we fully believe we can build. Therefore, we are expecting to commercialize Seladelpar at least in the U.S. on our own. We recognize that outside the U.S. there are additional challenges. We can certainly look to commercialize Seladelpar in other regions outside the U.S., but at least at present, we’re having discussions and evaluating opportunities to potentially license the rights to Seladelpar outside the U.S. Again, we’ve not made any final decisions. As I mentioned, this phase 3 study we believe would give us the ability to register Seladelparvin the U.S. and in Europe. So at a later date we’ll make a final determination around how to commercialize outside the U.S., but fundamentally it is absolutely a goal for us to commercialize ourselves in the U.S. and then work either ourselves or with others to bring this drug to as many patients outside the U.S. as possible that could benefit.

Daniel Levine: What are you doing to build a pipeline behind this?

Sujal Shah: So, today we are very focused on this opportunity for PBC patients, so a vast majority of our internal operations and our capital resources are in fact, dedicated to Seladelpar in PBC. The company has had a long history of drug discovery and development. In fact, we do have another asset in phase 2a, early proof of pharmacology study to assess the potential for that compound. MBX-2982, a GPR 119 agonist, another oral once daily GPCR compound that has the potential, we believe, to prevent hypoglycemia, particularly in type 1 diabetics. That’s at least what we’re exploring. It’s very early days I should caution. And that study is being fully funded today by the Helmsley Charitable Trust. So, we’re not having to spend our internal capital resources on this program today. That phase 2a study is enrolling patients. We believe we may have the opportunity to see that dataset sometime in 2022, and then make a decision on whether or not we progress that program ourselves through further into phase 2 development, or whether we look to out-license it to another player more specifically suited in metabolic disease. I will say that we think Seladelpar in chronic inflammatory liver disease may have the potential to be studied in a variety of rare diseases. PBC, again, is our central focus based on the significant amount of data we have amassed to date and the benefit we believe that Seladelpar has the potential to bring to patients, but there are other rare cholastatic liver diseases. One in particular is a disease called primary sclerosing cholangitis or PSC. There are no drugs approved for patients with PSC. It is a more complex disease than PBC, more heterogeneous in fact. And so, development in PSC carries significant risk as well and uncertainty, at least in terms of showing efficacy, but that’s a potential area where we do believe there’s an opportunity for us to develop Seladelpar at least to investigate in a phase 2 study the potential merits of addressing the needs for patients with PSC. So, within Seladelpar there are opportunities to expand. And then finally, we are always looking for opportunities to potentially in-license or bring in other assets or generate early lead compounds that could help us advance our pipeline. But again, I will finalize by saying, we are very dedicated to PBC patients and, in the near term, trying to advance care for those patients,

Daniel Levine: You recently completed a $75 million offering. How is that funding being used and how far will it take you?

Sujal Shah: We absolutely have done a great job over the last few years in ensuring that we have a balance sheet to execute on our goals. Our goal is really to bring Seladelpar all the way to patients. This recent $75 million raise backed by very experienced dedicated biotech focused investors really gives us the ability now with the cash already on hand to complete, not just the phase 3 Response study, but to complete the entirety of a phase 3 program that would position us to be able to file for registration and for approval. So this additional $75 million importantly takes us through the anticipated timeline to top line data with cushion with at least six to nine months of additional cash runway. Again, if we hit our timelines for enrollment and top line data, it gives us the ability to get through the study, to release the top line data and have adequate cushion thereafter.

Daniel Levine: Sujal Shaw, president and CEO of CymaBay Therapeutics, Sujal thanks so much for your time today.

Sujal Shah: I appreciate it. Thank you for having me.


This transcript has been edited for clarity and readability.

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