CymaBay's study of drug to help patients with persistent elevation of ALP has begun

05-Sep-2023 - Last updated on 05-Sep-2023 at 15:22 GMT

CymaBay announced recently the initiation of its 52-week, placebo-controlled, randomized, phase 3 study — 'Intended to Determine the Effects of seladelpar on normalization of Alkaline phosphatase (ALP) Levels in subjects with Primary Biliary Cholangitis (PBC)' known as IDEAL.

The study, the company says is an opportunity to evaluate the potential benefits of seladelpar in a population that has a persistent elevation of ALP but is not currently eligible for clinical research or second-line therapy under existing clinical guidelines.

Seladelpar is a first-in-class oral, potent, selective peroxisome proliferator-activated receptor (PPAR) delta agonist, or 'delpar', shown to regulate critical liver disease pathways. IDEAL will examine the effect of treatment with seladelpar on ALP normalization for this patient population, as well as its impact on itch (one of the more distressing symptoms associated with PBC).

OSP spoke to Sujal Shah, president and CEO at CymaBay Therapeutics to find out more.

Could you explain more about the population that has a persistent elevation of ALP and what the primary causes are?

Elevated levels of the enzyme alkaline phosphatase, or ALP, in patients with primary biliary cholangitis (PBC) is a marker of cholestasis, or impaired bile flow in the liver. High ALP is associated with higher risk of disease progression in PBC where persistent inflammation can lead to fibrosis, cirrhosis and eventually the need for liver transplant or death.

First-line treatment for PBC is ursodeoxycholic acid, or UDCA. UCDA is a naturally-occurring bile acid that increases bile acid flow and promotes secretion of bile acids. Patients on UDCA experience a decrease in ALP however, 60% or more may never experience fully normal ALP levels and thus remain at a higher risk of disease progression.

What impact does a persistent elevation of ALP have on the body? And please explain a little bit more about PBC in general.

PBC is a rare autoimmune, cholestatic liver disease. A patient’s immune system effectively begins to attack the small bile ducts of the liver, causing chronic inflammation and injury, eventually leading to a destruction of those bile ducts. Bile acids that are normally shuttled from the liver to the gall bladder and then the intestines for the necessary role they plan in digestion begin to accumulate in the liver and become toxic. This contributes to the persistent chronic inflammation that increases the risk of fibrosis, cirrhosis and eventually the need for a liver transplant or otherwise serious consequences, including death.

How does seladelpar regulate critical liver disease pathways?

There are a number of things that seladelpar does that we believe are important in chronic inflammatory liver diseases. It's really a mechanism that has pluripotent benefits. First, important in the setting of PBC, we know that seladelpar inhibits bile acid synthesis, reducing the toxic accumulation of bile acids in the liver resulting in a reduction in alkaline phosphatase and inflammation. These effects may reduce the risk of disease progression in PBC. In addition, we know that seladelpar is directly anti-inflammatory, reducing markers in the liver associated with liver injury and inflammation and anti-fibrotic. In the liver and in other tissues, seladelpar also drives lipid metabolism resulting in reductions in LDL-cholesterol and fatty acids.

Sujal Shah, CEO, CymaBay Therapeutics

Does seladelpar have the potential to work in PBC patients with cirrhosis?

While a majority of the patients we've studied to date with PBC are noncirrhotic, we do have a small subset of patients with compensated cirrhosis. To date, we've seen comparable efficacy and safety with seladelpar in patients with compensated cirrhosis as we've seen thus far in the noncirrhotic population. Seladelpar has the potential to offer clinical benefit in this population, but we are continuing to gather more of this data.

What is happening next in the IDEAL study, and are you optimistic?

We just kicked off screening in IDEAL and this is a study that is intended to enroll 75 total patients with PBC, 50 who would receive 10 milligrams of seladelpar, 25 who would be on placebo. We are targeting a patient population with elevated ALP in this study that does not meet current guidelines for second-line treatment. While we have not yet provided guidance around timelines for completing enrollment and announcing data, we are optimistic about our ability to advance this study efficiently for a segment of the PBC population that has not typically been included in clinical research despite still having risks for progression.

We have seen meaningful effects on ALP normalization in patients that have higher levels of ALP than those that will be enrolled in IDEAL and thus are optimistic about the ALP normalization rates we may see in this study.

Was it easy to recruit for the trial and do you think liver disease is always going to be a major blight on healthcare? If so, what do you think could be done about it on a big scale?

In terms of IDEAL, we've only initiated recruitment in August so it is still early days. The experience we have had running multiple global studies in PBC gives us the confidence that we can execute the study in an efficient manner.

As for liver disease broadly, there are numerous conditions that result in the need for liver transplantation and of course there are not enough livers available for all patients that need them. Whether you are looking at metabolic, autoimmune, or genetic disorders, there is significant need for new therapies for patients with liver disease.