Cynthia Levy, MD: Seladelpar for PBC and the IDEAL Trial

Cynthia Levy, MD

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A new phase 3 study from CymaBay Therapeutics is seeking outcomes associated with seladelpar on levels of alkaline phosphatase (ALP) in patients with primary biliary cholangitis (PBC).

The recently announced IDEAL trial intends to enroll 75 patients with a history of incomplete PBC to be treated with the targeted receptor agonist currently in investigation for a handful of hepatic and metabolic conditions.

In the second segment of a Q&A with HCPLive regarding seladelpar and the IDEAL trial, investigator Cynthia Levy, MD, professor of medicine at the University of Miami, detailed the makeup and mechanism of action seen with seladelpar, key outcomes set for the IDEAL trial, and what the late-stage assessment may bring to the field of PBC.

HCPLive: What is our understanding of seladelpar prior to this phase 3 trial? What may it provide in treating liver disease?

Seladelpar is a PPAR delta agonist. PPAR agonists have been shown to have anti-cholestatic, anti-inflammatory properties. In terms of seladelpar’s potential, what we’ve seen from the phase two clinical trials is that:

1. It significantly improves ALP levels and leads to normalization of ALP in a subset of patients
2. It has a favorable effect on the lipid profile, and
3. It seems to have similar efficacy and safety in both cirrhotics and non-cirrhotics.

Perhaps as remarkable as the efficacy in terms of biochemical endpoints, we are also seeing a favorable impact on pruritus. To me, this is extremely important because that is what the majority of patients are suffering from. In the phase 2 trial, we saw patients with severe itching experience significant improvement over the course of the trial period with treatment with seladelpar. We also learned that improvement in itching correlated with improvement in sleep. Upcoming trials will also investigate whether treatment with seladelpar leads to more significant improvement in fatigue.

HCPLive: Can you discuss both the planned 52-week alkaline phosphate outcome of IDEAL, as well as any key secondary endpoints you hope to observe with seladelpar?

What’s unique about IDEAL is that this study targets a subgroup of patients who don’t usually qualify for PBC clinical trials. To enter most trials, patients need to have an ALP greater than 1.67xULN, with the goal of lowering ALP below that threshold. With IDEAL, we’re enrolling patients whose ALP is above normal, but below 1.67x ULN, to see if they will normalize ALP with seladelpar treatment. This is of great interest as we have already learned that many patients within this subgroup of individuals with mild ALP elevation also have increased risk for disease progression.

Secondary endpoints will be looking at safety and the impact of seladelpar on itching. Hopefully we’ll also learn more about the subgroups of patients that can benefit from ALP normalization. As with any clinical trial, patients will be monitored closely for side effects and drug toxicity, although we already have a large body of information regarding safety of seladelpar based on phase 2 trials.

HCPLive: What would progression to significant outcomes with seladelpar in treating patients with PBC mean for the future treatment landscape?

We know that even patients who are on treatment with UDCA can progress toward cirrhosis, decompensation, and death or transplant. Those are usually the patients who have not normalized their ALP or who started with more significant fibrosis. If seladelpar can halt or slow down progression for those patients, it could have a major impact on the overall prognosis. Given the beneficial impact on itching and sleep, the drug could significantly improve their quality of life.

Seladelpar would be a new second line option for patients with PBC, potentially with improved safety and efficacy profile compared to existing alternatives. If seladelpar shows the improvement in outcomes that we are expecting in ongoing phase 3 trials, it could become the next generation of drugs in our standard of care.