Seladelpar

Seladelpar, originally known as MBX-8025, is a small-molecule drug that selectively activates the delta subtype of the peroxisome proliferator-activated receptor family, a group of nuclear receptors that regulate lipid metabolism and inflammation ^[4]. It was first investigated as a metabolic agent; early trials in overweight, dyslipidemic patients showed that it lowered LDL cholesterol, triglycerides, and inflammatory markers and reduced liver enzyme levels ^[4]. This effect on the liver helped redirect its development toward cholestatic liver disease ^[1].

Its approved use is in primary biliary cholangitis, an autoimmune disease in which the small bile ducts of the liver are progressively destroyed, causing bile acids to accumulate along with fatigue and severe itching, and eventually leading to cirrhosis ^[1]. Standard first-line therapy is ursodeoxycholic acid, but many patients respond inadequately, and seladelpar is used as an add-on in those cases or as monotherapy when ursodeoxycholic acid is not tolerated ^[1].

In the pivotal Phase 3 RESPONSE trial, seladelpar significantly improved biochemical markers of cholestasis, including alkaline phosphatase and bilirubin, and reduced itching compared with placebo ^[1]. An earlier Phase 3 study, ENHANCE, likewise showed benefit on these liver chemistries at three months ^[2]. Investigations into the itch specifically found that seladelpar lowers levels of interleukin-31, a cytokine closely tied to pruritus, which helps explain its effect on this symptom ^[3].

On the strength of these results, seladelpar received accelerated approval from the US Food and Drug Administration in 2024 and marketing authorization in the European Union in 2025, and it is marketed as Livdelzi in the United States and Lyvdelzi in Europe ^[1]. It is taken by mouth as a capsule and carries orphan drug designation for this rare condition, and it is now marketed by Gilead Sciences ^[1].

Because approval was accelerated and based largely on biochemical endpoints, its long-term effect on survival and disease progression is still being confirmed ^[1]. Reported adverse effects have generally been mild, and patients on seladelpar undergo periodic monitoring of liver and muscle enzymes, while gastrointestinal symptoms have also been noted ^[1][2].

It reached approval for PBC after clinical trials, so there is a real human dataset; it was generally well tolerated, with the usual monitoring of liver enzymes. Earlier development saw a muscle-enzyme signal that paused a program, which is why the class is watched for muscle effects. Prescription drug in the PBC setting; the research version is not for self-experimentation given it acts on the liver.

Seladelpar is a substrate of CYP2C9, CYP2C8 and CYP3A4 and of the transporters OATP1B1, OATP1B3, BCRP, P-glycoprotein and OAT3, so its interactions are mostly about what other drugs do to it rather than the reverse. It had no clinically relevant effect on tolbutamide, a CYP2C9 substrate, which suggests it is a poor perpetrator.

Strong CYP2C9 inhibitors are predicted to raise seladelpar exposure by roughly 3.7 fold, the largest signal in its profile. Transporter inhibition matters too: a single dose given with cyclosporine, which blocks OATP1B1, OATP1B3 and BCRP, increased total exposure 2.1 fold and peak concentration 2.9 fold. Drugs inhibiting several of those transporters at once carry the same concern.

Bile acid sequestrants such as cholestyramine and colesevelam bind seladelpar in the gut and reduce how much is absorbed, which is why the labeling separates the two by at least four hours.

Checking a whole stack? Run it through interactions + stacks.