Elafibranor in PBC
It has recently been granted Breakthrough Therapy Designation by the FDA for the treatment of Primary Biliary Cholangitis (PBC) in adults with inadequate response to ursodeoxycholic acid (UDCA), as well as Orphan Drug Designation by the FDA and the EMA (European Medicines Agency).
There currently is no cure for primary biliary cholangitis (PBC). Although there are medications that work to slow its progression, there is still a significant medical need for new therapies, as current treatments either are ineffective for a large portion of PBC patients, cause significant side effects or include safety risks.
Elafibranor: Significant effect on PBC hallmarks in a phase 2 study
In December 2018, we announced positive preliminary results, including achievement of the primary endpoint and the composite endpoint, from our Phase 2 multi-center, double-blind, randomized, placebo-controlled clinical trial to evaluate the efficacy and safety of elafibranor after 12 weeks of treatment in patients with PBC and inadequate response to ursodexoycholic acid or UDCA. The trial was conducted at multiple clinical centers in the United States and in three European countries and enrolled a total of 45 patients. The patients were randomized into one of three treatment arms, receiving either elafibranor 80 mg, elafibranor 120 mg or placebo.
The primary endpoint of “Change at week 12 in serum alkaline phosphatase (ALP) from baseline” was met. Both elafibranor doses demonstrated significant decrease in mean ALP: -48% for 80 mg -41% for 120 mg with +3% increase for placebo leading to highly significant treatment effect versus placebo: -52% for 80 mg (p<0.001) and -44% for 120 mg (p<0.001).
A key secondary endpoint was the responder rate for patients achieving the composite endpoint of serum ALP <1.67xULN, an ALP decrease >15%, and total bilirubin (TB) <ULN. On this endpoint, elafibranor achieved the substantially higher response rates of 67% for 80 mg and 79% for 120 mg as compared to 6.7% for placebo (p=0.001 and p<0.001, respectively).
Alongside substantial reductions in ALP, in both elafibranor-treated groups, patients showed improvement in other PBC markers such as gamma-glutamyl transferase and metabolic markers such as total cholesterol, LDL-C, and triglycerides. Improvement in pruritus was observed and will be confirmed in a study of longer duration.
In April 2019, we presented detailed results from its positive Phase 2 clinical trial evaluating elafibranor in PBC during the European Association for the Study of the Liver (EASL) annual International Liver Congress™ (ILC). In a 12-week double-blind randomized placebo-controlled Phase 2 trial of non-cirrhotic patients with PBC and with inadequate response to UDCA, elafibranor showed a significant decrease of alkaline phosphatase (ALP) levels, resulting in significant treatment effects versus placebo on the primary endpoint, whilst also meeting the composite endpoint used for drug registration.
In addition, patients on elafibranor showed improvements in other PBC markers, including gamma-glutamyl transferase (GGT), lipid markers (total cholesterol, LDL and triglycerides), and inflammatory markers (IgM, CRP, haptoglobin and fibrinogen) consistent with what was observed in our Phase 2 clinical trial in NASH. Treatment with both doses of elafibranor was generally well-tolerated.
Based on these preliminary results, we plan to advance our PBC program into Phase 3 development in 2019.
The PPAR rationale in both scientific literature and clinical trials
Targeting PPAR receptors has shown multiple beneficial activities, including the reduction of bile acid synthesis, improved detoxification of bile in the bile duct and anti-inflammatory activity. In third-party clinical trials, drugs targeting PPAR receptors resulted in a significant decrease in ALP and improved biochemical profiles and pruritus in PBC patients.
Patients with PBC often have elevated ALP, and studies have shown a correlation between elevated ALP levels and increased risk of adverse patient outcomes. We have observed elafibranor’s effect in lowering ALP levels in our clinical trials, including our Phase 2 clinical trial in PBC.
In addition, targeting PPARα is proven to have the potential to alleviate pruritus (itching)1, the major symptom of the disease, which is still not addressed by any of the therapies currently available.
Elafibranor consistently showed ALP reduction in previous studies
In a Phase 2a trial evaluating elafibranor in insulin-resistant patients, we observed a significant reduction in ALP compared to placebo over the course of two successive two-month treatment periods (p<0.001). In addition, in our GOLDEN-505 Phase 2b clinical trial in NASH, elafibranor 120 mg confirmed again its ability to reduce ALP compared to placebo (p<0.001).
Elafibranor’s dual mechanism of action in targeting PPARα and PPARδ, thereby lowering ALP, has sustained the rationale of positioning the drug candidate for patients suffering from PBC.
Elafibranor : Breakthrough Therapy Designation by the FDA & Orphan Drug Designation by the FDA and the EMA
Elafibranor was granted Breakthrough Therapy Designation by the U.S. Food and Drug Administration (FDA) for the treatment of Primary Biliary Cholangitis (PBC) in adults with inadequate response to ursodeoxycholic acid (UDCA).
Breakthrough Therapy Designation is granted by the FDA to expedite the development and review of drugs designed to treat serious conditions for which preliminary data and evidence indicate that the product candidate may demonstrate substantial improvements over existing therapies on one or more clinically significant endpoints.
A few months later, in July 2019, the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have both granted Orphan Drug Designation to elafibranor for the treatment of PBC.
1 Bolier et al. 2017