Linerixibat: A Potential First-in-Class Therapy in 60 Years for Cholestatic Pruritus in Primary Biliary Cholangitis

November 16, 2020 /BioValleyBIOON/ --GlaxoSmithKline(GSK) recently announced further progress in its R&D pipeline and presented clinical data for linerixibat. This drug is an ileal bile acid transporter (IBAT) inhibitor currently under development for the treatment of cholestatic pruritus in patients with primary biliary cholangitis (PBC).

The Phase 2b GLIMMER study was published as a late-breaking abstract at Liver Meeting® 2020. The report showed that linerixibat significantly improved pruritus (cholestatic pruritus) in certain treatment groups compared with placebo. These data suggest that by targeting bile acid reuptake, linerixibat has the potential to alleviate cholestatic pruritus in patients with primary biliary cholangitis (PBC).

GSK has planned to initiate Phase 3 clinical studies in 2021,Linerixibat has the potential to become the first new therapy for cholestatic pruritus in PBC in 60 years.

Cholestatic pruritus in primary biliary cholangitis (PBC) represents a serious unmet medical need, with no new pharmacological therapies introduced since the 1960s. Patients with cholestatic pruritus may experience persistent, intense, deep-seated itching that is difficult to relieve by scratching. Additional data indicate that cholestatic pruritus significantly impacts multiple aspects of patients’ quality of life, including fatigue, social functioning, emotional well-being, cognitive function, and other symptoms.

Christopher Corsico, Senior Vice President of Development at GSK, stated, “For the past 60 years, there have been no new therapeutic advances for cholestatic pruritus in primary biliary cholangitis (PBC). These data suggest that linerixibat has the potential to alleviate the debilitating impact of cholestatic pruritus caused by PBC. The GLIMMER study also marks our first collaboration with 23andMe to support patient recruitment. As we plan for Phase 3 studies, we are excited to further explore the impact of linerixibat.”

PBC (Image source: Genfit.com)

GLIMMER is the largest investigational study conducted to date in this population. A total of 147 patients received 12 weeks of double-blind treatment, including placebo; linerixibat 20, 90, or 180 mg once daily; or 40 or 90 mg twice daily. Throughout the study, patients recorded their pruritus daily using a numerical rating scale.

GLIMMER is GSK’s first study to leverage 23andMe to help identify, recruit, and enroll patients. 23andMe identified patients who might be eligible and chose to participate in the study. Approximately 80% of 23andMe customers agreed to participate in the study and were eligible to receive information regardingClinical Trialsinformation. Within just two weeks of engaging with potential eligible participants, 23andMe referred multiple patients to the study.

Although the preliminary analysis of the mean change in pruritus from baseline after 12 weeks of treatment did not reach statistical significance in the overall population, pruritus symptoms were significantly improved in the three linerixibat dose groups (40 mg twice daily, 90 mg twice daily, and 180 mg once daily) compared with the placebo group (N=22, 22, and 24, respectively, vs. N=36 for placebo; p=0.011, 0.037, and 0.042, respectively).

Encouragingly, in patients with moderate-to-severe pruritus (baseline NRS for itch ≥4), the twice-daily 40 mg group (N=15 vs. placebo N=24, p=0.037) showed a significant difference in pruritus compared with placebo. At this dose, linerixibat also demonstrated significant improvements in quality-of-life measures in the overall population, including the social and emotional domains of the disease-specific patient-reported outcome measure PBC-40.

Chemical Structure of Linerixibat (Image source: medchemexpress.cn)

Due to the mechanism of action of linerixibat, the most common adverse events are diarrhea and abdominal pain. The safety and tolerability profile is considered acceptable, allowing for the continuation of Phase 3 planning.

“Dr. Cynthia Levy of the University of Miami Miller School of Medicine stated, ‘The GLIMMER study offers some hope for patients with primary biliary cholangitis (PBC) suffering from cholestatic pruritus. This important study highlights the potential of linerixibat as a future treatment for moderate-to-severe pruritus, with the promise of positively impacting quality of life.’”

Based on these Phase 2b data, GSK is preparing to conduct a Phase 3 study and has partnered with 23andMe to help identify eligible patients for the trial, aiming to significantly shorten the recruitment timeline.(BioValley Bioon.com)

Original Source: GSK presents Phase 2b data on linerixibat for the treatment of cholestatic pruritus in primary biliary cholangitis (PBC)