13 November 2020 — GlaxoSmithKline plc (GSK) today announced further progression in its R&D pipeline with presentation of data for linerixibat, an investigational product for the potential treatment of cholestatic pruritus in patients with primary biliary cholangitis (PBC).
The Phase 2b GLIMMER study (GSK2330672 trial of IBAT inhibition with Multidose Measurement for Evaluation of Response), presented today at The Liver Meeting® 2020 as a late breaking abstract, reported that linerixibat significantly improved itch (cholestatic pruritus) in some treatment groups compared to placebo. These data show that targeting bile acid reuptake with linerixibat, an ileal bile acid transporter (IBAT inhibitor), could provide relief for patients with cholestatic pruritus in PBC.
Cholestatic pruritus in PBC is a condition in which there is a significant unmet need with no new pharmacologic therapy since the 1960s. Patients with cholestatic pruritus can have persistent, intense, and deep itch, which is rarely relieved by scratching. Additional data presented shows that cholestatic pruritus in PBC has a significant impact on many aspects of quality of life: fatigue, social, emotional, cognitive and other symptoms.
Christopher Corsico, Senior Vice President Development, GSK, said: “With no new treatment advances in the last 60 years, these data suggest that linerixibat may provide relief to patients suffering the debilitating impact of cholestatic pruritus associated with primary biliary cholangitis. The GLIMMER study also marks the first time we have collaborated with 23andMe to support patient recruitment. We are excited to explore the impact of linerixibat further as we plan for a Phase 3 study.”
GLIMMER is the largest investigational study in this population to date. A total of 147 patients received 12 weeks of double-blind treatment with placebo, 20, 90,180mg once daily or 40, 90mg twice daily linerixibat. Patients in the study recorded itch daily on a numeric rating scale.
GLIMMER was the first study at GSK to leverage 23andMe to help support the identification, recruitment and enrollment of patients. 23andMe identified patients who may be eligible and that had opted in to participate in research. Roughly 80% of 23andMe customers agree to participate in research and are eligible to receive information about relevant clinical trials. 23andMe surfaced multiple patient referrals for the study within only two weeks of reaching out to its potentially eligible customers.
While the primary analysis of mean change from baseline following 12 weeks of treatment was not statistically significant in the overall population, three linerixibat groups, 40 mg and 90mg twice daily, and 180mg daily, demonstrated significant improvement in itch vs. placebo over the 12-week treatment period (N=22, 22, 24, respectively, vs. placebo N = 36, p=0.011, 0.037, 0.042, respectively).
Encouragingly, a significant difference in itch versus placebo was achieved in the subset of patients with moderate to severe pruritus (baseline itch NRS ≥ 4) in the 40 mg twice daily group (N=15 vs placebo N = 24, p=0.037). This dose of linerixibat also showed significant improvements from baseline in measures of quality of life including social and emotional domains of the disease specific patient reported instrument, PBC-40 in the overall population.
Due to the mechanism of action of linerixibat, the most common adverse events were diarrhoea and abdominal pain. Safety and tolerability were considered acceptable to proceed to Phase 3 planning.
Cynthia Levy, MD, FAASLD, AGAF, University of Miami, Miller School of Medicine, stated: “The GLIMMER study offers some hope for patients with PBC suffering with pruritus. This important study highlights the potential of linerixibat as a future treatment for moderate to severe itching, with a positive impact on quality of life.”
Based on these Phase 2b data GSK is preparing for a Phase 3 study and working with 23andMe to help identify patients who may be eligible for this programme, in the hope this could significantly shorten recruitment timelines.
About cholestatic pruritis
In Primary Biliary Cholangitis (PBC), a cholestatic liver disease, bile flow from the liver is disrupted. The resulting excess bile acids in circulation are thought to cause cholestatic pruritus, an internal itch that cannot be relieved by scratching. Cholestatic pruritus can be debilitating, leading to fatigue, sleep disturbance, suicidal ideation and even liver transplant in the absence of liver failure. There is a significant unmet need with no new pharmacologic therapy approved for cholestatic pruritus associated with PBC since the 1960s.
Linerixibat is an investigational product for the treatment of cholestatic pruritus in patients with PBC and it is not currently approved for use anywhere in the world. In 2019, FDA granted orphan drug designation for linerixibat in the treatment of PBC and associated cholestatic pruritus. Linerixibat is a minimally absorbed small molecule inhibitor of IBAT administered as an oral tablet. By blocking resorption of bile acids in the small intestine, linerixibat reduces pruritic bile acids in circulation.
About the GLIMMER study
GLIMMER was a double-blind, randomized, placebo-controlled, Phase 2b study (NCT02966834; GSK study 201000) conducted in patients with cholestatic pruritus associated with PBC. The study assessed dose response and tolerability of linerixibat (20mg, 90mg, and 180 mg daily; 40mg and 90mg twice daily). Patients with pruritus (≥4 on 0–10 numeric rating scale [NRS]) were enrolled; and at Week 4, patients with an NRS ≥ 3 were randomized. Double-blind treatment was preceded and followed by 4 weeks’ single-blind placebo. Stable anti-itch therapy, with the exception of bile acid binding resins, was permitted. Worst daily itch: worst itch severity was recorded in an eDiary each morning and evening using 0–10 NRS.
GSK is a science-led global healthcare company with a special purpose: to help people do more, feel better, live longer. For further information please visit www.gsk.com/about-us.
Cautionary statement regarding forward-looking statements
GSK cautions investors that any forward-looking statements or projections made by GSK, including those made in this announcement, are subject to risks and uncertainties that may cause actual results to differ materially from those projected. Such factors include, but are not limited to, those described under Item 3.D “Risk Factors” in the company’s Annual Report on Form 20-F for 2019 and as set out in GSK’s “Principal risks and uncertainties” section of the Q3 Results and any impacts of the COVID-19 pandemic.
Source: GlaxoSmithKline plc
Posted: November 2020
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