Mirum Pharmaceuticals Says Volixibat Phase IIb VISTAS Hits Endpoint, Cuts PSC Itch vs Placebo

Key Points

• Volixibat met the Phase IIb VISTAS primary endpoint, producing a 2.7-point itch reduction versus 1.0 for placebo (placebo-adjusted improvement 1.64 points, P<0.0001), positioning it as a potential first approved therapy for PSC pruritus.
• Safety: adverse events were consistent with IBAT inhibition—diarrhea occurred in 40% of volixibat patients versus ~9% on placebo, leading to seven drug discontinuations versus two for placebo, with no treatment-related serious adverse events reported.
• Next steps: Mirum will present full VISTAS data at EASL in late May, has a pre-NDA meeting with the FDA planned this summer and intends an NDA submission in H2 while seeking priority review; separately, Phase II brelovitug showed strong virologic responses and Phase III top-line readouts are expected in H2.

Mirum Pharmaceuticals NASDAQ: MIRM said its Phase IIb VISTAS study of volixibat in patients with primary sclerosing cholangitis (PSC) met its primary endpoint, showing a statistically significant reduction in cholestatic pruritus compared with placebo, according to executives on the company’s business update call.

Chief Executive Officer Chris Peetz called the readout “a defining moment” for the company and for PSC patients, arguing the results represent “the first successful demonstration of a therapy addressing a core symptom of PSC in a controlled study.” Peetz said Mirum believes volixibat is positioned as a potential first approved medicine for patients with PSC, a progressive liver disease with “no approved therapies.”

VISTAS results: pruritus reduction and safety

Chief Medical Officer Joanne Kwong said VISTAS was a 28-week, randomized, double-blind, placebo-controlled Phase IIb study evaluating volixibat 20 mg twice daily versus placebo in PSC patients with pruritus. Patients with moderate-to-severe pruritus were included in the primary cohort, while those with mild pruritus were evaluated in a secondary cohort; all patients were included in the safety analysis. Kwong said baseline characteristics in the primary cohort were well balanced, with a mean baseline itch score of about 6 out of 10, and “slightly over 70%” of patients had concurrent inflammatory bowel disease.

The primary endpoint measured mean change from baseline in pruritus compared to the average of the last 12 weeks of treatment using mixed effects modeling with repeated measures, using a once-daily 0–10 numerical rating scale (Adult Itch Reported Outcome).

Kwong reported that volixibat produced a 2.7-point reduction in itch score versus a 1.0-point reduction on placebo, translating to a placebo-adjusted improvement of 1.64 points with a P value of less than 0.0001. She said the company views the effect size as meaningful and consistent with findings in other cholestatic indications.

On safety, Kwong said the profile was consistent with ileal bile acid transporter (IBAT) inhibition, characterized by gastrointestinal adverse events and changes in liver laboratory parameters such as ALT and total bilirubin. She said there were similar numbers of patients in both groups with grade 3 or higher treatment-emergent adverse events and “no treatment-related serious adverse events.” Eight patients in the volixibat group and five on placebo experienced serious adverse events, which management described as generally reflective of underlying disease.

Kwong said seven patients on volixibat discontinued early due to adverse events versus two on placebo; three volixibat discontinuations were due to diarrhea. Diarrhea occurred in 40% of volixibat-treated patients compared with about 9% on placebo.

Additional VISTAS observations: placebo response, mild cohort, and patient-reported outcomes

In response to analyst questions, management said the placebo arm showed persistent itch throughout the study, which they described as contributing to a low placebo response and supporting study conduct. An executive said the data did not reflect the notion that pruritus in PSC is highly intermittent in the enrolled population.

Regarding the mild pruritus cohort, management said the baseline itch score was “about 2.3” and that the group showed a statistically significant response, which they said was not necessarily expected given “less room to move” on the 0–10 scale. The company said additional details are planned for upcoming scientific presentations.

Management also said the study included fatigue and sleep assessments. They reported trends favoring volixibat for fatigue and sleep, and said the nominal P value for sleep was significant, while acknowledging the study was not designed to definitively assess those endpoints given the hierarchical testing approach.

On diarrhea characterization, management said cases were grade 1 or grade 2 in the double-blind portion, with a median onset within the first two weeks of therapy and a median duration of about two weeks. They added that the company looked for evidence of inflammatory bowel disease exacerbations—collecting fecal calprotectin and evaluating for other causes such as C. difficile—and said they did not see evidence that IBAT inhibition increased IBD exacerbation in this trial.

Regulatory and presentation timeline for volixibat in PSC

Kwong said Mirum plans to present full VISTAS results as an oral late-breaking presentation at the EASL International Liver Congress at the end of May. She added that Mirum plans to review the data with the FDA at a pre-NDA meeting scheduled for this summer, followed by a planned NDA submission in the second half of this year.

Peetz described the planned FDA interaction as a “routine pre-submission meeting” focused on alignment around analyses, datasets, and submission format, and said the company has had “good communication” with FDA through the PSC program.

In response to a question about review timelines, Peetz said Mirum intends to propose priority review, citing high unmet need in PSC.

AZURE-1 update: brelovitug in hepatitis delta

Kwong also reviewed top-line results previously announced from the Phase II portion of the AZURE-1 study of brelovitug in treatment-naïve hepatitis delta patients. She said patients were randomized to 300 mg once weekly, 900 mg once every four weeks, or delayed treatment, with a 24-week primary composite endpoint of virologic response and ALT normalization.

In the first 53 patients evaluated at week 24, Kwong said 100% of patients in the 300 mg arm and 75% in the 900 mg arm achieved virologic response versus 0% in the delayed-treatment arm. The primary composite endpoint was achieved in 45% and 35% of patients in the 300 mg and 900 mg arms, respectively, versus 0% in the delayed-treatment arm. She added that Mirum continues to see further reductions in ALT and hepatitis delta RNA beyond 24 weeks.

Kwong said brelovitug was well tolerated, with no treatment-related serious adverse events and “very low rates of flu-like symptoms.” She said the company expects top-line data from the Phase III AZURE-1 and AZURE-4 studies in the second half of this year, and plans to present Phase II results in a late-breaking posted presentation at EASL.

Commercial preparation and broader pipeline milestones

President and Chief Operating Officer Peter Radovich said Mirum expects the potential approval of a PSC pruritus therapy would require increased focus on identifying and addressing itch in adult care settings, noting that pruritus may not be proactively raised by physicians today “because there are no approved therapies.” He said Mirum plans to expand its field organization from roughly 15 sales personnel on the liver side to “somewhere in the 60s total,” and said the expanded team would also support brelovitug if approved and could help identify additional adult PFIC patients.

Peetz said Mirum is entering a new phase of growth, citing its commercial base and upcoming milestones. He highlighted additional programs including the VANTAGE study in PBC, with top-line data expected in the first quarter of next year, the LIVMARLI EXPAND study with top-line data expected in the fourth quarter, and top-line data from MRM-3379 in Fragile X syndrome expected next year.

About Mirum Pharmaceuticals NASDAQ: MIRM

Mirum Pharmaceuticals, Inc is a late-stage biopharmaceutical company dedicated to the development and commercialization of innovative therapies for rare cholestatic liver diseases. The company's primary focus lies in addressing the unmet medical needs of patients suffering from genetic and progressive forms of pediatric liver disorders, where limited treatment options currently exist.

Mirum's lead product candidate, maralixibat (Livmarli), is an ileal bile acid transporter inhibitor designed to reduce systemic bile acid accumulation and alleviate associated pruritus and liver damage.

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