• Largest multinational survey highlights impact of pruritus on quality of life for patients with primary sclerosing cholangitis

Mirum Pharmaceuticals, Inc. (Nasdaq: MIRM) presented data at the International Liver Congress™ of The European Association for the Study of the Liver (EASL) in London, United Kingdom. The first analysis featured a multinational survey of patient-reported outcomes showing the effects of pruritus in patients with primary sclerosing cholangitis (PSC). A second poster assessed gastrointestinal (GI) tolerability on time of dosing with ileal bile acid transporter inhibitors (IBATis) relative to meals.

“We are pleased to share new data at the 2022 EASL congress,” said Dr. Pam Vig, head of research and development at Mirum. “The large multinational PSC survey shows that adults with PSC often experience significant and debilitating pruritus which impacts their day-to-day quality of life, despite use of off-label antipruritic medications. Thus, there remains an urgency for a treatment to address this most burdensome symptom, and we are excited to be evaluating the potential of volixibat, a minimally absorbed IBAT inhibitor, in patients with PSC.”

Summaries of data presented during the congress are enclosed below. View the presentations in full within our Publications & Presentations section on our website.

Poster 756: Impact of pruritus in primary sclerosing cholangitis (PSC): a multinational survey

By Dr. Kris Kowdley, et al.

The multinational survey, conducted by Hetz Israel, PSC Australia, PSC Partners, and PSC Support, assessed results from a collection of patient-reported outcomes from people living with PSC (n=482). The aim of the survey was to assess the presentation and severity of cholestatic pruritus and its broader burden on patients with this rare liver disease. The 39-question survey captured the age and gender of respondents as well as whether they also have inflammatory bowel disease. In addition to pruritus, inflammatory bowel disease and chronic liver disease associated with PSC can negatively impact the quality of life and can lead to depression and anxiety.

The survey results showed that:

• Of the 91% of patients who reported experiencing itch following their diagnosis, 46.4% of respondents experienced >15 episodes (an episode is defined as a prolonged period of itching for at least 7 days).
• Respondents were asked to rate the worst itch experienced in the last 24 hours, and the median worst itch was 6 out of 10 in those who responded (scale from 0-10). Their previous itching episode was reported as 8 out of 10.
• 31% of patients who reported having a current itching episode stated that they have been continuously itching for >12 months.
• The survey assessed the overall impact of pruritus on respondents’ lives with responses indicating:
  • Itch was worst in the evening or nighttime (96%)
  • Mood changes including but not limited to anxiety, irritability, and feelings of hopelessness (58%)
  • Itch led to disruption of day-to-day activities (50%)
  • Itch lasted ≥1 month in duration (45%)
  • Disruption of daily responsibilities due to itch that lasted >30 days (32%), and reported it lasting >12 months (18%)
  • Missing school or work (22%)
• Other findings showed that half of respondents (235/482) reported using ≥2 medications but 75% (177/235) described only partial or no relief with the interventions.

Data from the survey concluded that pruritus related to PSC has a major adverse impact on quality of life (e.g., sleep, mood, fatigue), and interferes with daily activities in a substantial proportion of patients, yet it remains inadequately treated in most patients. There is a high unmet need for the development of safe and effective therapies to treat PSC.

View the presentation

Poster 634: Dosing ileal bile acid transporter inhibitors in the fasted state minimizes gastrointestinal adverse effects while maintaining pharmacodynamic effect

By Dr. Cory Kostrub, et al.

The analysis sought to assess the impact of timing of IBATis dosing relative to food, and the impact on gastrointestinal adverse events and pharmacodynamic effects to inform the optimal dosing approach for IBATis.

Adverse event data from three Phase 1 clinical studies of maralixibat and volixibat in healthy participants were compiled to assess the relative tolerability with different timing of dosing versus mealtime. Fecal bile acids (fBA) data were assessed from nonclinical studies and used as a marker of efficacy since fBA is often difficult to assess in clinical trials.

The data demonstrated that:

• There were 0% GI-related adverse events in the fasted state in two out of the three fasted studies.
• In all three studies where the drug was dosed at mealtime, there were 75%, 33% and 100% GI-related events, respectively.
• In general, lower rates of GI adverse events occurred when IBATis were dosed in a fasted state versus at mealtime.

Non-clinical pharmacodynamic data demonstrate that fasted versus fed dosing had no impact on fBA excretion.

• Maralixibat significantly increased fBA excretion across all dosing time schedules, relative to a daily meal.
• The highest increases in fBA excretion were seen when dosing 30 minutes prior to or four hours after mealtime, indicating flexibility in the timing of IBATi dosing versus mealtime to maintain maximal pharmacodynamic effect.

The analysis concluded that in healthy human participants, gastrointestinal tolerability was improved when dosing IBATis in a fasted state versus dosing immediately before or at mealtime. The data from animal studies showed that fBA excretion was maintained regardless of dosing time relative to mealtime, indicating that there is flexibility in the dosing of IBATis relative to food.

View the presentation

About LIVMARLI® (maralixibat) oral solution

LIVMARLI® (maralixibat) oral solution is an orally administered, once-daily, ileal bile acid transporter (IBAT) inhibitor approved by the U.S. Food and Drug Administration for the treatment of cholestatic pruritus in patients with Alagille syndrome (ALGS) one year of age and older and is the only FDA-approved medication to treat cholestatic pruritus associated with Alagille syndrome. For more information, please visit LIVMARLI.com.

LIVMARLI is currently being evaluated in late-stage clinical studies in other rare cholestatic liver diseases including progressive familial intrahepatic cholestasis (PFIC) and biliary atresia. LIVMARLI has received Breakthrough Therapy designation for ALGS and PFIC type 2 and orphan designation for ALGS, PFIC and biliary atresia. To learn more about ongoing clinical trials with LIVMARLI, please visit Mirum’s clinical trials section on the company’s website.

IMPORTANT SAFETY INFORMATION

LIVMARLI can cause side effects, including:

Changes in liver tests. Changes in certain liver tests are common in patients with Alagille syndrome and can worsen during treatment with LIVMARLI. These changes may be a sign of liver injury and can be serious. Your healthcare provider should do blood tests before starting and during treatment to check your liver function. Tell your healthcare provider right away if you get any signs or symptoms of liver problems, including nausea or vomiting, skin or the white part of the eye turns yellow, dark or brown urine, pain on the right side of the stomach (abdomen) or loss of appetite.

Stomach and intestinal (gastrointestinal) problems. LIVMARLI can cause stomach and intestinal problems, including diarrhea, stomach pain, and vomiting during treatment. Tell your healthcare provider right away if you have any of these symptoms more often or more severely than normal for you.

A condition called Fat Soluble Vitamin (FSV) Deficiency caused by low levels of certain vitamins (vitamin A, D, E, and K) stored in body fat. FSV deficiency is common in patients with Alagille syndrome but may worsen during treatment. Your healthcare provider should do blood tests before starting and during treatment.

Other common side effects reported during treatment were bone fractures and gastrointestinal bleeding.

Prescribing information

About Volixibat

Volixibat is an oral, minimally absorbed agent designed to selectively inhibit the ileal bile acid transporter (IBAT). Volixibat may offer a novel approach in the treatment of adult cholestatic diseases by blocking the recycling of bile acids, through inhibition of IBAT, thereby reducing bile acids systemically and in the liver. Phase 1 and Phase 2 studies of volixibat demonstrated on-target fecal bile acid excretion, a pharmacodynamic marker of IBAT inhibition, in addition to decreases in LDL cholesterol and increases in 7αC4 which are markers of bile acid synthesis. Volixibat has been evaluated in more than 400 individuals across multiple clinical trials. The most common adverse events reported were mild to moderate gastrointestinal events observed in the volixibat groups.

Volixibat is currently being evaluated in Phase 2b studies for primary sclerosing cholangitis (VISTAS Phase 2b clinical trial), intrahepatic cholestasis of pregnancy (OHANA Phase 2b clinical trial), and primary biliary cholangitis (VANTAGE Phase 2b clinical trial).

About Mirum Pharmaceuticals

Mirum Pharmaceuticals, Inc. is a biopharmaceutical company dedicated to transforming the treatment of rare liver diseases. Mirum’s approved medication is LIVMARLI® (maralixibat) oral solution which is approved in the U.S. for the treatment of cholestatic pruritus in patients with Alagille syndrome one year of age and older.

Mirum’s late-stage pipeline includes two investigational treatments for debilitating liver diseases affecting children and adults. LIVMARLI, an oral ileal bile acid transporter (IBAT) inhibitor, is currently being evaluated in clinical trials for pediatric liver diseases and includes the MARCH Phase 3 clinical trial for progressive familial intrahepatic cholestasis (PFIC) and the EMBARK Phase 2b clinical trial for patients with biliary atresia. In addition, Mirum has an expanded access program open across multiple countries for eligible patients with ALGS and PFIC.

Mirum has submitted a Marketing Authorization Application to the European Medicines Agency for LIVMARLI for the treatment of cholestatic liver disease in patients with Alagille syndrome.

Mirum’s second investigational treatment, volixibat, an oral IBAT inhibitor, is being evaluated in three potentially registrational studies including the VISTAS Phase 2b clinical trial for adults with primary sclerosing cholangitis, the OHANA Phase 2b clinical trial for pregnant women with intrahepatic cholestasis of pregnancy, and the VANTAGE Phase 2b clinical trial for adults with primary biliary cholangitis.

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Forward-Looking Statements

This press release includes forward-looking statements pertaining to the Company’s planned participation at a scientific conference, including data presentation title and synopsis, which may include discussion of the Company’s clinical and research data, including the discovery, development and commercialization of our product candidates and technologies, and the therapeutic potential thereof, the continuation of our clinical trials, and the success of our collaborations with partners and any potential future collaborations. Such forward-looking statements are subject to risks and uncertainties that could cause actual results to differ materially from those expressed or implied in such statements. Applicable risks and uncertainties include those relating to our preclinical research and clinical programs and other risks identified under the heading “Risk Factors” included in our most recent Form 10-Q and Form 10-K filings and in other future filings with the SEC. The forward-looking statements contained in this press release reflect Mirum's current views with respect to future events, and Mirum does not undertake and specifically disclaims any obligation to update any forward-looking statements, except as required by law.

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