Foster City, Calif.-based Mirum Pharmaceuticals entered 2020 with a significant bounce after the U.S. Food and Drug Administration (FDA) turned an end-of-phase meeting into a pre-New Drug Application (NDA) meeting for its lead asset, maralixibat, an investigational treatment being evaluated for pediatric patients with Alagille syndrome (ALGS).
Mirum, which launched in 2018, gained maralixibat, an oral inhibitor of the apical sodium-dependent bile acid transporter (ASBT) from Shire (now Takeda). Maralixibat is being developed for Alagille syndrome and progressive familial intrahepatic cholestasis (PFIC), both debilitating cholestatic liver diseases that tend to strike pediatric patients. Maralixibat received Breakthrough Therapy designation in PFIC2 and once Mirum acquired the therapy, they secured Breakthrough Therapy designation and Rare Pediatric Disease Designation for ALGS.
As a result of that meeting with the FDA, Mirum will be able to submit a rolling NDA for maralixibat in ALGS, according to Ian Clements, chief financial officer at Mirum. Mirum will be initiating the NDA in the third quarter of this year. It is likely the submission will be completed in the first quarter of 2021 following the completion of chemistry manufacturing and control testing, which are standard processes along the NDA submission route.
If maralixibat is approved, Clements said it could provide a truly impactful treatment option for ALGS patients, for whom there are currently no approved therapies. The pruritus, or itch, associated with this and other cholestatic liver diseases is debilitating. Clements further described the itch as “deep rooted,” meaning the itch is well below the surface level of the skin.
Pruritus can lead to significant wounding as patients claw at their skin trying to get to the source of the itch. As a result, Clements said many of the children suffering from pruritus associated with ALGS only sleep for short amounts of time due to the intense itching, leading to sleep deprivation, fatigue, poor school performance and other issues. Often, Clements said, the only treatment for these patients is a liver transplant, which is a significant surgery, and comes with a burden of cost and host of health issues such as lifelong immunosuppressive therapy.
Maralixibat has the potential to change the treatment paradigm for this condition. Mirum’s goal is to not only reduce the pruritus associated with ALGS, but to offset the need for a liver transplant. In addition to PFIC and ALGS, Mirum is also evaluating maralixibat as a potential treatment for biliary atresia, a disorder that necessitates liver transplantation.
As the company prepares to initiate its rolling NDA, Clements points to the strong relationships it has built with advocacy organizations in the ALGS and PFIC communities. “Effective patient engagement begins with having these strong relationships,” he said.
“Cultivating these relationships is a critical capability for us – to understand and help raise awareness about the unique patient needs. The connection is real with them,” Clements said, adding that it is “humbling” to interact with the families of patients.
Maralixibat isn’t the only asset Mirum has in development. A sister drug, volixibat, has the same mechanism of action as maralixibat. Initially developed by Sanofi, volixibat has a different formulation and preclinical potency. While Mirum has developed maralixibat at pediatric forms of cholestatic liver disease, volixibat is targeting adult indications, including primary sclerosing cholangitis (PSC), a rare liver disease that causes inflammation and blocking of the bile ducts that also brings about pruritus. The company is planning to initiate a Phase II study for this indication.
Another area of study for volixibat is Intrahepatic Cholestasis of Pregnancy (ICP), a liver disorder which occurs during pregnancy that can cause a buildup of bile acids in the blood. In this condition, Clements said untoward fetal outcomes including stillborn and preterm births can occur, as well as pruritus driven by increased serum bile acids during pregnancy. Mirum is looking to begin a Phase II study of the drug with pregnant women, Clements said.
With five potential indications in its sights, Clements said Mirum has its hands full, but could look for other opportunities down the line. Although he did not specify what that could be, he said the company could look at any cholestatic liver disease where its drugs could have an impact. One benefit of having a small molecule asset means you can explore multiple indications, Clements said.