RARE Daily

Mirum Reports Long-Term Transplant-Free Survival Data in Patients with PFIC2

June 2, 2020

Rare Daily Staff

Mirum Pharmaceuticals reported an analysis of its phase 2 INDIGO open-label study showed patients with progressive familial intrahepatic cholestasis type 2 treated with maralixibat who achieved serum bile acid control, have five-year transplant-free survival after treatment.

Progressive familial intrahepatic cholestasis (PFIC) is a rare genetic disorder that causes progressive liver disease typically leading to liver failure. In people with PFIC, liver cells are less able to secrete bile, resulting in its buildup in the liver. Signs and symptoms of PFIC typically begin in infancy and include severe itching, jaundice, failure to grow at the expected rate, and eventually liver failu re. The disease is estimated to affect one in every 50,000 to 100,000 births in the United States and Europe. Six types of PFIC have been genetically identified, all of which are similarly characterized by impaired bile flow and progressive liver disease The PFIC2 patient population accounts for approximately 60 percent of the PFIC patient population. PFIC2 is caused by a mutation in the ABCB11 gene, which normally encodes a bile salt export pump protein that moves bile acids out of the liver.

“Patients need alternatives to surgery or transplant to treat PFIC2, otherwise known as BSEP deficiency, and the long-term maralixibat data demonstrate the therapy’s potential to provide an efficacious and well-tolerated treatment for this condition,” said Richard Thompson, professor of molecular hepatology at King’s College London. “The long-term control of serum bile acids underscores the potential for maralixibat to transform the way PFIC2 is treated, as well as provide additional benefit across many of the quality of life measures that can be debilitating and significantly impact patients’ lives.”

A study recently published by the NAPPED Consortium established that serum bile acid (sBA) control (75 percent reduction) after interruption of the enterohepatic circulation by biliary diversion surgery was associated with native liver survival of up to 15 years. Similarly, maralixibat pharmacologically interrupts the enterohepatic circulation, and maralixibat responders from the INDIGO study surpassed the sBA thresholds described in the NAPPED study, which were statistically significant compared to baseline. In addition, maralixibat responders achieved normalization of liver enzyme and bilirubin levels, decreased pruritus, and improved z-scores in both height and weight.

Maralixibat is a novel, minimally-absorbed, orally administered experimental drug being evaluated in several rare cholestatic liver diseases for pediatric populations. Maralixibat inhibits the apical sodium dependent bile acid transporter, resulting in more bile acids being excreted in the feces, leading to lower levels of bile acids systemically, thereby potentially reducing bile acid mediated liver damage and related effects and complications.

The INDIGO phase 2 study is an ongoing, open-label study evaluating the long-term treatment effects of interruption of enterohepatic circulation with maralixibat in children with PFIC. INDIGO included 19 PFIC2 patients with non-truncating BSEP mutations who received maralixibat 280 µg/kg once daily. Patients without response or with partial treatment response could escalate to 280 µg/kg twice daily in the optional extension period. Study endpoints were sBA, pruritus, quality of life, safety and tolerability.

Patients treated with maralixibat exhibited a clinically meaningful and statistically significant acceleration in height growth, as well as a clinically meaningful and statistically significant reduction in pruritus.

Of the enrolled patients, seven achieved sBA control and remained on study as of week 237. Long-term treatment with maralixibat was well-tolerated. The treatment-emergent adverse events were mild to moderate in severity and included pyrexia, diarrhea, cough, abdominal pain, and vomiting.

Patients with an sBA response continue to be treated with maralixibat for more than five years with improvements demonstrated across multiple parameters.

The data and analysis will be presented at the Digital International Liver Congress 2020 being held August 27-29, 2020.

“These data confirm our belief that maralixibat has the potential to treat PFIC2, preventing transplant and surgical diversion and alleviating many of the symptoms associated with the condition,” said Chris Peetz, president and CEO at Mirum. “Supporting this, we have cases of maralixibat-treated patients being removed from the liver transplant waiting list.”

Photo: Chris Peetz, president and CEO at Mirum


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