dm+d

Unassigned

New Medicines

Progressive familial intrahepatic cholestasis (PFIC), in patients aged 1 year and older - first-line

Information

New molecular entity
Mirum
Mirum

Development and Regulatory status

Phase III Clinical Trials
Filing withdrawn
Phase III Clinical Trials
Yes
Yes
Sep 21Mirum withdraw EU filing with plans to re-submit after availability of results from ongoing PIII MARCH-PFIC study in a broader set of PFIC sub-types and with higher doses of maralixibat [13].
Nov 20Mirum Pharmaceuticals announces EMA validation of MAA for maralixibat in patients with PFIC2 [12].
Mar 20Mirium expects to complete enrolment in the PIII MARCH trial in Q2 2020 and report topline data in late-2020. In addition to the MARCH clinical trial, it is conducting comparisons on long-term outcomes from its ongoing PII program with natural history datasets [11].
Nov 18Shire grants Mirum Pharmaceuticals exclusive global rights to develop and market maralixibat - the company plans to initiate PIII trials in PFIC in 2019[9]
Nov 17A Phase III placebo-controlled study (NCT03353454) in children and adolescents with PFIC is due to start in March 2018, with an estimated completion date of June 2020 [8]
Jun 16Granted breakthrough therapy status in US for progressive familial intrahepatic cholestasis type 2 (PFIC2) [7].
Oct 15Shire is analysing results of PII trials in primary biliary cirrhosis, progressive familial intrahepatic cholestasis and Alagille syndrome as well as a PIb multiple dose study in SHP626 for the treatment of nonalcoholic steatohepatitis and continues to assess a path forward for these programs [6].
May 14Shire buys Lumena [2].
May 14Dosing of the first patient in the INDIGO Phase 2 clinical trial [1].
Mar 14LUM-001 receives Orphan Drug status for primary biliary cirrhosis, primary sclerosing cholangitis, Alagille syndrome and intrahepatic cholestatis in the EU [4].
Sep 13LUM-001 receives Orphan Drug status for Alagille syndrome, primary biliary cirrhosis, primary sclerosing cholangitis and intrahepatic cholestasis in the USA [4].

Category

Potent and selective inhibitor of the apical sodium-dependent bile acid transporter (ASBT), also known as ileal bile acid transporter
Estimated prevalence of PFIC varies between 1 in 50,000 and 1 in 100,000 [3].
Progressive familial intrahepatic cholestasis (PFIC), in patients aged 1 year and older - first-line
Oral

Trial or other data

Sep 21Estimated primary completion date of NCT03905330 is Oct 21 [14].
Jun 19Mirum Pharmaceuticals initiates the phase III MARCH-PFIC trial to evaluate the efficacy and safety of maralixibat for the treatment of PFIC in paediatric patients (NCT03905330) [10].
Feb 17INDIGO trial (NCT02057718) remains ongoing, but not recruiting; ten trial centres are involved, including 3 in the UK, and 24 patients have been recruited. Estimated primary completion date is August 2018 [8].
Aug 15INDIGO study expected to complete Oct 2016 [5].
May 14INDIGO is an open-label, Phase 2 clinical trial designed to evaluate the efficacy and safety of LUM001 for the treatment of cholestatic liver disease in patients with PFIC. This international trial will enroll approximately 12 patients under the age of 18 who have been diagnosed with PFIC. The primary endpoint of the trial is change from baseline in fasting serum bile acids. Secondary endpoints include changes from baseline in liver enzymes and pruritus (itching). [1]
May 14LUM001 is being developed as a therapy for cholestatic liver diseases including PFIC, PSC, Alagille syndrome and primary biliary cirrhosis. These diseases result in impaired bile acid flow and retention of bile acids in the liver, leading to progressive liver damage that may ultimately result in liver failure. Severe itching is generally the most debilitating symptom. LUM001 is an inhibitor of the apical sodium-dependent bile acid transporter (ASBT), which recycles bile acids from the intestine to the liver. Blocking bile acid transport in the intestine with ASBT inhibitors has the potential to lower bile acid levels in the body, slow disease progression, improve liver function and enhance the quality of life for patients suffering from cholestatic liver diseases. [1]

Alagille Syndrome (ALGS) in paediatric patients

Information

New molecular entity
Mirum
Mirum

Development and Regulatory status

Phase II Clinical Trials
Pre-registration (Filed)
Pre-registration (Filed)
Yes
Yes
Sep 21Filed in EU for the treatment of cholestatic liver disease in patients with Alagille Syndrome (ALGS) [12].
Sep 20Mirum Pharmaceuticals initiate rolling submission of a NDA for treatment of cholestatic pruritus in patients with alagille syndrome [10].
Mar 20Mirium plans a New Drug Application Rolling Submission for Alagille Syndrome to begin in Q3 20, and subsequently launch lopixibat chloride for Alagille syndrome in US in H2 2021. Plans for EU filings not described; presume will follow US [8,9].
Oct 19Maralixibat assigned Breakthrough Therapy Designation in US for treatment of pruritus associated with Alagille syndrome; the designation was granted based on evidence from ICONIC PIIb trial [7].
Nov 18Shire grants Mirum Pharmaceuticals exclusive global rights to develop and market maralixibat - the company plans to initiate PIII trials in ALGS in 2019[6]
Oct 17Shire presents the primary analysis of the phase II ITCH trial at the 68th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD-2017) [5]
Oct 15Shire is analysing results of PII trials in primary biliary cirrhosis, progressive familial intrahepatic cholestasis and Alagille syndrome as well as a PIb multiple dose study in SHP626 for the treatment of nonalcoholic steatohepatitis and continues to assess a path forward for these programs [4].
Mar 14SHP 625 granted orphan drug status in the EU for the treatment of Alagille syndrome [2].
Sep 13US FDA grants orphan drug status to SHP 625 for Alagille syndrome [2].

Category

Potent and selective inhibitor of the apical sodium-dependent bile acid transporter (ASBT).
ALGS syndrome is a form of liver disease called biliary hypoplasia. The prevalence of Alagille syndrome is estimated to be 1 in 70,000 [1].
Alagille Syndrome (ALGS) in paediatric patients
Oral

Further information

Yes

Trial or other data

Apr 15 In a PII trial in 20 pts, SHP-625 failed to meet the primary or secondary target of significantly improving serum bile acid levels or pruritus vs. placebo. However, a post-hoc analysis showed a positive correlation between percent changes from baseline in serum bile acid levels and pruritus in the SHP-625 treated group, though the number of patients in the placebo treated group was too small to make an accurate assessment of this relationship. There were no serious side effects observed in the treatment group, the most common adverse events being diarrhoea and abdominal pain, which were more frequent with SHP-625 than with placebo [3].
Nov 14Lumena initiates the PII ITCH trial of SHP 625, which will enrol paediatric patients, aged between 2 years and 18 years, with Alagille syndrome (LUM001-301; NCT02057692). The randomised, double-blind, placebo-controlled intends to enrol 24 patients in the US and Canada, and would be conducted in collaboration with the Childhood Liver Disease Research and Education Network (ChiLDREN). CHiLDREN is a network supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), a part of the National Institutes of Health (NIH),which has a Cooperative Research and Development Agreement (CRADA) with Lumena. Patients who complete the IMAGO or ITCH trials would be eligible to enrol in a long-term extension study (IMAGINE; NCT02047318; LUM001-303; 15605) [2].
Aug 14Lumena initiates the PII ICONIC trial to assess the safety, efficacy and drug withdrawal period of SHP 625 in children and adolescents with Alagille syndrome (LUM001-304; NCT02160782; EudraCT2013-005373-43). The trial will enrol 30 patients. Enrolment has begun in Canada, France, Poland and Spain, and is expected to extend to additional countries [2].
Aug 13Lumena initiates the 13-week PII IMAGO trial to assess efficacy, safety and tolerability of SHP 625 in the treatment of cholestatic liver disease in paediatric patients with Alagille syndrome (IMAGO; LUM001-302; NCT01903460; EudraCT 2012-005346-38). Patients are receiving treatment once-daily as a powder for oral solution, and the primary endpoint is the change from baseline in fasting serum bile acids over 13 weeks. Enrolment of 18 patients aged 12 months to 18 years was completed in the UK in Dec 14. Top-line data are expected in H1 15 [2].

Evidence based evaluations