Regulatory Decision Summary for Bylvay

This New Drug Submission (NDS) was submitted to obtain market authorization for Bylvay (odevixibat) for the treatment of pruritis in Progressive Familial Intrahepatic Cholestasis (PFIC) in patients 6 months of age or older. The submission was filed under the Priority Review Policy.

The Canadian regulatory decision on the review of Bylvay was based on a critical assessment of the data package submitted to Health Canada. The primary source of evidence that supported the efficacy and safety of Bylvay was a phase 3 randomized controlled trial in patients with PFIC1 and PFIC2. The foreign reviews completed by the United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA) were used as additional references.

Progressive Familial Intrahepatic Cholestasis (PFIC) describes a group of rare, severe, autosomal-recessive pediatric liver diseases associated with debilitating pruritis and progressive hepatic injury that requires liver transplant at a median age of 50 months. Current treatment options are all used off-label with limited success to treat PFIC disease manifestations, highlighting the unmet medical need.

Bylvay (odevixibat) is an orally administered medication that acts locally in the ileal lumen to inhibit the apical sodium-dependent bile acid transporter. Bylvay’s efficacy and safety in treating PFIC was evaluated primarily in the pivotal Phase 3 randomized controlled trial (RCT): A4250-005. Safety and secondarily efficacy were further assessed in an open-label, 72-week follow-up study (A4250-008). The pivotal Phase 3 study was a 24-week-long, multicenter, randomized, allocation-concealed, double-blind, placebo-controlled, parallel-group study with 62 patients that compared placebo (n = 20), Bylvay 40 μg/kg/day (n = 23), and Bylvay 120 μg/kg/day (n = 19). Participants were eligible if they were aged 6 months to 17 years, and had genetically confirmed PFIC1 or PFIC2, significant pruritis, and elevated serum bile acids. Participants were 50% female, had a mean age of 3.2 years (range 0.5 to 15.9 years), and 89% were taking either ursodeoxycholic acid or rifampicin at study entry.

The primary outcome for "Europe and the Rest of the World" was the proportion of patients with a reduction of serum bile acids ≥ 70% from baseline, or to a post-treatment level ≤ 70 µM. The United States Food and Drug Administration (FDA), used the primary outcome of the proportion of positive pruritis assessments, defined as the proportion of pruritis scores (performed twice daily) which either were ≤ 1, or had decreased from baseline by ≥ 1, on the novel ObsRO 5-point scale of caregiver-assessed pruritis severity.

Both of these outcomes were statistically significant with Bylvay compared with placebo. The end-of-study proportion of serum bile acid “responders” (≥ 70% serum bile acid reduction or post-treatment level ≤ 70 µM) were:

• 0% in the placebo group,

• 43.5% in the 40 µg/kg/day group (p = 0.0015 versus (vs) placebo),

• 21.1% in the 120 µg/kg/day group (p = 0.017 vs placebo), and

• 33% overall among patients treated with Bylvay (p = 0.0015 vs placebo).

The end-of-study “proportion of positive pruritis assessments” were:

• 28.7% in the placebo group,

• 58.3% in the 40 µg/kg/day group (p = 0.0019 vs placebo),

• 47.7% in the 120 µg/kg/day group (p = 0.016 vs placebo), and

• 53.5% overall amongst all patients treated with Bylvay (p = 0.0019 vs placebo).

Biostatistics assessed the validity of the Sponsor’s novel pruritis outcome (ObsRO) and found it reliable and valid in the context of this submission.

The 72-week open-label follow-up study (A4250-008) used a dose of 120 µg/kg/day. It included 56 patients who completed A4250-005 (“cohort 1”), and 56 patients with any type of PFIC (“cohort 2”), including PFIC1 (n = 35), PFIC2 (n = 66), PFIC3 (n = 7), PFIC4 (n = 2), and PFIC6 (n = 2), but not PFIC5 (n = 0). Interpretation of its efficacy data was limited by the lack of a concurrent control, and the allowance for adjustment of concurrent medications; however, it provided evidence to support Bylvay’s efficacy in PFIC3, PFIC4, and PFIC6.

In patients with PFIC3 (n = 7), the mean proportion of positive pruritus assessments (decrease of ≥ 1 or pruritus score ≤ 1) from weeks 0-72 was 92.4%. In the patients with PFIC4 (n = 2), scratching scores decreased from 4 and 2.8 at baseline to 2.8 and 1.4 at weeks 13-16 and weeks 1-4 (the last reported assessments). In the patients with PFIC6 (n = 2), scratching scores decreased from 3 and 2.1 at baseline, to 0 and < 1 at weeks 71-72. The acceptance of Bylvay’s indication in all PFIC subtypes was supported by this data and shared aspects of PFIC pathophysiology among all PFIC subtypes, in the context of PFIC’s rarity and unmet medical need.

The safety analysis included a total of 117 patients with PFIC treated with Bylvay in the two above-mentioned phase 3 clinical trials. The duration of the randomized controlled trial (RCT) was 24 weeks. Median duration of exposure to odevixibat at 120 µg/kg/day in the long-term follow-up study A4250-008 was 78.6 weeks.

The very common (incidence ≥ 10%) treatment emergent adverse event (TEAE) symptoms were gastrointestinal. Diarrhea was seen in 31% of Bylvay and 5% of placebo patients. Vomiting occurred in 17% of Bylvay and 0% of placebo patients. Abdominal pain occurred in 14% of Bylvay and 0% of placebo patients.

Lower-limb fractures occurred in 1 Bylvay patient (2.4%) and no placebo patient. Although causality was uncertain, the potential risk of fracture warranted labelling.

There were no deaths in either study, and no serious or severe TEAEs clearly attributable to treatment with Bylvay.

Alanine aminotransferase (ALT) increased in 14% of Bylvay and 5% of placebo patients. Bilirubin increased in 12% of Bylvay and 10% of placebo patients. Aspartate aminotransferase (AST) increased in 7% of Bylvay and 5% of placebo patients.

Bylvay could exhibit both mild hepatotoxic and protective effects. It was uncertain whether the variation seen in liver biochemistry and its causality were related to Bylvay or not. To address the potential risk of hepatoxicity, the Product Monograph indicates that an increased ALT, AST and bilirubin as abnormal laboratory findings may be expected with Bylvay treatment. Other abnormal laboratory findings included vitamin A and vitamin E deficiency, which each occurred in 1 Bylvay patient (2%): neither refractory to supplementation.

Bylvay should be taken with food. Based on clinical pharmacology data, food intake may be associated with a greater pharmacodynamic effect and less systemic toxicity compared to fasted condition.

The proposed Product Monograph suggested that the treatment indication should be for PFIC. The indication for treatment was changed to the treatment of pruritis in PFIC, to reflect the nature of study participants who were required to have a history of significant pruritis, and to reflect that the outcome that defined clinically relevant benefit with Bylvay was pruritus: a cardinal, often-debilitating feature of PFIC that is the primary reason for the invasive surgical treatment of children with PFIC.

Due to the rarity of PFIC, especially of pre-surgical PFIC in older ages, and the common pathophysiology of PFIC in children, adolescents, and adults, extrapolation of data from mostly pre-adolescent children to adolescents and adults was considered acceptable.

A Risk Management Plan (RMP) for Bylvay (odevixibat) was submitted by Medison Pharma to Health Canada. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will be put in place to minimize risks associated with the product. Upon review, the RMP was considered to be acceptable. The Sponsor will be requested to submit Periodic Safety Update Reports (PSURs)/Periodic Benefit-Risk Evaluation Reports (PBRERs) for review after 2 years and after 4 years following marketing in Canada, to allow further characterization of the safety profile associated with the use of the drug in the targeted population in the real-world setting. In addition, the Sponsor will be requested to submit interim/final results stemming from the ongoing/planned/post-market studies (including the ongoing open-label extension study A4250-008, and the post-marketing studies requested by the FDA and by the EMA) for review by Health Canada.

Taken together, there was substantial evidence to demonstrate a reduction of pruritis in PFIC patients with Bylvay. On the basis of the information reviewed, Bylvay presented an acceptable and manageable safety profile in consideration of the intended population. Based on the benefit-risk-uncertainty profile of the product, it was recommended that Bylvay (odevixibat) be granted authorization.

For further details about Bylvay, please refer to the Product Monograph, approved by Health Canada and available through the Drug Product Database.