FDA Approves Bylvay for Cholestatic Pruritus in Alagille Syndrome

Alagille syndrome (ALGS) is a rare genetic disorder that affects around one in every 30,000 live births. It results from a mutation in either one of the two genes, JAGGED1 (JAG1) or NOTCH2, involved in an important cell signalling pathway called NOTCH signalling. Most people with ALGS have a mutation in the JAG1 gene. Around four out of ten people with ALGS, have the mutated gene passed on from their parents, while the remaining six have the gene for an unknown reason. The number of possible mutations that can occur in any of these genes, is enormous. Therefore, the way ALGS affects people can be very different from person to person, even within the same family. Some can have very mild effects that they reach adulthood without knowing they have ALGS. Others have serious symptoms from their babyhood and childhood.

ALGS can affect different body parts, such as the liver, kidneys, heart, face, eyes, and bones resulting in different associated symptoms/features. One of the major features of ALGS is liver abnormalities such as bile duct paucity. Bile ducts carry bile from the liver to the gall bladder or small intestine, where it helps with the digestion of fats. Having fewer bile ducts leads to the restriction of bile flow and its accumulation in the liver. This in turn affects the normal roles of the liver, causing different symptoms. One of the most common prominent signs of liver problems is pruritus, where the build-up of bile salts in the body leads to itchiness. This type of itching is called cholestatic pruritus. It is usually felt all over the body; however, some parts are more severely affected than others. These include hand palms, feet soles, and the upper part of the body (trunk).

The itching may come and go in phases or in different seasons. Itch intensity could be very variable: Some people have it in a mild form, where it is only an annoyance, while others have it in a severe form, disrupting and interfering with sleep and daily life. Rarely, pruritus can become so severe that a liver transplant is considered to improve the child’s life.

The treatment of Alagille syndrome is directed towards the specific apparent symptom in each individual. However, pruritus (itching) associated with ALGS is often resistant to therapy. Around 95% of ALGS patients present with chronic cholestasis within the first few months of life. 88% also present with severe intractable pruritus. Therefore, new alternative treatments are required.

On the 13th of June 2023, Ipsen announced that the U.S. FDA approved a drug called Bylvay (odevixibat) for the treatment of cholestatic pruritus in patients from 12 months of age with ALGS.5 Bylvay is an ileal bile acid transport inhibitor (IBATi) that acts locally in the small intestine and has minimal systemic exposure. It is an oral capsule taken once daily in the morning, either as a whole unit or sprinkled on food.6,7 Although the exact mechanism of how Bylvay works is not completely understood, It is thought that the amount of itching is reduced due to the reduction of the bile acids level in the blood caused by Bylvay.

In 2021, Bylvay was already approved as the first drug option for the treatment of cholestatic pruritus in patients aged three months and older with progressive familial intrahepatic cholestasis (PFIC) in the U.S. and for the treatment of all types of PFIC in patients six months or older in Europe. Bylvay has achieved orphan exclusivity for the treatment of PFIC and orphan drug designation for the treatment of ALGS and biliary atresia (a rare pediatric cholestatic liver disease).

ASSERT study is a phase III double-blind, randomized, placebo-controlled clinical trial that was designed to evaluate the efficacy and safety of Bylvay in relieving pruritus in patients with ALGS. It took place in 32 sites across North America, Europe, the Middle East, and Asia Pacific. Patients enrolled in the trial were 0-17 years old and had a genetically confirmed ALGS diagnosis. The dose of Bylvay given was 120 μg /kg/day for 24 weeks. From baseline up until weeks 21 to 24, the study showed a statistically high significant improvement in pruritus, compared to the placebo arm (p=0.0002). This was measured by the PRUCISION Observer-Reported Outcome scratching score (0-4). More than 90% of patients were pruritus responders (≥ 1 point change at any time for 24 weeks), indicating that the trial had met its primary endpoint. The study has also reached the secondary endpoint, where from baseline up to weeks 20 and 24, a highly significant reduction in serum bile acid concentration was noticed, compared to the placebo arm (p=0.001). Moreover, one of the additional therapeutic advantages achieved was the improvement in multiple sleep parameters from weeks 1-4, with continued improvement through week 24. No patient discontinuation was observed, and 96% of patients rolled over into the open-label extension study. The overall incidence of adverse events with Bylvay was similar to that of placebo with the exception of diarrhea which was relatively higher than that of placebo (11.4% vs. 5.9%, respectively).

The most common adverse reactions experienced by patients with ALGS after taking Bylvay were: diarrhea, abdominal pain, hematoma, and weight decrease. Those patients with PFIC had similar adverse effects: diarrhea, abdominal pain, liver test abnormalities, vomiting, and fat-soluble vitamin deficiency. These adverse effects should be monitored throughout the whole treatment period with Bylvay. Dehydration caused by diarrhea should be treated. Also, patients should keep doing baseline liver tests as well as check for their baseline vitamin levels. If these adverse effects persist, treatment discontinuation may be considered.

Bylvay’s approval has added an additional treatment option with the potential to improve the management of pruritus in patients with Alagille syndrome, especially in young children.
Bylvay is also waiting for authorization from the European Medicines Agency (EMA), where the Committee for Medicinal Products for Human Use opinion is expected in Q2 2023 and the final EMA regulatory decision in the second half of 2023.

References:

Alagille Syndrome: A Guide [Internet]. Children’s Liver Disease Foundation; 2019. Available from: https://childliverdisease.org/wp-content/uploads/2019/07/Alagille-Syndrome.pdf
Alagille syndrome – symptoms, causes, treatment | nord [Internet]. [cited 2023 Jun 21]. Available from: https://rarediseases.org/rare-diseases/alagille-syndrome/
Ayoub MD, Kamath BM. Alagille syndrome: diagnostic challenges and advances in management. Diagnostics [Internet]. 2020 Nov [cited 2023 Jun 21];10(11):907. Available from: https://www.mdpi.com/2075-4418/10/11/907
Pruritus: A Guide [Internet]. Children’s Liver Disease Foundation; 2021. Available from: https://childliverdisease.org/wp-content/uploads/2021/08/Pruritus.pdf
S. FDA approves Bylvay® for patients living with cholestatic pruritus due to Alagille syndrome [Internet]. Global. [cited 2023 Jun 21]. Available from: https://www.ipsen.com/press-releases/u-s-fda-approves-bylvay-for-patients-living-with-cholestatic-pruritus-due-to-alagille-syndrome/
Bylvay [Internet]. European Medicines Agency. 2021 [cited 2023 Jun 21]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/bylvay
About bylvay [Internet]. [cited 2023 Jun 21]. Available from: https://bylvay.com/about-bylvay.html