Sodium phenylbutyrate/ursodoxicoltaurine explained

Type:combo
Component1:Sodium phenylbutyrate
Class1:Pan-histone deacetylase inhibitor
Component2:Ursodoxicoltaurine
Class2:bile acid
Tradename:Albrioza, Relyvrio
Dailymedid:Sodium phenylbutyrate/taurursodiol
Routes Of Administration:By mouth
Atc Prefix:None
Legal Ca:Rx-only
Legal Ca Comment:[1] [2] [3]
Legal Us:Rx-only
Legal Us Comment:[4] [5]
Kegg:D12439
Synonyms:AMX0035

Sodium phenylbutyrate/ursodoxicoltaurine, also known as sodium phenylbutyrate/taurursodiol and sold under the brand names Albrioza and Relyvrio, is a fixed-dose combination medication used for the treatment of amyotrophic lateral sclerosis (ALS).[6] It contains sodium phenylbutyrate and ursodoxicoltaurine (taurursodiol).

The most common adverse reactions experienced with sodium phenylbutyrate/ursodoxicoltaurine include diarrhea, abdominal pain, nausea and upper respiratory tract infection.

Sodium phenylbutyrate/ursodoxicoltaurine acts by blocking apoptotic pathways in the mitochondria and in the endoplasmic reticulum.[6] Sodium phenylbutyrate is a chemical chaperone that helps proteins maintain their normal conformation, preventing aggregation that may lead to cell death.[6] Ursodoxicoltaurine improves mitochondrial energy production.[6]

The combination was approved for medical use in Canada as Albrioza, in June 2022,[7] and in the United States, as Relyvrio, in September 2022.[8] [9] The European Union's drug regulators refused to approve it, citing concerns about effectiveness.[10] In April 2024, the manufacturer announced that it is withdrawing the medication from the US and Canadian markets, due to it failing a key phase III clinical trial. [11]

Medical uses

Sodium phenylbutyrate/ursodoxicoltaurine is indicated for the treatment of amyotrophic lateral sclerosis (ALS).

History

In the Phase II/III CENTAUR clinical trial, sodium phenylbutyrate/ursodoxicoltaurine (AMX0035) increased survival times for ALS patients.[12] [13] [14] [15] [16] The Phase II PEGASUS clinical trial found that the drug was safe and tolerated by patients with Alzheimer's disease.[17]

The efficacy of sodium phenylbutyrate/ursodoxicoltaurine for the treatment of ALS was demonstrated in a 24-week, multi-center, randomized, double-blind, placebo-controlled, parallel-group study.[18] Compared to members of the 137-adult cohort that received a placebo medication, those randomly assigned to treatment with sodium phenylbutyrate/ursodoxicoltaurine showed a slower rate of declining daily functioning and longer overall survival.

In September 2022, the United States Food and Drug Administration (FDA) approved Amylyx Pharmaceuticals' application for Relyvrio's approval under the priority review and orphan drug programs.

In March 2024, Amylyx Pharmaceuticals announced that its Phase III PHOENIX clinical trial of 664 American and European adults followed over 48 weeks showed no statistically significant difference in the functioning of ALS patients that were randomly assigned to treatment with Relyvrio, as compared to those receiving a placebo drug.[19]

Society and culture

Legal status

The FDA Peripheral and Central Nervous System Drugs Advisory Committee voted not to recommend approval, and then in an unusual second vote recommended approval.[20] [21]

In April 2024, after a disappointing phase III trial of the medication failed to produce significant differences versus a placebo,[22] Amylyx announced they would begin the process of withdrawing Albrioza and Relyviro from the North American market.[23]

Economics

In the United States, healthcare insurer Cigna decided, in 2023, to reverse its prior decision to cover the cost of the medication for all ALS patients, opting instead to cover "patients who meet certain clinical criteria", arguing that the drug is "experimental, investigational or unproven".[24]

Following the earlier announcement of plans to potentially withdraw the medication, the Institute for Clinical and Economic Review criticized the company for pricing the drug at $158,000 per year of treatment, given the uncertainty.[25]

Research

It is being studied as a treatment for Wolfram syndrome and progressive supranuclear palsy, despite the withdrawal of North American marketing authorization for amyotrophic lateral sclerosis (ALS).

Notes and References

  1. Web site: Qualifying notice for Albrioza . Health Canada . 13 June 2022 . 13 June 2022 . 14 June 2022 . https://web.archive.org/web/20220614034347/https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/notice-compliance/conditions/qualifying-notice-albrioza-253502.html . live .
  2. Web site: Albrioza monograph . 1 June 2022 . 14 June 2022 . 14 June 2022 . https://web.archive.org/web/20220614040012/https://pdf.hres.ca/dpd_pm/00066255.PDF . live .
  3. Web site: Summary Basis of Decision (SBD) for Albrioza . Health Canada . 23 October 2014 . 24 January 2023 . 24 January 2023 . https://web.archive.org/web/20230124031616/https://hpr-rps.hres.ca/reg-content/summary-basis-decision-detailTwo.php?lang=en&linkID=SBD00619&lang=en . dead .
  4. Web site: Relyvrio- sodium phenylbutyrate/taurursodiol powder, for suspension . DailyMed . 30 September 2022 . 16 October 2022 . 16 October 2022 . https://web.archive.org/web/20221016045518/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=126747c4-39f3-4e20-8f3c-7b8596d8ba7d . live .
  5. Web site: Drug Approval Package: Relyvrio . U.S. Food and Drug Administration (FDA) . 27 October 2022 . 18 November 2022 . 18 November 2022 . https://web.archive.org/web/20221118235613/https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/216660Orig1s000TOC.cfm . live .
  6. News: AMX0035 . alsnewstoday . 15 June 2021 . 28 May 2021 . https://web.archive.org/web/20210528222436/https://alsnewstoday.com/amx0035/ . live .
  7. Amylyx Pharmaceuticals Announces Health Canada Approval of Albrioza for the Treatment of ALS . Amylyx . 13 June 2022 . 13 June 2022 . 14 June 2022 . https://web.archive.org/web/20220614034318/https://www.amylyx.com/media/amylyx-pharmaceuticals-announces-health-canada-approval-of-albriozatm-for-the-treatment-of-als . live .
  8. Amylyx Pharmaceuticals Announces FDA Approval of Relyvrio for the Treatment of ALS . Amylyx . 29 September 2022 . 29 September 2022 . 29 September 2022 . https://web.archive.org/web/20220929232149/https://www.amylyx.com/media/amylyx-pharmaceuticals-announces-fda-approval-of-relyvriotm-for-the-treatment-of-als . live .
  9. FDA Approves New Treatment Option for Patients with ALS . U.S. Food and Drug Administration (FDA) . 29 September 2022 . 29 September 2022 . 29 September 2022 . https://web.archive.org/web/20220929232616/https://www.fda.gov/news-events/press-announcements/fda-approves-new-treatment-option-patients-als . live .
  10. Web site: Amylyx's ALS drug knocked back again in Europe . 12 February 2024 . BioPharma Dive . 19 January 2024 . https://web.archive.org/web/20240119204408/https://www.biopharmadive.com/news/amylyx-als-europe-chmp-rejection-albrioza/696564/ . live .
  11. Web site: Amylyx Pharmaceuticals Announces Formal Intention to Remove Relyvrio/Albrioza from the Market; Provides Updates on Access to Therapy, Pipeline, Corporate Restructuring, and Strategy . Amylyx Pharmaceuticals . Business Wire . 4 April 2024 . 5 April 2024 . 4 April 2024 . https://web.archive.org/web/20240404175353/https://www.businesswire.com/news/home/20240404501040/en/Amylyx-Pharmaceuticals-Announces-Formal-Intention-to-Remove-RELYVRIO%C2%AEALBRIOZA%E2%84%A2-from-the-Market-Provides-Updates-on-Access-to-Therapy-Pipeline-Corporate-Restructuring-and-Strategy . live .
  12. Paganoni S, Macklin EA, Hendrix S, Berry JD, Elliott MA, Maiser S, Karam C, Caress JB, Owegi MA, Quick A, Wymer J, Goutman SA, Heitzman D, Heiman-Patterson T, Jackson CE, Quinn C, Rothstein JD, Kasarskis EJ, Katz J, Jenkins L, Ladha S, Miller TM, Scelsa SN, Vu TH, Fournier CN, Glass JD, Johnson KM, Swenson A, Goyal NA, Pattee GL, Andres PL, Babu S, Chase M, Dagostino D, Dickson SP, Ellison N, Hall M, Hendrix K, Kittle G, McGovern M, Ostrow J, Pothier L, Randall R, Shefner JM, Sherman AV, Tustison E, Vigneswaran P, Walker J, Yu H, Chan J, Wittes J, Cohen J, Klee J, Leslie K, Tanzi RE, Gilbert W, Yeramian PD, Schoenfeld D, Cudkowicz ME . Trial of Sodium Phenylbutyrate-Taurursodiol for Amyotrophic Lateral Sclerosis . The New England Journal of Medicine . 383 . 10 . 919–930 . September 2020 . 32877582 . 10.1056/NEJMoa1916945 . 9134321 . free .
  13. Paganoni S, Hendrix S, Dickson SP, Knowlton N, Macklin EA, Berry JD, Elliott MA, Maiser S, Karam C, Caress JB, Owegi MA, Quick A, Wymer J, Goutman SA, Heitzman D, Heiman-Patterson TD, Jackson CE, Quinn C, Rothstein JD, Kasarskis EJ, Katz J, Jenkins L, Ladha S, Miller TM, Scelsa SN, Vu TH, Fournier CN, Glass JD, Johnson KM, Swenson A, Goyal NA, Pattee GL, Andres PL, Babu S, Chase M, Dagostino D, Hall M, Kittle G, Eydinov M, McGovern M, Ostrow J, Pothier L, Randall R, Shefner JM, Sherman AV, St Pierre ME, Tustison E, Vigneswaran P, Walker J, Yu H, Chan J, Wittes J, Yu ZF, Cohen J, Klee J, Leslie K, Tanzi RE, Gilbert W, Yeramian PD, Schoenfeld D, Cudkowicz ME . Long-term survival of participants in the CENTAUR trial of sodium phenylbutyrate-taurursodiol in amyotrophic lateral sclerosis . Muscle & Nerve . 63 . 1 . 31–39 . January 2021 . 33063909 . 7820979 . 10.1002/mus.27091 .
  14. Web site: Novel ALS Drug Continues to Show Survival Benefit . medpagetoday.com . 19 April 2021 . 15 June 2021 . 19 May 2021 . https://web.archive.org/web/20210519024044/https://www.medpagetoday.com/meetingcoverage/aan/92166 . live .
  15. Long-Term Survival of Participants in the CENTAUR Trial of AMX0035 for ALS (4550) . Neurology . 13 April 2021 . 96 . 15 Supplement . Paganoni S, Hendrix S, Dickson S, Knowlton N, Macklin E, Cohen J, Klee J, Leslie K, Yeramian P, Cudkowicz M . 10.1212/WNL.96.15_supplement.4550 . 266100302 . 15 June 2021 . 13 August 2021 . https://web.archive.org/web/20210813150826/https://n.neurology.org/content/96/15_Supplement/4550 . live .
  16. News: Long-term survival outcomes of AMX0035 for ALS . 22 April 2021 . 15 June 2021 . 14 June 2022 . https://web.archive.org/web/20220614040033/https://conferences.medicom-publishers.com/specialisation/neurology/aan-2021/centaur-trial-long-term-survival-outcomes-of-amx0035-for-als/ . live .
  17. Web site: AMX0035 Meets Primary Safety and Tolerability End Point in Alzheimer Disease . 9 April 2022 . Neurology live . 17 November 2021 . 21 November 2021 . https://web.archive.org/web/20211121035855/https://www.neurologylive.com/view/amx0035-meets-primary-safety-tolerability-end-point-alzheimer-disease . live .
  18. AMX0035 in Patients With Amyotrophic Lateral Sclerosis (ALS) (CENTAUR) . ClinicalTrials.gov . 25 April 2017 . 29 September 2022 . 23 September 2022 . https://web.archive.org/web/20220923163440/https://clinicaltrials.gov/ct2/show/NCT03127514 . live .
  19. News: Belluck . Pam . 8 March 2024 . A.L.S. Drug Relyvrio Fails Clinical Trial and May Be Withdrawn From the Market . 9 March 2024 . . 0362-4331 . 9 March 2024 . https://web.archive.org/web/20240309103504/https://www.nytimes.com/2024/03/08/health/als-drug-relyvrio.html . live .
  20. Web site: ALS drug's approval draws cheers from patients, questions from skeptics . NPR . 30 September 2022 . 30 September 2022 . 1 October 2022 . https://web.archive.org/web/20221001064041/https://www.npr.org/sections/health-shots/2022/09/30/1126267087/als-drugs-approval-draws-cheers-from-patients-questions-from-skeptics . live .
  21. Web site: Howard . Jacqueline . ALS drug gets FDA approval despite uncertainty about effectiveness . CNN . 29 September 2022 . 30 September 2022 . 29 September 2022 . https://web.archive.org/web/20220929225041/https://www.cnn.com/2022/09/29/health/als-drug-relyvrio/index.html . live .
  22. Web site: Amylyx Pharmaceuticals Announces Topline Results From Global Phase 3 PHOENIX Trial of AMX0035 in ALS . 8 March 2024 . https://web.archive.org/web/20240308170544/https://www.amylyx.com/news/amylyx-pharmaceuticals-announces-topline-results-from-global-phase-3-phoenix-trial-of-amx0035-in-als . 8 March 2024 .
  23. Web site: Dear health care professional letter: Albrioza . . 20 June 2024 . 21 June 2024.
  24. News: Bell . Jacob . 7 February 2023 . Cigna restricts coverage of new ALS drug, deepening fears about access . BiopharmaDive . 11 February 2023 . https://web.archive.org/web/20230208002017/https://www.biopharmadive.com/news/cigna-relyvrio-als-coverage-restrict-amylyx/642241/ . 8 February 2023.
  25. News: Saltzman . Jonathan . 8 March 2024 . In Setback for ALS Patients, Cambridge Biotech's Drug Fails Clinical Trial, Could Be Withdrawn From Market . 9 March 2024 . . 8 March 2024 . https://web.archive.org/web/20240308193628/https://www.bostonglobe.com/2024/03/08/business/als-amylyx-drug-relyvrio/ . live .

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