Pharmacokinetic and Pharmacodynamic Study of AMX0035 in Patients With ALS

NCT04987671 | Unknown Phase 1 FDA Drug

• 1 other identifier: A35-005
• Study Type: interventional
• Target: 14
• Locations: 1 country
• Sites: 1

Brief Summary

The purpose of this study is to evaluate the pharmacokinetic and pharmacodynamic effect after a single dose or at steady state after multiple doses of AMX0035 in adults with sporadic ALS.

Conditions

ALS

Keywords

Neurodegenerative Diseases; Motor Neuron Disease; Amyotrophic Lateral Sclerosis; Nervous System Diseases; Neuromuscular Diseases

Outcome Measures

Primary Outcomes (2)

• Blood concentration of PB and taurursodiol

  Maximum plasma concentration - Cmax of PB and taurursodiol

  Between Day 1 and Day 40

• Systemic exposure to PB and taurursodiol

  Area under the plasma concentration versus time curve - AUC of PB and taurursodiol

  Between Day 1 and Day 40

Secondary Outcomes (3)

• Effect of demographic characteristics on blood concentration of PB and taurursodiol

  Between Day 1 and Day 40

• Effect of demographic characteristics on systemic exposure of PB and taurursodiol

  Between Day 1 and Day 40

• Effect of a fixed dose combination of sodium phenyl butyrate (PB) and taurursodiol on pharmacodynamic activity

  Between Day 1 and Day 40

Study Arms (1)

Treatment with AMX0035

EXPERIMENTAL

Two sequential study period. In Period 1, subject receive AMX0035 daily for approximately 14 days. In Period 2, subjects receive AMX0035 twice a day, morning and evening, for up to 25 days.

Drug: AMX0035

Interventions

AMX0035 DRUG

Fixed dose combination of Sodium Phenylbutyrate and taurursodiol.

Treatment with AMX0035

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male or female, \>=18years of age;
• Diagnosis of sporadic ALS (definite, probable, laboratory probable, possible) made by physician experienced with management of ALS as defined by the World Federation of Neurology revised El Escorial criteria;
• If taking riluzole, must be on a stable dose for \>30 days prior to Day 1 and anticipated to remain at that dose until the final study visit.
• If taking edaravone, must be on a stable regimen for \> 30 days prior to Day 1 and infusion(s) can be scheduled to be performed at no less than 48 hours prior or after the planned pharmacokinetic and pharmacodynamic (PK/PD) sampling.
• Capable of providing informed consent and following trial procedures;
• Geographically accessible to the site;
• Able to undergo the study procedures (including planned sampling on 3 occasions) and to adhere to the visit schedule, as determined by Investigator;
• Women of child bearing potential (e.g. not post-menopausal for at least one year or surgically sterile) must agree to use adequate birth control for the duration of the study and 3 months after last dose of study drug;
• a. Women must not be planning to become pregnant for the duration of the study and 3 months after last dose of study drug
• Men must agree to practice contraception for the duration of the study and for at least 3 months after last dose of study drug;
• Men must not plan to father a child or provide sperm for donation for the duration of the study and 3 months after last dose of study drug
• Acceptable birth control methods for use in this study are:
• Hormonal methods, such as birth control pills, patches, injections, vaginal ring, or implants
• Barrier methods (such as a condom or diaphragm) used with a spermicide (a foam, cream, or gel that kills sperm)
• Intrauterine device (IUD)

You may not qualify if:

• Familial ALS
• Forced vital capacity \< 50% (or alternatively SVC) or presence of tracheostomy or under PAV (PAV is defined as more than 22 hours daily of non-invasive mechanical ventilation for more than 7 days);
• Planned elective surgery (such as feeding tube or edaravone access port placement) during the duration of the study;
• History of known allergy to PB or bile salts;
• Abnormal liver function defined as aspartate aminotransferase and/or alanine aminotransferase (AST and/or ALT) \> 3 times the upper limit of the normal;
• Renal insufficiency as defined by eGFR \< 60 mL/min/1.73m2;
• Ongoing Anemia with Hg concentration \< 10.0 g/dL
• Pregnant women or women currently breastfeeding;
• Current biliary disease which may lead to biliary obstruction or impedes biliary flow including active cholecystitis, primary biliary cirrhosis, sclerosing cholangitis, gallbladder cancer, gallbladder polyps, gangrene of the gallbladder, abscess of the gallbladder;
• History of Class III/IV heart failure (per New York Heart Association - NYHA);
• Patient under severe salt restriction where the added salt intake due to treatment would put the patient at risk, in the Site Investigator clinical judgement;
• Presence of unstable psychiatric disease, cognitive impairment, dementia or substance abuse that would impair ability of the subject to provide informed consent, according to Site Investigator judgment;
• Presence of an active infection requiring systemic antiviral or antimicrobial therapy at any time during the screening period.
• Clinically significant unstable medical condition (other than ALS) that would pose a risk to the subject if they were to participate in the study, according to Site Investigator judgment.
• Clinically significant, as determined by the Investigator, 12-lead ECG abnormalities at screening.

Sponsors & Collaborators

• Amylyx Pharmaceuticals Inc.: lead

Study Sites (1)

Norman Fixel Institute for Neurological Diseases

Gainesville, Florida, 32608, United States

Location

Related Publications (11)

• Cuadrado-Tejedor M, Ricobaraza AL, Torrijo R, Franco R, Garcia-Osta A. Phenylbutyrate is a multifaceted drug that exerts neuroprotective effects and reverses the Alzheimer s disease-like phenotype of a commonly used mouse model. Curr Pharm Des. 2013;19(28):5076-84. doi: 10.2174/1381612811319280006.

  PMID: 23448463 BACKGROUND

• Cudkowicz ME, Andres PL, Macdonald SA, Bedlack RS, Choudry R, Brown RH Jr, Zhang H, Schoenfeld DA, Shefner J, Matson S, Matson WR, Ferrante RJ; Northeast ALS and National VA ALS Research Consortiums. Phase 2 study of sodium phenylbutyrate in ALS. Amyotroph Lateral Scler. 2009 Apr;10(2):99-106. doi: 10.1080/17482960802320487.

  PMID: 18688762 BACKGROUND

• Nunes AF, Amaral JD, Lo AC, Fonseca MB, Viana RJ, Callaerts-Vegh Z, D'Hooge R, Rodrigues CM. TUDCA, a bile acid, attenuates amyloid precursor protein processing and amyloid-beta deposition in APP/PS1 mice. Mol Neurobiol. 2012 Jun;45(3):440-54. doi: 10.1007/s12035-012-8256-y. Epub 2012 Mar 23.

  PMID: 22438081 BACKGROUND

• Dionisio PA, Amaral JD, Ribeiro MF, Lo AC, D'Hooge R, Rodrigues CM. Amyloid-beta pathology is attenuated by tauroursodeoxycholic acid treatment in APP/PS1 mice after disease onset. Neurobiol Aging. 2015 Jan;36(1):228-40. doi: 10.1016/j.neurobiolaging.2014.08.034. Epub 2014 Sep 28.

  PMID: 25443293 BACKGROUND

• Lo AC, Callaerts-Vegh Z, Nunes AF, Rodrigues CM, D'Hooge R. Tauroursodeoxycholic acid (TUDCA) supplementation prevents cognitive impairment and amyloid deposition in APP/PS1 mice. Neurobiol Dis. 2013 Feb;50:21-9. doi: 10.1016/j.nbd.2012.09.003. Epub 2012 Sep 10.

  PMID: 22974733 BACKGROUND

• Ricobaraza A, Cuadrado-Tejedor M, Marco S, Perez-Otano I, Garcia-Osta A. Phenylbutyrate rescues dendritic spine loss associated with memory deficits in a mouse model of Alzheimer disease. Hippocampus. 2012 May;22(5):1040-50. doi: 10.1002/hipo.20883. Epub 2010 Nov 10.

  PMID: 21069780 BACKGROUND

• Ricobaraza A, Cuadrado-Tejedor M, Perez-Mediavilla A, Frechilla D, Del Rio J, Garcia-Osta A. Phenylbutyrate ameliorates cognitive deficit and reduces tau pathology in an Alzheimer's disease mouse model. Neuropsychopharmacology. 2009 Jun;34(7):1721-32. doi: 10.1038/npp.2008.229. Epub 2009 Jan 14.

  PMID: 19145227 BACKGROUND

• Rodrigues CM, Sola S, Sharpe JC, Moura JJ, Steer CJ. Tauroursodeoxycholic acid prevents Bax-induced membrane perturbation and cytochrome C release in isolated mitochondria. Biochemistry. 2003 Mar 18;42(10):3070-80. doi: 10.1021/bi026979d.

  PMID: 12627974 BACKGROUND

• Wiley JC, Pettan-Brewer C, Ladiges WC. Phenylbutyric acid reduces amyloid plaques and rescues cognitive behavior in AD transgenic mice. Aging Cell. 2011 Jun;10(3):418-28. doi: 10.1111/j.1474-9726.2011.00680.x. Epub 2011 Mar 22.

  PMID: 21272191 BACKGROUND

• Wright JM, Zeitlin PL, Cebotaru L, Guggino SE, Guggino WB. Gene expression profile analysis of 4-phenylbutyrate treatment of IB3-1 bronchial epithelial cell line demonstrates a major influence on heat-shock proteins. Physiol Genomics. 2004 Jan 15;16(2):204-11. doi: 10.1152/physiolgenomics.00160.2003.

  PMID: 14583596 BACKGROUND

• Zhou W, Bercury K, Cummiskey J, Luong N, Lebin J, Freed CR. Phenylbutyrate up-regulates the DJ-1 protein and protects neurons in cell culture and in animal models of Parkinson disease. J Biol Chem. 2011 Apr 29;286(17):14941-51. doi: 10.1074/jbc.M110.211029. Epub 2011 Mar 3.

  PMID: 21372141 BACKGROUND

MeSH Terms

Conditions

Neurodegenerative Diseases; Motor Neuron Disease; Amyotrophic Lateral Sclerosis; Nervous System Diseases; Neuromuscular Diseases

Interventions

sodium phenylbutyrate and taurursodiol

Condition Hierarchy (Ancestors)

Spinal Cord Diseases; Central Nervous System Diseases; TDP-43 Proteinopathies; Proteostasis Deficiencies; Metabolic Diseases; Nutritional and Metabolic Diseases

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 15, 2021
• First Posted: August 3, 2021
• Study Start: August 5, 2021
• Primary Completion: May 11, 2022
• Study Completion: September 1, 2023
• Last Updated: July 24, 2023

Record last verified: 2023-07

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)