High-Dose Ambroxol in GBA1-Related Parkinson

NCT06193421 | Recruiting Phase 1

• 1 other identifier: AGPI
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 1

Brief Summary

Parkinson's disease (PD), affecting 10 million people globally, lacks a cure, and current therapies only manage symptoms. A link between Gaucher disease (GD) and PD, particularly in carriers of glucocerebrosidase (GBA1) mutations, has sparked interest in developing new drugs. Despite pharmaceutical companies focusing on formulations, progress is slow. Agyany, with decades of experience in GD research, plans clinical trials using existing generic drugs for GBA-related PD and idiopathic PD. Their approach targets the misfolded enzyme glucocerebrosidase with pharmacological chaperons, inspired by success in GD using ambroxol. The strategy aims to provide a quicker path to novel therapeutic options for PD.

Conditions

Parkinson Disease; GBA Gene Mutation

Keywords

GBA1-related Parkinson Disease; Parkinson Disease; Glucocerebrosidase; Ambroxol

Outcome Measures

Primary Outcomes (5)

• Number of Participants With Treatment-Emergent Adverse Events (TEAEs), and Treatment-Emergent Serious Adverse Events (TESAEs)

  The outcome measure involves the assessment of adverse events (AEs) experienced by study participants throughout the duration of the trial. Adverse events will be documented, and their severity will be graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5. This comprehensive evaluation aims to provide a clear understanding of the safety profile of the intervention by specifically measuring and reporting the incidence and severity of treatment-emergent adverse events.

  12 months

• Number of Participants With Potentially Clinically Significant Laboratory Abnormalities: Hematology

  Criteria for potentially clinically significant abnormalities (PCSA): Hemoglobin: less than or equal to (\<=) 115 grams per liter (g/L) (Male\[M\]) or \<=95 g/L (Female\[F\]), greater than or equal to (\>=) 185 g/L (M) or \>=165 g/L (F), Decrease from baseline (DFB) \>=20 g/L; Hematocrit: \<=0.37 volume/volume (v/v) (M) or \<=0.32 v/v (F), \>=0.55 v/v (M) or \>=0.5 v/v (F); Red blood cells (RBC): \>=6 Tera/L; Platelets: less than (\<) 100 Giga/L, \>=700 Giga/L; White blood cells (WBC): \<3.0 Giga/L (Non-Black \[NB\]) or \<2.0 Giga/L (Black \[B\]), \>=16.0 Giga/L; Neutrophils: \<1.5 Giga/L (NB) or \<1.0 Giga/L (B); Lymphocytes: \<lower limit of normal (LLN), greater than (\>) 4.0 Giga/L; Monocytes: \<LLN, \>0.7 Giga/L; Basophils: \>0.1 Giga/L; Eosinophils: \>0.5 Giga/L or \>upper limit of normal (ULN) (if ULN \>=0.5 Giga/L).

  12 months

• Number of Participants With Potentially Clinically Significant Laboratory Abnormalities: Biochemistry (Metabolic, Electrolytes, Renal and Liver Function)

  Criteria for PCSA: Alanine Aminotransferase (ALT): \>3 ULN, \>5 ULN; Aspartate aminotransferase (AST): \>3 ULN; Alkaline phosphatase: \>1.5 ULN; Total Bilirubin: \>1.5 ULN; ALT and Bilirubin: \>3 ULN and \>2 ULN; Direct Bilirubin and Bilirubin: \>35% and \>1.5 ULN. Criteria for PCSA: Creatinine: \>=150 micromoles per liter (mcmol/L) (adults), \>=30% change from baseline, \>=100% change from baseline; Blood urea nitrogen: \>=17 millimoles (mmol)/L. Criteria for PCSA: Glucose: \<=3.9 mmol/L and \<LLN; \>=11.1 mmol/L (unfasted \[unfas\]) or \>=7 mmol/L (fasted \[fas\]); Albumin: \<=25 g/L. Criteria for PCSA: Sodium: \<=129 mmol/L, \>=160 mmol/L; Potassium: \<3 mmol/L, \>=5.5 mmol/L and Chloride: \<80 mmol/L, \>115 mmol/L.

  12 months

• Number of Participants With Potentially Clinically Significant Vital Signs Abnormalities

  Criteria for PCSA: Systolic blood pressure (SBP) supine: \<=95 millimeters of mercury (mmHg) and DFB \>=20 mmHg; \>=160 mmHg and increase from baseline (IFB) \>=20 mmHg; Diastolic blood pressure (DBP) supine: \<=45 mmHg and DFB \>=10 mmHg; \>=110 mmHg and IFB \>=10 mmHg; SBP (Orthostatic): \<=-20 mmHg; DBP (Orthostatic): \<=-10 mmHg; Heart rate (HR) supine: \<=50 beats per minute (bpm) and DFB \>=20 bpm; \>=120 bpm and IFB \>=20 bpm; Weight: \>=5% DFB; \>=5% IFB.

  12 months

• Number of Participants With Abnormal Physical Examination Findings

  Routine physical examinations will be conducted to assess participants for any physical manifestations of adverse effects or safety concerns. In the final report the number of participants with new abnormal physical examination findings will be reported.

  12 months

Secondary Outcomes (2)

• Number of Participants With Significant Change in Transcranial Ultrasonography (TCS) of Substantia Nigra Region

  12 months

• Difference of dopamine turnover rate measured by Fluoro-Dopa-PET in the putamen between baseline and after 12 months of treatment.

  12 months

Other Outcomes (14)

• Changes in motor evaluations

  12 months

• Changes in motor evaluations

  12 months

• Changes in motor evaluations

  12 months

Study Arms (1)

Ambroxol hydrochloride

EXPERIMENTAL

Daily administration of Ambroxol in newly diagnosed GBA1 PD.

Drug: Ambroxol Hydrochloride

Interventions

Ambroxol Hydrochloride DRUG

75mg slow release (SR), X16/day or 300mg X4/day oral capsules.

Ambroxol hydrochloride

Eligibility Criteria

• Age: 30 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Newly diagnosed PD patients:
• Individuals who exclusively carry at least one single GBA1 variant without any additional genetic variants.
• Confirmed diagnosis of PD, by a movement disorder specialist, according to MDS PD criteria, within a maximum of three years from the date of diagnosis, coupled with the following conditions:
• iii. Hoehn and Yahr staged between I-II, inclusive.
• iv. No motor fluctuations or L-dopa induced dyskinesia.
• Stable anti-PD medications for ≥ 4 weeks:
• Subjects can take PD medications including NMDA glutamate antagonists, monoamine oxidase B (MAO-B) inhibitors, dopamine agonists, and L-Dopa.
• Male or female, age 30-70 years; however, if female:
• must be using contraception measures if of childbearing potential.
• must not be lactating.
• Complying with study protocol.

You may not qualify if:

• Presence of any medical, emotional, behavioral, or psychological condition that in the judgment of the Investigator would interfere with the subject's compliance with the requirements of the study (such as clinical depression).
• Any other disorder that may interfere with the results of the efficacy endpoints.
• Currently taking another investigational drug for any condition.
• Use of dopaminergic treatment under these conditions:
• L-Dopa equivalent daily dose \> 400mg
• L-Dopa daily dose \> 300mg
• L-Dopa equivalent and L-Dopa daily dose has been changed in the past 4 weeks prior to screening visit.
• Medical history of psychosis.
• Exposure to ambroxol in the last 24 months prior to screening and/or history of adverse events to ambroxol.
• Exposure to dopamine receptor blocking agents, lithium, cinnarizine, amiodarone or valproic acid in the last 12 months prior to screening.
• Pregnancy or lactation; female subjects of a childbearing age who are unwilling to use contraceptive measures.

Sponsors & Collaborators

• Agyany Pharma LTD: lead

Study Sites (1)

Shaare Zedek Medical Center

Jerusalem, 9103102, Israel

RECRUITING

Related Publications (7)

• Zimran A, Altarescu G, Elstein D. Pilot study using ambroxol as a pharmacological chaperone in type 1 Gaucher disease. Blood Cells Mol Dis. 2013 Feb;50(2):134-7. doi: 10.1016/j.bcmd.2012.09.006. Epub 2012 Oct 22.

  PMID: 23085429 BACKGROUND

• Mullin S, Smith L, Lee K, D'Souza G, Woodgate P, Elflein J, Hallqvist J, Toffoli M, Streeter A, Hosking J, Heywood WE, Khengar R, Campbell P, Hehir J, Cable S, Mills K, Zetterberg H, Limousin P, Libri V, Foltynie T, Schapira AHV. Ambroxol for the Treatment of Patients With Parkinson Disease With and Without Glucocerebrosidase Gene Mutations: A Nonrandomized, Noncontrolled Trial. JAMA Neurol. 2020 Apr 1;77(4):427-434. doi: 10.1001/jamaneurol.2019.4611.

  PMID: 31930374 BACKGROUND

• Silveira CRA, MacKinley J, Coleman K, Li Z, Finger E, Bartha R, Morrow SA, Wells J, Borrie M, Tirona RG, Rupar CA, Zou G, Hegele RA, Mahuran D, MacDonald P, Jenkins ME, Jog M, Pasternak SH. Ambroxol as a novel disease-modifying treatment for Parkinson's disease dementia: protocol for a single-centre, randomized, double-blind, placebo-controlled trial. BMC Neurol. 2019 Feb 9;19(1):20. doi: 10.1186/s12883-019-1252-3.

  PMID: 30738426 BACKGROUND

• Becker-Cohen M, Zimran A, Dinur T, Tiomkin M, Cozma C, Rolfs A, Arkadir D, Shulman E, Manor O, Paltiel O, Yahalom G, Berg D, Revel-Vilk S. A Comprehensive Assessment of Qualitative and Quantitative Prodromal Parkinsonian Features in Carriers of Gaucher Disease-Identifying Those at the Greatest Risk. Int J Mol Sci. 2022 Oct 13;23(20):12211. doi: 10.3390/ijms232012211.

  PMID: 36293067 BACKGROUND

• Hannaway N, Zarkali A, Leyland LA, Bremner F, Nicholas JM, Wagner SK, Roig M, Keane PA, Toosy A, Chataway J, Weil RS. Visual dysfunction is a better predictor than retinal thickness for dementia in Parkinson's disease. J Neurol Neurosurg Psychiatry. 2023 Sep;94(9):742-750. doi: 10.1136/jnnp-2023-331083. Epub 2023 Apr 20.

  PMID: 37080759 BACKGROUND

• Giladi N, Alcalay RN, Cutter G, Gasser T, Gurevich T, Hoglinger GU, Marek K, Pacchetti C, Schapira AHV, Scherzer CR, Simuni T, Minini P, Sardi SP, Peterschmitt MJ. Safety and efficacy of venglustat in GBA1-associated Parkinson's disease: an international, multicentre, double-blind, randomised, placebo-controlled, phase 2 trial. Lancet Neurol. 2023 Aug;22(8):661-671. doi: 10.1016/S1474-4422(23)00205-3.

  PMID: 37479372 BACKGROUND

• Julien C, Hache G, Dulac M, Dubrou C, Castelnovo G, Giordana C, Azulay JP, Fluchere F. The clinical meaning of levodopa equivalent daily dose in Parkinson's disease. Fundam Clin Pharmacol. 2021 Jun;35(3):620-630. doi: 10.1111/fcp.12646. Epub 2021 Feb 23.

  PMID: 33458868 BACKGROUND

MeSH Terms

Conditions

Parkinson Disease

Condition Hierarchy (Ancestors)

Parkinsonian Disorders; Basal Ganglia Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases

Study Officials

• Ari Zimran, MD

  Agyany Pharma LTD

  STUDY CHAIR

Central Study Contacts

Majdolen Istaiti, MBA

CONTACT

+972526659995; joleen.istaiti@agyany-pharmaceuticals.com

Study Design

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

Model Details: Open label single arm study using ambroxol in newly diagnosed patients with motor Parkinson's disease.

Study Record Dates

• First Submitted: November 7, 2023
• First Posted: January 5, 2024
• Study Start: October 24, 2023
• Primary Completion: February 27, 2025
• Study Completion: April 30, 2025
• Last Updated: February 8, 2024

Record last verified: 2024-02

Data Sharing

• IPD Sharing: Will not share

Locations

IL (1)