Clinical trial NCT06193421: High-Dose Ambroxol in GBA1-Related Parkinson
Official title: An Open-Label Pilot Study for Assessing the Safety and Efficacy of High-Dose Ambroxol (HDA) in Newly Diagnosed GBA1 Parkinson Disease (PD)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Parkinson Disease
GBA Gene Mutation
Keywords: GBA1-related Parkinson Disease
Parkinson Disease
Glucocerebrosidase
Ambroxol
Lead sponsor: Agyany Pharma LTD
Sponsor class: INDUSTRY
First posted: 2024-01-05
Enrollment: 40
Sex: ALL
Minimum age (years): 30
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Open label single arm study using ambroxol in newly diagnosed patients with motor Parkinson's disease.
Primary purpose: TREATMENT

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.

Detailed description: Parkinson disease (PD) is the second most common neurodegenerative disease affecting around 10 million people worldwide. It is a debilitating disorder that despite many years and billions of dollars research - there is still no cure and none of the therapeutic options truly reverse its manifestations. The realization that the relationship between Gaucher disease (GD) - the rare lysosomal storage disease - and PD, also exists in carriers of the disease (with a mono-allele mutation in glucocerebrosidase (GBA1)) has led to several attempts to develop new drugs not just for GBA-related PD, but also for PD at large. However, heretofore all pharmaceutical companies have focused on finding new formulations, mostly based on what Agyany believe is not targeting the underlying pathology, but in any case, will require several years before new drugs will reach the market. With the background of three decades working at the world's largest center for GD at Shaare Zedek Medical Center in Jerusalem, and with a different understanding of the pathological processes leading to PD among a significant number of GD patients and carriers, Agyany plans to begin clinical trials in newly diagnosed PD patients using existing generic drugs that would enable a short path for introducing novel therapeutic approach to GBA-related PD and potentially also for so called idiopathic PD (when no genetic cause is known).

Based on our understanding of the underlying mechanism of GBA1-related PD, on research done in animal models and on our own anecdotal experience, Agyany believe that pharmacological chaperons are the most reasonable therapeutic modality to achieve success. Since the misfolding of the mutant enzyme, glucocerebrosidase, is the same both in GBA1-related PD and GD, and that the ambroxol impact is the same as well, Agyany can extrapolate from the success of ambroxol to achieve reversibility of neuronopathic features (that heretofore were considered irreversible, and the best expectation was lack of deterioration), in neuronopathic GD (nGD), to potential success in GBA-related PD.

The plan is to first use generic formulations with a confirmed safety profile and repurpose their indication to PD.

Eligibility criteria: Inclusion Criteria:

For inclusion into the trial, subjects are required to fulfill all of the following criteria:

Newly diagnosed PD patients:

1. Individuals who exclusively carry at least one single GBA1 variant without any additional genetic variants.
2. 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.
3. 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.
4. Male or female, age 30-70 years; however, if female:

   * must be using contraception measures if of childbearing potential.
   * must not be lactating.
5. Complying with study protocol.

Exclusion Criteria:

Eligible subjects may not have any of the following exclusion criteria:

1. 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).
2. Any other disorder that may interfere with the results of the efficacy endpoints.
3. Currently taking another investigational drug for any condition.
4. 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.
5. Medical history of psychosis.
6. Exposure to ambroxol in the last 24 months prior to screening and/or history of adverse events to ambroxol.
7. Exposure to dopamine receptor blocking agents, lithium, cinnarizine, amiodarone or valproic acid in the last 12 months prior to screening.
8. Pregnancy or lactation; female subjects of a childbearing age who are unwilling to use contraceptive measures.

Primary outcomes:
measure: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), and Treatment-Emergent Serious Adverse Events (TESAEs)
timeFrame: 12 months
measure: Number of Participants With Potentially Clinically Significant Laboratory Abnormalities: Hematology
timeFrame: 12 months
measure: Number of Participants With Potentially Clinically Significant Laboratory Abnormalities: Biochemistry (Metabolic, Electrolytes, Renal and Liver Function)
timeFrame: 12 months
measure: Number of Participants With Potentially Clinically Significant Vital Signs Abnormalities
timeFrame: 12 months
measure: Number of Participants With Abnormal Physical Examination Findings
timeFrame: 12 months
Secondary outcomes:
measure: Number of Participants With Significant Change in Transcranial Ultrasonography (TCS) of Substantia Nigra Region
timeFrame: 12 months
measure: Difference of dopamine turnover rate measured by Fluoro-Dopa-PET in the putamen between baseline and after 12 months of treatment.
timeFrame: 12 months
Other outcomes:
measure: Changes in motor evaluations
timeFrame: 12 months
measure: Changes in motor evaluations
timeFrame: 12 months
measure: Changes in motor evaluations
timeFrame: 12 months
measure: Change in cognitive and mental impairment
timeFrame: 12 months
measure: Change in cognitive and mental impairment
timeFrame: 12 months
measure: Change in cognitive and mental impairment
timeFrame: 12 months
measure: Change in cognitive and mental impairment
timeFrame: 12 months
measure: Change in cognitive and mental impairment
timeFrame: 12 months
measure: Change in sleep behavior
timeFrame: 12 months
measure: Change in sleep behavior
timeFrame: 12 months
measure: Changes in sensory and autonomic assessments
timeFrame: 12 months
measure: Changes in sensory and autonomic assessments
timeFrame: 12 months
measure: Changes in sensory and autonomic assessments
timeFrame: 12 months
measure: Changes in sensory and autonomic assessments
timeFrame: 12 months
Locations:
city: Jerusalem
country: Israel
facility: Shaare Zedek Medical Center
Study officials:
affiliation: Agyany Pharma LTD
name: Ari Zimran, MD
role: STUDY_CHAIR
References:
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