Ambroxol Therapy for Patients With Type 1 Gaucher Disease and Suboptimal Response to Enzyme Replacement Therapy

Ambroxol hydrochloride, an over-the-counter antitussive available in many markets , was identified as an interesting pharmacological chaperone. In addition to a mucolytic action, ambroxol has antioxidant and anti-inflammatory properties. Importantly, ambroxol therapy was found safe when given to pregnant women for prevention of neonatal respiratory distress syndrome .

Thus, ambroxol, an oral available drug on the market, may be a safe option for GD patients with potential disease-specific efficacy and should be expanded into a clinical trial using higher doses and placebo-controlled design. The investigators propose to start with a phase II study for patients with type 1 GD and suboptimal response to ERT. In addition the investigators plan to open an international registry of patients with GD currently receiving ambroxol (off study).

Study Overview

• Status: Completed
• Conditions: Gaucher Disease, Type 1
• Intervention / Treatment: Drug: Ambroxol

Detailed Description

Introduction:

Description of the Problem:

Enzyme replacement therapy (ERT) makes a significant impact on the clinical manifestations and quality of life of patients with Gaucher disease (GD) . The goals of therapy focus mainly on platelets, hemoglobin, spleen, liver, bones and growth parameters for children.

ERT is mostly effective in patients with type 1 GD; still some patients don't achieve normalization or near normalization of the therapeutic targets . Glucosylsphingosine (LysoGb1) is the most specific and sensitive, and hence is probably the best currently available GD biomarker. A level of LysoGB1 < 140 ng/ml is considered a marker for controlled GD (personal communication).

Patients with GD may also experience chronic fatigue that causes functional disability and adversely affects quality of life . The fatigue severity scale (FSS) is a 9-item tool; each item is scored on a scale from 1 to 7, with a mean score of 4 or higher considered to represent significant fatigue . Patients with GD have improvements in fatigue within 6 months of starting ERT, and that it may be among the first symptoms to show significant improvement. Using the FSS, no association was identified between fatigue and time on ERT (P = 0.57). In a survey of patients with Type 1 GD and physicians, patients ascribed greater importance to fatigue than other disease parameters, while physicians placed more emphasis on objective measures of visceral and hematologic disease manifestations.

B. Pharmacological chaperones:

The underlying pathology in GD is not only due to the lysosomal accumulation of glucosylceramide in the tissue macrophages. There is a broader spectrum of lysosomal dysfunction and various intracellular and molecular changes that could lead to additional disease manifestations that are not affected by ERT. In particular, the retention of the mutant glucocerebrosidase within the endoplasmic reticulum (ER) which causes ER stress, unfolding protein response (UPR) and early ER associated degradation (ERAD) . These ER related changes are the rationale behind the use of pharmacological chaperones which are capable of partially removing the misfolded proteins from the ER, thereby relieving ER stress, avoiding ERAD and preventing consequent complications . Pharmacological chaperones increase glucocerebrosidase activity by stabilizing the enzyme in the lysosome.

C. The Therapy to be Examined:

Ambroxol hydrochloride, an over-the-counter antitussive available in many markets, was identified as an interesting pharmacological chaperone. In addition to a mucolytic action, ambroxol has antioxidant and anti-inflammatory properties . Importantly, ambroxol therapy was found safe when given to pregnant women for prevention of neonatal respiratory distress syndrome. In skin fibroblasts derived from Type 1 and Type 2 GD patients, ambroxol increases both the lysosomal fraction and the enzymatic activity of several mutant glucocerebrosidase variants with low toxicity . Incubation of human induced pluripotent stem cell macrophages from patients with type I-III GD with ambroxol corrected the abnormal phenotypes of GD macrophages. Ambroxol, has a small molecule chaperone, has been shown in healthy nonhuman primates to cross the blood-brain barrier, and increase brain glucocerebrosidase activity . In Drosophila neuropathic model, ambroxol was show to alleviate the neuronopathic phenotype through reducing ER stress ].

The investigators have performed a pilot study to test the tolerability and efficacy of ambroxol as a pharmacological chaperone in patients with symptomatic, type 1 GD who present with measurable disease parameters but are not receiving ERT in order to provide proof of concept and/or ascertain the suitability of ambroxol for a larger clinical trial [29] . The Israeli Ministry of Health Form 29c was employed to prescribe ambroxol for off-label use. Twelve patients were dispensed 2 capsules of 75 mg of ambroxol daily for 6 months. One patient withdrew because of a hypersensitivity reaction, one because of elective splenectomy. No patient experienced clinically relevant deterioration in disease parameters measured. One patient achieved a robust response relative to baseline: +16.2% hemoglobin; +32.9% platelets; -2.8% liver volume; and -14.4% spleen volume. Three patients elected to continue on ambroxol for a further 6 months: hemoglobin levels and liver volumes were relatively stable, but platelet counts further increased in the above patient (+52.6% from baseline) and spleen volumes decreased further in all three patients (-6.4%, -18.6%, and -23.4% from baseline) . More recently, a pilot study of ambroxol was done in five patients with neuronopathic GD in combination with enzyme replacement therapy [30]. High-dose oral Ambroxol had good safety and tolerability with clinical and laboratory signs of activity.

Thus, ambroxol, an oral available drug on the market, may be a safe option for GD patients with potential disease-specific efficacy and should be expanded into a clinical trial using higher doses and placebo-controlled design [31]. The investigators propose to start with a phase II study for patients with type 1 GD and suboptimal response to ERT. In addition the investigators plan to open an international registry of patients with GD currently receiving ambroxol (off study).

• Study Type: Interventional
• Enrollment (Actual): 40
• Phase: Phase 2

Contacts and Locations

Study Locations

• Israel
  • Jerusalem, Israel
    • Shaare Zedek Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

*Adult patients ≥ 18 years with type 1 GD and suboptimal response to ERT defined as one or more than one of the following: platelet count < 100 x 103/mm3 bone mineral density < -2 T score Lyso-GB1 > 200 ng/ml.

*No change in dose or preparation of ERT in the last 12 months (Except for Naive patients)

Exclusion Criteria:

• Patients with comorbidity that may impact on the primary and/or secondary endpoint.
• Pregnant women will be excluded from the study.
• Inability to cooperate with the study procedure
• Hypersensitivity or any other contraindication listed in the local labeling of ambroxol
• Refusal of patients to participate in the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Ambroxol; Ambroxol therapy will be dosed up to 600 mg/day divided to twice a day starting 150 mg for the first month, 300 mg for the following month and 600 mg for the following month. The study was conducted in accordance with the provisions of the Declaration of Helsinki, Good Clinical Practice guidelines, and local laws and regulations.	Drug: Ambroxol; Ambroxol Hydrochloride therapy will be dosed up to 600 mg/day divided to twice a day starting 150 mg for the first month, 300 mg for the following month and 600 mg for the following month. The study was conducted in accordance with the provisions of the Declaration of Helsinki, Good Clinical Practice guidelines, and local laws and regulations.; Other Names: Ambroxol Hydrochloride

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Platelets count	Increase in platelet count	12 months.
bone mineral density evaluated by Dual Energy X-ray Absorptiometry (DEXA)	Bone Mineral Densitometry (BMD)	12 months.
Lyso-GB1 biomarker for Gaucher disease	decrease in Lyso-GB1.	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Patient-reported outcomes (PRO)	Improve in PRO from baseline	12 months
Fatigue Severity Scale (FSS)	Improve in FSS from baseline	12 months

Collaborators and Investigators

• Sponsor: Shaare Zedek Medical Center

Publications and helpful links

General Publications

• Ishay Y, Zimran A, Szer J, Dinur T, Ilan Y, Arkadir D. Combined beta-glucosylceramide and ambroxol hydrochloride in patients with Gaucher related Parkinson disease: From clinical observations to drug development. Blood Cells Mol Dis. 2018 Feb;68:117-120. doi: 10.1016/j.bcmd.2016.10.028. Epub 2016 Nov 12.

Study record dates

Study Major Dates

• Study Start (ACTUAL): March 1, 2019
• Primary Completion (ACTUAL): November 30, 2022
• Study Completion (ACTUAL): December 30, 2022

Study Registration Dates

• First Submitted: August 6, 2018
• First Submitted That Met QC Criteria: May 13, 2019
• First Posted (ACTUAL): May 15, 2019

Study Record Updates

• Last Update Posted (ESTIMATE): February 14, 2023
• Last Update Submitted That Met QC Criteria: February 12, 2023
• Last Verified: May 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Metabolic Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Genetic Diseases, Inborn; Metabolism, Inborn Errors; Lysosomal Storage Diseases; Lipid Metabolism Disorders; Brain Diseases, Metabolic; Brain Diseases, Metabolic, Inborn; Sphingolipidoses; Lysosomal Storage Diseases, Nervous System; Lipidoses; Lipid Metabolism, Inborn Errors; Gaucher Disease; Respiratory System Agents; Expectorants; Ambroxol
• Other Study ID Numbers: 0005-18-SZMC

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No