Ambroxol Therapy for Patients With Type 1 Gaucher Disease and Suboptimal Response to Enzyme Replacement Therapy
Condition: Gaucher Disease, Type 1
MeSH terms: Gaucher Disease
Study type: Interventional
Phase: Phase 2

Summary: 
      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).
    

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).
    

Intervention name(s): Ambroxol
Intervention type(s): Drug
Intervention description(s): 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 intervention name(s): Ambroxol Hydrochloride
Intervention MeSH terms: Ambroxol
Intervention model: Single Group Assignment
Intervention model description: The aim of this single arm, phase II study is to evaluate the efficacy and safety of adding ambroxol to patients with type 1 GD and suboptimal response to ERT.
HYPOTHESIS The addition of ambroxol will improve the disease related symptoms and disease impact of patients with GD with suboptimal response to ERT.
Masking: None (Open Label)
Primary purpose: Treatment