Gaucher’s disease is typical lysosomal storage disease, which is characterized by deficiency of β glucocerebrosidase (GBA), a hydrolytic enzyme of lysosomes, which is caused that accumulation of glucocerebroside that kind of sphingolipid in the multiple organs like liver, spleen, central nervous system, skeleton and lung. That disease is typical disease with proven efficacy of enzyme replacement therapy (ERT), ERT is known to be very helpful in improving hepatosplenomegaly and hematologic findings in Gaucher’s disease. About 1,400 in the libraries of approved from FDA screened that can improve the residual enzyme activity of GBA utilized the thermal denaturation assay. Among them, only ambroxol(ABX) is described to increase enzyme efficacy significantly.
The objective of this study is to evaluate the safety and impact of oral administration of high-dose ambroxol in combination with enzyme replacement therapy on enzyme activities and neurological symptoms in Gaucher disease patients thereby providing grounds for the future use of adjunctive treatment for Gaucher disease patients who are on enzyme replacement therapy. Additionally, it is to evaluate the pharmacokinetics of oral administration of high-dose ambroxol in combination with enzyme replacement
therapy in Gaucher disease patients.
The sample size is up to 10 subjects of this study. Gaucher disease patients who have been treated with standard-of-care therapy for the disease, i.e., enzyme replacement therapy (imiglucerase, Abcertin Inj. etc.), will continue to be treated with the same dose of the enzyme replacement therapy for 192 weeks (48 months). The patients divided into 2 group: patients who have been treated with ambroxol or not, and applies to the each method about the usage and dosage.

Treatment

Ambroxol is an oral administration drug.
1. Gaucher disease patients who have been treated with standard-of-care therapy for the disease, i.e., enzyme replacement therapy (imiglucerase, Abcertin Inj. etc.), will continue to be treated with the same dose of the enzyme replacement therapy for 192 weeks (48 months).
2. The patients divided into 2 group: patients who have been treated with ambroxol or not, and applies to the each method about the usage and dosage. Both group can be escalated by 3 mg/kg/day every 4-8 weeks (1-2 months) up to 35 mg/kg /day (dose should not exceed 1,300 mg/day). Given the objective of this study, ambroxol will be administered to subjects at the age of 17 or older at a dose that does not exceed 1,300 mg/day for at least 6 months, and then drug tolerability and status of serious adverse events (SAEs) will be determined.
Ambroxol dose will be maintained at a blood concentration of 10 µmol/L or below.

Arm Label

Target Number of Participant

Arm Type

Arm Description

Ambroxol is an oral administration drug.
1. Gaucher disease patients who have been treated with standard-of-care therapy for the disease, i.e., enzyme replacement therapy (imiglucerase, Abcertin Inj. etc.), will continue to be treated with the same dose of the enzyme replacement therapy for 192 weeks (48 months).
2. The patients divided into 2 group: patients who have been treated with ambroxol or not, and applies to the each method about the usage and dosage. Both group can be escalated by 3 mg/kg/day every 4-8 weeks (1-2 months) up to 35 mg/kg /day (dose should not exceed 1,300 mg/day). Given the objective of this study, ambroxol will be administered to subjects at the age of 17 or older at a dose that does not exceed 1,300 mg/day for at least 6 months, and then drug tolerability and status of serious adverse events (SAEs) will be determined.
Ambroxol dose will be maintained at a blood concentration of 10 µmol/L or below.

Gender

Age

Description

1) Male and female subjects aged between 2 and 60 years old, inclusive
2) Patients diagnosed with Gaucher disease by genetic testing or enzyme activity assay
3) Voluntarily signed written informed consent by patients or by both patients and their representatives

1) Patients with severe renal impairment (eGFR < 30 mL/min/1.73 m2)
2) Patients with severe hepatic impairment (Child-Pugh class C)
3) Patients with genetic predisposition to lactose intolerance, galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption
4) Patients with known active hepatitis, HIV positive, or other uncontrolled infectious diseases
5) Patients who are unable to orally administer the study drug 
6) Patients with hypersensitivities to the study drug or any of its components 
7) Pregnant and lactating women, men and women of childbearing potential who are not willing to practice abstinence or use appropriate methods of contraception during the study
8) Patients who participated in any clinical trials other than GD-AMBX-01 within 90 days from treatment with the investigational product
9) Patients who are unable to participate in the study for other reasons, according to the investigator

Adverse events (AEs) (Renal dysfunction, hepatic disease, digestive disorder, allergy and anaphylactoid reaction, Stevens-Johnson syndrome, Lyell syndrome, purulent rhinitis, etc.)

Whole period of study

Laboratory tests (hematology, blood chemistry, blood coagulation, and urinalysis)

Whole period of study

Vital signs (blood pressure, pulse, body temperature) and body measurements (body mass index)

Whole period of study

Electrocardiogram (ECG) and chest X-ray

Whole period of study

Primary efficacy endpoint_Change in modified severity scoring tool (mSST) score

Screening and each visits after administrative IP

Secondary efficacy endpoints_Change in residual enzyme activity of GBA before treatment with enzyme replacement therapy

Screening and each visits after administrative IP

Secondary efficacy endpoints_Change in residual enzyme activity of GBA after treatment with enzyme replacement therapy

Screening and each visits after administrative IP

Secondary efficacy endpoints_Change in latency and threshold of brainstem auditory evoked response (BAER)

Screening and each visits after administrative IP

Secondary efficacy endpoints_Change in N-acetyl acid/creatinine (NAA/Cr) and choline/creatinine (Cho/Cr) on brain magnetic resonance spectroscopy (MRS)

Screening and each visits after administrative IP

Secondary efficacy endpoints_Improvement rate of ocular motility disorders

Screening and each visits after administrative IP

Secondary efficacy endpoints_Change in angle of esotropia

Screening and each visits after administrative IP

Secondary efficacy endpoints_Change in biomarkers of Gaucher disease (acid phosphatase, angiotensin converting enzyme, and chitotriosidase)

Screening and each visits after administrative IP

Secondary efficacy endpoints_Change in hemoglobin concentrations

Screening and each visits after administrative IP

Secondary efficacy endpoints_Change in platelet levels

Screening and each visits after administrative IP

Secondary efficacy endpoints_Change in bone mineral density (BMD)

Screening and each visits after administrative IP

Secondary efficacy endpoints_Change in intelligence test scores

Screening and each visits after administrative IP

Secondary efficacy endpoints_Change in the frequency of seizures

every visit except of screening visit

Secondary efficacy endpoints_Change in the size of liver and spleen

Screening and each visits after administrative IP

Exploratory endpoints_Transfer ratio of ambroxol (CSF to serum ambroxol concentration ratio)

At the discretion of the investigator, a maximum of 2 times

Exploratory endpoints_Pharmacokinetic parameter: serum Cmax, Tmax, t1/2, CL, AUCτau, etc.

At the discretion of the investigator, a maximum of 2 times