ABSTRACT
Ambroxol hydrochloride is an oral mucolytic drug, available over-the-counter for many years as cough medicine, which was found to also act as a pharmacological chaperone for mutant glucocerebrosidase, albeit in a several-fold higher dose. Proof-of-concept reports have been published over the past decade in all three forms of Gaucher disease (GD). The current study aimed to assess the safety and efficacy of 12-months ambroxol 600 mg/day in 3 groups of type 1 GD patients with sub-optimal response, after a minimum of 3 years, to enzyme replacement therapy (ERT)/substrate reduction therapy (SRT) defined as lumbar spine bone density <−2.0 t-score, or platelet count<100 × 10−3/L, or LysoGb1 > 200 ng/ml, and for a group of naïve patients, i.e., never treated or stopped therapy >12 months prior to enrollment, who had abnormal values in 2 of the 3 above-mentioned parameters. Forty patients were enrolled: 28 ERT/SRT treated and 12 naïve;21 (52%) males, mean age 52 years (range 24–84). Safety aspects included several adverse effects (mainly gastrointestinal, excessive saliva, and vertigo) all mild and transient in nature, but led to drug discontinuation in 14 patients, additional dropouts were 7 patients due to COVID19 pandemic and 3 due to personal reasons. Of the remaining 16 patients, 14 have completed 12 months, and 2 are ongoing. Of the 14 completers, 5 (~36%) achieved significant improvement in at least one of the three parameters, and nine did not demonstrate any improvement nor deterioration. The interpretation of the results must take into account the fact that most of the enrolled patients have had poor response to ERT/SRT (including 10 of the 12 naïve patients) and therefore may not represent the majority of the patients. Further studies are needed in never-treated patients as well as an oral, less expensive, alternative to unselected stable patients currently treated with ERT/SRT with a favorable response.
ABSTRACT
The introduction of enzyme replacement therapy (ERT) has revolutionized the management of patients with Gaucher disease (GD). To improve the patients' quality of life, we have studied and published the safety and efficacy of a rapid 10-min infusion of high-dose velaglucerase-alfa, instead of one hour as labeled, in 15 previously treated patients. We herein present the 18-month results of the investigator-initiated research in naïve patients with GD (defined by at least one year off ERT or SRT). All patients received bi-weekly infusions of 60 unit/kgBW velaglucerase-alfa;the infusion rate was gradually reduced from 60 to 10 min over six infusions in the hospital setup, followed by home infusions. Each infusion was followed for safety, and efficacy parameters were assessed every 3 months. We enrolled 15 patients (77% males) at a median age (range) of 40 (10–72) years. Thirteen patients were never treated, and two patients were off-ERT for over one year. Ten-minute rapid infusions were well tolerated with no reported related severe or non-severe adverse events (AEs). Two patients reported a non-related SAE and another a non-related AE. Two patients dropped out due to unwillingness to attend follow-up visits during the COVID-19 pandemic. In addition, in 3 patients the infusion rate was increased back to 30 or 60 min due to different causes (2 due to sub-optimal response and one due to AE). All 13 remaining patients reached the 18-month time-point. The platelet counts increased by a median (range) of 75.1% [15.6%–206.9%] and the lyso-GB1 levels decreased by 60.15% [25.7%–85.6%]. Shortening the infusion time has shown to be safe and effective in both previously treated (Zimran et al., AJH2018) and in treatment-naïve patients (this report) and could therefore improve the quality-of-life of patients with GD who have a long-life commitment to this therapy.