Miglustat (Zavesca), is an oral medication marketed by Actelion for patients with Gaucher disease type 1 who cannot tolerate enzyme replacement therapy (ERT). The drug is also under investigation for the treatment of patients with Niemann-Pick type C (it is approved for both Gaucher and Niemann-Pick type C in the EU but only for Gaucher disease in the US).
Although it serves the convenience of being taken orally, gastrointestinal (GI) events, such as diarrhea, gas, stomach pain, loss of appetite, upset stomach, and constipation have been observed in 80% of patients treated with miglustat (the first 6 months). GI events are the most common reason for discontinuation.
These miglustat-related disturbances are thought to arise from the inhibition of intestinal disaccharidases, mainly sucrose isomaltase. Experts have recommended patients adhere to a high-calorie, low-carbohydrate diet in an effort to control debilitating gastrointestinal (GI) symptoms, but for some, these measures are not enough, leading researchers to look into the use of nutritional supplements.
Saccharomyces boulardii (S. boulardii) is widely used as a probiotic with the purpose of introducing beneficial active cultures into the large and small intestines.
The rationale for the co-administration of the yeast strain, S. boulardii, with miglustat is to restore the capacity of the human gut to digest sucrose. S. boulardii provides an exogenous sucrase (invertase) that hydrolyzes sucrose through a different mechanism from that of human sucrase. Co-administration of S. boulardii, researchers hypothesized, would improve GI tolerability, comfort and compliance with miglustat therapy.
In an attempt to prove this theory, a research team at Actelion conducted a Phase 1, double-blind, randomized, placebo-controlled trial. Their results were recently published in Orphanet Journal of Rare Diseases.1
In the cross-over study, 42 healthy male and female patients, ages 18-55, were randomly allocated to treatment sequences A-B and B-A (treatment A – miglustat 100 mg t.i.d + placebo; treatment B – miglustat 100 mg t.i.d. + S. boulardii [500 mg b.i.d.]).
The primary endpoint of the study was the total number of diarrhea days (>3 loose stools within a 24-hour period meeting Bristol Stool Scores [BSS]) based on World Health Organization (WHO) criteria.
The study began with a 30-day screening period, followed by two days where all subjects received S. boulardii or placebo alone (i.e., without miglustat). After an 11-day washout period, the treatments were reversed in the two groups.
Compliance with study treatment was monitored based on pill count at each study visit. Assessments were derivations of information collated from diaries that subjects filled out during three days before study initiation and kept during the study treatment periods (Days 1-16 and Days 29-44).
Safety and tolerability were evaluated based on adverse effects (AEs), serious adverse effects (SAEs), physical examination, vital signs, routine hematological, biochemical and urinalysis laboratory assessments, and body weight. Overall, treatment-emergent AEs were recorded in 30 (75%) of subjects during miglustat + S. boulardii and in 33 (85%) of subjects during miglustat + placebo treatment. No subjects reported SAEs and no subjects discontinued therapy due to AEs. No clinically relevant changes from baseline were observed in hematology or blood chemistry parameters, vital signs, ECG results or physical examination.
At the end of the study, 34 of the 42 subjects (81%) remained in the all-treated set. Eight (19%) were excluded due to premature discontinuation in treatment period or due to dosing compliance rate.
The mean number of diarrhea days was <1.5 days for both treatment sequences and for both treatment periods. The mean number of days was lower with miglustat + boulardii (0.8 ± 2.4 days) than with miglustat + placebo (1.3 ± 2.4 days) but the difference was not statistically significant.
Based on these results, no conclusion can be drawn as to whether the addition of S. boulardii to migalastat therapy is beneficial.
1. Remenova T, Morand O, Amato D, Chadha-Boreham H, Tsurutani S, Marquardt T. A double-blind, randomized, placebo-controlled trial studying the effects of Saccharomyces boulardii on the gastrointestinal tolerability, safety, and pharmacokinetics of miglustat. Orphanet J Rare Dis (2015) 10:81. Article URL http://dx.doi.org/10.1186/s13023-015-0297-7. Published online June 19, 2015.