GI Tolerability Study vs DMF
BLS-11-109: GI Tolerability Outcomes Assessed in Healthy Subjects Taking BAFIERTAM vs Healthy Subjects Taking Pro-drug dimethyl fumarate (Tecfidera®)1
- BLS-11-109 was a 5-week, randomized, double-blind, head-to-head, phase 1 study to evaluate subject-assessed gastrointestinal (GI) tolerability of BAFIERTAM (MMF, or monomethyl fumarate) versus dimethyl fumarate (DMF) in healthy subjects.
- The study was designed to evaluate bioequivalent doses of MMF versus DMF starting with a 1-week titration phase of MMF 95 mg versus DMF 120 mg administered twice daily, followed by a 4-week maintenance phase of MMF, 190 mg vs DMF, 240 mg administered twice daily*
- Subjects were randomized 1:1 into one of the treatment groups. As multiple sclerosis is more common in women than men, randomization was stratified by gender; (3:1, female:male)
Limitations and disclosures
- The study did not meet its primary endpoint. All analyses are therefore exploratory and statistics are descriptive
- The GI symptom intensity scales are not validated
- Results should be interpreted with caution due to the 5-week duration
- Subjects were excluded if they had a clinically significant history or presence of any clinically significant GI pathology unresolved GI symptoms, or other conditions known to interfere with the absorption, distribution, metabolism or excretion of the drug experienced within 7 days prior to first study drug administration, as determined by the Investigator
- The results from this study are not included in the full Prescribing Information for BAFIERTAM. The US Food and Drug Administration did not consider the results of this study when approving BAFIERTAM
- The study was conducted in healthy subjects, not patients with multiple sclerosis
- The study was not powered to show a difference between BAFIERTAM and dimethyl fumarate
Key eligibility criteria
- Healthy male and non-pregnant female subjects aged 18–65 years
- Subjects had no clinically significant history or presence of any clinically significant GI pathology, unresolved GI symptoms, or other conditions known to interfere with the absorption, distribution, metabolism or excretion of the drug experienced within 7 days prior to first study drug administration
GI tolerability assessments
- Subjects used a shortened version of the Modified Overall Gastrointestinal Symptom Scale (MOGISS) to self-assess and rate daily the severity of each symptom (abdominal pain [upper and lower], vomiting, diarrhea, nausea, flatulence, bloating, and constipation ) on a scale of 0 (did not have) to 10 (extreme)
- The primary endpoint was the Area Under the Curve (AUC) in each of the individual symptoms in the MOGISS over the 5-week treatment period.
- The Other endpoints included the AUC over the 5-week treatment period in the MOGISS Composite and Total scores; Duration and severity of GI events; Number and percentage of subjects reporting GI events during the overall treatment period, and assessment of safety/tolerability.
GI symptom differencesExploratory analyses of the Least Squares Mean AUC values for each GI symptom were consistently lower for MMF than DMF as shown in Figure 1.
GI symptom severity
Exploratory analysis of GI events with scores moderate to extreme exhibited a statistically significant difference between treatment groups in the proportion of subjects with at least one moderate to extreme GI event from Week 3 onward favoring Bafiertam (Figure 2).
GI symptom duration
Exploratory analysis of moderate to extreme GI events exhibited shorter mean duration of MOGISS during the treatment period for Bafiertam (mean: 4 days) than Tecfidera (mean: 5 days) overall. The overall difference between treatments became statistically significant from Week 3 onwards with shorter mean duration for Bafiertam (p=0.042 to 0.009). In analogous analyses of each MOGISS symptom, Diarrhea duration during the entire treatment period was statistically significantly lower for Bafiertam overall (p=0.036).
- A total of 120 (57%) subjects reported treatment-emergent AEs related to study drug during the study. 52% of subjects on BAFIERTAM reported AEs compared to 62% of subjects on DMF (not statistically significant)Mild flushing was the most reported AE by both groups occurring in 43% and 54% of subjects on BAFIERTAM and DMF, respectively
- No subjects stopped treatment due to GI AEs
- The table below summarizes GI AEs reported which were considered related to study drug
- Wynn D, et al. ScienceDirect 2020; Multiple Sclerosis and Related Disorders Volume 45