Association of Miglustat With Swallowing Outcomes in Niemann-Pick Disease, Type C1

Abstract

Importance: Niemann-Pick disease, type C1 (NPC1) is a progressive neurovisceral disease with no US Food and Drug Administration-approved therapy. Miglustat, a drug used off-label in the United States for the treatment of NPC1, appears to stabilize neurologic disease progression. Several prospective trials suggest that miglustat stabilizes oropharyngeal swallowing function; however, its effect on dysphagia and aspiration risk has not been demonstrated instrumentally.

Objective: To determine if miglustat therapy is associated with stabilized swallowing dysfunction in individuals with NPC1.

Design, setting, and participants: Patients with confirmed NPC1 diagnoses were evaluated in a single-center cohort study of NPC1 from April 1997 to November 2019. Longitudinal data from individuals with neurologic disease onset prior to age 15 years were analyzed. The study population was divided into those with neurologic disease onset in early childhood (age <6 years) and late childhood (age ≥6 years and <15 years). Analysis began September 2019.

Exposures: Oral miglustat at baseline and at follow-up.

Main outcomes and measures: Oropharyngeal swallowing function was assessed with videofluoroscopic swallowing studies. Overall swallowing ability and aspiration risk were evaluated using the American Speech-Language-Hearing Association National Outcome Measurement System swallowing domain and an adapted Rosenbek aspiration-penetration scale, respectively.

Results: Overall, 50 participants were evaluated at baseline (median [interquartile range] age, 9.4 [3.4-16.4] years; 26 [52%] female). The median (interquartile range) duration of follow-up was 3.0 (1.1-4.4) years. Miglustat use was associated with decreased odds of worse American Speech-Language-Hearing Association National Outcome Measurement System swallowing domain outcomes in all 3 subsets (overall: odds ratio [OR], 0.09 [95% CI, 0.02-0.36); P < .001; early childhood: OR, 0.17 [95% CI, 0.04-0.67]; P = .01; late childhood: OR, 0.05 [95% CI, 0.01-0.29]; P = .001). Miglustat use was associated with decreased odds of worse Rosenbek aspiration-penetration scale outcomes in the overall cohort (OR, 0.28 [95% CI, 0.08-0.95]; P = .04) but not in each subgroup (early childhood: OR, 0.27 [95% CI, 0.06-1.22]; P = .09; late childhood: OR, 0.38 [95% CI, 0.06-2.33]; P = .29).

Conclusions and relevance: These data suggest that miglustat use is associated with stabilized swallowing function and reduced aspiration risk in NPC1, thus supporting its use in this population. In addition, these data demonstrate that a quantification of swallowing dysfunction can be used as a clinically relevant, functional outcome measure in future therapeutic trials in NPC1.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Porter reports grants from National Institutes of Health and Ara Parseghian Medical Research Foundation during the conduct of the study; grants from National Institutes of Health, Ara Parseghian Medical Research Foundation, Together Strong NPC Foundation, and Firefly Fund outside the submitted work; other support from Mallinckrodt, Amicus Therapeutics, and UltraGenix outside the submitted work; and has patents on Niemann-Pick disease, type C biomarkers issued. No other disclosures were reported.

Figures

Figure 1.. Predicted Cumulative Probabilities of Disease Progression for Miglustat Use vs No Use From Longitudinal Models

A, Shaded regions indicate 95% CI for American Speech-Language-Hearing Association National Outcome Measurement System swallowing domain (ASHA-NOMS; range, 0 to 6 where 0 indicates ability to eat independently and 6 indicates swallowing is not safe by mouth) and Rosenbek aspiration-penetration scale (PAS; range, 0 to 4 where 0 indicates no obvious aspiration risk or penetration and 4 indicates profound aspiration). B, Analyses were performed using generalized linear models for repeated measures with independent working correlations for ordinal multinomial models. Each model also adjusted for baseline levels of the outcome variable. The full model was based on a priori hypothesis, and the final model retained variables following iterative model fitting, which are reflected in panel A. ECO indicates early childhood onset (age

Figure 2.. Association of Miglustat Use With Overall Ability to Eat and Swallow Safely and Aspiration Risk

Data are odds ratio (OR) and 95% CIs for miglustat use vs not. Longitudinal analyses of follow-up data were performed using generalized linear models for repeated measures with independent working correlations for ordinal multinomial models. Probabilities for severity of disease (disease progression) were modeled for the American Speech-Language-Hearing Association National Outcome Measurement System swallowing domain (ASHA-NOMS) and Rosenbek aspiration-penetration scale (PAS) outcomes. Models accounted for the association of miglustat use outcomes, seizure history, duration of neurologic symptoms, and duration of follow-up in the overall cohort, the early childhood onset subgroup (ECO; age