Miglustat as a Treatment for Adults with Tangier Disease Neuropathy: The MUSTANG N-of-1 Trial with 21 months Clinical Observation.
Cook A., Stuart B., Ochoa-Ferraro A., Condon N., Lawrence M., Webley F., Wallom K-L., Forbes C., Veeranna V., Wanninayake S., Oliver T., Davies N., Dawson C., Platt F., Hiwot T.
IMPORTANCE: Tangier disease (TD) is an ultra-rare disease, characterised by progressive peripheral neuropathy with no established treatment. OBJECTIVES: To determine whether miglustat improved the clinical status of a single patient with TD, and to investigate the possible mechanisms of miglustat in this patient. DESIGN, SETTING, AND PARTICIPANTS: An n-of-1 ABAB study, alternating on and off treatment for 6-month periods, total study duration of 2 years with an additional compassionate-access period of 21 months. EXPOSURE: Miglustat, an orphan drug licenced to treat Gaucher disease and Niemann-Pick disease, was repurposed. MAIN OUTCOMES AND MEASURES: The study was designed with two co-primary endpoints: (a) time taken to complete the nine-hole peg test (fine motor control and finger dexterity), and (b) hand strength: grip and three-point pinch strength tests. Secondary endpoints were quality-of-life measures and biomarkers. RESULTS: A 21-year-old (at baseline) left-handed male patient with TD, diagnosed at the age of 6 months, and disabling neuropathy was included in the study. Over 2 years, there was a small signal in our clinical measures that the drug may be beneficial. Compared with the 2 years prior to treatment, the patient had no relapse of neuropathy during his study period and further extension. During the 21-month treatment extension, he showed considerable improvement on primary endpoints. Biomarkers changed as expected based on the mechanism of action of miglustat. Nerve conduction studies showed a mild benefit. Importantly, the patient's reported experience suggested a meaningful benefit from miglustat. CONCLUSIONS AND RELEVANCE: Miglustat may be used to treat neurological complications of TD. This study showed that an n-of-1 study to inform a policy decision is practical and may offer hope to patients with rare diseases. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: ISRCTN17945917. Registration date: 07/06/2021; 'retrospectively registered'.