Efficacy and safety of efavirenz in Niemann-Pick disease type C

Abstract

Introduction: In search of disease-modifying treatments for the Niemann-Pick disease type C (NPC), this Phase II single-arm clinical trial evaluated the safety and efficacy of efavirenz, a reverse transcriptase inhibitor that potentially ameliorates neuronal cholesterol turnover, typically impaired in this rare lysosomal storage disorder.

Material and methods: Patients 14 years of age or older with genetically confirmed NPC received efavirenz 25 mg/day (Weeks 1-26) or 100 mg/day (Weeks 27-52) orally on top of standard care including miglustat. The primary endpoint was the proportion of response, defined as lack of deterioration in a composite outcome of cognitive performance. Secondary endpoints included the quantitative scores of several clinical neuropsychological assessment tools, some relevant neurological signs and symptoms, and imaging and biological specimen-based biomarkers. Measures were taken repeatedly over time and were analyzed using generalized linear mixed models.

Results: Sixteen patients 15-60 years of age were enrolled. All (100.0 %, 95 % exact confidence interval: 79.4-100.0 %) met the primary endpoint response criterion at Week 52. Quantitative neuropsychological assessments yielded more nuanced results, with relative preservation of learning, memory and executive control, and subtle impairments of verbal fluency, selective and divided attention, and cognitive inhibition. Some patients had better responses than others, allowing us to set two well-differentiated subgroups that differed essentially in the time since symptoms onset. No efavirenz-related or serious adverse events were reported.

Conclusion: Efavirenz appears to be a safe, easy-to-use, new targeted therapeutic option which slows the rate of NPC progression. The benefits of efavirenz are greater if started earlier.

Trial registration: Registered on the European Union Clinical Trials Register (EurdraCT) on December 20th, 2019 under the number: 2019-004498-18 (https://www.clinicaltrialsregister.eu/ctr-search/trial/2019-004498-18/ES/). The first patient was enrolled on May 25th, 2022.

Keywords: Clinical trial; Dementia; Lipid metabolism disorders; Lysosomal storage diseases; Neurodegenerative diseases; Neuropsychological tests.

Fig. 1

STROBE flow diagram.

Fig. 2

Proportion of patients presenting deterioration in each neuropsychological milestone and proportion of responders to efavirenz. CDR-SB, Clinical Dementia Rating scale – Sum of Boxes; FCSRT, Free and Cued Selective Reminding Test; r-BT, revised Barcelona Test; TMT, Trail Making Test; SCWT, Stroop Color-Word Interference Test. (A) Percentage (exact 95 ​% CI) of patients presenting deterioration in each cognitive performance domain at visits 4 (lighter colors) and 6 (darker colors). (B) Percentage (exact 95 ​% CI) of responders at visits 4 (lighter colors) and 6 (darker colors).

Fig. 3

Evolution of adjusted (least square) mean scores (95 ​% CI) of the components of the composite primary outcome throughout the trial. CDR, Clinical Dementia Rating scale; CDR-SB, Clinical Dementia Rating scale – Sum of Boxes; FCSRT, Free and Cued Selective Reminding Test; r-BT, revised Barcelona Test; TMT, Trail Making Test; SCWT, Stroop Color-Word Interference Test; V4, visit 4; V6, visit 6. The blue band within each scaled score indicates the mean and ±1 standard deviation for the scaled scores (mean ​= ​10, SD ​= ​3). Of note, due to the non-proportional relationship between raw and scaled scores, the 95 ​% CI limits do not necessarily reflect the actual (sample) distribution of the scaled scores; however, this distortion does not affect the adjusted means (point estimates). P values come from adjusted analyses (for age, time from symptom onset, ataxia and disability scores) and reflect the effects of changes over time in both subgroups combined (visit factor), sustained differences between subgroups (group factor), and differences in time trajectories between subgroups (visit ​× ​group factor).

Fig. 4

Evolution of the means (95 ​% CI) of the neurological outcomes. SARA, Scale for the Assessment and Rating of Ataxia; EAT-10, Eating Assessment Tool – 10; PDS, Pineda Disability Scale; WAIS, Wechsler Adult Intelligence Scale; V4, visit 4; V6, visit 6.