0726 Clinical Meaningfulness of Cognitive Improvements with Oveporexton (TAK-861) in Adults with Narcolepsy Type 1 (NT1)

Abstract Introduction Cognitive symptoms – particularly impairment in attention – are frequent in narcolepsy type 1 (NT1). In NT1, 12-week treatment with the orexin agonist oveporexton (TAK-861) significantly improved multiple cognitive domains, including attention. This study evaluated whether improvement reflected clinically meaningful change by examining relationships between change in performance on the Psychomotor Vigilance Test (PVT) and change in patient ratings of cognitive difficulties, disease severity, and function. Methods Blinded data from baseline and Week 12 assessments in The First Light (n=166) and The Radiant Light (n=105) phase 3 trials were analyzed using anchor- and distribution-based methods for determining meaningful within-person change (MWPC). Attention was assessed as number of lapses on the PVT (PVT lapses; 2 intraday sessions), and MWPC was identified as the smallest reliable improvement in PVT lapses associated with patient-reported change. Patient reported change was assessed using multiple anchors of cognitive difficulties, disease severity (Clinical/Patient Global Impression of Severity), and function, e.g., the Functional Impacts of Narcolepsy Instrument (FINI)–Cognitive Functioning domain, and the British Columbia Cognitive Complaints Inventory–Enhanced (BC-CCI-E) total score. Mean PVT lapse change was calculated across anchor change categories (no change/worsening, minimal improvement, much/very much improvement) to identify MWPC thresholds, which were applied to unblinded data to determine the percentage of responders in each treatment group. Results Patient reports of higher levels of improvement across anchor categories corresponded with progressively greater reductions in PVT lapses. Triangulated anchor- and distribution-based analyses supported selecting a reduction of ≥2 PVT lapses to represent an MWPC threshold that distinguishes change anchor categories from the no change/worsening category, i.e., a clinically meaningful improvement in attention. Applying the MWPC threshold to unblinded data from both studies showed 57.6%-71.9% of oveporexton-treated participants achieved clinically meaningful improvement at Week 12, versus 17.6%-25.7% of placebo-treated participants. The odds of achieving meaningful PVT lapse change were 5-7.5 times larger at Week 12 in oveporexton-treatment groups than in placebo groups. Conclusion Improvement of ≥2 PVT-lapses represented clinical meaningful improvement in attention. Application of this threshold to unblinded data indicated 12-week oveporexton treatment provided a clinically meaningful benefit to attention for most adults with NT1. Support (if any) Funding by Takeda Development Center Americas, Inc.