Takeda Pharmaceutical Company (4502) Study Update summary

Study background and rationale

• TAK-861 is an oral orexin receptor 2 agonist developed to address narcolepsy type 1 (NT1), a disease caused by loss of orexin neurons and resulting orexin deficiency.

• Previous compounds, such as TAK-994, showed efficacy but were discontinued due to liver toxicity, informing the safer design of TAK-861.

• TAK-861 aims to address the full spectrum of NT1 symptoms, including excessive daytime sleepiness, cataplexy, disrupted nighttime sleep, hallucinations, and sleep paralysis.

• The twice-daily dosing regimen was designed to mimic natural orexin fluctuations, optimizing efficacy while minimizing side effects.

Study design and patient population

• Phase IIb randomized, double-blind, placebo-controlled trial enrolled 112 NT1 patients, confirmed by HLA genotype and low orexin levels, who discontinued other narcolepsy medications before entry.

• Patients were randomized to placebo or four TAK-861 dosing arms (three BID, one QD) for eight weeks, with a blinded extension study offered.

• The study assessed both primary and multiple secondary endpoints, including sleep latency, subjective sleepiness, and cataplexy frequency.

• 95% of completers entered the extension study, with many now on treatment for over a year.

Efficacy results

• TAK-861 produced statistically significant and clinically meaningful improvements in objective wakefulness (MWT), subjective sleepiness (ESS), and cataplexy at all doses, sustained over eight weeks.

• Most patients achieved normal ranges for MWT and ESS by week 8, with up to 95% in the 2 mg BID arm reaching normative ESS scores.

• Cataplexy rates were reduced to near zero in BID arms, with all three BID regimens showing significant improvement over placebo.

• Exploratory endpoints showed meaningful improvements in narcolepsy symptoms and functioning.