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ORX750, an Oral Selective Orexin Receptor 2 Agonist, Promotes Wakefulness and Reduces Cataplexy in the Orexin/Ataxin-3 Mouse Sarah Wurts Black, Ph.D. October 25th World Sleep 2023, Rio de Janeiro, Brazil

• ORX750 is a novel, full OX2R agonist designed using high resolution crystal and cryo-EM structures • ORX750 potently activated the OX2R with an EC50 of 0.11 nM and 9,800-fold selectivity over OX1R • Oral administration of ORX750 achieved maximal wake times in highly predictive Atax and DTA mouse models of narcolepsy type 1 – Activity observed at 0.1 mg/kg, the lowest dose tested in DTA mice – Increased time awake, latency to sleep, latency to cataplexy, and consolidation of wakefulness – Suppressed cataplexy occurrences • ORX750 showed activity in wild type mice at the lowest dose tested (1 mg/kg) 3 We believe ORX750 has the potential to treat narcolepsy and other sleep/wake disorders ORX750 OX2R

Log concentration (M) Activation (% total) • Activation pattern was indistinguishable from OXA with lack of biased agonism1 • No significant differences in OX2R potency were observed across species2 • No significant pharmacological activity observed in GPCR selectivity and in vitro safety panels3 4 Fluorescent imaging plate reader (FLIPR) assay with Chinese hamster ovary (CHO) cells stably expressing recombinant human OX1R or OX2R; OXA EC50 at hOX2R = 0.035 nM; ORX750 EC50 at hOX1R = 1100 nM 1 Pathhunter β-arrestin recruitment assay with CHO cells co-expressing ProLink™ (PK)-tagged OX2R and Enzyme Acceptor (EA)-tagged β-arrestin 2 Human, mouse, rat, dog, monkey recombinant receptors in vitro 3 Safety 47 and GPCRMax168 from >60 receptor families EC50 0.11 nM for hOX2R 9,800-fold selectivity vs. hOX1RORX750 at hOX2R ORX750 at hOX1R OXA at hOX2R

High potency at native mouse OX2R ORX750 depolarized1 and increased firing rates2 of histaminergic neurons in the TMN 5 -50 mV 2 min 20 mV Application Period ORX750 (30 nM) Whole cell recordings of histaminergic neurons in ventral TMN in mouse brain slices • ORX750 EC50 5 nM; OXA EC50 32 nM • TMN=tuberomammillary nucleus, area enriched in OX2R and a component of the orexinergic wake-promoting neurocircuitry (Mignot, E., et al., Front Neurol Neurosci, 2021;45:103) 1. Performed in presence of tetrodotoxin 2. Performed in absence of tetrodotoxin Neuronal firing rate

6 • Age at first dose 20-22 wks in orexin/ataxin-3 (Atax) and 23-27 wks (7 wks after removal of doxycycline chow) in orexin/tTA;tetO diphtheria toxin fragment A (DTA) mice; males used • EEG, EMG recorded using intraperitonially implanted telemeters with video and manually scored in 10-sec epochs; dosing at start of dark period • *For all doses, all models p < 0.05 vs. 0 mg/kg, Holm-Sidak multiple comparisons test following repeated-measures analysis of variance (RM-ANOVA) per mouse model in counterbalanced design Atax mouse DTA mouse Wake time (% during 3 h post dose) Latency to NREM sleep (minutes) Time awake increased at ≥ 0.1 mg/kg (lowest dose tested in DTA mice) ORX750 (mg/kg, p.o.) ** Latency to sleep increased at ≥ 0.1 mg/kg (lowest dose tested in DTA mice) * *

7 • Manually scored 10-sec epochs by consensus criteria (Scammell, T et al., SLEEP 2009;32(1):111) in mice housed with running wheels; dosing at start of dark period • If no cataplexy was observed during the 6 h test window, the maximum possible latency was assigned (360 min); mice without cataplexy in baseline were excluded from analysis • For all doses, all models vs. vehicle, p < 0.05 vs. 0 mg/kg, Holm-Sidak multiple comparisons test following RM-ANOVA per mouse model in counterbalanced design 0 0.3 1 3 10 0 120 240 360 Atax mouse DTA mouse Latency to cataplexy (minutes) Cataplexy occurrences decreased at ≥ 0.1 mg/kg (lowest dose tested in DTA mice) Latency to cataplexy increased ≥ 0.1 mg/kg (lowest dose tested in DTA mice) ORX750 (mg/kg, p.o.) Cataplexy occurrences (count during 6 h post dose) * * * * 14 days of treatment did not attenuate the effect of ORX750

8 • Increase in EEG power in gamma frequency associated with enhanced alertness (Cantero, J.L., et al., NeuroImage, 2004;22:1271) • Data normalized as the percent of the mean power across all frequency bands in 6 h recording from 10-sec, artifact-free wakefulness epochs of manually scored EEG • * p < 0.05 vs. 0 mg/kg, Holm-Sidak multiple comparisons test following RM-ANOVA in counterbalanced design ORX750 increased EEG power during wakefulness in the alpha and gamma bands and decreased power in the theta band Wake EEG power (normalized % during 1 h post dose) Delta (0.5-4.5 Hz) Theta (4.5-9.5 Hz) Alpha (9.5-12.5 Hz) Beta (12.5-30.5 Hz) Gamma (30.5-80 Hz) ORX750 (mg/kg, p.o.) *** n.s.*** ****n.s.

9 • Age at first dose was 16-20 wks in male Atax mice and WT colony mates; mice dosed at 5 h after lights on • * p < 0.05 vs. 0 mg/kg, Holm-Sidak multiple comparisons test following RM-ANOVA per mouse model in counterbalanced design Wake bout duration (mean sec during 1 h post dose) Wake bout occurrences (count during 1 h post dose) Consolidation of wakefulness Wake time (% during 2 h post dose) Atax mouse WT mouse ORX750 (mg/kg, p.o.) In healthy WT mice, wake time and consolidation increased at ≥ 1 mg/kg (lowest dose tested) NT1 mouse models were more sensitive to OX2R agonism than WT mice * * * * * * • Data collected using PiezoSleep, in which wakefulness readouts based on movement & breath rate highly correlate with EEG/EMG measures (Black, et al., ESRS2022 presentation)

• ORX750 is a novel, full OX2R agonist designed using high resolution crystal and cryo-EM structures • ORX750 potently activated the OX2R with an EC50 of 0.11 nM and 9,800-fold selectivity over OX1R • Oral administration of ORX750 achieved maximal wake times in highly predictive Atax and DTA mouse models of narcolepsy type 1 – Activity observed at 0.1 mg/kg, the lowest dose tested in DTA mice – Increased time awake, latency to sleep, latency to cataplexy, and consolidation of wakefulness – Suppressed cataplexy occurrences • ORX750 showed activity in wild type mice at the lowest dose tested (1 mg/kg) 10 We believe these results support further progression of ORX750 as a potential best-in-class treatment for narcolepsy and other sleep/wake disorders