005 Samelisant (SUVN-G3031), a histamine H3 receptor inverse agonist in animal models of sleep disorders

Abstract Introduction Narcolepsy is a chronic sleep disorder characterized by overwhelming daytime drowsiness, sudden attacks of sleep and sometimes accompanied by cataplexy. Although the orexin deficiency is considered to be the primary cause of this disorder, lot of attention has been diverted on targeting histaminergic neurotransmission by blockade of histamine H3 receptor (H3R). Samelisant (SUVN-G3031) is one of the potent and selective H3R inverse agonist currently being evaluated in a Phase 2 study as monotherapy for the treatment of narcolepsy with and without cataplexy (ClinicalTrials.gov Identifier: NCT04072380). In the current research work, Samelisant was evaluated for neurotransmitter changes in rats and sleep EEG in orexin knockout mice, a reliable proof-of-concept study for treatment of excessive daytime sleepiness and cataplexy in narcolepsy. Methods Binding affinity of Samelisant towards human and rat histamine H3R was evaluated in in-vitro radioligand binding assay and functionality in GTP□S assay. Effect of Samelisant was studied in (R)-α-methyl histamine induced dipsogenia. In rat brain microdialysis, Samelisant was evaluated for its effects on modulation of neurotransmitters like histamine, dopamine and norepinephrine. Male orexin knockout mice were implanted with telemetric device for simultaneous monitoring of electroencephalography (EEG) and electromyography. Effects of Samelisant (3 and 10 mg/kg, p.o.) were evaluated during active period of animals. Results Samelisant is an inverse agonist at histamine H3 receptors with hKi of 8.7 nM and showed minimal binding against over 70 target sites. Samelisant produced significant increase in histamine, dopamine and norepinephrine levels in cortex. Samelisant produced no change in the striatal and accumbal dopamine levels in rats, suggesting no propensity to induce abuse liability. Samelisant blocked R-α-methyl histamine induced water intake and produced dose dependent increase in tele-methylhistamine levels in various brain regions and in cerebrospinal fluid of male Wistar rats. Samelisant produced significant increase in wakefulness with concomitant decrease in non-rapid eye movement sleep in orexin knockout mice. Samelisant also significantly decreased number of cataplectic episodes in orexin knockout mice. Conclusion Samelisant is an inverse agonist at histamine H3 receptor and results from the preclinical studies presented here provide a strong evidence for the potential utility of Samelisant in the treatment of narcolepsy with and without cataplexy. Support (if any):

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0072 Preclinical Characterization of SUVN-G3031, a Histamine H3 Receptor Inverse Agonist for the Treatment of Narcolepsy

SLEEP ◽

10.1093/sleep/zsaa056.070 ◽

2020 ◽

Vol 43 (Supplement_1) ◽

pp. A29-A29

Author(s):

P Jayarajan ◽

R Subramanian ◽

V Kamuju ◽

N Muddana ◽

R Palacharla ◽

...

Keyword(s):

Radioligand Binding ◽

Brain Regions ◽

Inverse Agonist ◽

Abuse Liability ◽

Histamine H3 Receptor ◽

H3 Receptor ◽

Pharmacokinetic Properties ◽

Male Wistar Rats ◽

Histamine H3

Abstract Introduction Narcolepsy is a chronic sleep disorder characterized by overwhelming daytime drowsiness, sudden attacks of sleep and sometimes accompanied by cataplexy. Although the orexin deficiency is considered to be the primary cause of this disorder, lot of attention has been focused recently on targeting histaminergic neurotransmission by blockade of histamine H3 receptor (H3R). SUVN-G3031 is one of the potent and selective H3R inverse agonist currently being evaluated in a Phase 2 study as monotherapy for the treatment of narcolepsy with and without cataplexy (ClinicalTrials.gov Identifier: NCT04072380). Methods Binding of SUVN-G3031 in human and rat histamine H3R was evaluated in in vitro radioligand binding assay and functionality was assessed in GTPγS assay. Pharmacokinetic properties were evaluated after oral administration in rat and dog. Neurotransmitters like histamine, dopamine and norepinephrine were estimated in rat cortex using microdialysis. Results SUVN-G3031 is an inverse agonist at histamine H3R with hKi of 8.7 nM and showed minimal binding against over 70 target sites. SUVN-G3031 exhibited desired pharmacokinetic properties in rat and dog with excellent brain penetration in rats. SUVN-G3031 produced significant increase in histamine, dopamine and norepinephrine levels in cortex. SUVN-G3031 produced no change in the striatal and accumbal dopamine levels in rats, suggesting no propensity to induce abuse liability. SUVN-G3031 blocked R-α-methylhistamine induced water intake and produced dose dependent increase in tele-methylhistamine levels in various brain regions and in cerebrospinal fluid of male Wistar rats. Conclusion SUVN-G3031 is an inverse agonist at histamine H3 receptor and results from the preclinical studies presented here provide a strong evidence for the potential utility of SUVN-G3031 in the treatment of narcolepsy with and without cataplexy. Support None

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0008 SUVN-G3031, A Histamine H3 Receptor Inverse Agonist Produces Robust Wake Promoting and Anticataplectic Activity in Orexin Knockout Mice

SLEEP ◽

10.1093/sleep/zsaa056.007 ◽

2020 ◽

Vol 43 (Supplement_1) ◽

pp. A3-A3

Author(s):

V Benade ◽

S Daripelli ◽

S Petlu ◽

R Subramanian ◽

G Bhyrapuneni ◽

...

Keyword(s):

Knockout Mice ◽

Animal Studies ◽

Preclinical Study ◽

Inverse Agonist ◽

Strong Basis ◽

Histamine H3 Receptor ◽

Histaminergic Neurons ◽

H3 Receptor ◽

Receptor Inverse Agonist ◽

Histamine H3

Abstract Introduction Narcolepsy is a sleep disorder characterized by excessive daytime sleepiness, sleep paralysis, hallucinations, and in some cases episodes of cataplexy. Results from animal studies indicate the involvement of deficient orexin transmission in narcolepsy which can be circumvented by the activation of histaminergic neurons. SUVN-G3031 is a potent and selective histamine H3 receptor inverse agonist with hKi of 8.7 nM and shows less than 50% inhibition at 1 µM against 70 other targets. SUVN-G3031 exhibited excellent pharmacokinetic properties and brain penetration in preclinical species. Oral administration of SUVN-G3031 produces significant increase in histamine, dopamine and norepinephrine levels in the rat cortex. Long-term safety studies in animals have been successfully completed without any concern for further development of SUVN-G3031. In the present study, the effects of SUVN-G3031 were evaluated in orexin knockout mice, a reliable animal model of narcolepsy as a proof-of-concept study for the treatment of narcolepsy with and without cataplexy. Methods Male orexin knockout mice (10 - 15 weeks old, 25 - 35 g at the time of surgery) were implanted with telemetric device for simultaneous monitoring of electroencephalography (EEG) and electromyography. Animals were allowed surgical recovery of 3 weeks prior to EEG recording. Effects of SUVN-G3031 (3 and 10 mg/kg, p.o.) were evaluated during active period of animals. Results SUVN-G3031 produced significant increase in wakefulness with concomitant decrease in non-rapid eye movement sleep in orexin knockout mice. SUVN-G3031 also significantly decreased the number of cataplectic episodes in orexin knockout mice. Conclusion Results from the current preclinical study provide a strong basis for the utility of SUVN-G3031 for the treatment of narcolepsy with and without cataplexy. SUVN-G3031 is currently being evaluated in a Phase 2 study as monotherapy for the treatment of narcolepsy with and without cataplexy (ClinicalTrials.gov Identifier: NCT04072380). Support None

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0155 SUVN-G3031, A Potent and Selective Histamine H3 Receptor Inverse Agonist - Differentiating Features Over Current Treatments of Narcolepsy

SLEEP ◽

10.1093/sleep/zsaa056.153 ◽

2020 ◽

Vol 43 (Supplement_1) ◽

pp. A61-A61

Author(s):

A Shinde ◽

R Subramanian ◽

R Palacharla ◽

S Pandey ◽

V Benade ◽

...

Keyword(s):

Binding Affinity ◽

Abuse Liability ◽

Species Variation ◽

Pharmacological Agents ◽

Histamine H3 Receptor ◽

Inverse Agonists ◽

H3 Receptor ◽

Histamine H3

Abstract Introduction Majority of pharmacological agents used in the treatment of narcolepsy have several limitations. Both nonclinical and clinical evidences suggest usefulness of the histamine H3 receptor (H3R) inverse agonists for the treatment of narcolepsy and addressing several of the current limitations. Methods Extensive nonclinical studies were carried out for SUVN-G3031 and other pharmacological agents that are currently being used for the treatment of narcolepsy. Nonclinical parameters like inter-species binding affinity, selectivity profile, in vivo and in vitro ADME features, nonclinical efficacy, neurochemistry and safety were compared. Results SUVN-G3031 has no inter-species variation in binding affinity at H3R with less than 50% inhibition at 1 µM against 70 other targets. Unlike pitolisant, SUVN-G3031 has no significant binding affinity at sigma 1 and 2 receptor. SUVN-G3031 has no inhibition and induction liability towards major CYP enzymes and transporters. Pitolisant is reported to be a CYP3A4, CYP2B6, and CYP1A2 inducer and a CYP2D6 and OCT1 inhibitor. SUVN-G3031 has robust wake promoting effects. SUVN-G3031 showed negligible affinity towards hERG channel with IC50 > 10 µM and had no effects on any ECG parameters in dog telemetry study. SUVN-G3031 did not show convulsion in rats up to the tested dose of 100 mg/kg, p.o. Most of the pharmacological agents used for the treatment of narcolepsy have abuse liability; SUVN-G3031 produced no change in the striatal and accumbal dopamine levels in rats suggesting no propensity to induce abuse liability. Unlike competing H3R inverse agonists, SUVN-G3031 has no effects on fertility and embryo-fetal development up to the highest tested doses. Conclusion Nonclinical studies demonstrate superiority of SUVN-G3031 over pharmacological agents currently used in the treatment of narcolepsy. SUVN-G3031 is being evaluated in a Phase 2 study as monotherapy for the treatment of narcolepsy with and without cataplexy (ClinicalTrials.gov Identifier: NCT04072380). Support None

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