Pipeline of Medications to Treat Substance Use Disorders

Pipeline of Medications to Treat Substance Use Disorders Iván D. Montoya, M.D., M.P.H. Clinical Director and Deputy Director Division of Therapeutics and Medical Consequences NIDA • Cocaine • Methamphetamine • Cannabis Outline Past-Year Prevalence NSDUH, 2018 Past-Year Prevalence NSDUH, 2018 Number of Overdose Deaths CDC, 2018 Molecular Neurobiology of Stimulant Use Disorders Glutamate Excitatory Input Enkephalin or Dynorphin Inhibitory Neuron k Opioid Receptors Dopamine Receptors Enkephalin Inhibitory Neuron Dopamine Neuron GABA Neuron m Opioid Receptors REWARD GABA-A Receptors GABA Inhibitory Feedback Presynaptic Opioid Receptors (m, d?) GABA Inhibitory Neuron Ventral Tegmental Area (VTA) Nucleus Accumbens (NAc) Adapted from Koop, 2016 •••••••5HT2c Agonist - Lorcaserin (Belviq XR®) Orexin 1 antagonists Cocaine EMB-101 (Oxazepam + Metyrapone) Buprenorphine + Opioid Antagonist Ketamine – Clinical Studies Oxytocin L-Tetrahydropalmatine (L-THP) 5-HT2C Agonist - Lorcaserin • Clinically available • Selective agonist • Modulate mesolimbic dopamine, decreasing dopamine release • FDA-approved for weight loss • Lorcaserin (Belviq®)10 mg bid • Lorcaserin XR (Belviq XR®) 20 mg qd • Schedule IV • Arena Pharmaceuticals - Eisai Inc. Lorcaserin Pre-clinical Studies - Stimulants • Decrease cocaine self-administration and the reinstatement of responding for cocaine (Grottick et al., 2000; Burmeister et al., 2004; Burbassi and Cervo 2008; Cunningham et al., 2011; Manvich et al., 2012; RüediBettschen et al., 2015, Howell and Cunningham 2015). • Attenuates self-administration of cocaine (Collins et al., 2016; Harvey-Lewis et al., 2016) and nicotine (Levin et al., 2011; Higgins et al., 2012, 2013) • Tolerance does not develop to the effects of lorcaserin on cocaine self-administration (Collins et al., 2016) • Attenuates the ability of stress or conditioned cues to stimulate cocaine-seeking behavior in rats with a prior history of cocaine self-administration (Fletcher et al., 2008) • Efficacy against methamphetamine cue reinstatement and nicotine Selective serotonin 2C receptor agonist Modulates the dopaminergic reward system. Approved by the FDA for chronic weight management Lorcaserin – Clinical Trials NCT03007394 • Phase 2 multicenter RCT - NIDA • N=272 • 10 mg bid * 13 weeks • Recruitment complete • Data analysis in progress • Primary endpoint:proportion of subjects that successfully achieve abstinence from cocaine during the last three weeks of treatment in the "pre-qualified for primary efficacy endpoint" (PPEE) population [ Time Frame: Treatment weeks 11 - 13 ] NCT03192995 • Pilot RCT (n=45) UCSF Orexin (Hypocretin) Neurons - 10,000–20,000 orexin-producing neurons in the human brain - Located predominantly in the perifornical area and lateral hypothalamus - Project widely throughout the central nervous system - There are two types of orexin peptide and two types of orexin receptor - Regulates arousal, wakefulness, reproduction, and appetite. Peyron et al. J. Neurosci. 1998;18:9996-10015 OX1 Antagonists and Cocaine • Reduce dopamine transporter sensitivity to cocaine in the VTA and NAc • Disrupt the expression of Pavlovian associations formed by cocaine • Reduce compulsive-like cocaine taking under long access self- administration conditions • Suppress motivation to obtain cocaine under high effort conditions • Reduce the strength of stress-,cue- and context-induced cocaine reinstatement. Orexin 1 Antagonists – Why clinically? • Sleep problems frequently precede SUD • Sleep is directly impaired by SUD • Drug (opioids) modify the sleep-wake cycle (Orexin system) • Drug withdrawal associated with sleep disruptions • Sleep problems have been independently associated with increased comorbidity • Benzodiazepines are frequently abused in conjunction with opioids • Benzodiazepines co-administration with opioid agonists is associated with increased lethality Suvorexant • Dual OX1R/OX2R antagonist and schedule IV compound, FDA approved for treatment of insomnia • Suvorexant (10 mg vs placebo) in reducing anxiety, improving sleep, and reducing cocaine cravings or cocaine use(n=20) • Urine samples positive for cocaine: 90% vs 82% • Preliminary evidence favoring Suvorexant for inhibitory control, sleep, stress reactivity, and craving. (Lane, 2018) • NCT03937986: Human lab Study. PI: Bill Stoops. • Mirtazapine • Monoclonal Antibody • Vaccine Methamphetamine • Naltrexone • Ibudilast – Clinical Studies • Bupropion • Buspirone • Oxytocin Mirtazapine • Potent antagonist or inverse agonist of the α2A-, α2B- , and α2C-adrenergic receptors, the serotonin 5- HT2A, 5-HT2C, and the histamine H1 receptor • Does not inhibit the reuptake of serotonin, norepinephrine, or dopamine, nor does it inhibit monoamine oxidase. • Safe and no abuse potential • SE: somnolence, weight gain, dry mouth • May reduce meth craving (Kingsakon, 2005) Mirtazapine N=56 Mirtazapine 30 mg qd D-B RCT Weekly urine Colfax, 2011 • Phase 1, double-blind, randomized, placebo-controlled, ascending single-dose safety and tolerability study • ch-mAb7F9 administered as an intravenous infusion to healthy volunteers • Forty-two subjects were treated in 5 dose groups ranging from 0.2 to 20 mg/kg ch-mAb7F9, with 10 of the 42 subjects receiving normal saline as a placebo control. • Subjects were followed for 147 d after dosing with regular safety assessments and for pharmacokinetic and immunogenicity analyses. • It is predicted that 20 mg/kg will be effective in humans • The concentration of ch-mAb7F9 required to bind this much METH is »50 mg/mL • Ch-mAb7F9 concentrations remain above 50 mg/ml for 1 to 2 weeks after 6 mg/kg, and for about 5 weeks after 20 mg/kg Past-Year Prevalence NSDUH, 2018 • Fatty acid amide hydrolase (FAAH): enzyme that degrades the endocannabinoid anandamide • FAAH inhibition  Increase anandamide • double-blind, placebo-controlled, parallel group phase 2a trial at one site in men aged 18–55 years with cannabis dependence • Participants were admitted to hospital for 5 days (maximum 8 days) to achieve abstinence and precipitate cannabis withdrawal, after which they were discharged to continue the remaining 3 weeks of treatment as outpatients FAAH Inhibitor F-04457845 Neuropsychopharmacology, Dec 2018 Summary • Cocaine • Lorcaserin • Methamphetamine • Mirtazepine • Monoclonal antibody • Cannabis • FAAH Inhibitor Preclinical Pharmacological Targets • Vesicle Monoaminte Transporter 2 (VMAT2) • Neurotensing Receptor 1 (NTR1) • Trace Amine-Associated Receptor 1 (TAAR1) • Organic Cation Transporter 3 • Chemokine receptor type 4 (CXCR-4) • Ghrelin Receptor Antagonist • Muscarinic M5 • Nociceptive Orphanin Receptor (NOP/ORL) • Metabotropic Glutamate 2/3 Receptor (mGLUR2/3) Past-Year Prevalence – Thousands of People Bolliger, 2019

Pipeline of Medications to Treat Substance Use Disorders

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