Research Priorities of NIDA s Medications Development Program

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1 Research Priorities of NIDA s Medications Development Program Iván D. Montoya, M.D., M.P.H. Deputy Director, Division of Therapeutics and Medical Consequences NIDA No Disclosures

2 NIDA Medications Development Program In 1989, the U.S. Congress mandated that a Medications Development Program (MDP) be established within NIDA In 1990, NIDA created the Medications Development Division (MDD), now the Division of Therapeutics and Medical Consequences. Mission To use science as a vehicle for improving the pharmacological treatment of Substance Use Disorders with an emphasis on the identification, evaluation, and development of safe and effective medications and biologics to treat them.

3 NIDA MDP Division of Therapeutics & Medical Consequences of Drug Abuse Kurt Rasmussen Ivan Montoya Chemistry & Pharmaceutics Med Discovery & Toxicology Clinical Research Grants Clinical Medical Regulatory Affairs Rik Kline Jane Acri Kevin Walton Shwe Gyaw Robert Walsh

4 Medication Development Program Modeled after a typical pharmaceutical company Supports all phases of medications development Grants Contracts Interagency Agreement

5 Medications Development Marketed medications with good rationale to test in addicted subjects Basic science, discovery driven process based on the emerging Neurobiology of Addiction

6 MDP Emphasis Opioids Marijuana Cocaine Amphetamines Nicotine

7 SAMHSA, 2017

8 Based on CDC MMWR Report 2017 Any opioid 49,900

9 Challenges of the Opioid Crisis Has claimed about 200,000 lives Overdose deaths continue to rise. There is no end in sight. Efficacious treatments are available to treat opioid use disorders and to prevent/reverse overdose; however: Few FDA approved medications Efficacy needs improvement Side-effects Limited access Underutilized Minimal industry investment

10 Clinical Priorities Prevent initiation and progression of OUD Improve OUD treatment outcomes Facilitate opioid agonist discontinuation Improve tx opioid withdrawal (including neonatal) Reduce lethality of opioid overdose Reduce overdose relapses Reduce need/dose of opioids analgesics Reduce risk of opioid respiratory depression

12 Lofexidine Selective alpha2 adrenergic agonist Pre-synaptic inhibitor of NE release Reduces NE release during opioid withdrawal FDA indication: for the mitigation of withdrawal symptoms to facilitate abrupt discontinuation of opioids in adults for tx for up to 14 days in > 18 years old.

13 Lofexidine

15 N=264 Lofexidine: 3.2 mg/day

16 Lofexidine - Dosing Dosage is three 0.18 mg tablets taken orally 4 times daily at 5- to 6-hour intervals The total daily dosage of should not exceed 2.88 mg (16 tablets) and no single dose should exceed 0.72 mg (4 tablets) Dosing guided by symptoms Discontinue with a gradual dose reduction over 2 to 4 days Hepatic or Renal Impairment: Dose adjustments

17 Lofexidine - Risks Hypotension, bradycardia, somnolence, dizziness, dry month, few cases of syncope Rebound hypertension Change in opioid tolerance may lead to overdose QT prolongation (methadone) May potentiate CNS depressants CYP2D6 inhibitors (e.g., paroxetine) may increase plasma levels

18 Naloxone Nasal Spray Development Needle-free, unit-dose, ready-to-use opioid overdose antidote. Image courtesy of ADAPT Pharma, Inc.

19 PROBUPHINE Rosenthal et al., Addiction 2013;105.

20 Meds for OUD - Clinical Gabapentin Pregabalin CB1 agonists CBD VLY-686 Tradipitant (NK1 antagonist)

21 Meds for OUDs - Preclinical Promising Targets Mechanisms to reduce stress-induced drug seeking Kappa Opioid Receptor Antagonists OX-1 Receptor Antagonists NOP Receptor Agonists α2-adrenergic Receptor Agonists PDE7 Inhibitors Mechanisms to reduce cue-induced drug seeking D3 Receptor Antagonists OX-1 Receptor Antagonists 5-HT2C Receptor Agonists 5-HT2A Receptor Inverse Agonists mglur2 Positive Allosteric Modulators 5-HT6 Receptor Inhibitors PDE7 Inhibitors

22 Respiratory Stimulants Almitrine (Duxil by Servier) Agonist of peripheral chemoreceptors located on the carotid bodies. Increase arterial oxygen tension while decreasing arterial carbon dioxide tension in patients with chronic obstructive pulmonary disease Indicated for COPD Oral activity, prolonged duration of effect, and an improved adverse effect profile. Well tolerated (headache and minor GI disturbances)

23 Heroin Vaccine Morphine-conjugate vaccine (M-KLH) Vaccinated rats compared to controls: Heroin and its active metabolites, 6- acetylmorphine (6-AM) and morphine, were retained in plasma Metabolite concentrations were reduced in brain Consistent with the changes in heroin selfadministration rates Raleigh, Pentel LeSage, 2014

24 Fentanyl Vaccine IgG titers determined by ELISA against a fentanyl-bsa conjugate i= vaccine injection Bremer, 2017

25 Question To NIDA: Could you give us a breakdown of the funds provided to NIH for the opioid epidemic? How much to NIDA/year for how long? Could you provide some insight into how funds be used by NIDA and other NIH institutes (that is, basic v clinical; genomics?, drug development, etc.)

27 HEAL: Helping to End Addiction Long-term NIH Initiative to Address the Opioid Crisis $500M just added by Congress Adds to $600M current funds = $1.1B for FY18 Will propel HEAL Collaborative, cross-cutting research From basic to behavioral and everything between Innovative partnerships across agencies, sectors, organizations will ensure rapid progress Advances national priorities for pain and OUD research.

29 Based on CDC MMWR Report 2017 Any opioid 49,900

30 CANNABIS LAWS IN THE U.S. As of Jan. 22, 2018, the Vermont legislature passed adult-use legalization legislation and the governor signed the bill. The measure does NOT set up a regulatory system for sales or production. 29 states have legalized medical marijuana along with D.C., Guam and Puerto Rico States with MML vary on: Allowable conditions and routes of administration. Dispensaries/home growth and registries. Testing, regulatory requirements. States with Recreational Laws vary on: Marketing, product labeling, distribution (home growth). Taxation.

Drug Abuse & Addiction Research: Progress, Priorities, & Challenges

Drug Abuse & Addiction Research: Progress, Priorities, & Challenges National Institute on Drug Abuse Bringing the full power of science to bear on drug abuse and addiction Nora D. Volkow, M.D. Director