Medications for Use Disorder: Responding to Public Health Priorities

Wilson M. Compton, M.D., M.P.E. Deputy Director National Institute on Drug Abuse

Advancing Addiction Science # U.S.2 Public Health Crisis: Increased Drug Overdose Deaths

Estimated Age-adjusted Death Rates per 100,000 for Drug Poisoning by County 2003 2017

+

SOURCE: National Center for Health Statistics, National Vital Statistics System, mortality data (http://www.cdc.gov/nchs/deaths.htm). Evolution of Drivers of Overdose Deaths: “”

30,000 31,335“Fentanyl”

25,000 67,367 Deaths in 2018 20,000 46,802 from (Prescription and Illicit) 14,975 Prescribed 15,000 14,996 Heroin 10,000

5,000

0

1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 See: Compton WM & Jones CM, Ann NY Acad Sci, 2019; Updated for 2018 from WONDER Database and Hedegaard et al. NCHS Data Brief, no 356. January, 2020 # 8 AVAILABILITY: Direct and Indirect Pathways from Prescriptions to Misuse

• People misusing analgesics Directly & Indirectly obtain them by prescription Source where relievers obtained for most recent misuse

Prescription Prescription 36% Friend/ 87% Relative 54% 10% Friend/Relative 10% 3% Other Other Source: Han, Compton, et al. Annals of Internal Medicine 2017 ECONOMICS: Heroin Increases Due to Lower Price andand GreaterGreater AvailabilityAvailability

"Retail" Price Per Pure Gram $3,500 $3,000 $2,500 $2,000 $1,500 $1,000 $500 $-

1981 1982 1983 1984 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012

National Drug Control Strategy--Data Supplement 2014. https://www.whitehouse.gov/sites/default/files/ondcp/policy-and- research/ndcs_data_supplement_2014.pdf # 11

ECONOMICS: CHEAP Fentanyl Precursor Chemicals Methamphetamine# 25 (and other stimulants): An Emerging Issue

Primary Heroin Admissions 100 600,000 Treatment Admissions Involving 90 Methamphetamine Primary Heroin Admissions Involving 80 Heroin and Methamphetamine (%) Methamphetamine 70 Treatment 400,000 60 Admissions in the 50 U.S. 40 30 200,000 20

10 Involving Methamphetamine Involving

0 Jones, Underwood, 0 Compton Addiction Number of Treatment Admissions Number of Treatment

2019 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 Percent of Primary Heroin Treatment Admissions Evolution of Drivers of Overdose Deaths: Analgesics Heroin “Fentanyl” Stimulants

30,000 31,335“Fentanyl”

25,000 25,877 Stimulants (e.g. & methamphetamines) 20,000 14,975 Prescribed 15,000 14,996 Heroin 10,000

5,000

0

1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 See: Compton WM & Jones CM, Ann NY Acad Sci, 2019; Updated for 2018 from WONDER Database and Hedegaard et al. NCHS Data Brief, no 356. January, 2020 # 27OVERDOSE DEATHS BY DRUG (CDC, August 2020) 12 MONTH-ENDING PROVISIONAL NUMBER OF DRUG OVERDOSE DEATHS BY DRUG OR DRUG CLASS, UNITED STATES

40,000

35,000 • National provisional estimates include deaths occurring 30,000 within the 50 states and the District of 25,000 Columbia

• All 50 states 20,000 reported and of year final data through 15,000 2019.

10,000

5,000

0 Jul-15 Jul-16 Jul-17 Jul-18 Jul-19 Jan-15 Jan-16 Jan-17 Jan-18 Jan-19 Jan-20 Sep-15 Sep-16 Sep-17 Sep-18 Sep-19 Nov-15 Nov-16 Nov-17 Nov-18 Nov-19 Mar-15 Mar-16 Mar-17 Mar-18 Mar-19 May-15 May-16 May-17 May-18 May-19 # 28

OTHER ALL NAT & SEMI – SYNTHETIC HEROIN COCAINE PSYCHO- DRUGS SYNTHETIC OPIOIDS STIMULANTS JANUARY 68,211 15,205 12,566 3,058 31,961 14,876 13,323 2019 * JANUARY 72,707 14,144 12,075 2,789 38,015 16,496 16,854 2020*

Change 6.59% -6.98% -3.91% -8.80% 18.94% 10.89% 20.95% # 29

• 61% of ODMAP participating counties reported an increase in overdoses after stay-at-home orders issued • There was a 17.59% total increase in that timeframe

Source: http://www.odmap.org/Content/docs/news/2020/ODMAP-Report-June-2020.pdf # 22 Polydrug Use is Common: Other Substance Use Among Past Year

60% Opioid Misusers Aged 18+ (NSDUH, 2018) 52.1% 49.4% 50%

40%

30%

20% 16.9% 16.7%

10% 3.8% 3.3% 0% Opioids Heavy Cigarettes Marijuana Cocaine Methamphetamine Among Adults (PM) Aged 18+ Among Past Year Opioid Misusers Aged 18+ in the Past Year # 16 Percent of Synthetic Opioid-Related Overdose Deaths Involving Illicit or Psychotherapeutic Drugs or Alcohol, United States, 2016

100.0

90.0 79.7 80.0

70.0 Involved Deaths Involved - 60.0 47.9 50.0

40.0 29.8 30.0 21.6 20.9 20.0 17.0 11.1 10.0

Percent of Synthetic Opioid 5.4 5.2 2.0 0.7 0.5 0.0

Heroin (n=5,781)Cocaine (n=4,184) Alcohol (n=2,150) Barbiturates (n=88) Other opioids (n=9,299) Antipsychotics (n=385) Antidepressants (n=1,002) Other illicit drugs (n=144) Benzodiazepines (n=3,308) Psychostimulants (n=1,042) Prescription opioids (n=4,055) Other drug or alcohol (n=15,472) Source: CM Jones, EB Einstein, WM Compton JAMA 2018;319(17):1819-1821. # 12Opioid Use and Misuse Increasing Foster Care During Pregnancy Removals

NICU Admissions for Neonatal Abstinence Syndrome NAS (Number per 1000 Admissions) U.S. Foster Care Removals for Infants < 1 Y.O. Overall

Parental Substance Use

Source: Tolia VN, Patrick SW, et al.,NEJM 2015;372:2118-2126.

17% of pregnant women are prescribed an opioid 2011 2012 2013 2014 2015 2016 2017 during pregnancy Source: Patrick SW, Frank RG, et al. Hospital Pediatrics, 2019. # 14 Rising rates of HCV Counties Deemed Highly Vulnerable to Rapid Dissemination of HCV or HIV

Acute Cases of HCV in USA Zibbell et al. Am J Public Heath 2018;108:175-181

HIV (and Hepatitis C) Outbreak Linked to Injection Use in Source: Van Handel et al, JAIDS 2016 Indiana, 2015 Peters et al. The New England Journal of Medicine 2016;375:229-239 # 15 Other Adverse Outcomes Associated with Injection Drug Use

Endocarditis and IDU Injection of Rx opioids (and attendant crushing, cooking, and injection practices) are associated with: – Scarring – Abscesses and cutaneous infections – Endocarditis – Thrombotic microangiopathies Source: Hartman et al 2016 # 30 HHS Five-Point Opioid Strategy # Solutions31 toward Responsible Prescribing: Guidance

Opioid Prescribing Dowell, Compton, Giroir. 2019;322(19):1855–1856 Guidelines March 2016 Patient-Centered Reduction or Discontinuation • Intended for primary care providers of Long-term Opioid Analgesics: • Applies to patients >18 years old in The HHS Guide for Clinicians chronic pain outside of end-of-life Focuses on: care (1) Criteria for reducing or discontinuing opioid therapy (2) Considerations prior to deciding to taper opioids • Focuses on: (3) Ensuring patient safety prior to initiating taper Ø Determining when to initiate or (4) Shared decision-making with patients continue opioids for chronic (5) Rate of opioid taper pain (6) Opioid withdrawal management (7) Behavioral health support Ø Opioid selection, dosage, (8) Challenges to tapering duration, follow-up and Dosage changes, particularly rapid reductions in discontinuation dose, can harm patients or put them at risk if not Ø Assessing risk and addressing made in a thoughtful, deliberative, collaborative, harms of opioid use and measured manner. # 31 Coverage Studies: Are Non-Opioid Treatments Available?

Prescription Drug Coverage for Treatment of Low Coverage of Nonpharmacologic Treatments for Low Back Pain Among US Medicaid, Medicare Back Pain Among US Public and Private Insurers Advantage, and Commercial Insurers • Utilization management strategies • Near universal coverage of common for opioids; many physical and occupational nonopioids also subject to quantity therapy limits and prior authorization • acupuncture and psychological • Step therapy rarely used. intervention coverage less consistent • Emphasis on utilization management • Prior authorization and visit and other strategies to decrease opioid overuse rather limits common than broader initiatives to comprehensively improve • Out-of-pocket expense for the quality of care nonpharmacologic treatments • Opportunities among insurers and pharmacy benefit may be prohibitive (potentially managers to recalibrate the role of opioids in pain care, multiplied if multipronged expand access to opioid alternatives through coverage approaches used) and reimbursement policies, and measure the impact of such changes on patient outcomes Heyward J, Jones CM, Compton WM, Lin DH, Losby JL, Lin DH, Jones CM, Compton WM, Heyward J, Losby JL, Murimi IB, Baldwin GT, Murimi IB, Baldwin GT, Ballreich JM, Thomas DA, Bicket M, Ballreich JM, Thomas DA, Bicket M, Porter L, Tierce JC, Alexander GC. Porter L, Tierce JC, Alexander GC. JAMA Network Open 2018;1(2):e180235 JAMA Network Open 2018;1(6):e183044. Universal Drug Use Prevention: Three studies suggest impact of universal prevention on Rx drug misuse

18.0% FamilyFamily Program Program 16.0% 15.5 ControlControl Targeting Youth to Prevent 14.0% 13.5 ** p < .01 *** p < .001 Later Substance Use 12.0% Disorder: An Underutilized 10.0% 9.3 8.7 Response to the US Opioid 8.0% Crisis 6.0% 5.4** 4.7** Compton WM, Jones CM, Baldwin GT, Harding 4.0% FM, Blanco C, Wargo EM American Journal of Public Health 2.0% 1.2** 0.6*** 2019;109:2185-S189. 0.0% Age 21 General Age 21 Age 25 General Age 25 Narcotics In**p<.01; this study,***p<.001; forRRRs =100 65-93% young adults in general population starting Rx misuse, only 35 young adults from an intervention community started.

Notes: General=Misuse of opioids or CNS depressants or stimulants. Source: R Spoth et al. American Journal of Public Health 2013 # 34 Distribution Direct intervention to save lives: Nasal spray and Auto-injector formulations

April 5, 2018 Surgeon General’s Advisory on Naloxone and I, Surgeon General of the United States Public Health Service, VADM Jerome Adams, am emphasizing the importance of the overdose-reversing drug naloxone. For patients currently taking high doses of opioids as prescribed for pain, individuals misusing prescription opioids, individuals using illicit opioids such as heroin or fentanyl, health care practitioners, family and friends of people who have an , and community members who come into contact with people at risk for opioid overdose, knowing how to use naloxone and keeping it within reach can save a life.

BE PREPARED. GET NALOXONE. SAVE A LIFE. Medication Medication Assisted Treatment (MAT) Relapse rates are very high! MATBut highlyis underutilized! • • INCREASES DECREASES: • • • • • • Opioid Effect Social functioning Retention in treatment in Retention Infectious disease transmission Criminal activity Opioid use Opioid Log Dose Log - related overdose deaths ( Full ( Partial Agonist Methadone: Daily Dosing) Daily Methadone: : 3 Buprenorphine: ( Antagonist : ER 1 month 1 ER Naltrexone: - 4X week 4X ) ) Williams, Nunes, Nunes, Williams, Opioid Opioid Treatment “Cascade of Care” Bisaga , Levin Levin , Am J Drug Alcohol Abuse Abuse Alcohol Drug J Am 2019 2019 Science = Solutions: Improving Addiction Treatment • Initiating buprenorphine treatment in the emergency department improves treatment engagement and reduces illicit opioid use • Extended release naltrexone initiated in criminal justice settings lowers relapse rates and overdoses • BUP-Nx more effective overall than XR-Naltrexone BUT appears to be equally safe and effective after induction • Lofexidine for opioid withdrawal treatment approved by FDA May 16, 2018 ED-Initiated Buprenorphine Relapse-free survival Increased Tx Engagement 100% 78% 80%

60% 37% 40%

20%

0% Lee JD, et al., Addiction 2015;100:1005-1014 Buprenorphine Referral and New Eng J Med 2016;374:1232-1242 Lee JD et al., The Lancet 2018 D’Onofrio et al. New Eng J Med 2018 Brief History of Medication Development at NIDA

• Long-standing Congressional mandates and support • Minimal historical interest by pharma • NIDA supports basic science that can identify potential targets • For promising targets, NIDA’s approach has been to “de-risk” a product by supporting key, early stage studies (less commonly, pivotal studies)

Fast-Track the Discovery and Development of Medications 24 # 34 Naloxone Easy to Use Formulations to save lives: Nasal spray and Auto-injector formulations

How did we get here? Prevention: Overdose Intervention

• Naloxone Distribution for administration to opioid overdose victims. The potential for direct intervention to save lives both by first responders and by persons who inject drugs. # 34 Naloxone

Workshop—April 12, 2012 FOOD AND DRUG ADMINISTRATION CENTER FOR DRUG EVALUATION AND RESEARCH OFFICE OF THE ASSISTANT SECRETARY FOR HEALTH NATIONAL INSTITUTES OF DRUG ABUSE CENTERS FOR DISEASE CONTROL AND PREVENTION Role of Naloxone in Opioid Overdose Fatality Prevention # 34 Naloxone

NIDA Supported Two Companies Developing an Intranasal Formulation of Naloxone: • SBIR • Contracts/Collaborations # 34 Naloxone

Auto-injector formulation approved by FDA April 3, 2014

Nasal Spray formulation approved by FDA November 18 2015 Naloxone: Implementation Issues EXPLORING NALOXONE UPTAKE AND USE PUBLIC MEETING July 1-2, 2015

Sponsored by FDA, NIDA, CDC, SAMHSA, HRSA Enacted WEST Legislat ion SOUTHWEST CoCo ntrtollerolled SudbstSuance/bstPance/araphernaliPaaraphernaliPossession ProatectiPossessioons (23‡Stnates)Protections (23‡ UT WA WY Lay Administration Criminal Liabilit yProtections (24) OR AZ )Lay Administration Criminal Liability Protections (24) NV NM LLayyAdminiAdministratisotnrCiat v i loLiabilitn CiviyPlroLiabilittections (21)y Protections (21) MT ‡ OK Prrescribeescriber Criminar Criminal Liabilit ylPLiabilitrotectionys (14)Protections (14) ID TX PPrescriberescriber Ci v irl LiabilitCivilyLiabilitProtectionysP(13)rotections (13) HI * AR SOUTHEAST AllowAllowsThisrdThiPartrydPrPescriartpytionPrsescri(23) ptions (23) CO AL CA * FL AK GA WI State KY SD LA Naloxone and † † OH Good Samaritan † MS NE Legislation NC † SC ND * as of July 15, 2014 † MIDWEST MO (Please check the individual statute TN as the language is nuanced and MN † varies from state to state.) VA (only via pilot program) MI WV † * * Only if person has received training. KS CT †Only applies to 1st responders. ‡

‡In Utah and Indiana, evidence of providing assistance to someone experiencing an IN DC overdose can be presented as a mitigating factor at sentencing to a convictionfor possession of a controlled substance and/or paraphernalia. Utah allows evidence IL DE of providing assistance to someone experiencing an overdose to be used as an affirmative defense to an allegation of possession of a controlled substance IA MA and/or paraphernalia. VT MD So u rce: O ce of Nat ional Dr ug Control Policy (ONDCP) searches of st at e legislat ive information from RI ME the following online dat abases yielded the informat ion on the chart , and were current as of PA NY NJ NH July 15, 2014: https:/ /advance.lexis.com http://www.cqst at etrack.com/ NORTHEAST http://openst at es.org/ Creat ed by ONDCP: July 29, 2014 Office of Management and Budget (OMB) Agency Priority Goals: DHHS Key Indicator for Opioids Number of naloxone prescriptions dispensed 400,000 Q1FY17 46,218 350,000 Q2FY17 47,166 Q3FY17 73,014 300,000 Q4FY17 70,395 FINAL FY21 GOAL TARGET 250,000 Q1FY18 85,497 Q2FY18 87,429 200,000 Q3FY18 134,539 150,000 Q4FY18 171,540 Prescriptions Dispensed Q1FY19 170,575 100,000 Q2FY19 233,896 50,000 Q3FY19 225,618 Q4FY19 238,609 0 Q1FY20 220,407 Q2FY20 226,723 Q1FY17 Q3FY17 Q1FY18 Q3FY18 Q1FY19 Q3FY19 Q1FY20 Q3FY20 Q1FY21 Q3FY21 Q3FY20 249,017

Source: IQVIA National Prescription Audit. Retrieved July 2020. Note: These data are for the retail and mail service channels only and do not include the long-term care channel. • Scientific solutions to the opioids crisis • $500M/year effort • > $945M obligated in FY2019 • 40+ funding opportunity announcements • 41 states • 400 Investigators • > 25 HEAL research programs • 12 NIH Institute and Centers • From prevention, basic and translational research, clinical trials, to implementation science • Research ongoing for years to come # 38 SM HELPING END ADDICTION LONG TERM (HEAL) Initiative

ENHANCING PAIN MANAGEMENT Advance Effective Accelerate Treatments For Discovery And Pain Through Development Of Clinical Research Pain Treatments IMPROVING TREATMENTS Expand Enhance Therapeutic FOR MISUSE AND Treatments for Options ADDICTION Infants with NAS/NOWS Develop New and Improved Optimize Prevention & Effective Treatment Treatments Strategies Main Research Gaps - 2018

1. Low medication adherence 2. Poor response to some OOD treatment, re-narcotization 3. Lack of treatments for respiratory depression (main cause of death) 4. Few effective medications for Opioid Use Disorder (OUD) 5. No FDA-approved immunotherapies for OUD

Fast-Track the Discovery and Development of Medications 35 Goal: Advance towards FDA-approval

1. Long-acting formulations of medications 2. Longer duration, more effective overdose treatment 3. New approaches to reverse respiratory depression 4. New targets and approaches for treating Opioid Use Disorder (OUD) 5. Immunotherapies for opioids to prevent relapse and overdose

Fast-Track the Discovery and Development of Medications 36 Portfolio of Medications Development for OUD and OOD Before HEAL

Early Preclinical Late Preclinical Phase I Phase Ib Phase II Phase III New Formulation

ANS6637 Guanfacine ALDH2 inhibitor a2 adren agonist C4X3256 OX-1 antagonist NMDA antagonist Mor, Her, Oxy, Hydro vaccine

Cannabidiol Lorcaserin 5HT2c agonist

Fentanyl Heroin Vaccine Tradipitant vaccine NK-1 antagonist VDCC blocker

Heroin/Fent Naloxone vaccine Hi-dose nasal spray Fentanyl mAb

37 Portfolio of Medications Development for OUD and OOD After HEAL

Early Preclinical Late Preclinical Phase I Phase Ib Phase II Phase III New Formulation

DM24 SBI-553 ITI-333 KLS13019 ANS6637 Guanfacine Pregab + Lofex Olani LAAM MOR/DOR het NT-1 biased MOR PA/5HT2a CBD analogue ALDH2 inhibitor a2 adren VDCC inh/a2 6 mo naltr Oral, re-intro antagonist PAM antagonist agonist agonist implant

PZM21 NAN/NAQ PF5190457 C4X3256 Ketamine BICX102 Naltrexone MOR biased MOR implant GHS1aR antag OX-1 antagonist NMDA 3 mo naltr 1 yr implant agonist modulator MOR antag antagonist implant

MOR biased GPR151 N0RS-033 Mor, Her, Oxy, Semiglutide Suvorexant OPNT003 Naloxone agonist antagonist Nalmefene Hydro vaccine GLP-1R agonist OX-1/2 Nasal Hi-dose nasal prodrug antagonist nalmefene spray

Oxy/Fentanyl AT-121 LYN-014 NYX-783 Lorcaserin Bupren/Nalox AP003 nano-vaccine NOP/MOR Long acting NMDA 5HT2c agonist Oral, long Mlt-dose nlx partial agonist methadone modulator acting nasal spray

Fentanyl PTPRD KNX100 Heroin Vaccine Tradipitant Gabapentin Naltrexone AP004 vaccine inhibitor Unknown NK-1 antagonist VDCC blocker 2 mo injection Nlx prefilled mechanism syringe

Heroin/Fent R-methadone AP007 NP10697 AZD4041 Naltrexone vaccine prodrug Extd-release GluN2B OX-1 antagonist 6 mo implant nalmefene antagonist

Fentanyl Muscarinic M5 Nalmefene mAb NAM Transmucosal

Metho- cinnamox MOR antag

38 Progress • RFA DA-19-002 o 8 receipt dates (last one 1/1/2020) o 204 applications received o 42 applications funded (22 from industry) o UG3/UH3 “game changer” o Reissued

• PAR-20-092

• Other FOAs

Fast-Track the Discovery and Development of Medications 39 Progress to date

Fast-Track the Discovery and Development of Medications 40 Research Priorities for 2021 • Support PAR 20-093 ($20M in 2021 to fund 8-10 grants) • Promote clinical development of compounds • New targets and meds for respiratory depression (NHLBI) • Fast-track the development of medications towards FDA approval for: o Comorbid OUD and Stimulant (methamphetamine/cocaine) Use Disorder o Comorbid OUD and other mental disorders o Comorbid OUD and pain conditions o OUD during pregnancy o Neonatal Opioid Withdrawal Syndrome o Opioid physical dependence with no OUD

Fast-Track the Discovery and Development of Medications 41 1. Long-Acting Formulations

Compound Mechanism PI, Institution EPC LPC Ph1 Ph2 Ph3

Nalmefene 6-month implant MOR Antagonist Beebe, Titan Pharmaceuticals

Naltrexone 1-year implant MOR Antagonist Cohen, Drug Delivery Co

Naltrexone 1-year titanium implant MOR Antagonist Martin, Delpor

BICX102: Naltrexone implant (3 months) MOR Antagonist Brar, BioCorX

Naltrexone 2-month injection MOR Antagonist Park, Purdue U.

AP007: Nalmefene PGLA monthly IM MOR Antagonist Barry, Emergent Product Dev

NRS-033: Nalmefene prodrug (>28d) MOR Antagonist Tusche, Nirsum Labs

Weekly Oral Buprenorphine MOR Agonist Bellinger, Lyndra Pharmaceuticals

Weekly R-Methadone MOR Agonist Bellinger, Lyndra Pharmaceuticals

OLANI: Naltrexone implant (6 months) MOR Antagonist Bisaga,GO Medical/Columbia U.

Fast-Track the Discovery and Development of Medications 42 2. Longer duration, more powerful overdose reversal Compound Mechanism PI, Institution EPC LPC Ph1 Ph2 Ph3 Methocinnamox MOR Antag (LA) Woods, U Tx Nafamostat/methadone Trypsin inhibitor (OOD protection) Kirkpatrick, Ensyce Nafamostat/ prodrug Trypsin inhibitor (OOD protection) Kirkpatrick, Ensyce Nalmefene buccal film MOR Antagonist Vasisht, Avior Inc, R43 OPNT003: Intranasal nalmefene MOR Antagonist Skolnick, Opiant ***

Fast-Track the Discovery and Development of Medications 43 3. New approaches to reverse respiratory depression

• Almitrine: Peripheral, stimulating chemoreceptors in the carotid bodies to enhance respiration. Collaboration with IRP • Collaboration with NHLBI RFA HL-20-031

o “Pharmacotherapies to Reverse Opioid Overdose Induced Respiratory Depression without Central Opioid Withdrawal (Target Validation and Candidate Therapeutic Development (R61/R33 - Clinical Trial Not Allowed)

o https://grants.nih.gov/grants/guide/rfa-files/RFA-HL-20-031.html

Fast-Track the Discovery and Development of Medications 44 4. New Targets and Approaches to Treat OUD Compound Mechanism PI, Institution EPC LPC Ph1 Ph2 Ph3 MTX-1604 Synthetic analog Lark, Artys Biotech D24M MOR/DOR Heterodimer antagonist Morgan, Washington St U. PZM21 MOR biased agonist Gehlhert, Epiodyne Inc. PTPRD Protein Tyrosine Phosphatase Recp D G. Uhl, U NM NAN/NAQ MOR modulator Zhang, VCU GPR151 Antag GPR151 Antag Kenny, ISMMS AT-121 NOP-MOP PA Zaveri, Astraea SBI-553 NTR1 modulator Pinkerton, Sanford-Burnham KNX100 Oxytocin-like Alsop/Kinoxis NYX-783 NMDA modulator DiLeone, Yale NP10679 Inh GluN2B subtype NMDA (relapse prev) Zaczek, NeuroOP PPL103 KOR Antag (cocaine) Toll, Phoenix Pharm PF5190457 Growth horm secretagogue 1α R antag/inv Cunningham,ag U Tx ASP8062 GABA-B PAM (Stimulant) Blahunka, Astellas ANS6637 ALDH2 Inhib. (craving, cocaine) Amygdala C4X3256 OX-1 Antag (sleep, OW) Heidbreder, Indivior Tradipitant (VLY686) NK-1 Antag (OW) Walsh, Vanda CBD (Craving, anxiety) Hurd, NYU Leraglutide & Semiglutide GLP1R Ag (short & long acting)(Craving) Grigson, Penn St, Ketamine NMDA Antag Dakwar, Columbia Suvorexant Ox1/2 Antag (sleep) Dunn, JHU Gabapentin Ca2+ Inhibitor Comer, Columbia + Lofexidine Ca channel inh + Alpha2 Ag Kampman, U Penn (WO)

Fast-Track the Discovery and Development of Medications 45 5. Immunotherapies

Compound Mechanism PI, Institution EPC LPC Ph1 Ph2 Ph3 Oxycodone/Fentanyl Vaccine Zhang, VA Poly Heroin vaccine Vaccine Janda, Scripps Tetravalent opioid vaccine Vaccine Pentel/Pravetoni, U MN Heroin vaccine Vaccine Matyas, Opiant Carfentanyl mAb Monoclonal Janda, Scripps Fentanyl mAb Monoclonal Janda, Scripps/Cessation Ther Fentanyl mAb Monoclonal Praventoni, U MN

Fast-Track the Discovery and Development of Medications 46 6. Prevention of OUD and OOD

Compound Mechanism PI, Institution EPC LPC Ph1 Ph2 Ph3 MEB-1166 or MEB-1170: (Mebias) Highly ‘biased’ MOR (pain) Kuo, Mebias MP1000 Arylepoxamide (pain) Pan, MSK Kindolor Nav 1.7 & 1.8 Na channels, NMDA gly antag (pain)Tabakoff, Lahocla ST-2427 Nav1.7 Inhib Hunter, SiteOne KLS-13019 Hydrophilic analog CBD (pain) Ward, KannaLife EC5026 Soluble epoxide hydrolase inhibitors (pain)Buckpitt, Eicosis Duloxetin SNRI (pain) Mao, Mass Gen H CBD Cannabinoid (pain) Campbell, JHU Brivoligide Select inh transcrip factor EGR1 (pain mastect)Mamet, ADYNXX Inc. • Significant increase in the number of compounds advancing towards FDA approval • Adequate number of compounds in most priority areas except respiratory stimulants • More compounds needed in advanced clinical phases • Transition of UG3 to UH3 start in August 2020 • New research gap areas identified

Fast-Track the Discovery and Development of Medications 48 Stimulant (cocaine and methamphetamine) Use Disorder Medication Pipeline Early Preclinical Late Preclinical Ph I Ph Ib Ph II Ph T2L: (>12 yrs) (10-12 yrs) (6-10 yrs) (5-9 yrs) (4-6 yrs) III SBI-0069330 or GLT-1 up-regulator * Orexin-1 antagonist * dAdGNE * * NS2359 * Mavoglurant * SBI-0801315 * + M. Abou-Gharbia; Heptares Anti-cocaine NE/5HT antagonist DAT/NET/SERT inhib. mGluR5 antagonist mGluR2 PAM Temple R01-DA039553 vaccine P.Coffin; Public Health K. Kampman; U Penn Novartis N. Cosford; Sanford R01-DA037270 R. Crystal; Cornell Foundation Enterprises Dana Foundation Burnham U01-DA048524 U01-DA051080 U01-DA041731

NOP/Kappa/Mu ligands Meth vaccine + IXT-m200 + Cocaine hydrolase Duloxetine & Bupropion * Guanfacine * * M. Taffe; UC San Diego Long-duration anti- gene therapy * Methylphenidate + DAT/NET inhibitor α2A agonist S. Husbands; U of Bath R01-DA024705 meth mAb W.S. Brimijoin; NET/SERT inh. & CNS K. Dunn; Johns R. Sinha; Yale U R01-DA007315 Intervexion Mayo stim. Hopkins R01-DA047094 U01-DA045366 UH3-DA042492 C. Rush; U Kentucky R01-DA034047 U01-DA051078 R01-DA047391

PTPRD ligands * + Cocaine hydrolase * Methamphetamine h2E2 * Clavulanic acid * Adderall * EMB-001 * G. Uhl; U New Mex. C.-G. Zhan; U Kentucky Conjugate Vaccine Anti-cocaine mAb GLT-1 activator Mixed amph. salts Metyrapone/oxazopam U01-DA047713 UH3-DA041115 Intervexion A. Norman; U M. Morrison; Temple F. Levin; Columbia U GC synth inhib/benzo. U01-DA35511 Cincinn. R01-DA048517 R01-DA034087 Embera U01-DA048525 U01-DA038879

Peptidic KOR agonists * VMAT-2 inhibitor + Cariprazine * Ketamine * J. Aldrich; U Florida L. Dwoskin; U Kentucky D3/D2/5HT1A partial NMDA antag. R01-DA023924 U01-DA043908 agonist E. Dakwar; Columbia A.R. Childress; U Penn U R01-DA039215 U01-DA040647

Pomaglumetad IXT-m200 + methionil + Updated: 20Aug20 Black – New Molecular Entity Red – New Indication Blue – Anti-meth mAb mGluR2/3 agonist Intervexion Biologic Green – Gene Therapy * cocaine + meth * + cocaine or meth prodrug U01-DA045366 K. Heinzerling; UCLA U01-DA051078 R01-DA043238 # 40 Summary:

• The opioid crisis remains driven by illicit fentanyl; stimulant overdose deaths are also rising • Medications for opioid use disorder are effective but improvements are needed; medications lacking for stimulants • NIDA’s program for medication development has been markedly expanded by HEAL support • Ongoing research will build future solutions www.drugabuse.gov Science = Solutions Advancing Addiction Science www.nih.gov/heal-initiative