General Session: Federal Response to the Rx Drug Abuse Epidemic - Dr. Francis Collins

1. Advancing Pain Relief, Preventing Abuse
Francis S. Collins, M.D., Ph.D.
Director, National Institutes of Health
National Rx Drug Abuse Summit
April 22, 2014

2. “Science in pursuit of fundamental
knowledge about the nature and
behavior of living systems
and the application of that
knowledge to extend healthy life
and reduce illness and disability.”
...
NIH: Steward of Medical and Behavioral
Research for the Nation

3. NIH: Advancing Pain Relief;
Preventing Abuse of Pain Relievers
 NIH supports wide array of programs and projects that
– Enhance our understanding and treatment of pain
– Improve our ability to monitor and prevent abuse of pain
relievers
 Examples include:
– NIH Pain Consortium
– “Monitoring the Future” study
– Supporting research to curb
epidemic of opioid abuse

4. NIH Pain Consortium
Centers of Excellence in Pain Education
12 CoEPEs in 9 states, >100 schools

5. “Monitoring the Future”
 Survey measures drug, alcohol, and cigarette use and
related attitudes among adolescent students nationwide
– Started in 1975
– Conducted at the University of Michigan
– Supported by NIH’s National Institute on
Drug Abuse (NIDA)
 2013 survey included 41,675 students
from 389 public and private schools

6. Percent of Students Reporting Nonmedical Use
of Vicodin in Past Year, by Grade
0
5
10
15
20
02 03 04 05 06 07 08 09 10 11 12 13
8th Grade 10th Grade 12th Grade
SOURCE: University of Michigan, 2013 Monitoring the Future Study
*Denotes significant difference between 2012 and 2013
*
Year

7. Percent of Students Reporting Nonmedical Use
of OxyContin in Past Year, by Grade
0
5
10
15
20
02 03 04 05 06 07 08 09 10 11 12 13
8th Grade 10th Grade 12th Grade
SOURCE: University of Michigan, 2013 Monitoring the Future Study
Year

8. Research: Finding New Responses to
Opioid Abuse
 Develop abuse-resistant drug formulations
 Devise user-friendly methods of antidote (naloxone)
administration
 Create mHealth interventions to help prevent opiate
overdose
 Produce new immunotherapies to treat addiction

9. Abuse-Resistant Drug Formulations:
Prodrugs
 Problem: changing method of taking opioids – i.e.,
crushing, injecting – increases euphoria; abuse
 Challenge: develop drugs that resist tampering; abuse
 Research response: oxycodone prodrug
– Prodrugs: inactive compounds metabolized in the body to
produce active drug
– NIH-supported Signature Therapeutics’ Bio-MD™ opioid prodrug
• Resists extraction, tampering
• 2 prodrug types, for:
- Hydromorphone
- Oxycodone: priority

10. Abuse-Resistant Drug Formulations:
Oxycodone Prodrug
 Two-step activation process in the body
– Taken orally, bioactivation by trypsin in GI tract
– Cyclization release reaction
 Without activation, very little active opioid released
 NIH support:
– NIDA
– National Center for Advancing Translational Sciences’ “Bridging
Interventional Development Gaps” (BrIDGs) program
• Supports application to FDA

11. User-Friendly Antidote Administration:
Naloxone
 Opioid overdose antidote: naloxone
– Effective: reversed >10,000 overdose cases, 1996–2010*
– Until recently, only available in injectable formulation
• Practically, limited use to emergency medical personnel
 New formulation, Evzio, approved April 3, 2014
– Hand-held auto-injector quickly delivers single dose
– Facilitates use by family members, caregivers
 Simpler systems could expand availability even further
– NIH/NIDA supporting development of intranasal delivery systems
*Centers for Disease Control and Prevention

12. User-Friendly Antidote Administration:
NIH-Supported Naloxone Nasal Sprays
AntiOp
 Developing single-dose, disposable nasal spray
– Combines proven nasal spray device with
stable, concentrated, specially-formulated
naloxone solution
– Investigational New Drug (IND) application
filed with FDA in 2012
– Could be on the market ~18 months
Lightlake Therapeutics
 Conducting clinical trials with intranasal naloxone for
treatment of binge eating disorder
– Applying technology to treatment of opioid overdose
– Clinical trials began last fall

13. mHealth Interventions May Help Prevent
Opiate Overdose
Wireless Sensors
• Respiration
• Oximeter
• Arrhythmias
Naloxone Delivery
• Automatic
• Patient
• Third party
Alarm
• Set up delivery
• Alert patient
• Alert third party

14. A Shift from Abuse of Prescription Pain
Relievers to Heroin
Cicero TJ et al. N Engl J Med 2012;367:187-189.
A recent increase in heroin use accompanied a downward trend in
OxyContin abuse – following introduction of an abuse-deterrent
formulation of OxyContin.

15. Antibodies reduce amount of drug in the brain
Capillary
Blood Flow
Brain
Immunotherapies to Treat Addiction:
Vaccines
Targets drugs,
not receptors
Capillary
Blood Flow
Brain
Antibodies
Vaccine
Binding
sites

16.  Vaccines using immune molecules to diminish effects of
abused drugs have been developed
 Heroin vaccine development trickier
– Heroin is metabolized into many substances –
each with psychoactive effects
 NIH-supported researchers used dynamic approach to
develop heroin vaccine
– Targets not only heroin, but chemicals into which it degrades
 Recent tests promising
 George Koob, co-PI, now at NIH….
Immunotherapies to Treat Addiction:
Heroin Vaccine

17. Learning the Language of the Brain
New Insights on the Horizon?
“The Next Great American Project”

18. BRAIN Buzz 2014

21. 2013 Monitoring the Future Study
Prevalence of Past Year Drug Use Among 12th graders
Drug Prev. Drug Prev.
Alcohol 62.0 Sedatives* 4.8
Marijuana/Hashish 36.4 Tranquilizers* 4.6
Hookah 21.4 Hallucinogens 4.5
Small cigars 20.4 MDMA (Ecstasy) 4.0
Amphetamines* 8.7 Hall other than LSD 3.7
Synthetic Marijuana 7.9 OxyContin* 3.6
Snus 7.7 Salvia 3.4
Adderall* 7.4 Cocaine (any form) 2.6
Narcotics o/t Heroin* 7.1 Inhalants 2.5
Vicodin* 5.3 Ritalin* 2.3
Cough Medicine* 5.0 LSD 2.2
* Nonmedical use Categories not mutually exclusive

22. Percent of Students Reporting Use of
Heroin in Past Year, by Grade
0
5
10
15
20
95 96 97 98 99 00 01 02 03 04 05 06 07 08 09 10 11 12 13
8th Grade 10th Grade 12th Grade
Year
SOURCE: University of Michigan, 2013 Monitoring the Future Study

23. Percent of High School Seniors Reporting Use
of Narcotics Other than Heroin
0
5
10
15
20
91 92 93 94 95 96 97 98 99 00 01 02 03 04 05 06 07 08 09 10 11 12
12th grade
SOURCE: University of Michigan, 2013 Monitoring the Future Study
Year

24. Percent Reporting Narcotics Other Than Heroin
as ‘fairly easy’ or ‘very easy’ to Obtain, by Grade
0
20
40
60
80
100
92 93 94 95 96 97 98 99 00 01 02 03 04 05 06 07 08 09 10 11 12 13
8th Grade 10th Grade 12th Grade
SOURCE: University of Michigan, 2013 Monitoring the Future Study
*Denotes significant difference between 2012 and 2013
*

25. • Collaborator: Signature Therapeutics (Palo Alto, CA)
• Compound: Oral prodrug formulation of oxycodone
 Tamper-resistant - Common methods of tampering do not
release appreciable amounts of the active opioid.
• Novel Project Intake Model
 MOU between NIDA and NCATS
 3-way CRADA including Signature
• Pending BrIDGs Studies:
 GMP synthesis
 Packaging of drug supply
 PK/ADME and GLP toxicology studies
• IND Goal: End of 2014

26. Binding Site
Capillary
Blood Flow
Brain
Antibodies
VACCINE
Antibodies Can Reduce Brain Concentrations
Immunotherapies for Addiction Treatment
(i.e., Vaccines)
Capillary
Blood Flow
Brain
Targeting the drugs,
not the receptors

27. ##p<0.01, ###p<0.001, significant reduction
of analgesia vs. Control/KLH group,
### p<0.001, significant reduction of
analgesia vs. Control/KLH group
Heroin
1
mg/kg,
s.c.
30
min
Hot Plate Test
The Vaccine(s)
Immunotherapies to Treat Addiction:
Heroin Vaccines
*K.D. Janda & G.F. Koob Laboratories at TSRI
Dr. Koob now at NIH