6/6/2017. The Role of ADFs in Curbing Opioid Abuse Can ADFs Reduce Opioid Abuse? 12-Month Financial Disclosures* Objectives

Transcription

1 The Role of ADFs in Curbing Opioid Abuse Can ADFs Reduce Opioid Abuse? Lynn R. Webster, M.D. Vice President of Scientific Affairs PRA Health Sciences Salt Lake City, UT (801) Month Financial Disclosures* Daiichi Sankyo Depomed, Inc. Egalet Elysium Insys Kempharm Pain Therapeutics Pfizer Shionogi Teva *Updated 5/10/17 2 Objectives Participants will increase their knowledge of the problems contributing to the opioid crisis Participants will increase their knowledge of how Human Abuse Potential Studies are used to determine ADF labeling Participants will increase their knowledge of the differences in ADF labeling for approved ADFs 3 1

2 Problems The Problem with Pain The Problem with Addiction / Abuse The Problem with People in Pain The Problem with Pain Doctors The Problem with Public Perceptions The Problem with Politics of Pain The Problem with Payers / Insurance The Problem with Pain funding The Problem with Pain factions 4 Too Many Problems And the result is our current approach to pain. 5 The Problem With Politics in Pain 6 2

3 FDA commissioner Gottlieb calls for more forceful steps to curb opioid epidemic Food and Drug Administration Commissioner Scott Gottlieb, speaking at his confirmation hearing last month before the Senate Committee on Health, Education, Labor and Pensions. (J. Scott Applewhite/AP) 7 FDA Task Force to Address Opioid Misuse Prescriber Education Drug Development Opioid Labeling Exploring Innovative Packaging/Storage to Prevent Abuse Encouraging the Development of Products that Treat Abuse and Overdose Patient Education Role of Other Agencies 8 Create Incentives 9 3

4 Input and output of category 1-3 studies for ADF opioid development Lynn R. Webster, John Markman, Edward J. Cone & Gwendolyn Niebler (2017) Current and future development of extended-release, abusedeterrent opioid formulations in the United States, Postgraduate Medicine, 129:1, , DOI: / Mechanisms of abuse deterrence Mechanism Physical/chemical barriers (may not deter all of these) Agonist/antagonist combinations Aversion Delivery system Prodrugs or new molecular entities Combination of technologies Novel approaches Characteristics Prevent chewing, crushing, cutting, grating, or grinding (physical barrier) Impede extraction of opioids with common solvents (chemical barrier) Addition of a sequestered or non-sequestered opioid antagonist Component(s) added that produces an unpleasant effect after manipulation, after administration by alternate routes (e.g. mucous membrane irritant), or if used at doses higher than indicated Long-acting injectable or depot formulations that are difficult to manipulate Require chemical or enzymatic transformation in vivo to active drug; may have inherent pharmacodynamic or pharmacokinetic properties that lower abuse potential Contain greater than 2 of the other defined technologies Technologies that are not characterized by one of the defined categories (e.g. technology that provides protection against multiple-pill overdose) Lynn R. Webster, John Markman, Edward J. Cone & Gwendolyn Niebler (2017) Current and future development of extended-release, abusedeterrent opioid formulations in the United States, Postgraduate Medicine, 129:1, , DOI: / Labeling is the first tool the Food and Drug Administration is looking at to incentivize the development of successful abuse-deterrence Opioids. Douglas Throckmorton, MD, Deputy Director for Regulatory Programs FDA s Center for Drug Evaluation and Research 12 4

5 Labeling Claims Expected to Reduce abuse via the intranasal route (IN) Expected to Reduce abuse via the oral route Expected to Reduce IN abuse and oral abuse when chewed Expected to Deter IN and IV Abuse Expected to Make abuse by/via injection Difficult 13 Common Routes of Administration or Abuse Crushing and Swallowing Crushing and Snorting Crushing and Smoking Crushing and/or Extracting for Injection Oral intact Co-ingestion with alcohol/benzodiazepines 14 Estimated Prevalence of Routes of Abuse Prescription Opioid Analgesic Oral Snort Inject Hydrocodone 88% 25% <10% Oxycodone 76% 45% 22% Morphine 40% 29% 66% Methadone 71% 10% <10% ICER Abuse Deterrent Formulations of Opioids: Effectiveness and Value. Draft Evidence Report, May 5,

6 Drug Embeda ER (120mg/4.8mg) Hysingla ER (60mg) Oxycontin ER (30mg) Xtampza ER (36mg) Vantrela ER (45mg) Morphabond ER (60mg) Arymo ER (60mg) Targiniq ER (40mg/20mg) Troxyca ER (40mg/4.8mg) Comparator Expected to Reduce Abuse via the IN route ER Morphine or IR Morphine Hydrocodone powder Oxycodone powder Expected to Reduce Abuse via the Oral route Expected to reduce IN abuse and oral abuse when Expected to Deter IN and IV chewed Abuse Root of ADF Deterrence Expected to make Labeling Abuse by/via Updates injection difficult X X Approved Aug/2009 Labeling Oct/2014 X X X X Approved Nov 2014 X Approved Label X Apr 2013 Oxycodone IR X X Approved Apr 2016 Hydrocodone X X Approved Jan 2017 MS Contin X X Approved Oct 2015 MS Contin X Approved Jan 2017 Oxycodone X Approved X Solution Jul 2014 Oxycodone IR X X Approved Aug 2016 FDA Briefing Book 16 System Dynamics Modeling Wakeland W, Schmidt T, Gilson AM, Haddox D, Webster LR. System dynamics modeling as a potentially useful tool in analyzing mitigation strategies to reduce overdose deaths associated with pharmaceutical opioid treatment of chronic pain. Pain Medicine. 2011;12(s2):S Opioid Overdose Deaths Among Medical Users Time (year) Adapted from Wakeland W, Schmidt T, Gilson AM, Haddox D, Webster LR. System dynamics modeling as a potentially useful tool in analyzing mitigation strategies to reduce overdose deaths associated with pharmaceutical opioid treatment of chronic pain. Pain Medicine. 2011;12(s2):S

7 3 Perceived Risk of Treating with Opioid Products 20 M Total Opioid-Treated Patients M M M 0 '95 '97 '99 '01 '03 '05 '07 '09 '11 Time (year) 0 M Time (year) Adapted from Wakeland W, Schmidt T, Gilson AM, Haddox D, Webster LR. System dynamics modeling as a potentially useful tool in analyzing mitigation strategies to reduce overdose deaths associated with pharmaceutical opioid treatment of chronic pain. Pain Medicine. 2011;12(s2):S Opioid Overdose Deaths Among Medical Users Increased Tamper Resistant Formulations Physician Education Program Lower Addiction Rates '95 '97 '99 '01 '03 '05 '07 '09 '11 Time (year) Adapted from Wakeland W, Schmidt T, Gilson AM, Haddox D, Webster LR. System dynamics modeling as a potentially useful tool in analyzing mitigation strategies to reduce overdose deaths associated with pharmaceutical opioid treatment of chronic pain. Pain Medicine. 2011;12(s2):S '07 '09 '11 '07 '09 ' Deaths Per 100,000 Patients Increased Tamper Resistant Formulations Physician Education Program Lower Addiction Rates '07 '09 '11 '07 '09 '11 '95 '97 '99 '01 '03 '05 '07 '09 '11 Time (year) Adapted from Wakeland W, Schmidt T, Gilson AM, Haddox D, Webster LR. System dynamics modeling as a potentially useful tool in analyzing mitigation strategies to reduce overdose deaths associated with pharmaceutical opioid treatment of chronic pain. Pain Medicine. 2011;12(s2):S

8 Opioid Concentration Tmax Human Abuse Potential Study Subjective Measures Related to Abuse Potential: Ratings of positive response to drug: Do you like the drug? High Take drug again? Ratings of negative response to drug: Bad Drug Effect Feel Sick 22 Speed of CNS Entry & Concentration Determines Liking The abuse potential of a drug increases as the value of the AQ increases C max / T max Cmax In this ratio, as C max INCREASES and as T max DECREASES, the ratio becomes relatively larger, signaling potentially increased attractiveness as a drug of abuse Time Webster L 2009 Drug Discovery and Development 23 Key Assessments Subjective Abuse Liability Assessments Bipolar VAS Drug Liking TDA Unipolar VAS Drug High Likert, T/F ARCI, POMS 24 8

9 mm Difference in Emax Do you LIKE the drug? E max E max 10% or less 75 Comparator 68.5 Generic ADF TIME (hours post-dose) 25 Extended-Release Opioid Analgesics with Abuse Deterrent Labels Drug brand name ADF approach Year approved FDA approved Morphine products Embeda Agonist/Antagonist combination 2014 MorphaBond Physical and chemical barriers 2015 Oxycodone products OxyContin Physical and chemical barriers 2013 Xtampa ER Physical and chemical barriers 2016 Troxyca ER Agonist/Antagonist combination 2016 Hydrocodone product Hysingla ER Under FDA review Morphine product Morphine-ADER-IMT (ARYMO ER) Hydrocodone product CEP (Vantrela ER) Physical and chemical barriers Physical and chemical barriers Physical and chemical barriers Lynn R. Webster, John Markman, Edward J. Cone & Gwendolyn Niebler (2017) Current and future development of extended-release, abuse-deterrent opioid formulations in the United States, Postgraduate Medicine, 129:1, , DOI: / Targiniq ER is approved but not currently commercially available in the United States. ADER-IMT: Abuse-deterrent, extended-release, injection-molded tablets; ADF: abuse-deterrent formulation; ER: extended-release; FDA: Food and Drug Administration 26 Drug Embeda ER (120mg/4.8mg) Hysingla ER (60mg) Oxycontin ER (30mg) Xtampza ER (36mg) Vantrela ER (45mg) Morphabond ER (60mg) Arymo ER (60mg) Targiniq ER (40mg/20mg) Troxyca ER (40mg/4.8mg) FDA Briefing Book Comparator Expected to Reduce Abuse via the IN route ER Morphine or IR Morphine Hydrocodone powder Oxycodone powder Expected to Reduce Abuse via the Oral route Expected to reduce IN abuse and oral abuse when Expected to Deter IN and IV chewed Abuse Root of ADF Deterrence Expected to make Labeling Abuse by/via Updates injection difficult X X Approved Aug/2009 Labeling Oct/2014 X X X X Approved Nov 2014 X Approved Label X Apr 2013 Oxycodone IR X X Approved Apr 2016 Hydrocodone X X Approved Jan 2017 MS Contin X X Approved Oct 2015 MS Contin X Approved Jan 2017 Oxycodone X Approved X Solution Jul 2014 Oxycodone IR X X Approved Aug

10 Clinical Relevance of Results 28 Meta-analysis: Reduction in Overall Drug Liking Associated with Decrease in Non-Medical Use 5 mm reduction in Overall Drug Liking E max for ADF ER oxycodone ~10.1% reduction in non-medical use White et al. J Opioid Manag 2015;11: Clinically Important Difference for Drug High E max Determined clinically important difference for Drug High E max in treatment setting mm differences in Drug High E max led to clinically significant changes in drug-taking behavior 1. Eaton et al. Qual Life Res 2012;21:

11 Liking and TDA Emax Deltas ORAL ORAL (Chewed) INTRANASAL Drug Comparator Mean Mean Take Mean Mean Take Mean Drug Mean Take Drug Drug Again Drug Drug Again Liking Drug Again Liking (Emax) Liking (Emax) (Emax) (Emax) (Emax) (Emax) FDA Briefing Book Embeda ER ER 21.4mm, 12.6mm 19.4mm 27.9mm (120mg/4.8 Morphine 15.4mm mg) Hysingla Hydrocodon 30.7mm 25mm 45.4mm 25mm 48.8mm ER (60mg) e powder (intact) Oxycontin Oxycodone 8.9mm 8.9mm 22.6mm ER (30mg) powder Xtampza Oxycodone 8.4mm 1.7mm 20.9mm 23.7mm ER (36mg) IR Vantrela ER Hydrocodon 19.4mm 19.2mm 21.6mm 19.1mm (45mg) e Morphabon 9.96mm d ER MS Contin 13.65mm (60mg) 31 Liking and TDA Emax Deltas ORAL ORAL (Chewed) INTRANASAL INTRAVENOUS Drug Comparator Mean Mean Take Mean Drug Mean Take Mean Drug Mean Take Mean Drug Mean Take Drug Drug Again Liking Drug Liking Drug Again Liking Drug Again Liking (Emax) (Emax) Again (Emax) (Emax) (Emax) (Emax) (Emax) (Emax) Arymo ER MS Contin 5mm 7.2mm (60mg) Targiniq ER Oxycodone (40mg/20m 16.1mm 35.7mm 39.9mm 45mm Solution g) Targiniq ER Oxycodone (60mg/30m 23.3mm 28.8mm 51mm Solution g) Troxyca ER (40mg/4.8m Oxycodone IR 16.1mm 26.2mm g) Troxyca ER (60mg/7.2m Oxycodone IR 15.7mm 9.5mm g) FDA Briefing Book

12 Sources of Funding: 2017 Source: ICER Funding Blue Cross Blue Shield of Massachusetts Pharmaceutical Care Management Association (PCMA) Blue Shield of California Foundation University of New Hampshire California Health Care Foundation Washington State Health Care Authority Decision Resources Aetna Guggenheim Securities America s Health Insurance Plans (AHIP) Harvard Pilgrim Health Care Anthem Kaiser Permanente National Community Benefit Fund at the East Bay Community AstraZeneca Foundation Blue Shield of California Laura and John Arnold Foundation CVS Caremark NESCSO/University of Massachusetts Express Scripts Partners Healthcare Genentech Source: GlaxoSmithKline Harvard Pilgrim Health Care Health Care Service Corporation (HCSC) Johnson & Johnson Kaiser Permanente Merck & Co. National Pharmaceutical Council OmedaRx Premera Blue Cross Prime Therapeutics Sanofi Spark Therapeutics United HealthCare 35 ICER Evidence Rating Matrix ICER Abuse Deterrent Formulations of Opioids: Effectiveness and Value. Draft Evidence Report, May 5,

13 C+ 37 Follow Up Interview with RAPID Participants (N=153), Subset of RADARS SKIP Did ADF OxyContin influence the drugs that participants used for recreational purposes? ICER Abuse Deterrent Formulations of Opioids: Effectiveness and Value. Draft Evidence Report, May 5, Changes in the Abuse Routes of Oxycontin Among Participants That Have Taken the Pre- and Post-Reformulated Forms ICER Abuse Deterrent Formulations of Opioids: Effectiveness and Value. Draft Evidence Report, May 5,

14 Changes in the Abuse Routes of Oxycontin Among Participants That Have Taken the Pre- and Post-Reformulated Forms ICER Abuse Deterrent Formulations of Opioids: Effectiveness and Value. Draft Evidence Report, May 5, ICER Summary "ADFs have the potential to substantially reduce the incidence of opioid abuse relative to non-adf formulations among patients initially prescribed these drugs"... "but will also increase overall costs to the health system"... ICER Abuse Deterrent Formulations of Opioids: Effectiveness and Value. Draft Evidence Report, May 5, CDC Opioid Guidelines CDC Opioid Guidelines ADFs not included in the guidelines because they do not prevent misuse through oral intake or unintentional overdose CDC Guideline for Prescribing Opioids for Chronic Pain United States, Recommendations and Reports/ March 18, 2016/65(1);

15 Future ADFs 43 Self-Attenuating Opioids New Class of Opioids with Oral Overdose Protection (O2P) Designed to combat opioid epidemics by controlling exposure without compromising patient care Takes advantage of well-established efficacy of existing opioids (e.g. HC, OC) When prescribed doses are ingested Via a highly selective, well-defined, predictable, and clinically-validated mechanism Auto-attenuated delivery of opioid agonist When multiple pills are orally ingested (i.e. overdoses) in a concentrationdependent manner Removes dose-proportional reward to disrupt the progression from patient to misuser to abuser Reduces risk of respiratory depression to protect against fatal overdose Courtesy Elysium 44 O2P: In Vivo Proof of Concept Dog n=4 per dose group Courtesy Elysium 45 15

16 ADF Legislation 2015 Introduced Voted Passed 46 ADF Legislation 2016 Introduced Voted Passed 47 ADF Legislation 2017 Introduced Voted Passed 48 16

17 ADF Legislation Pending legislation Passed legislation 49 Conclusion 1. ADFs are designed to deter or prevent abuse through specific routes of administration 2. Human abuse potential studies appear to predict real world effects of ADFs 3. ADFs appear to be associated with less abuse and overdose deaths 51 17

18 Thank You!