198 Oral Abuse Potential of Benzhydrocodone, a Novel of

Presented at the 1 1 1 1 2 2 3 3 2 American Academy of Pain Medicine (AAPM) Sven Guenther, PhD ; Travis Mickle, PhD ; Nelson Meléndez, BS ; Leone Kirk, BS ; Michael Smith, PharmD ; Rosemary Ndolo, PhD ; Kathryn Roupe, PhD ; Jing Zhou, MS ; Daniel Dickerson, MD, PhD, FAAFP February 18 –21, 2016 • Palm Springs, CA 1KemPharm, Inc., Coralville, IA, USA; 2PRA Health Sciences, Raleigh, NC, USA; 3Worldwide Clinical Trials, King of Prussia, PA, USA

• Due to concerns over abuse risk, hydrocodone IR combi - • Subjects were excluded who had Statistical Analysis —However, the potential influence of APAP on the present • Systemic exposure was similar at the low 4-tablet doses Safety Assessment Introduction nation products were changed from Schedule III to the —Received or sought treatment for substance-related • Pharmacodynamic assessment of abuse potential was Drug Liking results was not assessed of KP201/APAP and HB/APAP • Exposure more restricted Schedule II classification by the US Drug disorders within the previous 5 years, or a history conducted using a mixed-effects model of analysis of • No statistically significant differences in T of hydro - Background 8 PK Parameters max —A total of 119 subjects received 1 dose of study drug, Enforcement Administration in October 2014 of/current dependency on drugs or variance (ANOVA) for the completer population codone, as reflected in P values from the Wilcoxon signed • combination products containing hydrocodone including placebo; this cohort co≥mprised the safety —Although the number of prescriptions of these products • Systemic exposure to hydrocodone as measured by rank test, were observed for any comparison between 1 —A recent history of suicidal ideation or suicidal behavior —Study completers were subjects who completed all 7 population bitartrate (HB) are the second most commonly pre - decreased following the rescheduling, survey data sug - Cmax and total (AUC last ) as well as partial (AUC 0-1 through 1 as assessed by the Columbia-Suicide Severity Rating dosing periods of the Treatment Phase, and completed corresponding doses of KP201/APAP and HB/APAP scribed drugs in the US gest the absolute prevalence of abuse of hydrocodone AUC ) was statistically lower for KP201/APAP at the —During the Treatment Phase, 69 subjects received a Scale 14 1 postdose assessment of the DL-VAS and 1 postdose 0-24 IR combination products increased, via all routes of high- (12 tablets) and mid- (8 tablets) doses • At mid-dose (8 tablets), approximately 39% and 38% total of 197 single doses of HB/APAP and 67 subjects • However, misuse and abuse of prescription , drug concentration assessment from each dosing period administration, in the first half of 2015 6 —Failed to pass either the Challenge Test or ≥ ≥ of subjects had 20% cumulative reductions in C max and received a total of 194 single doses of KP201/APAP including the use of alternate routes of administration to —Cmax was 10.0% and 11.5% lower at the mid- and • Based on the ANOVA, pairwise comparisons of least- AUC 0-1 measures of exposure to hydrocodone, respectively, achieve the desired effects more quickly or intensely, is • In addition, a final US Food and Drug Administration Drug Discrimination Test high-doses of KP201/APAP, respectively, versus the ≥ • AEs square (LS) means between individual treatments were with KP201/APAP versus HB/APAP ( Figure 5A ) an ongoing public health concern 2-4 (FDA) Guidance for Industry was issued in April 2015 to corresponding HB/APAP doses ( Figure 3 ) Study Treatments conducted at the significance level of 0.05 (2-sided) for —A total of 117 of 119 treated subjects (98.3%) experi - —Immediate-release (IR) hydrocodone combination provide a framework for evaluating and obtaining label • At high-dose (12 tablets), approximately 25% and 34% 9 consistency with the 95% confidence interval (CI), using enced 1 treatment-emergent AE (TEAE); no serious claims for abuse-deterrent formulations of opioids • All subjects were to receive 7 oral treatments including Figure 3. Mean Plasma Hydrocodone Concentration- of subjects had 20% cumulative reductions in C max and products, typically including acetaminophen (APAP), a model-based t-test AEs we≥re reported are the most commonly abused opioids 5,6 (Figure 1A ) • Although 2 extended-release (ER), stand-alone HB prod - a placebo dose alone and active treatments KP201/APAP, Time Profiles Following Single Oral Doses of AUC 0-1 measures≥ of exposure to hydrocodone, respectively, a b —All 62 completers of the Treatment Phase (100%) ucts with abuse-deterrent reformulations have recently 6.67 mg/325 mg (test drug) and HB/APAP, 7.5 mg/ • A linear mixed-effects model was used to analyze the KP201/APAP and HB/APAP with KP201/APAP versus HB/APAP ( Figure 5B ) —While opioids are most frequently abused via oral e xperienced 1 AE; the most common were euphoric gained FDA approval, Hysingla® ER 10 and Zohydro® ER 11 325 mg (comparator) at low (4 tablets), mid (8 tablets), natural log-transformed PK parameters administration, recent survey data indicate that no hydrocodone IR products with abuse-deterrent or high (12 tablets) doses in a computer-generated 250 Figure 5. Cumulative Percent Reduction in C max mood (97.2%≥) and somnolence (90.1%) approximately 23% of hydrocodone IR combination properties have been marketed 12 randomized sequence ( Table 1 ). KP201, 6.67 mg is and AUC 0-1 of Hydrocodone at Mid- Doses (A) and —TEAE rates during the Treatment Phase were similar product abusers use an intranasal (snorting), and 1% Results High-Doses (B) of KP201/APAP a Versus HB/APAP b overall for KP201/APAP treatment (98.5%) and HB/APAP 6 equivalent to HB, 7.5 mg.

use an intravenous (IV), route of administration A Novel IR Opioid Product with ) 200

L treatment (98.6%), and higher for both versus placebo —All KP201/APAP and HB/APAP tablets were over- Study Population A. • Although the percentage of respondents who have Abuse-Deterrent Properties m / 100 (26.2%) encapsulated and placebo was administered in • Of 151 enrolled subjects, 71 entered and 62 completed g snorted hydrocodone IR combination products was n • KP201/APAP tablet 6.67 mg/325 mg is an IR combination ( capsules to maintain blinding Cmax —However, overall rates of hypoxia were lower with the Treatment Phase and were included in the analyses n 150 lower versus other opioids, the absolute number was product of KP201 (benzhydrocodone HCl) and APAP. o i AUC 0-1

t KP201/APAP (23.9%) versus HB/APAP (36.2%), due to

(Figure 2 ) a

similar to other opioid categories due to high usage KP201 is a prodrug of hydrocodone chemically bound to r Table 1. Oral Treatments Administered in Crossover t 80 differences at the mid-and high-doses n

of hydrocodone IR combinations ( Figure 1B ) , which may have abuse-deterrent properties a e Fashion to All Subjects Figure 2. Disposition of All Enrolled Subjects c n 100 —TEAEs were considered possibly or probably related to at the molecular level, rather than through formulation o

b C

No. Tablets (Active Drug)/ Total Dose study treatment in 115 treated subjects overall (96.6%) Figure 1. Past 30-Day Abuse Per 100 Assessments —Breaking of the covalent bond between benzoic acid a 60

a Treatment Capsules (Placebo) Active Drug (mg) Number of Subjects Enrolled m (A) and Frequency of Routes of Administration Over and hydrocodone is required for the release of hydro - s a KP201/APAP, 6.67/325 mg N=151 Not eligible for Naloxone Challenge, n=26 l the 1/1/2014 –6/30/2015 Period (B) for Hydrocodone codone, which occurs most rapidly and efficiently in P 50 High-dose 12/0 80.04/3900 • Washout criteria, n=1 IR Combination Products and Comparator Opioids the intestinal tract (ie, after oral administration) • Positive UDS, n=1 40 Conclusions Within the ASI-MV® Network b,6 • KP201 has shown decreased bioavailability at high oral Mid-dose 8/4 53.36/2600 • Withdrew consent, n=2 Low-dose 4/8 26.68/1300 Received Naloxone Challenge • Inclusion/exclusion critiera, n=22 doses (ie, above therapeutic use) and when snorted 0 P •Statistically significant reductions in peak n=125 e

A. 0.0 0.25 0.5 0.75 1.0 1.25 1.5 1.75 2.0 r

HB/APAP, 7.5/325 mg c

—KP201 has demonstrated high tamper resistance and e 20 exposure (C max ) and cumulative systemic

12.0 Time (h) n

High-dose 12/0 90/3900 Not eligible for Drug Discrimination Phase, n =6 t its physicochemical properties may deter IV abuse a exposure (AUC) to hydrocodone were 4 Tablets of KP201/APAP 4 Tablets of HB/APAP g Mid-dose 8/4 60/2600 e

—Overall, the data show that KP201/APAP provides Received Drug Discrimination Test 8 Tablets of KP201/APAP 8 Tablets of HB/APAP o observed for KP201/APAP versus HB/APAP f

10.0 Withdrew prior to Treatment Phase, n=48 0 equivalent hydrocodone exposure and thus the same Low-dose 4/8 30/1300 n=119 S • Adverse events, n=1 12 Tablets of KP201/APAP 12 Tablets of HB/APAP u

b >0 ≥10 ≥20 ≥30 ≥40 ≥50 ≥60 ≥70 ≥80 ≥90 ≥100 at oral doses of 8 and 12 tablets, while Drug s efficacy as hydrocodone IR combination products Placebo 0/12 0 j t

• Failed Drug Discrimination, n=37 e n

a a b c Percent Reduction in C max and AUC 0-1 of Hydrocodone for e Each tablet of KP201/APAP contains 6.67 mg benzhydrocodone HCl/325 mg acetaminophen; Each tablet of HB/APAP contains 7.5 mg when taken as indicated, but reduces exposure at Subjects received each oral treatment once, each separated by a 72-hour washout, in a computer-generated randomized sequence • Labs, n=1 t Liking scores were similar for both treatments

8.0 s m b hydrocodone bitartrate/325 mg acetaminophen. Single Oral Doses of 8 Tablets of KP201/APAP vs HB/APAP s based on a Williams’pair design; All tablets of active drugs were o≥ver-encapsulated. • Positive UDS, n=4 s supratherapeutic oral doses and when snorted at equivalent dose levels e APAP, acetaminophen; HB, hydrocodone bitartrate. • Investigator termination, n=2 APAP, acetaminophen; HB, hydrocodone bitartrate; HCl, hydrochloride. B. s s Entered Treatment Phase • Withdrew consent, n=3 100 A a 6.0 n=71 •Both KP201/APAP and HB/APAP were 0 —AUC 0-0.5 through AUC 0-24 percent differentials ranged Cmax

0 Pharmacokinetic (PK) Sample Collection 1 AUC 0-1 r Objectives Withdrew During Treatment Phase, n=9 from approximately –18% to –4% with KP201/APAP generally well tolerated, with primarily mild e

P • Serial blood samples were collected during the Treatment 4.0 • Investigator termination, n=2 versus HB/APAP at the high-doses (12-tablets) of each 80 e • Study KP201.A01 was conducted to assess the abuse AEs reported that were typical of opioids t Phase for PK analysis before each dose and up to • Withdrew consent, n=3 a (Figure 4 ), and from –14% to –5% at the mid-doses R liability, relative bioavailability, and safety of KP201/APAP, 24 hours after each dosing for the measurement of • Adverse events, n=2 •Considering the large patient and abuser compared with that of HB/APAP (Norco®), when adminis - Completed Treatment Phase • Not qualified after check-in, n=1 (8 tablets), with the exception of AUC 0-1 at mid-dose, 2.0 KP201 and hydrocodone in plasma tered at supratherapeutic oral doses to non-dependent, n=62 • Lost to follow-up, n=1 at which exposure was similar 60 populations that take hydrocodone IR com - recreational opioid users • Blood samples were also collected before each dose a a binations, the lower exposure to hydrocodone 0.0 and at 0.5, 2, and 8 hours after each dosing for the One additional subject failed the Drug Discrimination Test but was re-enrolled and completed the study. Figure 4. Forest Plot of Geometric Mean Ratios Hydrocodone Oxycodone All Other IR All ER/LA All ADF All Non-ADF UDS, urine drug screen. and 90% Confidence Intervals of the Pharmacokinetic 40 along with the lower incidence of hypoxia IR IR IR Single- Prescription Opioids ER/LA ER/LA measurement of APAP in plasma Combination Combination entity Opioids Opioids Opioids • Among treatment completers (n=62), approximately 82% Parameters of Hydrocodone Following Oral Adminis - reported for KP201/APAP versus HB/APAP Methods • All blood samples were analyzed using validated liquid b Products Products (SE) tration of High- (12-Tablet) Doses of KP201/APAP P of subjects were male, 50% were Black and 38.7% White, e may decrease the overall risk of oral overdose chromatography with tandem mass spectrometry c r B. c Study Design and 90.3% were not Hispanic or Latino and HB/APAP e 20 methods n and as a result the risk for morbidity and

9,000 Ⅵ Hydrocodone IR combination products t • This was a single-center, randomized, double-blind, active- a Ⅵ Oxycodone IR combination products • Mean age (range) was 29.1 (19 –54) years g e mortality following overdosage of KP201/APAP

and placebo-controlled, 7-period, crossover study consisting 8,000 Ⅵ Oxycodone IR single-entity (SE) Study Endpoints Cmax o f

) 0 of Screening, Qualification, Treatment, and Follow-Up phases PD Parameters S compared to currently marketed hydroco - s Ⅵ All other IR prescription opioids l • Pharmacodynamic (PD) analysis u a

AUC 0-0.5 b >0 ≥10 ≥20 ≥30 ≥40 ≥50 ≥60 ≥70 ≥80 ≥90 ≥100

u 7,000 Ⅵ All ER/LA opioids • During the Qualification phase, subjects underwent a j done IR combination products • The mean (standard deviation) E max scores on the DL-VAS e d i All ADF ER/LA opioids c Percent Reduction in C max and AUC 0-1 of Hydrocodone for v Ⅵ —Maximum, or peak, effect (E max ) of subject-rated Drug t i AUC 0-1 Naloxone Challenge Test to confirm that they were not among completers (n=62) were similar for KP201/APAP s d 6,000 Ⅵ All Non-ADF ER/LA opioids Single Oral Doses of 12 Tablets of KP201/APAP vs HB/APAP n Liking (DL-VAS) in study completers, assessed on a I

physically dependent on opioids. Those who passed this and HB/APAP at high-, mid-, and low-doses: f AUC 0-2 Sven Guenther , Travis Mickle , Nelson Meléndez , and Leone Kirk

o a b Disclosures

bipolar 100-point Visual Analogue Scale after each Each tablet of KP201/APAP contains 6.67 mg benzhydrocodone HCl/325 mg acetaminophen; Each tablet of HB/APAP contains 7.5 mg

r 5,000 test were administered a Drug Discrimination Test to —Emax scores were 87.8 (14.8), 82.4 (16.4), and 72.6 (17.2) are employees of KemPharm, Inc. Daniel Dickerson , Jing Zhou , Kathryn Roupe , Rosemary e hydrocodone bitartrate/325 mg acetaminophen.

b dose was administered during the Treatment Phase AUC 0-4 Ndolo , and Michael Smith have no conflicts of interest to declare. Funding for editorial, ensure that subjects could differentiate between effects APAP, acetaminophen; AUC , area under the plasma concentration versus time curve from 0 hour to 1 hour; C , maximum observed m for KP201/APAP versus 87.4 (15.6), 83.4 (16.4), and 0-1 max design, and production support was provided by KemPharm, Inc., Coralville, IA, USA, to

u 4,000 of HB/APAP and placebo plasma concentration; HB, hydrocodone bitartrate; HCl, hydrochloride. The Curry Rockefeller Group, LLC, Tarrytown, New York, USA. N • PK parameters 72.5 (16.5) for HB/APAP at high-, mid-, and low-doses, AUC 0-8 (

y • Each of the 7 double-blind treatment periods were c 3,000 —Area under the plasma concentration versus time curve respectively, and 51.5 (3.4) for placebo n AUC 0-24 1. Anson P. U.S. hydrocodone prescriptions dropping. Pain News Network. April 14, 2015. http://www.painnewsnetwork.org/stories/2015/4/14/us-hydrocodone- e separated by a minimum 72-hour washout period References u (AUC) from 0 hour to 0.5, 1, 2, 4, 8, and 24 hours; to the • The statistical analysis for the DL-VAS results revealed prescriptions-dropping. Accessed January 26, 2016. 2. Office of National Drug Control Policy (ONDCP). Epidemic: Responding to America’s Prescription Drug Abuse Crisis. Washington, DC: q 2,000 e AUC last Executive Office of the President of the United States; 2011. https://www.whitehouse.gov/sites/default/files/ondcp/issues-content/prescription-drugs/rx_abuse_plan_0.pdf. Accessed February r last quantifiable sample (AUC last ); and extrapolated to no significant LS mean differences in E max of Drug Liking F Study Population 1, 2016. 3. National Institutes of Health. Prescription Opioids and . Rockville MD: National Institute on Drug Abuse; December 2015. http://www.drugabuse.gov/publications/research- reports/relationship-between-prescription-drug-abuse-heroin-use/increased-drug-availability-associated-increased-use-overdose. Accessed January 26, 2016. 4. Califf RM, Woodcock J, 1,000 infinity (AUC inf ) between KP201/APAP and HB/APAP at high-, mid-, or AUC inf • Eligible subjects were healthy men and women aged Ostroff S. A proactive response to prescription opioid abuse. N Engl J Med. 2016 Feb 4 [Epub ahead of print] 5. Butler SF, Black RA, Cassidy TA, Dailey TM, Budman SH. Abuse risks and low-doses —Maximum observed plasma concentration (C max ) routes of administration of different prescription opioid compounds and formulations. Harm Reduct J. 2011;8:29. 6. NAVIPPRO® National Addictions Vigilance Intervention and Prevention 0 18 to 55 years old at the time of screening and engaged 60 70 80 90 100 110 120 Program Drug Abuse Surveillance Baseline Report. Analysis of Data for Hydrocodone Combination Products: 1/1/2012 through 6/30/2015. Final report issued 2 November 2015. 7. Butler SF, Oral Snorted Injection Smoked Other in recreational opioid use without opioid dependency, as —Time at which C occurs (T ) • Therefore, the DL-VAS results did not demonstrate a Percent Ratio and 90% Confidence Interval of PK Paramenters Budman SH, Goldman RJ, et al. Initial validation of a computer-administered Addiction Severity Index: the ASI-MV. Psychol Addict Behav. 2001;15(1):4 –12. 8. Federal Register: The Daily Journal max max of the United States Government. 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