Pharmacokinetics and Dose Proppyortionality of Sublingual Sufentanil NanoTab™ in Healthy Volunteers

Pamela P. Palmer, MD, PhD AcelRx Pharmaceuticals, Inc. October 20, 2009

1 Sufentanil: A Superior Opioid

ƒ Approved for intravenous (IV) Opioid Therapeutic index2 and epidural administration1 Methadone 12 ƒ High therapeutic index2 Meperidine 28

ƒ No active metabolites3 Morphine 70

ƒ Rapid transmucosal uptake Hydromorphone 232 Fentanyl 300

Sufentanil 25,000

Therapeutic index = median lethal dose (LD50)/ lowest median effective dose (ED50)

1. Sufenta (sufentanil citrate) [package insert]. Decatur, IL: Taylor Pharmaceuticals; 2007. 2. De Castro J. Practical applications and limitations of analgesic anesthesia: a review. Acta Anaesthesiol Belg. 1976;27:107-128. 2 3. Monk JP, Beresford R, Ward A. Sufentanil. A review of its pharmacological properties and therapeutic use. Drugs. 1988;36:286-313. NanoTab: Efficient Transmucosal Delivery

ƒNanoTab: a novel oral transmucosal dosage form ƒKey attributes: –Bioadhesive –Low saliva response • Minimal swallowed drug • Enhanced transmucosal uptake

–Consistent pharmacokinetics NanoTab –High bioavailability

3 AcelRx Development Programs

Indication PreclinicalPhase 1Phase 2 Phase 3 Approved

Inpatient acute postoperative pain

ARX-01SftilNTbtit01: Sufentanil NanoTab patient-contro lled anal gesi a (PCA) S yst em

Cancer breakthrough pain

ARX-02: Sufentanil NanoTab breakthrough pain (BTP) Management System

Procedural sedation anxiolysis and analgesia

ARX-03: S uf ent anil/T r iazol am N anoT ab

4 Study Objective and Methods

Objective: ƒ To determine the pharmacokinetics and dose proportionality of varying strengths of sublingual Sufentanil NanoTabs

Methods: ƒ Design: open-label, single-dose, crossover design ƒ 24 healthy volunteers (12 males, 12 females, 18 -45 years of age) in 2 cohorts ƒ Treatments: – Cohort 1 (n = 12) received lower dosage strengths (2.5, 5, and 10 mcg) – Cohort 2 (n = 12) received higher strengths (10 and 80 mcg) – All subjects received IV sufentanil 5 mcg – All subjects were blocked with oral naltrexone 50 mg bid ƒ Plasma sufentanil concentrations were determined for 640 minutes following Sufentanil NanoTab dosing

5 Linear Dose Proportionality

10 mcg vs 80 mcg (80 mcg dose normalized to 10 mcg) (pg/mL) nn oncentratio cc nil plasma aa Sufent

Time (min)

6 Mean (± SD) Cmax of Sufentanil versus Dose

Cmax = 2.31 x dose + 1.2 R2 = 0.9852 pg/mL) (( max C

Dose (mcg)

7 SD, standard deviation; Cmax, maximum concentration. Mean (± SD) Cmax of Sufentanil versus Dose

Cohort 2 C max Proportionality

Cmax = 1.67 x dose + 5.95 R2 = 0.9785 pg/mL) (( max C

Dose (mcg)

8 SD, standard deviation; Cmax, maximum concentration. Oral Transmucosal Products: Sufentanil vs Fentanyl

ARX-02 Actiq Fentora Onsolis 80 mcg 400 mcg 400 mcg 800 mcg

Activ e ingredient SfentanilSufentanil Fentany l Fentany l Fentany l

Bioavailability 79% 47%1,* 65%1 71%3

1,* 1 3 Tmax 53 min 91 min 47 min 60 min (range) (30-90) (35-240) (20-240) (45-240)

2 1 3 t1/2 423h4.23 h 643h6.43 h 11. 09 h 14 h (range) (2.89-5.79) (NA) (4.63-20.59) (NA) (%CV) (21%) (115%) (NA) (NA)

T , time to maximum concentration; t , half-life; max 1/2 1. Fentora (fentanyl citrate) [package insert]. Frazer, PA: Cephalon; 2006. CV, coefficient of variation; NA, not available. 2. Actiq (fentanyl citrate) [package insert]. Salt Lake City, UT: Cephalon; 2007. *Dose adjusted (800 mcg to 400 mcg). 9 3. Onsolis (fentanyl citrate) [package insert]. Somerset, NJ: Meda Pharmaceuticals; 2009. Sufentanil NanoTab BTP Management System

ƒ First transmucosal formulation of sufentanil – Allows opioid rotation

ƒ Highly consistent Cmax and Tmax – Avoids dose stacking ƒ Shorter half-life than fentanyl products – More closely matches BTP episode ƒ Compact smart dispenser to monitor dosing in an outpatient setting

10 Thank You

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