Phase 3 Efficacy and Safety Results of the Sufentanil Sublingual Tablet 30 mcg (DSUVIA )

Transcription

1 Phase 3 Efficacy and Safety Results of the Sufentanil Sublingual Tablet 30 mcg (DSUVIA ) 2017 SOMSA Plenary Session Mark Evashenk VP Clinical Affairs, AcelRx Pharmaceuticals, Inc.

2 Challenges with Management of Acute Pain in Emergency Situations 2

3 Current Concerns with Acute Pain Management in Battlefield & Emergency Medicine Battlefield and Emergency Medicine IV route IV lines challenging to start in the field or in ambulances 1 Difficult access: obese, elderly and vasoconstricted 2 Patients presenting directly to ED can experience long delays in obtaining IV access 3 Current IV Opioid Therapy IM route Reduced bioavailability during shock 4 Painful to administer Intra-nasal Route off-label for most analgesics; unpredictable absorption Immediate access to an atomizer required Burning sensation of nasal mucosa not uncommon 3 IV morphine Delayed CNS penetration resulting in poor analgesic onset and slow offset which can delay discharge Active metabolite morphine-6-glucuronide can cause delayed side effects 1 IV hydromorphone Slightly more rapid onset than morphine but known for delayed and prolonged side effects (e.g., sedation, respiratory depression) 1 IV fentanyl Known brain penetration results in rapid analgesia but alpha distribution of lipophilic drug (1.7 minutes) results in quick offset; requires frequent re-dosing to maintain analgesia 3 1. Sweeney, T. and Marques, A. Prehospital Vascular Access for the Trauma Patient. In Soreid E. and Grande, C. (Eds) Prehospital Trauma Care (Page 291). CRC Press Feb 02, Stein, J. et al. Ultrasonographically guided peripheral intravenous cannulation in emergency department patients with difficult intravenous access: a randomized trial. Ann Emerg Med Jul;54(1): Todd KH et. Al.. J Pain Jun;8(6): Epub 2007 Feb 15. Pain in the emergency department: results of the pain and emergency medicine initiative (PEMI) multicenter study. 4. de Moya, M. A. Shock. In Merck manual online, professional version. Accessed 5/19/17

4 Treatment Considerations for Acute Pain in the Battlefield Additional concerns with current battlefield treatments IM morphine may be less bioavailable during periods of shock due to peripheral vasoconstriction 1 Oral transmucosal fentanyl lozenge can take over 30 minutes to dissolve 2 Ketamine can produce dissociative effects that may be undesirable in combat scenarios de Moya, M. A. Shock. In Merck manual online, professional version. Accessed 5/19/17 2. Actiq package insert, Dec 2011, Cephalon, Inc. 3. Curran HV, Morgan C (2000) Cognitive, dissociative and psychotogenic effects of ketamine in recreational users on the night of drug use and 3 days later. Addiction 95: Accessed 5/19/17

5 Profile of Desired Battlefield Analgesic Excerpted from - Combat Anesthesia: The First 24 Hours (eds. Buckenmaier C and Mahoney PF, 2015) 1 Robust stability in the face of environmental challenges Straightforward method of delivery to increase potential caregivers Rapid onset with a rarity of adverse events Minimize altered mental status Large therapeutic index 1. Published by Office of the Surgeon General, United States Army, Falls Church, Virginia, p

6 Sublingual Sufentanil Research and Development Background and Rationale 6

7 Why Sublingual Sufentanil? U.S. Department of Defense aware of our development of small sublingual sufentanil tablets for post-operative pain Sufentanil Sublingual Tablet System (Zalviso ) is a PCA product currently approved in Europe for treatment of post-operative pain 1 Requested single-dose, easy to use applicator for field-based scenarios Sublingual delivery of sufentanil offers potential for field-based analgesia Lipophilic: 1500 times more fat-soluble than morphine 2 Fat-soluble, non-ionized molecules = rapid penetration through BBB Sublingual tissue perfusion maintained during shock 3 Clinical data has shown greater pain intensity reduction in the first 4 hours compared to IV morphine in post-operative patients 3 Eliminates needle-stick injury and associated risk of infection Accessed Banks, W. Characteristics of compounds that cross the blood-brain barrier. BMC Neurol 2009; 9(Suppl 1): S3. 3. de Moya, M. A. Shock. In Merck manual online, professional version. Accessed 5/19/17 4. Melson TI, Boyer DL, Minkowitz HS, et al (2014) Sufentanil sublingual microtablet system versus intravenous patient-controlled analgesia with morphine for postoperative pain control: a randomized, controlled trial. Pain Pract 14:

8 Sufentanil Penetrates CNS Due to Lipophilicity (t ½ k e0 ) Commonly used IV opioids have delayed equilibration between plasma and CNS Morphine t ½ k e0 = 2.8 hours 1 Hydromorphone t ½ k e0 = 46 min 2 Sufentanil rapidly penetrates the CNS due to its very lipophilic nature Sufentanil t ½ k e0 = 6 min 3 t ½ k e0 Morphine 2.8 hrs Hydromorphone 46 min P-Glycoprotein Plasma Blood Brain Barrier (BBB) Central Nervous System (CNS) 8 1. Lotsch et al., Anesthesiol 95: , Shafer et al., Geriatric Anesthesiology. 2 nd ed. New York, NY: Springer; Chapter 15:209 28, Scott et al., Anesthesiol 74:34-42, 1991

9 Sufentanil: High Therapeutic Index and No Active Metabolites Opioid Therapeutic index [lethal dose (LD 50 )/effective dose (ED 50 ) in animal studies] Morphine 71 1 Hydromorphone Fentanyl Sufentanil 26,716 1 Other Opioid Active Metabolites 3-7 Normeperidine M6G M3G H6G H3G 9 1. Mather, Clin Exp Pharmacol Physiol 1995; 22: Kumar, Eur J Pharmacol 2008; 597:39 (ED50) and Purdue Pharma MSDS, 2009 (LD50) 3. Clark et al., J Emerg Med 1995 ;13: Smith et al., Clin J Pain 2011;27: Smith et al., Clin Exp Pharmacol Physiol 2000;27: Wright et al., Life Sci 2001;69: Smith, H. Mayo Clin Proc 2009;84(7):

10 Sufentanil Pharmacokinetics Sublingual delivery of sufentanil blunts C max and extends plasma half-time compared to IV administration 1 Sublingual Sufentanil 30 mcg IV Sublingual Bioavailability, %, mean C max pg/ml, mean CST ½ h, median CST½ = context-sensitive half-time (time from C max to 50% of C max ) SAP101, data on file, AcelRx

11 Clinical Program Overview Study Number Phase # Number of patient(n) Study Design Patient Population Current Study Status SAP202 Phase 2 Dose-finding Pivotal 100 Multicenter, randomized, placebo-controlled Postoperative bunionectomy Published SAP301 Phase 3 Pivotal 161 Multicenter, randomized, placebo controlled SAP302 Phase 3 76 Multicenter, Open- Label SAP303 Phase Multicenter, Open- Label Total 477 Ambulatory surgery - Postoperative abdominal Trauma/injury in the ED Postoperative; 40 years, 25% with organ impairment Published Completed 2016; In Press Completed 2016; manuscript submitted 1. Singla NK, et al. A dose-finding study of sufentanil sublingual microtablets for the management of postoperative bunionectomy pain. J. Trauma. Acute. Care. Surg. 2014;77 (Suppl 2):S198 S Minkowitz H, et al. Sufentanil Sublingual Tablet 30 mcg for the Management of Pain Following Abdominal Surgery: A Randomized, Placebo-Controlled, Phase-3 Study. Pain Pract. E-pub Feb American Journal of Emergency Medicine 11

12 Pre-filled Applicator Designed in collaboration with DoD (light-weight, disposable, extremeenvironment tested, easily handled with gloves) 1 Removable lock to avoid premature actuation (not shown) Non-retractable pusher Clear plastic to allow tablet visibility Pre-filled tablet Data on file, AcelRx ( )

13 Proprietary Sufentanil Sublingual Tablets Have Unique Properties Lipophilic so absorbed sublingually Sufentanil Potent so small tablet possible Wide therapeutic index 1 Low GI bioavailability minimizes delayed effect of swallowed drug Small size dissolves in minutes Tablet Minimizes saliva production to limit swallowed drug and maintain sublingual bioavailability Bioadhesive to keep in place under tongue Discrete dosing unit may reduce dosing errors and circumvent risk of diversion with clear liquids Mather LE. Opioids: a pharmacologist s delight! Clin Exp Pharmacol Physiol 1995; 22:833-6.

14 SAP301 and SAP303 Phase 3 Post-operative Studies 14

15 Study Design: SAP301 & SAP Design 303 Design Multicenter, Randomized, Placebo-controlled Trial Key Inclusion: 18 years and older Moderate-to-severe acute pain following abdominal surgery Multicenter, Open-label, Single-arm Trial Key Inclusion: 40 years and older Moderate-to-severe postoperative pain Sites encouraged to screen patients with co-morbidities Outcome Measures 15 Primary Efficacy: Summed pain intensity difference to baseline over 12-hr study period (SPID12) Safety: Adverse events, vital signs, concomitant medications

16 Demographics Post-operative Patients SAP301 SAP303 Number of Patients Sex, female, % Age, years, mean BMI 30 kg/m ASA Status Age 65, % Renal and/or hepatic impairment, % NR 29 16

17 Surgery Types and Numbers SAP301: Surgery Type n(%) Total (n=161) Abdominoplasty 80 (49.7%) Hernioplasty 33 (20.5%) Laparoscopic Abdominal 48 (29.8%) SAP303: Surgery Type n(%) Total (n=140) Knee Replacement 12 (8.6%) Hip Replacement 6 (4.3%) Bunionectomy 9 (6.4%) Laparoscopic Abdominal 58 (41.4%) Open Abdominal 25 (17.9%) Breast Augmentation/Reconstruction 23 (16.4%) 17 Other 6 (4.3%)

18 SAP301: Primary Efficacy - SPID-12 Pain intensity (PI) measured on a scale of 0 10 Assessment DSUVIA Placebo P-value Baseline PI NS SPID < (p<0.001) SPID ARX-04 DSUVIA Placebo 18

19 SAP301: PID Over First Hour by Surgery Type Pain Intensity Difference * p<0.01 ** p< ** ** ** * Time (Minutes) Abdominoplasty Hernia repair Lap. Abd Placebo (All) 19

20 SAP303: Pain Intensity by Time Point (All) 27% Reduction in Pain Intensity by 1 Hour 49% Reduction in Pain Intensity by 2 Hours 7 Pain Intensity Score Mean Pain Intensity Mod Mild Time (hours) 20

21 SAP303: Pain Intensity by Surgery Type Pain Intensity Score TKA/THA BUN ABD OTHER Time (Hours) 21

22 SAP301 & SAP303: Number of Doses Required to Manage Pain Study Period Mean # Doses Used, 0-12 hours Number of DSUVIA Doses SAP301 (n=107) SAP303 (n=140) Median 4 3 Mean # Doses Used, 0-24 hours 7.0 NC Median 7 NC 22

23 SAP301 & SAP303: Use of Rescue Analgesia Low rate of rescue opioid utilization Study Period Patients Requiring Use of Rescue Opioid* DSUVIA (n=107) SAP301 Placebo (n=54) SAP303 DSUVIA (n=140) Use over 24-hrs 27% 65% 14% Mean # doses *IV Morphine 1 mg 23

24 SAP301 Adverse Events (>3% in Either Group) No statistical difference for DSUVIA compared to placebo Adverse Event, % DSUVIA Placebo No Adverse Event Nausea/Procedural Nausea Headache Vomiting 8 2 Dizziness 6 4 Hypotension 5 4 Flatulence 4 7 Somnolence 3 4 Pruritus

25 SAP303 Adverse Events (>2%) Adverse Event, n(%) DSUVIA (n=140) No Adverse Event 88 (62.9%) Nausea/Procedural Nausea 38 (27.1%) Headache 8 (5.7%) Dizziness 6 (4.3%) Pruritus 4 (2.9%) O 2 Sat Decreased 3 (2.1%) Hypotension 3 (2.1%) 25

26 SAP302 Emergency Department 26

27 SAP302: Study Design Study Details Multicenter, Single-Arm, Openlabel Study Two Cohorts: Single-dose (after 1 hour, other opioids administered if needed) Multiple-dose up to 5 hours (rescue opioids allowed if study drug not effective) Inclusion/Exclusion Key Inclusion: 18 years and older moderate-to-severe acute pain due to trauma or injury Key Exclusion: Opioid-tolerant (>15mg oral MSO 4 equivalent daily) Dependent on supplemental oxygen Pregnant 27

28 SAP302: Outcome Measures Study sites Hennepin County Medical Center, Minneapolis, MN (James Miner, MD) Memorial Hermann-Memorial City Medical Center, Houston, TX (Harold Minkowitz, MD) Baylor College of Medicine, Ben Taub General Hospital, Houston, TX (Zubaid Rafique, MD) Primary Endpoint Sum of the pain intensity difference to baseline over the first hour of treatment (SPID1) Key Secondary Efficacy Endpoints Pain Intensity Difference by time point Pain intensity by time point Use of rescue medication Safety Endpoints Adverse Events Vital Signs Six-item Cognitive Screener 28

29 SAP302: Demographics (n=76) Category Sex, male, % 61 Age, years, mean 42 Race, % Caucasian 45 African American 34 Native American 7 Ethnicity, % Hispanic/Latino 16 Category BMI, % < 30kg/m 2 61 > 30kg/m 2 39 ASA Classification, % Baseline Pain 8.1/10 29

30 SAP302: Demographics (n=76) Trauma classifications % 4 5.3% % 2 2.6% 1 1.3% % % Injury Type Fractures Sprains/strains Contusion/hematoma (soft tissue) Laceration Joint dislocation Burns Total patients

31 SAP302: Mean Pain Intensity by Evaluation Time Point 35.7% Reduction in Pain Intensity by 60 Minutes Pain Intensity Score severe pain 8.08 Mean Pain Intensity 6.99 moderate pain mild pain Time (minutes) 31

32 SAP302: Adverse Events (> 2% of patients) Majority of patients experienced no side effects DSUVIA n=76 No Adverse Event 79% Nausea 9% Somnolence Vomiting 5% 1 4% Oxygen Desaturation 3% All 4 patients with somnolence were rated as mild 2. Two patients experienced transient room air oxygen desaturations below 95% (88% and 94% which immediately improved with nasal cannula oxygen)

33 SAP302 Emergency Department: Six-Item Screener (SIS) Cognitive Test SAP302 SIS results suggested that DSUVIA was not associated with cognitive impairment 73 2 Patients either had the same score or increased their score Patients had a decrease of 1 point compared to baseline DoD requested cognitive test before and 1 hour after dosing of DSUVIA DoD concerned about impaired cognitive skills with other field-based analgesics used in the military 33

34 Positive Phase 3 Data in the Treatment of Moderate-to-Severe Acute Pain DSUVIA demonstrated effectiveness for the management of acute post-operative pain across a variety of surgical procedures Single dose of DSUVIA resulted in approximately a 3-point drop in pain intensity within 60 minutes, with clinically meaningful analgesia in < 20 minutes 1 DSUVIA was well-tolerated in clinical studies and did not show cognitive impairment in study patients Nausea and headache were the most common AEs DSUVIA is still investigational, but if approved, could provide an analgesic option for opioid-naïve patients Additional research is indicated to assess safety and efficacy in actual field-based environments Bijur, Polly E., et al.. Validation of a Verbally Administered Numerical Rating Scale of Acute Pain four Use in the Emergency Department. Academy Emergency Medicine. 2003;10:

35 Thank you