Efficacy and Safety of Sublingual Sufentanil 30 mcg for the Management of Acute Pain Following Ambulatory Surgery. Pamela P.

Transcription

1 Efficacy and Safety of Sublingual Sufentanil 30 mcg for the Management of Acute Pain Following Ambulatory Surgery Pamela P. Palmer, MD, PhD

2 Disclosures for Dr. Pamela Palmer AcelRx employee Currently own stock and stock options 2 MRC JAN2016

3 Unmet Needs and Rationale for Sublingual Sufentanil 3

4 Pharmacokinetic Limitations of Current IV Opioid Therapy 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 Rapid brain penetration results in quick onset of analgesia but alpha distribution of this lipophilic drug (1.7 minutes) results in quick offset and requires frequent redosing to maintain analgesia 2,3 1. Lötsch J. J Pain Symptom Manage 2005; 29(5 Suppl):S90-S Scott JC, Cooke JE, Stanski DR. Anesthesiol 1991; 74: MRC JAN Shafer, S and Varvel, J. Anesthesiol 1991; 74:53-63

5 Clinical Need for Rapid-Acting Non- Invasive Analgesic Ambulatory Surgical Centers Allows adequate analgesia while discontinuing IV lines in the process of moving the patient towards discharge readiness Emergency Department IM route Reduced bioavailability during shock Painful to administer IV route Long delays and cost of obtaining IV access Difficult access: obese, elderly and vasoconstricted (e.g., dehydration or shock) patients IV opioid pharmacokinetics not optimal 5 MRC JAN2016

6 Why Sublingual Sufentanil? Sufentanil first synthesized by Janssen in First approved in US for IV delivery in Approved for induction of anesthesia Later approved for epidural delivery as an analgesic in combination with bupivacaine 1 Molecular Properties Lipophilic: 1500 times more fat-soluble than morphine 2 20% non-ionized at physiological ph (fentanyl only 8%) 2 Fat-soluble, non-ionized molecules = more rapid brain penetration than lipid-insoluble, charged molecules 2 1. Stanley TH, Egan TD, Van Aken H. A tribute to Dr Paul AJ Janssen: entrepreneur extraordinaire, innovative scientist, and significant contributor to anesthesiology. Anesth. Analgesia. 2008;106(2): MRC JAN De Leon-Casasola et al. Anesth Analg 1996; 83:

7 Sufentanil has Rapid Plasma/ CNS Equilibration (t ½ k e0 ) Commonly used IV opioids have a delayed equilibration time between plasma and CNS t ½ k e0 Morphine 2.8 hrs 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 high lipophilicity Sufentanil t ½ k e0 = 6 min 3 Hydromorphone 46 min P-Glycoprotein Plasma Blood Brain Barrier (BBB) Central Nervous System (CNS) 1. Lotsch et al., Anesthesiol 95: , Shafer et al., Geriatric Anesthesiology. 2 nd ed. New York, NY: Springer; Chapter 15:209 28, 2007 MRC JAN Scott et al., Anesthesiol 74:34-42, 1991

8 Plasma Versus Brain Morphine Concentrations Cp\Ce (ng/ml) Delayed brain uptake leads to disconnect between IV dosing and effect 1 Plasma concentrations with IV morphine dosing Morpine + M6G* Plasma Effect Site Morphine/M6G in brain Time (hours) * Assumes equipotency of morphine and M6G; other potency ratios achieved similar results 1. IV PCA dosing frequency based on IAP309 Phase 3 study; plasma and brain concentrations modelled from published plasma 8 MRC JAN2016 and CNS equilibration values by D.Fisher consultant to AcelRx

9 Sufentanil has Rapid Plasma/ CNS Equilibration (t ½ k e0 ) Cp\Ce (pg/ml) Uptake of sublingual sufentanil leads to potential for real-time tracking between dosing and effect 1 Sufentanil Sublingual sufentanil plasma and brain concentrations track together Plasma Effect Site Time (hours) 9 1. Sublingual sufentanil dosing frequency based on IAP309 Phase 3 study; plasma and brain concentrations modelled from published plasma MRC JAN2016 and CNS equilibration values by D.Fisher consultant to AcelRx

10 ARX-04 Clinical Studies Study number Phase # SAP202 Phase 2 dosefinding Clinicaltrials. gov NCT # Patient population Current status of study NCT Bunionectomy Complete/publish ed SAP301 Phase 3 NCT Ambulatory abdominal surgery SAP302 Phase 3 NCT Trauma/injury in the ER SAP303 Phase 3 TBD Ambulatory surgery - All Completed 2015 Recruiting Study Start-up 1. Singla NK, et al. A dose-finding study of sufentanil sublingual microtablets for the management of postoperative 10 MRC JAN2016 bunionectomy pain. J. Trauma. Acute. Care. Surg. 2014;77(3 Suppl 2):S198 S203

11 SAP301 Study Design Postoperative ambulatory surgery patients following abdominal surgery Open herniorrhaphy Abdominoplasty Any laparoscopic abdominal surgery Randomized 2:1, active:placebo Total of 163 randomized and 161 dosed (ITT population) Study completed at 24 hours after first dose These types of surgery are usually outpatient and the patient often discharged by 12 hours Dosing could extend out to 48 hours, if needed Primary efficacy variable: Time-weighted SPID-12 Essentially an area under the curve measurement of the drop in pain intensity from baseline over the first 12 hours of the study 11 MRC JAN2016

12 SAP301 Key Secondary Endpoints Efficacy: TOTPAR: total pain relief as measured on a 0 4 scale (summed) SPRID: summed pain intensity/pain relief composite measure PGA: patient global assessment HPGA: healthcare professional global assessment Safety: Adverse events Vital signs and oxygen saturation Concomitant medications 12 MRC JAN2016

13 SAP301 Results: Demographics Category Category Sex, female, % 68 Surgery, % Age, years, mean 41 Abdominoplasty 50 Race/ethnicity, % Laparoscopic 30 Caucasian 40 Open hernia 20 Hispanic 38 ASA status, % African American Asian BMI <30, % MRC JAN2016

14 SAP301 Patient Disposition ITT population: 107 active; 54 placebo Completed 24 hr: 102 active; 41 placebo Reason for early termination ARX-04 (%) Placebo (%) Adverse event 0 3.7* Lack of efficacy Protocol violation Withdrawal by subject *Two patients in the placebo arm experienced serious adverse events that caused drop-out prior to 24 hours: hemiparesis and syncope. 14 MRC JAN2016

15 SAP301 Results: Primary Endpoint: SPID-12 Pain intensity (PI) measured on a scale of 0 10 (0 = no pain, 10 = worst pain imaginable) Assessment ARX-04 Placebo P-value Baseline PI NS SPID < NS, not significant MRC JAN2016

16 Summed pain intensity difference SAP301 SPID Over First Hour of Treatment (LS Mean) Sufentanil Tablet Placebo Tablet *** *** ** *** **P<0.01, ***P< Time (minutes) 16 MRC JAN2016

17 SAP301 Key Secondary 12-Hour & 24-Hour Endpoints Endpoint ARX-04 Placebo P-value TOTPAR <0.001 SPRID <0.001 SPID <0.001 TOTPAR SPRID <0.001 PGA-24 a <0.001 HPGA-24 a <0.001 a Percent of patients reporting good or excellent. 17 MRC JAN2016

18 SAP301 Number of ARX-04 Tablets Dosed Time period Number of tablets, median (range) Interdosing interval, mean 0 12 Hours 4 (1 9) 185 minutes 0 24 Hours 7 (1 15) 221 minutes 18 MRC JAN2016

19 SAP301 Adverse Events (>3% in either group) No statistical difference for ARX-04 compared to placebo Adverse Event, % ARX-04 Placebo No Adverse Event Nausea Headache Vomiting Dizziness Hypotension Flatulence Somnolence Procedural nausea Pruritus MRC JAN2016

20 Conclusions Efficacy and tolerability results from this study suggest that sufentanil 30 mcg tablets dispensed sublingually via single-dose applicator may offer a viable alternative to IM or IV dosing in an ambulatory surgery population Nausea and headache were the most commonly reported AEs for both treatment arms Additional studies are indicated to assess potential applications within emergency medicine or other medically supervised venues 20 MRC JAN2016

21 Thank You 21