IMMPACT-VIII Single-dose and short-term Proof of Concept trials in Neuropathic Pain

1. IMMPACT-VIIISingle-dose and short-term Proof of Concept trials in Neuropathic Pain Srinivasa N. Raja Johns Hopkins University

2. Proof of Concept StudiesNew Drug Development • Early stage clinical drug development of a compound that has shown potential in animal models and early safety testing • Help make an early Go-No Go decision

3. POC studies in Neuropathic Pain Potential uses • Is neuropathic pain resistant to certain drugs? • Opioids in neuropathic pain (PHN and postamputation pains) • Test a new route of therapy/ site of action-Topical lidocaine/capsaicin • Are there predictors of drug effects? • Genetic polymorphisms, Pain mechanisms • Testing novel formulations of an existing drug for better safety • Abuse deterrent opioids • Can neuropathic pain be prevented or the disease modified? • Persistent post-surgical NP pain; Diabetic neuropathy and dietary supplements • Testing and validating objective measures of drug effects

4. Phantom Pain 10 Placebo PHN Opioid Lidocaine P=0.001 8 P=0.88 P<0.001 P=0.08 6 Pain Score on Numeric Rating Scale (0-10) 4 PrePost PrePost PrePost 2 0 Placebo Diphenhydramine 50 mg Morphine 0.25mg/kg Lidocaine 5 mg/kg Single fixed dose-based on body weight over 60 min Infusion pain rating correlated with MS blood levels, but not lidocaine levels Rowbotham MC et al. Neurol 1991;41:1024 Wu et al. Anesthesiology 2002;96:841-848 Is neuropathic pain resistant to opioids?I.V. morphine and lidocaine infusions in PHN and Phantom Pain: 3-session double-blind cross-over studies N=19

5. CON PRO Single dose infusion cross-over trials: Pros and Cons • Minimizes effects of inter-subject variability • Fewer subjects required • Early signal to help predict efficacy • Short study duration • Slow offset or prolonged duration of effect may lead to carry over effects • May not help predict side effects • No information on oral bio-availability • No dose-response information • May miss effect if inappropriate dose chosen

6. Placebo Maintenance Pain Score Opioid Maintenance Pain Score Mexiletine Maintenance Pain Score 10 P<0.001 P<0.001 8 6 * 4 2 0 Postamputation Pain: Oral morphine vs mexiletine on pain intensity ratings (3-period crossover) Wu et al. Anesthesiology 2008 (in press) * Pain Score on Numeric Rating Scale (0-10) * Placebo n=43 Opioid n=50 Mexiletine n=42

7. Can topical therapies be effective in neuropathic pain? Single-dose cross-over design with vehicle control Vehicle and Lidocaine patches for 12 hrs vs Observation alone Outcome measure: Change in VAS scores of pain Rowbotham et al., Pain 1996;65:39

8. Single dose cross-over trials with topical agents: Balancing the pros and cons PRO CON • Helps establish new routes of therapy, mechanistic implications? • Minimizes effects of inter-subject variability • Fewer subjects required • Early signal to help predict efficacy • Short study duration • Short duration of observation may not be predictive of long-term effects • May not help predict side effects with longer term treatment • No dose-response information

9. 100 80 60 40 Decrease in Pain Intensity, % 20 0 -20 -40 5 10 15 20 25 30 35 40 45 50 55 60 65 Subject No. Predicting responders? Variability in Opioid Response: PHN Trial Side Effects Lack of response Tella et al. 2007, Proceedings of 11th World Congress on Pain

10. Post-hoc analysis prospective study Is this a phenotype for a genetic polymorphism? e.g., MOR Predictors of Opioid Response in PHN: Phenotype: Heat pain threshold at unaffected site • Quantitative Sensory Testing • Heat pain sensitivity at unaffected site prior to opioid exposure (baseline) 48 † P=0.09 P=0.04 47 * 46 45 Baseline Heat Pain Threshold, °C 44 43 42 41 <30% Pain Reduction ≥30% Pain Reduction <30% Pain Relief ≥30% Pain Relief Edwards R et al. Anesthesiology 2006;104:1243

11. Irritable Nociceptor PHN (Intact C-fibers) Deafferentation Subtype P<0.04 P=0.86 3.0 3.0 P<0.001 2.5 P<0.001 2.5 P<0.001 2.0 2.0 P=0.04 Pain Intensity Pain Intensity 1.5 1.5 1.0 1.0 0.5 0.5 0.0 0.0 Placebo Opioid TCA Placebo Opioid TCA Irritable Nociceptor PHN subgroup of patients more responsive to opioids TCA=Tricyclic antidepressant. Tella et al. IASP 11th World Congress on Pain; 2005.

12. MSS Placebo Screening Randomization Placebo MSS Testing novel formulations of existing drugAbuse-deterrent opioid(ALO-01/Embeda) • Healthy men and women, non-dependent recreational opioid users aged 18 to 55 years • Ability to tolerate single dose of 120 mg of morphine sulfate andto distinguish morphine from placebo (2-day crossover design) 3-phase study: Screening/Qualifying, Treatment, Followup 43+ 32 Jones et al. 2008, APS and AAPM Adapted from Stauffer J. 2008 MSS = morphine sulfate solution.

13. Capsules, crushed pellets in apple juice, and apple juice Washout Washout Washout Post-treatment Follow-up Session 2 Session 4 Session 3 Session 1 14-21d 14-21d 14-21d Negative control Positive control ALO-01W ALO-01C Placebo MSS ALO-01W ALO-01C MSS Placebo Safety Assessments ALO-01W MSS ALO-01C Placebo Placebo ALO-01W MSS ALO-01C Outcomes: PK and PD measures (subjective and objective measures) Treatment Phase Study DesignRandomized, double-blind, triple-dummy, 4-way crossover Aim: If study drug taken intact less desirable than crushed capsule or MS sol. for recreation users Jones et al. 2008, APS and AAPM

14. Screened N=160 Placebo N=29 20 mg DB N=29 10 mg DB N=30 Randomized N=30 4-wk Multi-dose N=28 5-60 mg/ day Phase II Open-label, extension Multi-dose study All patients offered entry POC Designs: Two phase studyDronabinol as adjuvant for patients on opioid therapy Chronic non- cancer pain on stable opioid Phase I Double-blind, randomized, Placebo-controlled, 3 period Single-dose croosover study Three 8-hour visits Narang et al. J Pain 9;245:2008

15. Pros and Cons • Single dose cross-over design established a POC of effects as an adjuvant analgesic with a small N • Established that higher dose not associated with better pain relief but more common side effects • Pain relief sustained during the open label phase • Limitations • Effectiveness demonstrated only as an adjuvant • Open label phase II could be non-specific- no placebo control • Design useful only for drugs with rapid onset of action

16. 12 responders N=41 Stage 1- 3-period crossover Stage 2- Four double blind randomized 1 wk treatment periods Enriched study: Clonidine in diabetic neuropathy • Two stage design- Selection and Efficacy Byas-Smith et al., Pain 1995

17. Active treatment Placebo treatment Active treatment Placebo treatment Individual patient Assessment Patient preference randomize N N of 1 or single-patient designs • To test statistically within a single patient whether or not an intervention improves clinical outcome • Within patient response vs group response Ideal Design: randomized allocation, blinding, measurements of outcomes, formal statistical analysis Ideal Drug: Rapid onset, rapid offset, reversible action Ideal Disease: Stable pain over long duration Scuffham PA Value in Health 11;97:2008

18. N of 1 trials: the pros and cons PRO CON • Minimizes effects of inter-subject variability • Potential to identify subset of patients who are responders • Can influence clinical decision for the patient • Has been used for cost-benefit analysis • Slow onset drug effects may lead to long duration study • Slow offset or prolonged duration of effect leads to carry over effects • Potential for drop out and less enthusiasm to continue with paired comparisons Australian studies: to improve access to selected high cost medications Celecoxib vs sustained release paracetamol for osteoarthritis Gabapentin vs placebo for neuropathic pain Scuffham PA Value in Health 11;97:2008

19. Is an ounce of prevention better than a pound of cure?NMDA antagonists for postmastectomy pain • Randomized D-B, PC trial in patients undergoing mastectomy, lumpectomy with axillary node dissection • Amantadine 100mg bid, day before to 14 day after surgery • Rescue drugs OK Eisenberg E. J Pain 2007;8;223

20. Prevention of disease progression and improved pain Acetyl-L-Carnitine in Diabetic Neuropathy • Double-blind placebo-controlled RCT in 333 subjects, 1 yr followup • 1 g im for 10 d, 2 g orally for 355 d • NCV (motor and sensory) and amplitude primary OM, pain secondary • 6m and12 m- NCV increased in active group in all nerves; decrease or no change in placebo • 199 pts had pain at baseline- 39% decrease at 12 m * ** VAS De Grandis and Minardi Drugs R&D 2002; 3:223

21. Testing drugs for chronic pain Core outcome measures • Pain • Physical functioning • Multidimensional Pain Inventory Interference Scale  • Brief Pain Inventory interference items • Emotional functioning • Participant rating of global improvement and satisfaction • Symptoms and adverse events • Patient disposition IMMPACT recommendations Dworkin RH et al Pain 2005;113:9

22. 37.4% Validating a measure of function:Pain relief with Opioids objective increase in activity Transdermal fentanyl- 25-150 mcg/h Intent to treat: 33.7 + 14% decrease in pain Agarwal S et al. Pain Medicine 2007; 8:554-62

23. Early stage drug developmentSensitivity vs Specificity • Wrong disease state • Wrong dose • Wrong duration of treatment (exposure-response relationship) • Outcome measure- no biomarkers (surrogate endpoint) for pain • Not considering the natural course of the disease- disease progression or regression • Active comparators with proven efficacy to distinguish negative from failed trials

24. 2.5 yr 1980-84 1995-99 Median 6.5 yr Dosage changes in new molecular entities approved between 1980-1999 • 499 NME, 354 evaluable • Dosage changes occurred in 21% of 354 NME post approval • 79% safety-motivated dosage decrease • 27% neuropharm. drugs • Smallest dose that produces near maximal effect rather than maximal tolerated dose Cross et al., 2002 Pharmacoepidemiol & Drug safety

25. Lessons learnt from failed neuropathic pain RCTsRelation to study characteristics • Aim: to identify factors associated with + vs – outcomes of placebo-controlled neuropathic pain trials • 106 clinical trials with 123 Rx-group comparisons • + studies: medication response rates greater, placebo response lower, larger sample size, cross-over design, published earlier (1995 vs 1998.5) • Greater placebo response: • greater medication response & trial duration, parallel design • -ve vs + outcome: 27% vs 16% placebo responders (>50%) Katz JK, Finnerup NB, Dworkin RH Neurology 2008;70:263 Polydefkis M, Raja SN Neurology 2008;70:250

26. Study Designs • Parallel vs Crossover • Enriched enrollment design • Excluding high placebo responders? • N-of-1 studies • Adaptive designs • Time-to-exit designs (see Galer et al Pain 1999-Lido patch) • Mechanism-based clinical studies (Wallace MS 2002 J Pain) • Genetic screening: e.g. MOR polymorphism • Split-trial strategy- pooled data from few centers with extensive testing Rowbotham M Neurology 2005;65:S67

27. Summary • Study design- adaptive, depending on nature of question being asked • Consider the balance of pros and cons of the design relative to the question

28. New strategies to test and develop new drugs efficiently for neuropathic pain: A combined effort Stakeholders Patients Health-care providers Insurers Industry Agencies Academia NIH Regulatory Agencies Industry