Novel Peripheral Kappa Opioid Product Candidates: Efficacy Without Opioid Side Effects. Canaccord Healthcare. August 2016

Transcription

1 Novel Peripheral Kappa Opioid Product Candidates: Efficacy Without Opioid Side Effects Canaccord Healthcare August 2016

2 Forward Looking Statements This presentation contains certain forward-looking statements that involve risks and uncertainties that could cause actual results to be materially different from historical results or from any future results expressed or implied by such forwardlooking statements. In some cases, you can identify forward-looking statements by the words anticipate, believe, continue, estimate, expect, objective, ongoing, plan, propose, potential, or up-coming and/or the negative of these terms, or other comparable terminology intended to identify statements about the future. Forward-looking statements in this presentation include, among other things, the expected timing of our other planned clinical trials; the potential results of ongoing and planned clinical trials; future regulatory and development milestones for the Company's product candidates; the size of the potential markets for pain management, including the postoperative and chronic pain market, and the uremic pruritus market; and the Company's expected cash reach. These statements involve known and unknown risks, uncertainties and other factors that may cause our actual results, levels of activity, performance or achievements to be materially different from the information expressed or implied by these forward-looking statements. Although we believe that we have a reasonable basis for each forward-looking statement contained in this presentation, we caution you that these statements are based on a combination of facts and factors currently known by us and our expectations of the future, about which we cannot be certain. Factors that may cause actual results to differ materially from any future results expressed or implied by any forward-looking statements include the risks described in the Risk Factors section of the Company s Annual Report on Form 10-K for the year ended December 31, 2015, as well as those set forth from time to time in the Company s other SEC filings, available at Any forward-looking statements speak only as of the date of this presentation. We undertake no obligation to publicly update any forward-looking statements, whether as a result of new information, future events or otherwise except as required by law. 2

3 Cara: Developing First-in-Class Peripheral Opioid Novel opioids without traditional opioid side effects Kappa opioid agonists with unique pharmacology and chemotype NCEs with patent protection through at least 2027 MOA: Anti-Nociceptive/Anti-Inflammatory & Anti-Pruritic Lead candidate, I.V. CR845 - Phase 3 Program post-op pain 9/15 Positive results in three Phase 2 trials in over 250 patients Statistically significant reductions in pain and opioid-related adverse events across all three trials Successful Phase 2 Trial of I.V. CR845 in Uremic Pruritus Primary & Secondary Endpoints: Reduction in worst itch & improved QoL Initiated Phase 2/3 Trial Q Completed Phase 2a Osteoarthritis Trial Q4, 2015 June 30th, 2016 Cash - $84.8M 3

4 μ-opioid Versus κ-opioid Receptor Agonist Effects μ-opioid κ-opioid Central BBB Peripheral Respiratory depression Analgesia Nausea & vomiting Constipation Histamine release Euphoria Addiction Urinary retention Miosis Hallucinations Dysphoria Diarrhea Miosis Analgesia Anti-inflammatory Anti-emetic Anti-pruritic Aquaresis CR845 Central Peripheral BBB 4

5 CR845: A Peripherally-Acting κ-opioid Receptor Agonist With Less Baggage Unique properties 30,000-fold selectivity for κ-opioid receptors compared with μ- or δ- opioid receptors Peptidic structure limits entry into CNS, preventing: Euphoria and abuse liability Sedation and respiratory depression Dysphoria and hallucinations Properties inherent to molecule Not a formulation approach 5

6 CR845 Effects Mediated by Peripheral κ-opioid Receptors KOR CR845 acts at on: Immune cells: anti-inflammatory KOR in the brain: dysphoria and hallucinations DRG: antinociceptive Sensory nerves: anti-nociceptive and anti-pruritic DRG=dorsal root ganglion 6

7 2016 CDC Guidelines For Opioid Prescription Practices We know of no other medication routinely used for a non-fatal condition that kills patients so frequently. C.D.C. March 15 th,

8 I.V. CR845 Human Abuse Liability Trial Relative abuse potential vs. pentazocine* and placebo Non-dependent recreational opioid and hallucinogen users Study assessments with 3 bipolar visual analog scales (VAS) Periodically from 5 minutes to 8 hours after dose: Do you like the drug effect you are feeling now? Strong disliking Neither like nor dislike Strong liking At 8 hours post dose: Overall, my liking for this drug is: Would you want to take the drug you just received again, 8 *A schedule IV opioid with κ activity

9 Human Abuse Liability Trial: CR845 Drug Liking Over 8-Hour Test Session Strong liking Mixed-model repeated measures analysis of drug liking Neither like nor dislike Overall drug liking VAS mean +1 SE * P<0.0001* * * P<0.0001* P<0.0001* 49.2 Strong disliking 0 Placebo CR845 5 μg/kg CR μg/kg Pentazocine 0.5 mg/kg 9 *p<0.001 Comparisons to pentazocine (Schedule IV)

10 Secondary Endpoint: Take Drug Again Definitely would Results are consistent with reduced risk of abuse of CR Do not care Take drug again VAS mean +1 SE * * * P<0.0001* 49.2 P<0.0005* 49.5 P<0.0001* Definitely would not 0 Placebo CR845 5 μg/kg CR μg/kg Pentazocine 0.5 mg/kg 10 *p<0.01 Comparisons to pentazocine

11 Mean Pupillometry Assessments Over Time Neither dose of CR845 produced any change in pupillometry assessment over the 8 hour duration A: CR845 IV MG/KG B: CR845 IV MG/KG C: CR845 IV Placebo D: Pentazocine IV 0.5 MG/KG Hours 11

12 Cara s Product Pipeline 2016 Product Candidate (Class) Indication Status Commercial Rights IV CR845 (kappa opioid) Acute Pain Phase 3 Ongoing Cara (worldwide ex. below) Maruishi (Japan) CKD Pharma (S.Korea) Oral CR845 Acute/Chronic Pain Phase 2b Cara (worldwide ex. below) Maruishi (Japan) CKD Pharma (S.Korea) IV (oral) CR845 CKD-Assoc. Pruritus Phase 2/3 Ongoing Cara (worldwide ex. below) Maruishi (Japan) CKD Pharma (S.Korea) Oral CR701 (cannabinoid) Neuropathic Pain Pre-clinical Cara (worldwide) Japanese License for CR845 in Dialysis-Related Pruritus* 12 * Maruishi License Agreement Japan.

13 Clinical Needs In Post-Op Pain Unmet Market Needs Multimodal analgesia (ASA and ERAS) Different MOAs to maximize analgesia Anti-inflammatory benefits vs. mu opioids Reduction in mu opioid usage and side effects Respiratory Depression Nausea / Vomiting Abuse Liability Results in better patient outcomes, decreased length of stay and reduction in overall health care costs 13

14 Surgical Database Research: Opioid-Related AEs Significantly Increase Length of Hospital Stay and Costs Mean Length of Stay Mean Total Visit Cost 10 $25 ~$10,000 Length of Stay (Days) Total Visit Cost (USD 000s) $20 $15 $10 $5 0 With ORAE Without ORAE $0 With ORAE Without ORAE Source: T. J. Gan et. al. Opioid-Related Adverse Events Increase the Length Of Stay and Drive Up Total Cost of Care in A National Database of Post-Surgical Patients ; International Anesthesia Research Society Meeting, 2012 (unmatched means based on 324,568 patients; p < ). 14

15 CLIN2002 Trial CR845 Phase 2 Hysterectomy Study: Significantly Reduced Post-Op Pain Primary FDA Endpoint Met for Acute Pain Pre-Op: Placebo CR845 Placebo CR845 Post-Op: Placebo Placebo CR845 CR845 0 Lower Pain Intensity Summed Pain Intensity Difference (SPID), 0 24 Hours p = % -63% p = % p = SPID 0-24 (mitt), Mean ± SEM. N = 71, 19, 71 and 20, respectively.

16 CR845 Phase 2 Bunionectomy Trial: Reduced Post-Operative Bunionectomy Pain CLIN2003 Trial Completer Population mitt Population Summed Pain Intensity Difference (SPID) SPID 0-24 SPID 0-36 SPID 0-48 * * * Summed Pain Intensity Difference (SPID) SPID 0-24 SPID 0-36 SPID 0-48 Placebo (n=15) CR845 (n=26) Placebo (n=17) CR845 (n=33) 16 *p,0.05,one-sided ANOVA with Treatment Group as a Main Effect.

17 CR845 Provides Post-operative Analgesia and Reduces Post-operative Nausea and Vomiting 60% 50% Incidence of N/V across all Post-Op. Phase 2 Trials* 55% 57% P = % 30% 34% 36% 20% 10% 12% 4% 0% Nausea Vomiting N/V Combined Placebo CR845 (n=152) (n=216) * Three Phase 2 post-operative pain studies: CLIN2001 (laparoscopic hysterectomy), CLIN2002 (laparoscopic hysterectomy), CLIN2003 (bunionectomy) 17

18 Ongoing CLIN3001 Post-Op Pain Adaptive Phase 3 Abdominal Surgeries: Pre- and Post-Surgical Treatment CLIN3001 Trial CR845 : 1 & 0.5ug/kg or Placebo Primary: Pain Intensity 0-24hrs q6hrs 0 24 h Abdominal Surgery: Secondary: Nausea & Vomiting 18 Multi-center: 25 U.S. hospital sites, max. 450 patients Randomized, double-blind Endpoints: Pain intensity 0-24hrs Nausea & Vomiting Rescue medication used (IV morphine) Global evaluation of medication

19 Pruritus And Pain Common Pathway 19 Source: Paus et al.,j Clin Inv, 2006.

20 CKD-Associated Pruritus Chronic itching experienced by ESRD (End-Stage-Renal- Disease) patients Reduces quality of life, increases negative health outcomes, mortality and cost Unresponsive to conventional itch medications: antihistamines, steroids Most common on back, abdomen & arms Typically bilateral Excoriations in severe cases 20

21 Patient Populations of CKD-Associated Pruritus in US Non-Dialysis 9.3M patients diagnosed with CKD in US 1 32% of patients treated for pruritus 1 Potential patient population of 3.0M Dialysis 456K patients on dialysis in US % of patients with pruritus 3,4 Potential patient population of K IMS Health, Pruritus Market Landscape Analysis, October ESRD Patients in A Global Perspective. Fresenius Medical Care Pisoni RL, Wikstrom B, Elder SJ, et al. Pruritus in haemodialysis patients: international results from the Dialysis Outcomes and Practice Patterns Study (DOPPS). Nephrol Dial Transplant. 2006;21: Ramakrishnan et al. Clinical characteristics and outcomes of end-stage renal disease patients with self-reported pruritus symptoms. International Journal of Nephrology and Renovascular Disease. 2014:7 1 12

22 Uremic Pruritus POC Phase 2 - Study Design Screening Day -21 to -7 Run-In Day -7 to -1 Treatment Week 1 Day 1 to 8 Treatment Week 2 Day 9 to 15 1, Report daily pruritus for 6 weeks prior to Screening AND 2. Self-Categorization as type B or C Mean VAS >40 mm for 8 of 14 scores (Baseline) Daily Itch Vas (Day and Night) Primary Endpoint Mean VAS for Day (Week 2) Secondary Endpoints Skindex-10 Itch MOS Predose Day 8 Day U.S. Sites: Randomized, double-blind, placebo-controlled 22

23 CR845 Significantly Reduced Itch Intensity Placebo CR845 1 µg/kg -54% p = Mean change from baseline (Run-in) to the average of Week 2 scores (Day 12 through 15) 23 Mean ± SEM MITT population.

24 Itch Intensity Over 2 Weeks Of Treatment 24 Reduction of itch intensity for patients treated with CR845 beginning on Week 1 that continues to improve through Week 2. Patients on placebo show initial improvement that plateaus

25 CR845: Significant Reduction In Worst Itch Intensity Reported For Both Day And Night Time By Week CR845 (n=33) Placebo (n=31) Day % p = % 40 p = Run-In Week 1 Week 2 CR845 (n=33) Placebo (n=31) Night % p = % p = Run-In Week 1 Week 2

26 Example Individual Patient VAS Profile Placebo CR845 Placebo 26

27 CR845 Improves Itch-Related Quality Of Life Skindex-10 is a validated scale that consists of 10 questions used to evaluate how the patient s itch affects their Quality of Life Skindex-10 Score C hange fro m B aseline (Day 15) Placebo CR845 1 µg/kg -71% p = Mean ± SEM MITT population.

28 CR845 Improves Itch-Related Quality Of Life Scores Across All Skindex 10 Domains Skindex-10 Score Change from Baseline (Day 15) Disease Domain -55% p = Mood/Emotional Distress -60% p = Social Functioning -120% p = CR845 (N = 33) Placebo (N = 31) After 2 weeks of treatment, patients reported trend for improvements across all aspects of their Quality of Life Trend in MOS Scale for patients treated with CR845 on overall improvement in their sleep: - 62% compared to placebo (non-statistical) 28 Mean ± SEM MITT.

29 Ongoing CR845-CLIN2101 Phase 2/3 Study Design 40 U.S. Sites: Randomized, double-blind, placebo-controlled Design: Study consists of two parts Part A: 3 CR845 doses vs placebo; 160 patients Screening Period: Two (2) weeks Treatment Period: Eight (8) weeks Part B: 1 CR845 dose vs placebo; 240 patients Screening Period: Two (2) weeks Treatment Period: Twelve (12) weeks Primary Endpoint Change from baseline with respect to the weekly mean of the daily 24-hour Worst Itching Intensity NRS score during Week 8 (Part A) or Week 12 (Part B) of the Treatment Period. 29

30 Oral CR845 Significantly Expands Commercial Opportunity Acute Pain Chronic Pain/ Inflammatory Diseases Hospital-Discharge Osteoarthritis/ Pruritus Safety, PK & Effectiveness Phase 2a OA Trial Complete 30 Single-Blind, Multiple Ascending-Dose, with repeat doses of CR845 over a two-week period in patients with moderate-tosevere pain ( 4) associated with OA. Four treatment arms: oral b.i.d. doses: 0.25mg 0.5mg, 1mg & 5mg tablets (80 patients; 5 US Sites)

31 Study CR845-CLIN2001-PO CR845 Plasma Concentration Over Time Mean CR845 Conc (pg/ml) Day 1 Day Hours C1: 0.25 mg C2: 0.5 mg C3: 1 mg C4: 5 mg 31

32 Study CR845-CLIN2001-PO Mean NRS Score by Cohort and Treatment Day LOCF 7 Cohort 1 Cohort 2 Cohort 3 Cohort Pain Score Cohort 1: 0.25 mgs b.i.d. Cohort 2: 0.5 mgs b.i.d. Cohort 3: 1.0 mgs b.i.d. Cohort 4: 5.0 mgs b.i.d Treatment Day 32 LOCF analysis

33 Study CR845-CLIN2001-PO Area Under the Curve (AUC) for Pain NRS: Days 1 to AUC for Pain (NRS) p = Cohorts 1 to 3 ( mg) Cohort 4 (5 mg) 33

34 Study CR845-CLIN2001-PO Rescue Medication Use Over Time Tablets per Week p = 0.03 p = Cohort 1-3 (.25mg,.5mg, 1mg) Cohort 4 (5mg) Baseline Week 1 Week 2 59% of Patients in Cohort 4 (5mg) Did Not Require Any Rescue Medication, Week 2 34

35 Study CR845-CLIN2001-PO Patient Global Assessment (PGA) % of Patients Where PGA = Very Much Improved and Much Improved 35 Percent Responders 60% 50% 40% 30% 20% 10% 0% p=0.02 Cohort 1 (.25mg) Cohort 2 (.5mg) Cohort 3 (1mg) Cohort 4 (5mg) Week 1 Week 2 (Cochran-Mantel-Haenszel test, p=0.02, 2-sided).

36 Comparative Efficacy in NRS Pain in OA Studies Drug Time Change from BL % Change from BL Naproxen 1 2 weeks % Celecoxib 1 2 weeks % Duloxetine 2 (30mg/day) 2 weeks % Oxycodone CR 3 12 weeks % CR845 (1mg) 2 weeks % CR845 (5mg) 2 weeks % 36 1 Benson, et. al. Treatment of Osteoarthritis with Celecoxib, a Cyclooxygenase-2 Inhibitor: a Randomized Controlled Trial. Mayo Clin Proc. 1999;74: Chappell et. Al., Duloxetine, a centrally acting analgesic, in the treatment of patients with osteoarthritis knee pain: A 13-week, randomized, placebo-controlled trial. PAIN. Volume 146, Issue 3, 5 December 2009, Pages Markenson, et. al., Treatment of Persistent Pain Associated With Osteoarthritis With Controlled-Release Oxycodone Tablets in a Randomized Controlled Clinical Trial. Clin J Pain Volume 21, Number 6, November/December 2005.

37 Planned Osteoarthritis Phase 2b Trial CLIN2002-PO: Protocol Overview Main Study Objective Efficacy of oral CR845 in patients with osteoarthritis (OA) of the hip or knee Safety and tolerability over 8 week period in patients Study Design Double-blind, with repeat doses of CR845 over an eight week treatment period in patients with moderate-to-severe pain ( 5) associated with OA. Four treatment arms: oral b.i.d. doses: placebo, 3 CR845 tablet strengths Patients ~330 male and female patients ~15 U.S. sites 37

38 Cara: Financial Highlights As of June 30th, 2016 Cash and Marketable Securities Net loss Q1, 2016 $84.8M $13.1M Shares outstanding 27,282,863 IPO completed 2/5/2014 $56M: Follow-On Offering 7/29/15 - $75M 38