CR845 s Potential for Chronic Kidney Disease-Associated Pruritus

Transcription

1 s Potential for Chronic Kidney Disease-Associated Pruritus

2 Forward Looking Statements. This presentation contains certain forward-looking statements within the meaning of the Private Securities Litigation Reform Act of Examples of these forward-looking statements include statements concerning: the expected timing of the initiation of Part B of the Phase 2/3 trial for I.V. for uremic pruritus; the timing of meetings with the FDA and any initiation of enrollment of a Phase 3 trial for I.V. for uremic pruritus: the ability of these trials to demonstrate an extended patient benefit; the potential for I.V. to be a therapeutic option for uremic pruritus; the expected timing for announcement of the results of other ongoing and planned clinical trials; future regulatory and development milestones for the Company's product candidates; and the size of the markets that are potentially addressable by the Company s product candidates. 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, 2016, 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. The Company undertakes 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 Agenda 8:30-8:40am 8:40-9:00am 9:00-9:30am 9:30-9:50am 9:50-10:00am 10:00-10:30am Welcome & Introductions; Pipeline Overview Derek Chalmers, Ph.D., D.Sc., President and Chief Executive Officer, Cara Therapeutics CKD-Associated Pruritus Prevalence and Pathogenesis Shayan Shirazian, M.D., Nephrologist and Clinical Researcher, Winthrop- University Hospital and Stony Brook University School of Medicine Review of Phase 2/3 CKD-Associated Pruritus Data Joseph Stauffer, DO, MBA, Chief Medical Officer, Cara Therapeutics s Potential to Improve Current Standard of Care for Patients with CKD-Associated Pruritus Steven Zeig, M.D., Principal Investigator, Pines Clinical Research Inc., Hollywood, FL. Path Forward & Brief Closing Remarks Derek Chalmers, Ph.D., D.Sc., President and Chief Executive Officer, Cara Therapeutics Q&A Derek Chalmers, Ph.D., D.Sc. CEO Joseph Stauffer, DO, MBA CMO Shayan Shirazian, M.D. - Nephrologist Steven Zeig, M.D. - Nephrologist 3 Frederique Menzaghi, Ph.D. VP R&D

4 Cara: Developing First-in-Class Peripheral Opioid Novel opioids designed to function without traditional opioid side effects Kappa opioid agonists with unique pharmacology and chemotype NCEs with patent protection through at least 2027 MOA: Anti-Nociceptive (1) /Anti-Inflammatory & Anti-Pruritic Completed Part A Phase 2/3 Trial in CKD-associated pruritus Positive Multi-Dose Results: Reduction in Worst Itch & improved Quality of Life (QoL) I.V. - Phase 3 Trial in Post-Op Pain Interim Assess. Q2, 2017 Positive results in three Phase 2 trials in over 250 patients Oral Phase 2b Trial In Osteoarthritis Topline Q2, 2017 Positive Phase 2a results: Dose-related reduction in worst joint pain score 4 1. Blocking the detection of pain or injurious stimulus by sensory neurons

5 Effects Mediated by Peripheral κ-opioid Receptors Novel Chemical Class hydrophilic tetrapeptide KOR acts at on: Immune cells: anti-inflammatory KOR in the brain: dysphoria and hallucinations DRG: antinociceptive DRG=dorsal root ganglion Sensory nerves: anti-nociceptive and anti-pruritic 5

6 Human Abuse Liability Trial: Drug Liking Over 8-Hour Test Session Overall drug liking VAS mean +1 SE Strong liking Mixed-model repeated measures analysis of drug liking 100 Neither like nor dislike * P<0.0001* * * P<0.0001* P<0.0001* Strong disliking 0 Placebo *p<0.001 Comparisons to pentazocine (Schedule IV) 5 μg/kg 15 μg/kg Pentazocine 0.5 mg/kg

7 Pruritus And Pain Common Pathway 7 Source: Paus et al.,j Clin Inv, 2006.

8 Chronic Kidney Disease-Associated Pruritus Prevalence and Pathogenesis Shayan Shirazian, M.D. Attending Nephrologist Director of Nephrology Clinical Research Program Director, Nephrology Fellowship Winthrop-University Hospital Assistant Professor of Medicine, Stony Brook University School of Medicine

9 Definition Chronic Kidney Disease associated Pruritus (CKD-aP) also known as Uremic Pruritus (UP) has been defined as itching directly related to kidney disease without another condition explaining itch Very common: Itching in end stage renal disease (ESRD) should be considered related to UP unless there is a clear alternative explanation Occurs with dry skin in 50%-85% of patients Superimposed complications of itching including impetigo, linear crusts, papules, ulcerations, and prurigo nodularis are commonly seen 9

10 Patient Populations of CKD-Associated Pruritus: US Non-Dialysis 12.2M patients diagnosed with CKD in US 1 32% of patients treated for pruritus 2 Potential patient population of 4.0M Dialysis 456K patients on dialysis in US 3 Up to 70% of patients with pruritus 4,5 Potential patient population of K Coresh et al. JAMA (2007) 298: 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

11 CKD-aP Prevalence: US 11 Pisoni et al. NDT. (2006) 12:

12 Example of Anatomical Distribution of Uremic Pruritus (Data from -CLIN2005 clinical study) 12 Mettang et al. Kidney Int. (2015) 87,

13 Outcomes of CKD-Associated Pruritus Dialysis patients have worse quality of life than patients with any other chronic illness including lung disease, congestive heart failure or cancer (Fishbane et al. NDT 2001) Itching severity is associated with worse QOL scores including mental and physical scores (Pisoni et al. NDT. (2006) 12: , Mathur et al. CJASN (2010) 5: ) CKD-aP is associated with poor sleep quality (Shirazian et al. Int J Nephrol Renovasc Dis. (2017) 10:11-26) CKD-aP is associated with depression (Pisoni et al. NDT. (2006) 12: , Mathur et al. CJASN (2010) 5: ) CKD-aP is associated with a 21% higher adjusted mortality risk (Pisoni et al. NDT. (2006) 12: ) 13

14 Etiology and Pathophysiology Immune mediated Ultraviolet light Gamma-linolenic acid Evening primrose oil Nicotinamide Sericin cream Tacrolimus cream Pentoxifylline Ergocalciferol Thalidmoide Opioid imbalance Naloxone Naltrexone Nalbuphine Nalfurafine Acupuncture Peripheral Neuropathy Gapapentin Pregabalin Capsacin Pramoxine CKD- Associated Pruritus Histamine Release Diphenhydramine Atarax Loratadine Cetirizine Cromolyn sodium Ketotifen Zinc sulfate Other Nicergoline Seritonin receptor antagonists: Ondansetron, Tropisetron, Granisetron 14 Xerosis Glycerol 15% and paraffin 10% Emollient Creams Aqueous gels Physiological lipids and endogenous cannabinoids Uremic toxin Increased dialysis intensity High-flux membranes Synthetic membranes Activated charcoal Cholestyramine Hyperparathyroidism Parathyroidectomy Cinacalcet Active vitamin D analogs Low magnesium or calcium dialysate Shirazian et al. Int J Nephrol Renovasc Dis. (2017) 10:11-26

15 Etiology and Pathophysiology (cont.) Multi-factorial Abnormalities related to uremia, including elevated calcium, phosphorus and parathyroid hormone Peripheral neuropathy Immune system systemic inflammation Increased levels serum CRP, IL-6, IL-2 Endogenous Opioid dysregulation β-endorphin-mu and Dynorphin-A-kappa activation of the mu opioid receptor results in itching while antagonists can inhibit itching Pathophysiology Supporting the Use of 15

16 Increased Levels of Inflammatory Markers in CKD-Associated Pruritus Kimmel et al. NDT (2006) 21:

17 Prior Trials of Medications for CKD-aP Trials limited by small sample sizes and poor design Currently used treatments, i.e. gabapentin, have serious side effects To date there are no FDA approved medications to treat CKD-aP 17 Shirazian et al. Int J Nephrol Renovasc Dis. (2017) 10:11-26

18 Newer Treatments The current standard of care for uremic pruritus is to ensure patients are meeting defined goals for dialysis efficiency and mineral and bone disease treatment, and to treat dry skin if present. If pruritus persists, there is no current standard of care treatment. may change this. is a potent and selective kappa receptor agonist that has demonstrated modulation of itch, pain, and inflammation. Unlike other kappa receptor agonists it has demonstrated limited CNS diffusion and preferentially activates peripheral kappa receptors limiting sedating side effects. 18

19 -CLIN2101: Part A A Two-Part, Phase 2/3, Multicenter, Double-blind, Randomized, Placebocontrolled Study to Evaluate the Safety and Efficacy of Intravenous in Hemodialysis Patients with Moderate-to-Severe Pruritus Study Results

20 -CLIN2101-A Study Design Randomized, Double-Blind, Placebo-Controlled Study in Hemodialysis Patients with Moderate-to Severe Pruritus Doses of IV evaluated: 0.5, 1.0 and 1.5 mcg/kg 8-week treatment period Dosing after each dialysis (3 times per week) Multi-center: 33 U.S. sites 174 patients randomized Placebo: 45 :

21 Patient Population: Demographics Subject demographics well balanced across all treatment groups Gender Female Male Age, Mean (range) Race Black or African American White Placebo (N=45) n (%) 17 (37.8) 28 (62.2) 59.0 (27-84) 25 (55.6) 16 (35.6) 0.5 mcg/kg (N=44) n (%) 18 (40.9) 26 (59.1) 57.9 (29-80) 24 (54.5) 17 (38.6) 1.0 mcg/kg (N=41) n (%) 18 (43.9) 23 (56.1) 58.2 (26-84) 22 (53.7) 19 (46.3) 1.5 mcg/kg (N=44) n (%) 16 (36.4) 28 (63.6) 54.1 (29-74) 31 (70.5) 10 (22.7) 21 9% of Patients 75 years old Average time on chronic dialysis = 5.8 years Average time with pruritus = 4.4 years

22 Baseline Disease Characteristics: Etiology of Patients Chronic Kidney Disease Primary Causes of Renal Failure Placebo (N= 45) 0.5 mcg/kg (N= 44) 1.0 mcg/kg (N= 41) 1.5 mcg/kg (N= 44) Diabetes 21 (46.7%) 24 (54.5%) 20 (48.8%) 19 (43.2%) Hypertension and Large Vessel Disease 21 (46.7%) 21 (47.7%) 20 (48.8%) 24 (54.5%) Glomerulonephritis/Vasculitis 5 (11.1%) 6 (13.6%) 4 ( 9.8%) 2 ( 4.5%) Interstitial Nephritis/Pyelonephritis 1 ( 2.2%) Cystic/Hereditary/Congenital Disease 0 2 ( 4.5%) 2 ( 4.9%) 1 ( 2.3%) Urologic ( 2.4%) 0 Unknown ( 2.3%) Other 2 ( 4.4%) 2 ( 4.5%) 4 ( 9.8%) 1 ( 2.3%) 22 The primary causes of renal failure was reflective of the US CKD population (US Renal Data System)

23 Safety Summary: Treatment-Related Adverse Events ( 5% Any Treatment Group) No Safety Findings Raised By IDMC System Organ Class Preferred Term Nervous system disorders Dizziness Headache Paraesthesia Somnolence Placebo (N=45) n (%) 1 (2.2) 0 (0.0) 0 (0.0) 1 (2.2) 0.5 mcg/kg (N=44) n (%) 4 (9.1) 0 (0.0) 1 (2.3) 1 (2.3) 1.0 mcg/kg (N=41) n (%) 2 (4.9) 3 (7.3) 1 (2.4) 2 (4.9) 1.5 mcg/kg (N=44) n (%) 2 (4.5) 0 (0.0) 3 (6.8) 4 (9.1) 23

24 Validated Worst Itching Intensity Numeric Rating Scale in Patients with Uremic Pruritus Worst Itching Intensity scale used for Primary Endpoint defined as the change in weekly average of daily 24-hour Worst itching Intensity NRS score from Baseline to Week 8 of treatment 24 24

25 -CLIN2101- A Study Design Schematic and Patient-Reported Outcomes Screening Day -14 to -1 Treatment Week 1 to Week 8 Day 1 to 57 Follow-up Day 63 *Must have completed at least 4 of 7 daily NRS scores to qualify Mean NRS >4 for Week prior to Randomization* (Baseline) Primary Endpoint Change from Baseline in Worst Itching Intensity Mean NRS for Week 8 (Day 51 to 57) Secondary/Exploratory Endpoints Change from Baseline in QOL Predose (Baseline=Day 1) Week 8 (Day 57) 25 Skindex-10 5-D Itch Scale (multidimensional) Sleep disturbance subscale (MOS) Patient Global Impression of Change Patient Global impression of Worst itch Severity 25

26 Disease Domain Mood/ Emotional Distress Social Functioning Skindex-10 Quality of Life (Used for Secondary Endpoint) Skindex-10 consists of 10 questions used to evaluate how the patient s itch affects three important domains of quality of life. During the past WEEK, how often have you been bothered by : 1. Your itching. 2. The persistence/reoccurrence of your itching. 3. The appearance of your skin from scratching. 4. Frustration about your itching. 5. Being annoyed about your itching. 6. Feeling depressed about your itching. 7. Feeling embarrassed about your itching. 8. The effects of your itching on your interactions with others. 9. The effects of your itching on your desire to be with people. 10.The effect of your itching making it hard to work or do what you enjoy. 0 = Never bothered 6 = Always bothered 26 26

27 Baseline Scores for Worst Itch Intensity (NRS) and Quality of Life (Skindex-10) Baseline Scores Comparable Across All Treatment Groups Mean ± SD Placebo (N=45) 0.5 mcg/kg (N=44) 1.0 mcg/kg (N=41) 1.5 mcg/kg (N=44) NRS Skindex (1.50) 35.5 (12.37) 7.1 (1.35) 35.1 (13.43) 6.7 (1.47) 33.1 (11.69) 6.7 (1.42) 32.4 (12.35) NRS Scale ranges from 0-10 Skindex-10 ranges from

28 NRS Itch Change from Baseline Skindex-10 Score Change from Baseline -CLIN2101-A Primary and Secondary Endpoints Reduced itch (NRS) and improved Quality of Life (Skindex-10) at end of the 8 week treatment period Worst Itch Intensity Quality of Life 0 Placebo 0 Placebo % -15 p = % p = Pearson s Correlation of the Worst Itching Intensity NRS with Skindex-10: r=0.67, p< Full Analysis Population: all randomized patients who received at least 1 dose of double-blind study drug. LS Mean ± SEM Full Analysis Population 28

29 Skindex-10 Improved Quality of Life (Skindex-10) Measures 0 Disease Domain Mood / Emotional Distress Social Functioning Change from Baseline p < p = p = Placebo Mean ± SEM Full Analysis Population -treated Patients Exhibit Statistically Significant Improvement Across All Qol Domains 29 Baseline defined as assessments collected on Day 1 prior to first dose

30 Change in NRS Worst Itch Intensity Not Different Based on Prior Use of Anti-Itch Medications NRS Itch Change from Baseline * * With anti-itch medications Without anti-itch medications LS Mean ± SEM * p < 0.05 vs Placebo 30 42% of all patients reported prior use of anti-itch medication and were stratified prior to randomization Anti-itch medications included primarily antihistamines and corticosteroids

31 NRS Average Worst Daily Itching Time Course - Worst Itching Score (NRS) 8 (n=129) Placebo (n=45) Severe 7 6 * * * * *** ** Moderate 5 4 Mild 3 Baseline Treatment Week Mean ± SEM * p < 0.05; ** p < 0.01 *** p < vs Placebo Reduction of Worst itch intensity begins on Week 1 and continues to improve through Week 8. Patients on placebo show initial improvement that plateaus 31 Severity Bands based on Reich et al, Acta Derm Venereol 2012

32 S k i n d e x A v e r a g e T o t a l S c o r e Time Course Skindex-10 Total Score 4 0 C R ( n = ) P l a c e b o ( n = 4 5 ) 3 0 ** * *** B a s e l i n e T r e a t m e n t W e e k Mean ± SEM * p < 0.05; ** p < 0.01; *** p < vs Placebo 32

33 NRS Itch Reduced Itch Intensity Across Doses mcg/kg Change from Baseline Placebo *** * LS Mean ± SEM N = *p<0.05, ****p<0.001 vs Placebo Effect Size by Doses 0.5 mcg/kg 1 mcg/kg 1.5 mcg/kg All doses Full Analysis

34 Mean (pg/ml) All Doses of Post-Dialysis (3x/Week) : Maintenance of Receptor-Saturating Plasma Concentrations mcg/kg 1.0 mcg/kg Human Kappa Receptor K d = 140 nm = 96 pg/ml 320 pg/ml >75% occupancy Day 1 Day 5 34

35 Skindex-10 Score Change from Baseline 5D Score Change from Baseline Improvement in Quality-of-Life Measures Across All Dose Groups Skindex-10 mcg/kg 5-D Itch mcg/kg 0 Placebo Placebo ** * * -6-8 ** ** * LS Mean ± SEM * p <0.05, ** P<0.001 vs Placebo Pearson s Correlations of the Worst Itching Intensity NRS and Skindex-10 with 5-D Itch: r=0.71 and r=0.74, respectively; p< The 5-D Itch scale covers 5 domains: duration of itch/day, degree, direction (improvement/worse), disability (sleep, social, housework/errands, work/school), distribution (parts of the body)

36 Reduced Sleep Disturbance as measured by the MOS Sleep Scale Sleep Disturbance MOS Sleep Disturbance Scale Change from Baseline mcg/kg Placebo * * LS Mean ± SEM * p <0.05 vs Placebo Items contain in the Sleep Disturbance subscale: Trouble falling asleep Awaken during sleep 36 Sleep restlessness Time to fall asleep

37 Proportion of Patients We ek 8 : Analysis of Clinically Meaningful Change in Worst Itching Intensity 100 Responder Analysis at 0.5 mcg/kg Placebo (n=45) 0.5 mcg/kg (n=44) % 50% % 31% 0 10% 30% 50% 70% 90% Treatment Response 37 Analysis demonstrated change of 2 points on the Worst Itching Intensity NRS represents a clinically meaningful improvement in NRS scores (results based on distribution- and anchor-based methods, taking into account all of the results for the -CLIN2101 study, i.e., primary, secondary, and exploratory endpoints)

38 Percent of Patients (%) Patient Global Assessments of Improvement evaluated at the End of Treatment Period Percent of Patients (%) Worst Itch Severity Impression of Change * ** Placebo Placebo 38 Improvement over baseline = reduction in 24 hr itch severity (ex. Change from category moderate to mild ) Improvement = Much Improved or Very Much Improved * p < 0.05 vs Placebo ** p < 0.01 vs Placebo

39 39 CLIN2101-A: Summary Met primary and secondary endpoints reduction in itch intensity and improvement of quality of life measures Validated sustained treatment benefit over 2 months across multiple measures Demonstrated clinically meaningful effect (responder analysis) Demonstrated clinically meaningful reduction in itch intensity confirmed with statistically significant improvement across multiple Quality-of-Life measures for the 0.5 mcg/kg dose group and with all dose groups combined: 5-D Itch Scale Sleep disturbance subscale (MOS) Patient Global Impression of Change Patient Global impression of Worst itch Severity Demonstrated favorable safety profile, consistent with previous studies

40 s Potential to Improve Current Standard of Care for Patients with CKD-Associated Pruritus Steven Zeig, M.D. Principal Investigator, Pines Clinical Research Inc., Hollywood, Florida

41 Impact on Clinical Practice has demonstrated robust efficacy in clinical program to date Own experience, impressive compared to previous clinical trials Patients feel the difference Generally well tolerated Convenient dosing regimen Only dosed when patients come to dialysis Great for patient compliance 41

42 Next Steps: Initiation Phase 3 Program Initiation open-label long-term safety extension trial (2Q2017) 0.5 mcg/kg dose administered at end of each dialysis for up to 52 weeks Patients who previously participated in the Phase 2 studies - CLIN2005-B and CLIN2101-A Data from PK study of Oral to determine bioequivalent tablet strengths (2Q2017) End-of-Phase 2 meeting (3Q2017) Initiate Pivotal Phase 3 trial (4Q2017) 42