Welcome to 2021 R&D Day WEDNESDAY, APRIL 7, 2021 Forward Looking Statements Statements contained in this presentation regarding matters that are not historical facts are "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995. Examples of these forward- looking statements include statements concerning the expected timing of the enrollment and data readouts from the Company’s ongoing clinical trials, the potential results of ongoing clinical trials, timing of future regulatory and development milestones for the Company’s product candidates and potential commercialization of KORSUVA Injection for CKD-aP, the expected timeline for conducting meetings with the FDA concerning the Company’s product candidates, the potential for the Company’s product candidates to be alternatives in the therapeutic areas investigated, the Company’s expected cash reach, and the potential impact of COVID-19 on the Company’s clinical development and regulatory timelines and plans. Because such statements are subject to risks and uncertainties, actual results may differ materially from those expressed or implied by such forward-looking statements. Risks are described more fully in Cara Therapeutics’ filings with the Securities and Exchange Commission, including the “Risk Factors” section of the Company’s most recent Annual Report on Form 10-K for the year ending December 31, 2020 and its other documents subsequently filed with or furnished to the Securities and Exchange Commission. All forward-looking statements contained in this press release speak only as of the date on which they were made. Cara Therapeutics undertakes no obligation to update such statements to reflect events that occur or circumstances that exist after the date on which they were made.

2 Confidential. For internal use only. Today’s Guest KOLs

Dr. Brian S. Kim, MTR, FAAD Dr. Mark Lebwohl Co-Director, Center for the Study of and Professor and Dean for Clinical Therapeutics Sensory Disorders Chairman Emeritus, Kimberly and Eric J. Waldman Washington University School of Medicine Department of Dermatology Icahn School of Medicine at Mount Sinai; NY

3 Confidential. For internal use only. Today’s Speakers From Cara Therapeutics

Derek Chalmers, Ph.D., D.Sc. Joana Goncalves, M.D. Eric Vandal Tom Reilly Chief Executive Officer and Chief Medical Officer Senior Vice President, Chief Financial Officer President Commercial

4 Confidential. For internal use only. Agenda Introduction to Cara & Opportunities in the KORSUVA1 (Difelikefalin) Pipeline Dr. Derek Chalmers, Ph.D., D.Sc., President and CEO, Cara Therapeutics Emerging Landscape of Chronic Itch Dr. Brian Kim, M.D., Washington University School of Medicine, MO Notalgia Paresthetica: The Unmet Need in Neuropathic Pruritus Dr. Mark Lebwohl, M.D., Icahn School of Medicine at Mt. Sinai, NY KORSUVA1 (Difelikefalin) For Chronic Kidney Disease-associated Pruritus (CKD-aP) Dr. Jo Goncalves, M.D., CMO, Cara Therapeutics Commercial Opportunity for KORSUVA1 (Difelikefalin) Injection Eric Vandal, SVP of Commercial, Cara Therapeutics Oral KORSUVA1 (Difelikefalin) as a Potential Broad Anti-Pruritic Dr. Jo Goncalves, M.D., CMO, Cara Therapeutics Financial Overview Tom Reilly, CFO, Cara Therapeutics

Q&A Session

5 Confidential.1The FDA has Forconditionally internal accepteduse only. KORSUVA™ as the trade name for difelikefalin injection. Difelikefalin injection is an investigational drug product and its safety and efficacy have not been fully evaluated by any regulatory authority. Introduction to Cara Therapeutics & Opportunities in the Korsuva(1) (Difelikefalin)Pipeline DR. DEREK CHALMERS PH.D., D.SC. President and CEO Cara Therapeutics

1The FDA has conditionally accepted KORSUVA™ as the trade name for difelikefalin injection. Difelikefalin injection is an investigational drug product and its safety and efficacy have not been fully evaluated by any regulatory authority. Creating life-changing pruritus therapeutics

Cara Therapeutics is a close-knit group of scientists, medical experts, and industry leaders deeply committed to the science of changing lives. Our proprietary, novel therapies are poised to make a significant impact for the millions who have been overlooked.

Our Mission: Our Vision: Transform the way pruritus is treated to bring Inspire new ways of thinking about pruritus quality to the lives of those who suffer. treatment to elevate the standard of care far beyond what has been considered possible. The Far-Reaching Impact of Pruritus

Chronic Kidney Disease (CKD) Pruritus occurs in both patients on hemodialysis and those with CKD not yet on dialysis ~40-50%

Chronic Liver Disease (CLD) Patients with CLD, especially cholestatic liver disease experience significant pruritus ~20-30%

Atopic (AD) Pruritus is a defining symptom of AD ~100%

U.S. Patients Treated for Pruritus: Notalgia Paresthetica (NP) >20 Million Pruritus is the defining symptom of NP ~100% SCRIPTS ANNUALLY1

8 Source:Confidential. 1IQVIA For Analysis, internal 2013. use only. Large and Addressable TAM Across Multiple Therapeutics Areas

Prevalent U.S. patient populations1 A significant portion of patients with CLD are often undiagnosed and its real prevalence is underestimated

Atopic Dermatitis (AD): Chronic Liver ~31mm Patients Disease (CLD): 2 Chronic Kidney ~7mm Disease (CKD): Patients

CAGR TAM: $10.4bn Patients ~30mm TAM: $12.8bn CAGR3: 13.2% CAGR5: 9.7%

TAM: $12.4bn CAGR4: 8.4%

2020 Estimated TAM

9 Confidential.Source: Market For Watch, internal Market use Data only. Forecast, ChildStats.gov, NKF. 1. Based on U.S. total population as of 2013; 2. Represents diagnosed patient population only; 3. From 2020 – 2025; 4. From 2020 – 2023; 5. From 2020 – 2027. KORSUVA1 (Difelikefalin) Directly Blocks Pruritus Sensory Neurons K K K K

Macrophages Keratinocytes Mast Cells Tissue Injury T cells

KORSUVA

TNF R RTK TGR5 ETA 5HT PAR IL-31RA Mrgprs TLR3/7 R 2 H1 TRPV1 TRPA1 OSMR

K

Kappa Pruritus Receptor

10 Confidential.Source: Adapted For from internal Pflugers use Arch only. . 2013 December ; 465(12): doi:10.1007/s00424-013-1284-2. 1The FDA has conditionally accepted KORSUVA™ as the trade name for difelikefalin injection. Difelikefalin injection is an investigational drug product and its safety and efficacy have not been fully evaluated by any regulatory authority. Cara Therapeutics Pipeline

STAGE OF DEVELOPMENT Commercial Rights Program Indication Phase 1 Phase 2 Phase 3 NDA Review (ex-Japan and S. Korea)^

KORSUVATM US- Vifor* Pruritus CKD-HD** Injection EU/Other- VFMCRP# Oral Pruritus CKD (III-V) Cara KORSUVA™ Oral Pruritus Atopic Cara KORSUVA™ Dermatitis Oral Pruritus PBC Cara KORSUVA™ Oral Pruritus in NP Cara KORSUVA™

. ^ Commercialization rights to CR845 in defined indications - Japan: Maruishi Pharma; South Korea: CKD Pharma. ** Breakthrough Designation for IV CR845 for Pruritus CKD-HD; Q1 2021 NDA accepted with priority review. # VFMCRP and Cara have rights to promote in Fresenius Medical Care dialysis clinics in the US under a profit share 11 agreement.Confidential. * Vifor For hasinternal commercial use only. rights in Non-US Fresenius clinics under a profit-share arrangement. CKD-HD: Chronic Kidney Disease- Hemodialysis; ; PBC: Primary Biliary Cholangitis; NP: Notalgia Paresthetica KORSUVA1 (Difelikefalin) Development

Difelikefalin Phase 3 Difelikefalin Difelikefalin Difelikefalin Phase 1/2 Injection IND KALM-1, Injection Injection Injection CKD-aP Filing HD KALM-2 NDA FDA Planned Planned HD Complete Patients US/Global Submitted U.S. Launch EU Launch

2014 2016 2018 2020 2021 2022

Oral Oral Oral Oral Difelikefalin Difelikefalin Difelikefalin Difelikefalin Planned Phase 2 IND Filing Phase 2 Phase 3: CKD-aP AD, PBC & CKD-aP CKD-aP & Atopic Derm NP

12 Confidential.1The FDA has Forconditionally internal accepteduse only. KORSUVA™ as the trade name for difelikefalin injection. Difelikefalin injection is an investigational drug product and its safety and efficacy have not been fully evaluated by any regulatory authority. The Emerging Landscape Of Chronic Itch BRIAN S. KIM, MD, MTR, FAAD Co-Director, Center for the Study of Itch and Sensory Disorders Washington University School of Medicine

@itchdoctor What is Itch?

Itch An uncomfortable sensation on the skin that causes a desire to scratch

Pain Physical suffering or discomfort caused by illness or injury

14 Confidential. For internal use only. The Problem and the Unmet Need

• Chronic itch affects >15% of the population

• Negative impact on quality of life comparable to chronic

• Incidence is increasing

• No FDA-approved medications

15 Confidential. For internal use only. Itch May Be the Most Common Medical Symptom

Dermatologic Medication-induced • (AD), , • , checkpoint inhibitors chronic , lichen planus, Neurologic nodularis, psoriasis • Shingles, disc herniation, notalgia Infection paresthetica • HIV, mites/parasites Systemic Malignancy • Kidney and liver disease • Polycythemia vera, leukemia, lymphoma Idiopathic • Chronic pruritus of unknown origin (CPUO)

16 Confidential. For internal use only. The Opportunity in Chronic Itch

• Large population of discouraged patients

• Accessible population of 50 million in U.S.

• Discovery of potent itch-specific pathways

• Billions spent annually on drugs with no proven efficacy • >$2 billion annually on alone for itch

17 Source:Confidential. IMS Health For internal use only. What is the Biology of Itch?

Skin DRG Spinal cord Brain (Input) (Transduction) (Processing) (Perception)

Interneuron Projection neuron Histamine Sensory neuron

18 Source:Confidential. IMS IMS Health HealthFor internal use only. Misconception: Itch Is a Mild Form of Pain

Low intensity

Sensory neuron Itch

High intensity

Sensory neuron Pain

19 Source:Confidential. Max von For Frey internal 1922 use only. Atopic Dermatitis (AD) as a Classic Chronic Itch Disorder

• High incidence, costly

• Therapeutic options limited

• Negative impact on quality of life

• Itch is the central symptom

20 PhotoConfidential. courtesy For of William internal James, use only. M.D. Andrews’ Disease of the Skin Atlas 2018 Conventional Paradigm of Atopic Dermatitis Pathogenesis

Immune Cell Inflamed skin

JAK

STAT

Cytokines

21 Confidential. For internal use only. Discovery of Novel Itch Targets in the Nervous System

22 Confidential.Source: Oetjen For et al. internal Cell 2017. use only. New Itch-Centric Paradigm of Atopic Dermatitis

Immune Cell Sensory Neuron

JAK

STAT JAK

STAT

TRP Channel

23 Confidential. For internal use only. Itch is Emerging as Central Focus of Atopic Dermatitis

24 Confidential. For internal use only. Primary Itch Disorders Becoming Recognized

Prurigo Nodularis Notalgia Paresthetica

25 Confidential.Source: Mülkoğlu For and internal Nacır useBMC only. Neurology 2020. Breakthrough in

26 Confidential. For internal use only. What is the Mechanism of Action of Difelikefalin?

Skin DRG Spinal cord (Input) (Transduction) (Processing)

JAK1 Interneuron Itch stimuli Itch Sensory neuron

Difelikefalin Sensory neuron

27 Confidential. For internal use only. How is Difelikefalin Different?

Primary Primary Inflammatory Itch Neurogenic Itch

Anti-inflammatory agents: Neuromodulatory agents: • Abrocitinib • • Baricitinib Scabetic Itch • Neurontin • Delgocitinib Chronic Pruritus of • Aprepitant • Dupilumab Unknown Origin • (Japan) • Lebrikizumab • Postherpetic Itch • Nemolizumab Atopic Dermatitis Itch • Difelikefalin • Ruxolitinib Prurigo Nodularis • Tralokinumab • Upadacitinib Dry Skin Itch Notalgia Paresthetica

Uremic Pruritus Insect Bite Itch Scalp Pruritus

28 Confidential. For internal use only. Itch is a Broad Medical Landscape for New Therapies

29 Confidential. For internal use only. Notalgia Paresthetica: Unmet Need in Neuropathic Pruritus DR. MARK LEBWOHL Professor and Dean for Clinical Therapeutics Chairman Emeritus, Kimberly and Eric J. Waldman Department of Dermatology Icahn School of Medicine at Mount Sinai; NY Neuropathic Itch

• Neuropathic itch syndromes ~ 8% of chronic pruritus cases ▪ Disturbances at any level of the somatosensory system (cervical, lumbar, sacral) ▪ Neural hypersensitivity and allokinesis ▪ Mu receptor (e.g., ) exacerbate itch

31 Confidential.Source: Weisshaar For internal et al. European use only. S2k Guideline on Chronic Pruritus. Acta DV April 2019; 99(5): 469-506. Pereira Manuel et al ActaDV 2018; 98:82-88. Hachisuka et al Pain 2018; 159(3): 603-609. Notalgia Paresthetica

• Likely mechanical irritation along the spinal cord • Believed to be caused by compression of the dorsal branches Notalgia of the spinal nerves (T2-T6) and Paresthetica leads to circumscribed pruritus between the scapulae • Under the scapulae, usually unilateral but occasionally bilateral

32 Confidential.Source: Weisshaar For internal et al. European use only. S2k Guideline on Chronic Pruritus. Acta DV April 2019; 99(5): 469-506. Pereira Manuel et al ActaDV 2018; 98:82-88. Hachisuka et al Pain 2018; 159(3): 603-609. Notalgia Paresthetica Epidemiology

• Believed to be relatively common but almost certainly underdiagnosed ▪ The reason the back scratcher was invented ▪ Yet only a small number of reports are published

• Higher in women than men

• Occurs in mid to late adulthood

33 Source:Confidential. Howard For et internalal 2017 Internationaluse only. Journal of Dermatol 57, 388-392 Notalgia Paresthetica Clinical Presentation

• Symptoms: ▪ Chronic, intermittent, paroxysmal pruritus in the subscapular and paravertebral region with periodic remissions and exacerbations ▪ Often accompanied by pain, hyperesthesia and other paresthesias ▪ May be unilateral or bilateral • Condition lasts multiple years, with mean duration between 21 months and 3 years • Diagnosed clinically • Differential diagnoses that should be excluded: pigmented contact dermatitis, parapsoriasis, neurodermatitis, cutaneous amyloidosis

34 Source:Confidential. Howard For et internalal 2017 Internationaluse only. Journal of Dermatol 57, 388-392 Notalgia Paresthetica Treatment

• Often resistant to multiple therapies • Conventional therapies (i.e., antihistamines, topical ) show poor effect • commonly used as first line treatment by dermatologists • Other anecdotal off-label therapies (no robust clinical studies):

● Topical ● Surgical decompression ● Spinal manipulation ● Tacrolimus ● Paravertebral local blocks ● Physical therapy ● Intralesional steroids ● Transcutaneous electrical ● Osteopathic ● Botulinum toxin A nerve stimulation (TENS) manipulative therapy ● Gabapentin ● Electrical Muscle Stimulation ● Oxcarbazepine (EMS) ● Acupuncture ● ● UV-B ● Cryotherapy

35 Source:Confidential. Howard For et internalal 2017 Internationaluse only. Journal of Dermatol 57, 388-392 KORSUVA1 (Difelikefalin) Injection for Dialysis Patients DR. JO GONCALVES Chief Medical Officer Cara Therapeutics

1The FDA has conditionally accepted KORSUVA™ as the trade name for difelikefalin injection. Difelikefalin injection is an investigational drug product and its safety and efficacy have not been fully evaluated by any regulatory authority. CKD-associated Pruritus (CKD-aP) in Patients Undergoing Hemodialysis (HD) xtreme discomfort th at can persist both day and night

xtreme discomfort th at can persist both day and night

Patients on hemodialysis

20-40% 60% CKD-aP is Have CKD-aP moderate to severe

CKD-associated pruritus CKD-aP can begin at any point CKD-aP is under-reported, (CKD-aP): a serious condition in CKD, but its prevalence causing the condition to be defined by chronic itch that is and severity increase across dramatically underestimated caused by the underlying CKD the stages of CKD in its prevalence and impact

37 Source:Confidential. Pisoni Foret al. internal Nephrol use Dial only. Transplant (2006); Rayner et al. CJASN (2017); Ramakrishnan et al. Int J Nephrol Renovasc Dis (2014) Recognizing the Signs and Symptoms Of CKD-aP

• CKD-aP affects CKD patients across all ages, ethnicities, and genders

• Patients with CKD-aP report uncomfortable itch that often persists both day and night

• In contrast to dermatological pruritus, primary skin lesions are not observed

• However, some patients with CKD-aP will scratch their skin to the point of visible skin damage

• CKD-aP adds to the burden of dialysis patients and reduces their quality of life.

38 Source:Confidential. Pisoni Foret al. internal Nephrol use Dial only. Transplant (2006); Rayner et al. CJASN (2017); Ramakrishnan et al. Int J Nephrol Renovasc Dis (2014); Mettang et al. Kidney Int (2015) Cara Therapeutics has Conducted the Largest Worldwide Clinical Development Program in HD Patients With CKD-aP

KALM-1 trial (US) KALM-2 trial (Global) Open-label long- term safety studies Completed April 2019 Completed March 2020 (US/Global) n=189 DFK, n=189 placebo n=236 DFK, n=237 placebo

• > 1,550 hemodialysis subjects exposed to Difelikefalin.

• KALM-1 efficacy and safety data published in the New England Journal of Medicine (Fishbane, 2019)

• Difelikefalin NDA accepted with priority review, PDUFA date August 23, 2021

39 Confidential.Source: Fishbane For et internal al. NEJM use (2019) only. KALM-1/2: General Pivotal Study Design Endpoints Week 12 SCREEN 1:1 RANDOMIZATION END OF TREATMENT Primary

RUN-IN INTRAVENOUS BOLUS TREATMENT ⚫ Proportion of subjects achieving ≥3 point improvement from baseline in KORSUVA1 (Difelikefalin) 0.5 mcg/kg weekly mean of daily worst after each hemodialysis session 52 Week itching intensity NRS (WI- Open-Label NRS) Extension Secondary Placebo ⚫ Proportion of subjects achieving after each hemodialysis session ≥4-point improvement in WI- NRS

⚫ Change from baseline in itch- 7 Days 12 Weeks related Quality of Life as measured by Skindex-10 and Subjects Undergoing Hemodialysis 5-D Itch questionnaires With Moderate-to-Severe Pruritus (WI-NRS > 4 or ≥ 5) ⚫ Safety assessments

40 Confidential.1The FDA has Forconditionally internal accepteduse only. KORSUVA™ as the trade name for difelikefalin injection. Difelikefalin injection is an investigational drug product and its safety and efficacy have not been fully evaluated by any regulatory authority. Primary Endpoint: ≥3 point improvement WI-NRS (Week 12)

U.S. KALM-1 Trial Global KALM-2 Trial

P = 0.020 P = 0.00002 60% 60%

54% 51% 40% 40% 42%

20% 28% 20%

0% 0% Placebo (N = 189) Difelikefalin (N = 189) Placebo (N = 236) Difelikefalin (N = 237)

41 Confidential.Estimated percentage For internal & P-value use only.based on a logistic regression model with terms for treatment group, baseline WI-NRS score, region and strata. Missing data imputed using multiple imputation (MI) under missing at random (MAR) assumption ≥3-point Improvement in WI-NRS by Baseline Use of Anti-itch Medication

(KALM-1 and KALM-2 Pooled)

Baseline Use of Anti-itch Medication No Baseline Use of Anti-itch Medication

P = 0.002 P < 0.001 60% 60%

56% 40% 48% 40%

35% 34%

20% 20%

0% 0% Placebo (N=163) Difelikefalin (N=159) Placebo (N=262) Difelikefalin (N=267)

42 Confidential. For internal use only. Key Secondary Endpoint: ≥4-point improvement WI-NRS (Week 12)

U.S. KALM-1 Trial Global KALM-2 Trial

P = 0.010 P = 0.00003 60% 60%

40% 40% 41% 39%

28% 20% 20% 18%

0% 0% Placebo (N = 189) Difelikefalin (N = 189) Placebo (N = 236) Difelikefalin (N = 237)

43 Confidential.Estimated percentage For internal & Puse-value only. based on a logistic regression model with terms for treatment group, baseline WI-NRS score, region and strata Missing data imputed using multiple imputation (MI) under missing at random (MAR) assumption Change from Baseline in WI-NRS Over Time Significant differences observed in WI-NRS starting at Week 1 and sustained through treatment period U.S. KALM-1 Trial Global KALM-2 Trial

0 0

-1 -1 * Placebo (N=189) * * Placebo (N=236) -2 -2 * ** * ** * ** * * -3 ** ** ** -3 * * * * ** Baseline from Change ** ** ** * * * * * Difelikefalin (N=189) Difelikefalin (N=237) -4 -4 Baseline 1 2 3 4 5 6 7 8 9 10 11 12 Baseline 1 2 3 4 5 6 7 8 9 10 11 12 Weeks in Double-blind Treatment Period Weeks in Double-blind Treatment Period LS Means over time LS Means over time

44 *Confidential. P < 0.05, ** P For < 0.001. internal LS Meansuse only. from MMRM with terms for treatment group, week, week by treatment interaction, baseline score, region and strata. Missing data imputed using multiple imputation (MI) under missing at random (MAR) assumption KORSUVA1 (Difelikefalin): Sustained Benefit over 15 Month Treatment Period

5D-Itch Scale Double-Blind Phase Open Label Extension Phase Primary 0

⚫ Multidimensional D ItchD - PBO/DFK questionnaire evaluating -2 Itch-related Quality of DFK/DFK Life

⚫ Questions on -4 ** characteristic Clinically meaningful threshold of itch (degree, Scores ** ** direction, duration, -6 * disability and distribution) -8 Clinically meaningful threshold in HD * P < 0.05 patients with CKD-aP: Mean (SE) Reduction in Total 5 Total in Reduction (SE) Mean ** P ≤ 0.001 -10 ≥ 5 points reduction 0 wks 10 wks 20 wks 30 wks 40 wks 50 wks 60 wks

45 Confidential.1The FDA has Forconditionally internal accepteduse only. KORSUVA™ as the trade name for difelikefalin injection. Difelikefalin injection is an investigational drug product and its safety and efficacy have not been fully evaluated by any regulatory authority. Incidence of Common TEAEs: KALM-1 & KALM-2

(~2% in Difelikefalin (DFK) arm and ~1% Difference versus PBO )

PBO (n=424) Difelikefalin (n=424) Preferred term

Subjects with any event 277 (65.3%) 302 (71.2%)

Diarrhea 24 (5.7%) 38 (9.0%) Most common adverse events Dizziness 16 (3.8%) 29 (6.8%) >5% in KORSUVA1 Nausea 19 (4.5%) 28 (6.6%) (Difelikefalin) arm

Headache 11 (2.6%) 19 (4.5%)

Hyperkalaemia 15 (3.5%) 20 (4.7%)

Somnolence 10 (2.4%) 18 (4.2%)

Back pain 4 (0.9%) 11 (2.6%)

46 Confidential.1The FDA has Forconditionally internal accepteduse only. KORSUVA™ as the trade name for difelikefalin injection. Difelikefalin injection is an investigational drug product and its safety and efficacy have not been fully evaluated by any regulatory authority. Commercial Opportunity For KORSUVA1 (Difelikefalin) Injection in Dialysis Patients ERIC VANDAL Senior Vice President, Commercial Cara Therapeutics

1The FDA has conditionally accepted KORSUVA™ as the trade name for difelikefalin injection. Difelikefalin injection is an investigational drug product and its safety and efficacy have not been fully evaluated by any regulatory authority. KORSUVA1 (Difelikefalin) Injection For CKD-associated Pruritus (CKD-aP) in Dialysis Patients

>500K2 60% ~40% patients on of ESRD patients have moderate to dialysis have pruritus3,4 severe pruritus

1.The FDA has conditionally accepted KORSUVA™ as the trade name for difelikefalin injection. Difelikefalin injection is an investigational drug product and its safety and 48 Confidential.efficacy have not For been internal fully evaluateduse only. by any regulatory authority. 2. National Kidney Foundation. 3. Pisoni RL, Wikstrom B, Elder SJ, et al. Nephrol Dial Transplant. 2006;21:3495-3505. 4. Ramakrishnan et al. International Journal of Nephrology and Renovascular Disease. 2014:7 1–12. 5. Current projected timeline with Priority Review KORSUVA1 (Difelikefalin) Injection For CKD-associated Pruritus (CKD-aP) in Dialysis Patients

Serious intractable KORSUVA granted NDA Priority Review systemic pruritus Breakthrough Therapy • NDA filing – Q1, 2021 2 CKD-aP associated with worsening Designation for CKD-aP 2 QoL, sleep disturbance, depressed • U.S. launch - 2H, 2021 mood/anxiety, socialization, increased • Significant unmet need mortality risk • No FDA approved therapies

49 Confidential. For internal use only. 1.The FDA has conditionally accepted KORSUVA™ as the trade name for difelikefalin injection. Difelikefalin injection is an investigational drug product and its safety and efficacy have not been fully evaluated by any regulatory authority. 2. NDA accepted by FDA with priority review PDUFA date Q3 2021 With No Approved Treatments, NEPHs Try Multiple Approaches with Limited Success

Optimize Dialysis, Calcium Emollients, Lotions, Antihistamines: Gabapentin Dermatology Phosphorus or Parathyroid and Creams Benadryl, Atarax Consult, Hormone Levels UVB Light

NEPHROLOGISTS WILL OFTEN: • First try to optimize/intensify dialysis and increase compliance with phosphate binders • Believe emollients may help coincidental dry skin, but does not truly address CKD-aP • Have limited success with antihistamines and gabapentin. Concerns over side effects • Believe there are no satisfactory treatment options for severe CKD-aP • Rule out other skin issues or appease patients via Derm. Referral

1 50 Confidential.The FDA has For conditionally internal use accepted only. KORSUVA™ as the trade name for difelikefalin injection. Difelikefalin injection is an investigational drug product and its safety and efficacy have not been fully evaluated by any regulatory authority. Most NEPHs Intend to Add KORSUVA1 (Difelikefalin) to Conservative Treatments

Optimize Dialysis, Calcium Emollients, Lotions, Antihistamines: KORSUVA Gabapentin Dermatology Phosphorus or Parathyroid and Creams Benadryl, Atarax Consult, Hormone Levels UVB Light

NEPHROLOGISTS: • Do not envision KORSUVA supplanting lower cost options, i.e., emollients and antihistamines ▪ Initially, KORSUVA will be added to conservative treatments, i.e., emollients, antihistamines as there is little concern of drug-drug interactions or negative outcomes • Envision most CKP-aP patients would be appropriate for KORSUVA based on the current product profile

51 Confidential.1The FDA has Forconditionally internal accepteduse only. KORSUVA™ as the trade name for difelikefalin injection. Difelikefalin injection is an investigational drug product and its safety and efficacy have not been fully evaluated by any regulatory authority. KORSUVA1 (Difelikefalin) Qualitative Primary Market Research with NEPHs Efficacy and AE Profile Elicit Most Positive Responses

“There’s nothing here to keep me from giving this a try [for “For someone who is miserable [with pruritus], of course I’m itching dialysis patients], the side effects are very low.” willing to prescribe it! Why would I deny anyone this?”

% of Dialysis Patients Projected by Physicians to Receive KORSUVA (~50% of Patients that Itch) Dialysis Patients

5.5 31%

Very Neutral Extremely Unwilling (1) (4) Willing (7)

52 Confidential. For internal use only. Highly Consolidated Market Can Lead to Rapid Uptake

Number of Hemodialysis Patients by Dialysis Organization - 2019 Parsabiv - Most Recent Launch into HD Space had Rapid Uptake Net Sales ($M) $700

$600

$500

$400

$300

$200

$100

$0 2018 2019 2020

~80% of Dialysis Patients in 2 Customers; ~90% of Dialysis Patients in 6 Customers Net Sales ($M)

53 Source:Confidential. Leading For dialysis internal providers use only. by number of patients U.S. 2019 | Statista. KORSUVA1 (Difelikefalin) Injection: U.S. Commercial Strategy Cara / Vifor Commercial License

• Employ Vifor and FMC RTG Established Nephrology Commercial Organization ▪ 200+ sales FTEs: Mircera, Velphoro, Venofer, Veltassa ▪ Existing relationships with US LDOs, MDOs and IDOs ▪ Established market access team ▪ Existing supply chain organization • Leverage Existing Cara/Vifor Synergies From Ongoing Collaboration ▪ Global brand development

54 Confidential. For internal use only. Oral KORSUVA1 (Difelikefalin): Potential Broad Anti-Pruritic DR. JO GONCALVES Chief Medical Officer Cara Therapeutics

The FDA has conditionally accepted KORSUVA™ as the trade name for difelikefalin injection. Difelikefalin injection is an investigational drug product and its safety and efficacy have not been fully evaluated by any regulatory authority. Key Chronic Pruritus Categories

Chronic Pruritus ✓ ✓ ✓ Neurological Systemic Dermatological Neuropathic Endocrine & Metabolic Inflammatory Dermatoses CKD; PBC AD Notalgia Paresthetica

Infectious diseases Infectious dermatoses Systemic Systemic Systemic Autoimmune dermatoses Hematologic & Brachioradial pruritus lymphoproliferative diseases Neoplasms Visceral neoplasms Genodermatoses Post-herpetic Neuralgia Drug-induced pruritus Dermatoses of pregnancy

Adapted from: Weisshaar et al. European S2k Guideline on Chronic Pruritus. Acta Derm Ven April 2019; 99(5): 469-506; Stander et al Clinical 56 ClassificationConfidential. ofFor Itch internal Acta Derm use Venonly. 2007; 87:291-294. Cara Therapeutics Pipeline

STAGE OF DEVELOPMENT Commercial Rights Program Indication Phase 1 Phase 2 Phase 3 NDA Review (ex-Japan and S. Korea)^

KORSUVATM US- Vifor* Pruritus CKD-HD** Injection EU/Other- VFMCRP# Oral Pruritus CKD (III-V) Cara KORSUVA™ Oral Pruritus Atopic Cara KORSUVA™ Dermatitis Oral Pruritus PBC Cara KORSUVA™ Oral Pruritus in NP Cara KORSUVA™

The FDA has conditionally accepted KORSUVA™ as the trade name for CR845 / difelikefalin for pruritic indications. CR845 / difelikefalin is an investigational drug product, and its safety and efficacy have not been fully evaluated by any regulatory authority. ^ Commercialization rights to CR845 in defined indications - Japan: Maruishi Pharma; South Korea: CKD Pharma. ** Breakthrough Designation for IV CR845 for Pruritus CKD-HD; Q1 2021 NDA accepted with priority review. # VFMCRP and Cara have rights to promote in Fresenius Medical Care dialysis clinics in the US under a profit share 57 agreement.Confidential. * Vifor For hasinternal commercial use only. rights in Non-US Fresenius clinics under a profit-share arrangement. CKD-HD: Chronic Kidney Disease- Hemodialysis; PBC: Primary Biliary Cholangitis; NP: Notalgia Paresthetica Oral KORSUVA1 (Difelikefalin) for CKD-aP: Phase 2 Trial Design

Endpoints Week 12 RANDOMIZE END OF SCREEN (N = 240; 1:1:1:1) TREATMENT Primary

RUN-IN TREATMENT (Once Daily) ⚫ Change from baseline in weekly mean of daily Worst Itching Intensity NRS (WI-NRS) score KORSUVA: 0.25 mg Secondary & Additional

KORSUVA: 0.5 mg ⚫ Change from baseline in itch-related QoL

KORSUVA: 1.0 mg ⚫ Skindex-10 ⚫ 5-D Itch

Placebo ⚫ Proportion of subjects achieving >3 points improvement from baseline in weekly mean of daily WI-NRS score 7 Days 12 Weeks ⚫ WI-NRS complete responder; patient global impression of change Baseline Mean Change Mean WI-NRS > 5 WI-NRS at Week 12 ⚫ Safety Assessments

58 Confidential. For internal use only. Primary Endpoint: Change From Baseline in the WI-NRS at Week 12

Difelikefalin Placebo 0.25 mg 0.50 mg 1.0 mg (N=67) (N=69) (N=66) (N=67) 0

Patients in the -1 Difelikefalin 1.0-mg group -3.3 -2 -4.0 -3.8 demonstrated -4.4 significantly greater improvement in the mean -3 WI-NRS vs placebo

-4 LS LS baseline from (SE)change mean -5 P = 0.018

P value vs placebo (P=NS for 0.25 mg and 0.5 mg DFK vs placebo). Statistical tests were 2-sided (alpha=0.5). LS mean from MMRM with terms for treatment group, week, week by treatment interaction as fixed effects; baseline score and strata as covariates; patient as a repeated measure. Analyzed in the full analysis population (patients receiving ≥1 dose based on randomized treatment). Error bars represent standard error (SE). Missing data imputed using MI under MAR assumption. LS, least 59 Confidential.squares; MAR, For missing internal at random; use only. MI, multiple imputation; MMRM, mixed model for repeated measures/ Change From Baseline in WI-NRS Over Time

0 Placebo (n=67) Difelikefalin 1.0 mg (n=67)

-1 Significantly greater improvements in WI-NRS were observed with Difelikefalin 1.0 -2 mg vs placebo as early as week * 2 and were maintained up to -3 week 12 ** ** ** -4 ** * * * * LS mean (SE) change from baselinefrom change mean (SE) LS -5 * 0 1 2 3 4 5 6 7 8 9 10 11 12 Weeks

*P<0.05. **P<0.01. Statistical tests were 2-sided (alpha=0.5). LS mean from MMRM with terms for treatment group, week, week by treatment interaction as fixed effects; baseline score and strata as covariates; patient as a repeated measure. Analyzed in the full analysis population (patients receiving ≥1 dose based on randomized 60 Confidential.treatment). Error For bars internal represent use only.SE. Missing data imputed using MI under MAR assumption. Achievement of ≥3-Point Improvement in WI-NRS at Week 12

More than 70% of patients achieved 72% of Difelikefalin 1.0 mg subjects experienced ≥ 3 point ≥3-point improvement in WI-NRS with Difelikefalin 1.0 mg improvement from baseline at week 12 Placebo (n = 67) Difelikefalin (n = 67) * 80 80.00 72.0 72.1 70.00 66.9 ** 61.8 57.4 57.9 60 60.00 ** ** 51.8 50.9 * point point 60.5 - 57.9 50.00 * 53.5 50.2 50.4 40 40.00 47.5 48.5 72.1 40.7 30.00 29.0 57.9 32.8 30.4 20 20.00 25.3 % Subjects % of 22.1 5.9 17.1 improvement (%) improvement 10.00 4.5 0 0.00 Patients achieving ≥3 achieving Patients Placebo 1.0 mg 1 2 3 4 5 6 7 8 9 10 11 12 (N=67) (N=67) DifelikefalinDFK Weeks in Double-blind Treatment Period P value vs placebo (P=NS for all DFK doses vs placebo). Statistical tests were 2-sided (alpha=0.5). Estimated percentage & P-value based on a logistic regression model with terms for treatment group, Estimated percentage and P values are based on a logistic regression model with terms for treatment baseline WI-NRS score, and renal disease status group, baseline WI-NRS score, and renal disease status. Analyzed in the full analysis population Missing data imputed using multiple imputation (MI) under missing at random (MAR) assumption (patients receiving ≥1 dose based on randomized treatment). Error bars represent 95% confidence * P < .05, ** P < .01 interval (CI). Missing data imputed using MI under MAR assumption.

1.0 mg dosage to be advanced into Phase 3 clinical study

61 Confidential. For internal use only. Complete Response at Week 12

60 P = 0.006 P = 0.027 Significantly greater P = 0.037 proportions of patients who 40 received Difelikefalin at all 3 dose levels achieved a (%) Patients 20 38.6 complete response 33.0 31.6 compared with placebo 14.4 0 Placebo 0.25 mg 0.5 mg 1.0 mg (N=67) (N=69) (N=66) (N=67)

Difelikefalin

P value vs placebo. Statistical tests were 2-sided (alpha=0.5). Estimated percentage and P values are based on a logistic regression model with terms for treatment group, baseline WI-NRS score, and renal disease status. Error bars represent 95% CI. Analyzed in the full analysis population (patients receiving ≥1 dose based on randomized 62 Confidential.treatment). Complete For internal response use isonly. defined as achievement of ≥80% of the non-missing daily NRS scores equal to 0 or 1 in a week. Executive Summary & Next Steps

• Oral KORSUVA1 (Difelikefalin) met the primary endpoint:1mg dose advancement to Phase 3 – Primary: Change from baseline in weekly mean WI-NRS score – Dose-dependent statistically significant improvement in Complete Responders • Oral KORSUVA1 (Difelikefalin) was generally well-tolerated: safety profile similar to Phase 3 Injection KORSUVA1 (Difelikefalin) studies

EOPII Meeting: Q2 2021

63 Confidential.1The FDA has Forconditionally internal accepteduse only. KORSUVA™ as the trade name for difelikefalin injection. Difelikefalin injection is an investigational drug product and its safety and efficacy have not been fully evaluated by any regulatory authority. Oral KORSUVA1 (Difelikefalin) For Atopic Dermatitis- Associated Pruritus Oral KORSUVA: Potential Broad Application Moderate-Severe Pruritus

30 million US patients ~80% ~20% Mild-Moderate Disease* Moderate-Severe Disease*

Approved Therapies Topical Steroids & Immunomodulators Injectable Biologic

64 Confidential.1The FDA has Forconditionally internal accepteduse only. KORSUVA™ as the trade name for difelikefalin injection. Difelikefalin injection is an investigational drug product and its safety and efficacy have not been fully evaluated by any regulatory authority. Atopic Dermatitis Associated Pruritus: Topline Data Q2, 2021

Endpoints Week 12 SCREEN Study

RUN-IN TREATMENT EXTENSION ⚫ ~400 adult patients with AD and moderate to severe pruritus Primary Endpoints

KORSUVA: 0.25 mg BID ⚫ Change from baseline in the weekly mean of the daily 24-hour I-NRS score at Week 12 KORSUVA: 0.5 mg BID Secondary Endpoints KORSUVA: 1 mg BID ⚫ Responder analysis (Week 12): Change from baseline in I-NRS score of >4 points

Placebo: BID ⚫ Change in itch related QoL: Skindex-10, 5-D Itch scales & Sleep Quality Assessment at week 7 Days 12 Weeks 4 weeks 12

Baseline: ⚫ Safety assessments Mean NRS > 5

65 TheConfidential. FDA has conditionally For internal accepted use only. KORSUVA™ as the trade name for difelikefalin injection. Difelikefalin injection is an investigational drug product and its safety and efficacy have not been fully evaluated by any regulatory authority. Notalgia Paresthetica Associated Pruritus: POC / Phase 2 Study (KOMFORT)

Week 8 Placebo-Controlled Active Extension Treatment Endpoints Week 8

KORSUVA 2 mg BID KORSUVA 2 mg BID Study: • ~120 adult patients with NP and moderate-to- severe pruritus Screening Run-in Primary Endpoint: • Change from BL in weekly mean of daily 24-hr WI- Baseline Placebo BID KORSUVA 2 mg BID NRS at week 8 Mean NRS ≥ 5 Other Endpoints: Up to 30 days 1 Week 8 Weeks 4 Weeks • QoL, Sleep, Responder Analyses, Safety

Endpoint Analysis

66 Confidential. For internal use only. Pruritus Associated with Primary Biliary Cholangitis (PBC): Phase 2

SCREEN 1:1 RANDOMIZATION END OF TREATMENT Endpoints Week 16

RUN-IN TREATMENT Study: • A 16-week, double blind, randomized, PBO- controlled study in PBC patients with moderate to severe pruritus Oral KORSUVA 1 mg BID (N=30) Primary Endpoint: • Change from baseline in the weekly mean of the daily 24-hour WI-NRS score at week 16 Secondary Endpoints: Placebo BID (N=30) • Change in itch related QoL: Skindex-10 & 5-D Itch scales at week 16 • Responder analysis (Week 16): Change from baseline in weekly main of daily worst NRS 7 Days 16 Weeks score of >3 points • Safety assessments

67 Confidential. For internal use only. Finance Summary TOM REILLY Chief Financial Officer Cara Therapeutics Financial Highlights

(AS OF DECEMBER 31, 2020) Cash/marketable securities (Q4 2020) $252M

(*) Proforma Net loss (4th Qtr. 2020) ($32.7M)

Shares outstanding ~49.9M

69 Confidential.(*) Reported For internal Q4 Net use Income only. of $78.9M which includes $111.6M revenue due to Vifor license agreement one-time payment Closing Summary DR. DEREK CHALMERS Chief Executive Officer and President Cara Therapeutics Projected Milestones–2021 & 2022

⚫ NDA Acceptance ⚫ NDA Approval ⚫ MAA Approval Pruritus / Priority Review ⚫ U.S. Commercial Launch KORSUVA1 ⚫ E.U.. Commercial Launch (Difelikefalin) Injection

1H 2021 2H 2021 2022

Pruritus / Oral KORSUVA1 (Difelikefalin) ⚫ Topline Data: ⚫ Topline Data: Phase 2 Atopic Dermatitis Phase 2 Chronic Liver Disease ⚫ Initiate Phase 3 Programs: CKD-aP (Stage III-V CKD) & Atopic Dermatitis

71 Confidential. For internal use only. Thank you