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Cara Therapeutics Announces Summary Data From Phase 1 Trial of Oral CR845 in Hemodialysis Patients with Chronic Kidney Disease

Cara Therapeutics, Inc. (CARA), a biopharmaceutical company focused on developing and commercializing new chemical entities designed to alleviate pain and pruritus by selectively targeting peripheral kappa opioid receptors, today announced summary results from its Phase 1 safety and pharmacokinetic trial of Oral CR845 in chronic kidney disease (CKD) patients undergoing hemodialysis.

The Phase 1 results showed that all four tablet strengths of Oral CR845 (0.25, 0.5, 1.0 and 2.5 mg) were generally well-tolerated when administered either daily or after dialysis three times per week. Top-line pharmacokinetic analysis indicated that plasma levels of CR845 attained after oral administration of doses up to 2.5 mg were comparable to or exceeded those attained with clinically efficacious intravenous (I.V.) doses of CR845 for the treatment of moderate-to-severe CKD-associated pruritus (CKD-aP) in hemodialysis patients. The plasma levels of CR845 attained after oral administration of the 1.0 mg tablet strength approximated those attained with the 1.0 mcg/kg I.V. CR845 dose, which demonstrated significant clinical benefit in the recently reported Phase 2/3 trial in hemodialysis patients with CKD-aP.

“We are pleased to establish that plasma levels of CR845 attained with oral tablets equaled or exceeded plasma levels previously associated with clinically efficacious I.V. CR845 doses in hemodialysis patients with moderate-to-severe CKD-associated pruritus,” said Frédérique Menzaghi, Ph.D., Vice President of Research and Development at Cara Therapeutics. “These data will inform the design of our planned Oral CR845 pruritus clinical program in the non-dialysis CKD-aP population, which we aim to initiate later this year.”

Phase 1 Trial Design and Results

The Phase 1 trial was a three-part, randomized, placebo-controlled study to evaluate the safety and pharmacokinetics of Oral CR845 tablets in 90 hemodialysis patients. In Part A, ascending repeated oral doses of 0.25, 0.5, 1.0 and 2.5 mg were given to four cohorts of patients (n=47) after each dialysis (i.e., three times) over a one-week treatment period. In Part B, ascending repeated oral doses of 0.25, 0.5 and 1.0 mg were given daily to three cohorts of hemodialysis patients (n=36). In Part C, the final crossover phase of the study, patients were administered a single 1.0 mg oral dose of CR845 or a single 1.0 mcg/kg I.V. dose of CR845 (n=7) given after hemodialysis with a one-week washout period between treatments to determine the absolute bioavailability of Oral CR845. Parts A and B randomized up to 12 patients per dose group (nine active and three placebo). Part C was conducted as an open-label phase with seven patients receiving active drug.

Overall, the frequency of treatment emergent adverse events (TEAEs) in CR845-treated patients was similar to the group administered placebo. All TEAEs were generally mild and comparable to those reported in the Phase 2/3 trial after I.V. CR845 administration in CKD-aP patients undergoing hemodialysis. Absolute oral bioavailability of the 1.0 mg tablet strength was determined to be similar in hemodialysis patients to that obtained in non-CKD patients.

About CR845 for the Treatment of CKD-associated Pruritus

The U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy designation to I.V. CR845 for the treatment of moderate-to-severe pruritus in CKD patients undergoing hemodialysis. Breakthrough Therapy designation is granted to expedite the development and review process for new therapies addressing serious or life-threatening conditions, where preliminary clinical evidence indicates that the drug candidate may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints. There are currently no FDA-approved drugs for the treatment of CKD-aP.

About CKD-associated Pruritus

CKD-aP is an intractable systemic itch condition that occurs with the greatest frequency and intensity in CKD patients undergoing hemodialysis and peritoneal dialysis; however, pruritus has also been reported in CKD patients who are not yet on dialysis. Aggregate, longitudinal, multi-country studies estimate the weighted prevalence of CKD-aP to be approximately 50 percent of patients with CKD stages 3-5 with approximately 25 percent of patients reporting moderate-to-severe pruritus. This represents approximately 4-5 million patients in the United States alone. Similarly, the majority of dialysis patients (approximately 60-70 percent) report pruritus, with 30 to 40 percent reporting moderate or severe pruritus. Recent data from the ITCH National Registry Study showed that among those with pruritus, 59 percent had experienced symptoms daily or nearly daily for more than a year. Given its association with CKD/ESRD, most afflicted patients will continue to have symptoms for months or years with currently employed anti-pruritic treatments, such as anti-histamines and corticosteroids, which are unable to provide consistent adequate relief. Moderate-to-severe chronic pruritus has repeatedly been shown to directly decrease quality of life, contribute to symptoms that impair quality of life (such as poor sleep quality), and is associated with depression. CKD-aP is also an independent predictor of mortality among hemodialysis patients, mainly related to increased risk of inflammation and infections.

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Cara Therapeutics Reports Continuation of Phase 3 Trial of I.V. CR845 in Postoperative Pain Following Interim Assessment

- Trial will continue to test two doses of CR845 and aims to enroll up to 450 patients -

- Both doses of CR845 well tolerated -

- Trial completion expected in the fourth quarter of 2017 -

 Cara Therapeutics, Inc. (CARA), a biopharmaceutical company focused on developing and commercializing new chemical entities designed to alleviate pain and pruritus by selectively targeting peripheral kappa opioid receptors, today announced the completion of a prespecified interim conditional power analysis of its adaptive Phase 3 trial of I.V. CR845. Based on the guidance of the Independent Data Monitoring Committee (IDMC), the trial will continue to test two doses of CR845 (1.0, and 0.5 μg/kg I.V.) versus placebo in up to 450 patients undergoing abdominal surgery. The IDMC also reviewed the available safety information, including serum sodium levels, and confirmed that both doses of CR845 were well tolerated with no significant changes in the monitored safety parameters.

“We look forward to continuing to test both doses of I.V. CR845 in our ongoing adaptive Phase 3 trial following the IDMC’s interim assessment analysis, and are encouraged by the overall clinical safety profile of CR845 for use in the postoperative setting,” said Joseph Stauffer, D.O., M.B.A., Chief Medical Officer of Cara Therapeutics. “There remains a clear unmet need for effective analgesic agents that lack the serious safety risks inherent in current opioids. We anticipate completing enrollment of this trial later this year.”

About the Ongoing CLIN3001 Postoperative Pain Trial

The CLIN3001 Phase 3 trial is a multi-center, randomized, double-blind, placebo-controlled, parallel-group adaptive design trial with repeated doses of I.V. CR845 or placebo administered both prior to and following abdominal surgery in male and female patients. The trial is enrolling up to 450 patients at 30 clinical trial sites within the United States. Two doses of I.V. CR845 (1.0, and 0.5μ g/kg I.V.) are being compared to placebo. The primary efficacy measure is the Change in Pain Intensity over the 24-hour postoperative period (AUC-24) using the patient-reported Numeric Rating Scale (NRS) score collected at prespecified time points through 24 hours. Postoperative nausea and vomiting (PONV) will be evaluated as a secondary efficacy measure.

About CR845

CR845 is a peripherally acting kappa opioid receptor agonist currently in development for the treatment of acute and chronic pain and pruritus. In multiple randomized, double-blind, placebo-controlled Phase 2 trials in patients undergoing laparoscopic hysterectomy or bunionectomy procedures, I.V. CR845 treatment resulted in statistically significant reductions in pain intensity and opioid-related side effects. In more than 1200 subjects dosed to date, CR845 was observed to be well tolerated, without incurring the dysphoric and psychotomimetic side effects that have been reported with centrally acting (CNS-active) kappa opioid receptor agonists, and lacking the respiratory depression and abuse liability of mu opioid receptor agonists. Top-line data from a Phase 2b trial of Oral CR845 in chronic pain associated with osteoarthritis are expected in the second quarter of 2017.

About Cara Therapeutics

Cara Therapeutics is a clinical-stage biopharmaceutical company focused on developing and commercializing new chemical entities designed to alleviate pain and pruritus by selectively targeting peripheral kappa opioid receptors. Cara is developing a novel and proprietary class of product candidates, led by CR845, that target the body’s peripheral nervous system and have demonstrated initial efficacy in patients with moderate-to-severe pain without inducing many of the undesirable side effects typically associated with currently available opioid pain therapeutics.

Forward-looking Statements

Statements contained in this press release 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 completion of the ongoing CLIN3001 postoperative pain trial of I.V. CR845 and the safety and efficacy results of the ongoing CLIN3001 clinical trial. 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’s filings with the Securities and Exchange Commission, including the “Risk Factors” section of Cara’s Annual Report on Form 10-K for the year ended December 31, 2016 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. Except to the extent required by law, Cara undertakes no obligation to update such statements to reflect events that occur or circumstances that exist after the date on which they were made.

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Cara Therapeutics to Present at the 17th Annual Conference on Pain Therapeutics

  • Dr. Joseph Stauffer to deliver opening remarks and discuss kappa opioid receptor agonists as a novel approach to acute and chronic pain management

  • Dr. Stauffer serves as co-chair and on the event’s Scientific Advisory Board

Cara Therapeutics, Inc. (CARA), a biotechnology company focused on developing and commercializing new chemical entities designed to alleviate pain and pruritus by selectively targeting peripheral kappa opioid receptors, today announced that Dr. Joseph Stauffer, Cara’s Chief Medical Officer, has been selected to speak at the 17th Annual Conference on Pain Therapeutics to be held May 22-23, 2017 in London. Dr. Stauffer also serves as an event co-chair and on the conference’s Scientific Advisory Board.

On Tuesday, May 23, Dr. Stauffer will deliver opening remarks and the opening address, during which he will discuss kappa opioid receptor agonism as a new approach to managing acute and chronic pain. This discussion will highlight positive clinical trial results and human abuse liability data for CR845, the Company’s first-in-class peripherally selective kappa opioid agonist. To date, results support the view that CR845 is unlikely to be recreationally abused or lead to physical dependence.

For more information on the 17th Annual Conference on Pain Therapeutics, visit https://www.smi-online.co.uk/pharmaceuticals/uk/pain-therapeutics.

About CR845

CR845 is a peripherally acting kappa opioid receptor agonist currently in development for the treatment of acute and chronic pain and pruritus. In multiple randomized, double-blind, placebo-controlled Phase 2 trials in patients undergoing laparoscopic hysterectomy or bunionectomy procedures, I.V. CR845 treatment resulted in statistically significant reductions in pain intensity and opioid-related side effects. In more than 1200 subjects dosed to date, CR845 was observed to be well-tolerated, without incurring the dysphoric and psychotomimetic side effects that have been reported with centrally acting (CNS-active) kappa opioid receptor agonists, and lacking the respiratory depression and abuse liability of mu opioid receptor agonists. Top-line data from a Phase 2b trial of Oral CR845 in chronic pain associated with osteoarthritis are expected in the second quarter of 2017.

About Cara Therapeutics

Cara Therapeutics is a clinical-stage biotechnology company focused on developing and commercializing new chemical entities designed to alleviate pain and pruritus by selectively targeting kappa opioid receptors. Cara is developing a novel and proprietary class of product candidates, led by CR845, that target the body’s peripheral nervous system and have demonstrated, in Phase 2 trials, preliminary efficacy in patients with moderate-to-severe pain and pruritus without inducing many of the undesirable side effects typically associated with currently available pain therapeutics.

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CARA Therapeutics, Inc. breached its 50 day moving average in a Bullish Manner : CARA-US : May 15, 2017

CapitalCube
Capital Cube

CARA Therapeutics, Inc. breached its 50 day moving average in a Bullish Manner : CARA-US : May 15, 2017

*Disclaimer : This is as of previous day’s closing price. Technical Indicators Below is a quick look at 5 technical indicators for CARA Therapeutics, Inc.. More studies are available on the Technical Chart. View these and more technical studies for CARA Therapeutics, Inc. Share Price Performance Relative to Peers With respect to peers, relative outperformance over the last year is in contrast to the more recent underperformance. CARA-US‘s change in share price of 229.75% for the last 12 months is better than its peer median. However, the 30-day trend in its share price performance of -5.50% is below the peer median suggesting that the company’s recent performance has faded significantly relative

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Cara Therapeutics to Announce First Quarter 2017 Financial Results on May 4, 2017

Cara Therapeutics, Inc. (CARA), a biotechnology company focused on developing and commercializing new chemical entities designed to alleviate pain and pruritus by selectively targeting peripheral kappa opioid receptors, today announced that the Company will host a conference call and live audio webcast on Thursday, May 4, 2017, at 4:30 p.m. ET to report first quarter 2017 financial results and provide a corporate update.

To participate in the conference call, please dial 855-445-2816 (domestic) or 484-756-4300 (international) and refer to conference ID 10052639. A live webcast of the call can be accessed under “Events and Presentations” in the News & Investors section of the Company’s website at www.CaraTherapeutics.com.

An archived webcast recording will be available on the Cara website beginning approximately two hours after the call.

About Cara Therapeutics

Cara Therapeutics is a clinical-stage biotechnology company focused on developing and commercializing new chemical entities designed to alleviate pain and pruritus by selectively targeting peripheral kappa opioid receptors. Cara Therapeutics is developing a novel and proprietary class of product candidates that target the body’s peripheral nervous system and have demonstrated initial efficacy in patients with moderate-to-severe pain without inducing many of the undesirable side effects typically associated with currently available pain therapeutics.

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Cara Therapeutics Announces Positive Data From Quantitative Phase 1 Trial Measuring Respiratory Safety of I.V. CR845

Cara Therapeutics, Inc. (CARA), a biopharmaceutical company focused on developing and commercializing new chemical entities designed to alleviate pain and pruritus by selectively targeting peripheral kappa opioid receptors, today announced summary results from its Phase 1 safety trial showing that I.V. CR845 did not significantly differ from placebo across three quantitative measures of respiratory drive in healthy individuals. Respiratory depression remains the most life-threatening side effect of traditional, centrally acting, opioid analgesics, the most commonly used drug class for current treatment of postoperative pain in the United States.

“We are very pleased that I.V. CR845 demonstrated no significant alteration in any measure of respiratory drive, even at doses five-fold greater than the projected therapeutic dose,” said Joseph Stauffer, D.O., M.B.A., Chief Medical Officer of Cara Therapeutics. “These data further underscore the overall clinical safety profile of CR845 for use in postoperative pain management and continue to differentiate it from traditional mu opioids.”

“There remains a clear unmet need for effective analgesic agents that lack the risk of serious, potentially fatal respiratory depression that is inherent in current opioids,” said Christopher Wu, M.D., Department of Anesthesiology and Critical Care, Johns Hopkins University. “The ability to administer I.V. CR845 without any direct effect on respiratory function is a significant advantage in the acute post-surgical care setting where patients are already at heightened risk of respiratory depression. CR845’s profile also aligns with the most recent standard of care guidelines for postoperative pain, which call for minimizing opioid-related side effects.”

Respiratory Safety Phase 1 Trial Design and Results

The Phase 1 trial was a randomized, double-blind, placebo-controlled, three-way crossover trial of two doses of I.V. CR845 (1.0 ug/kg, and 5.0 ug/kg) versus placebo on three measures of respiratory drive in 15 healthy volunteers. Each subject was randomized to one of three treatment sequences and was administered I.V. bolus placebo, CR845 (1.0 ug/kg) and CR845 (5.0 ug/kg) on sequential 24-hour periods, with CR845 at 5.0 ug/kg representing a projected five-fold supra-therapeutic dose. After each administration, and continuing through four hours post-dosing, end-tidal CO2 (ETCO2), oxygen saturation (SpO2) and respiratory rate were continuously monitored. The primary safety endpoints were: a >10 mmHg sustained (>30 seconds duration) increase in ETCO2 above baseline or to >50 mmHg, and a sustained reduction in SpO2 to <92 percent.

Mean ETC02 pre-dosing ranged from 36.1 ± 3.9 to 37.8 ± 2.9 mmHg across treatment groups. At one hour post-administration, ETC02 values for placebo, CR845 1.0 ug/kg and CR845 5.0 ug/kg treatment groups were numerically and statistically equivalent at 38.1 ± 2.8, 38.1 ± 3.1, and 38.3 ± 2.9 mmHg, respectively. Pre-treatment levels of SpO2 ranged from 98.3 percent ± 1.2 to 98.9 percent ± 1.0 and were measured at 97.8 percent ± 1.2, 98.2 percent ± 1.5 and 97.9 percent ± 1.0 for placebo, CR845 1.0 ug/kg and CR845 5.0 ug/kg treatment groups respectively, at one hour post-treatment. There were no statistically significant differences in any respiratory measures between groups throughout the four-hour observation period and no individual patient met the threshold for a respiratory safety event.

All reported treatment-emergent adverse events were previously reported with CR845 administration and were mild, resolving without intervention.

An oral presentation of this dataset will be part of the Journal Anesthesiology Symposium on Sunday, October 22, 2017 at the American Society of Anesthesiology (ASA) Annual Meeting in Boston, MA.

About Respiratory Depression

Respiratory depression is the most life-threatening side effect of conventional opioids, which act primarily at the mu opioid receptor subtype. Mu opioid receptors are present in high amounts in brainstem areas that control respiration, similar to midbrain and spinal areas that regulate pain perception. A wide variety of factors are involved in determining the effects of mu opioids on breathing, with high potency and speed of onset being well known risk factors, in addition to the presence of sedating medications, the site of surgery and surgical technique used, the presence of underlying disease, and the patient’s age, sex, genetics, and hormonal status, as well as arousal and pain, which can vary substantially between patients. Although death rates from opioid-induced respiratory arrest have declined in many hospitals due to more aggressive patient monitoring, it remains the leading concern of anesthesiologists and pain specialists (1). However, such monitoring is generally not available when patients are discharged home with powerful opioids, and the increasingly high rate of deaths associated with both opioid use and misuse is presently considered a national health crisis.

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marijuana stocks

Today’s Research Reports on Biotech Stocks to Watch: Cara Therapeutics and Incyte

RDI Initiates Coverage on:

Cara Therapeutics Inc.
https://ub.rdinvesting.com/news/?ticker=CARA

Incyte Corporation
https://ub.rdinvesting.com/news/?ticker=INCY

Cara Therapeutics’ shares declined 2.97 percent to close at $17.01 a share on Monday. The stock traded between $16.76 and $17.90 on volume of 2.02 million shares traded. Cara’s most advanced compound, CR845, is currently undergoing clinical testing for acute pain, chronic pain and uremic pruritus (itch). On March 28th, the company announced positive top-line results from Part A of its Phase 2/3 trial of I.V. CR845 in patients with uremic pruritus (UP). Shares of Cara Therapeutics have gained approximately 83.1 percent year-to-date.

“We are extremely pleased with these results, where I.V. CR845 demonstrated sustained clinical and quality of life benefits in dialysis patients suffering from UP and supports the viability of this therapeutic approach for the long-term treatment of this unmet medical need,” said Derek Chalmers, Ph.D., D.Sc., President and CEO of Cara Therapeutics. “As a next step, we plan to meet with the FDA to finalize the trial design of Part B of this Phase 2/3 study and to initiate patient recruitment later this year.”

Access RDI’s Cara Therapeutics Research Report at:
https://ub.rdinvesting.com/news/?ticker=CARA

Incyte’s shares dropped 10.49 percent to close at $126.07 a share on Monday. The stock traded between $124.05 and $127.43 on volume of 6.92 million shares traded. The company and Eli Lily announced that the FDA did not approve the New Drug Application (NDA) for baricitinib, a treatment for moderate-to-severe rheumatoid arthritis. The FDA has requested additional clinical data to determine the most appropriate doses. Shares of Incyte have gained approximately 25.73 percent year-to-date.

“We are disappointed with this action. We remain confident in the benefit/risk of baricitinib as a new treatment option for adults with moderate-to-severe RA,” said Christi Shaw, President of Lilly Bio-Medicines. “We will continue to work with the FDA to determine a path forward and ultimately bring baricitinib to patients in the U.S.”

Access RDI’s Incyte Research Report at:
https://ub.rdinvesting.com/news/?ticker=INCY

Our Actionable Research on Cara Therapeutics Inc. (NASDAQ: CARA) and Incyte Corporation (NASDAQ: INCY) can be downloaded free of charge at Research Driven Investing.

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Cara Therapeutics Announces Positive Top-Line Data From Part A of Phase 2/3 Trial of I.V. CR845 in Chronic Kidney Disease-Associated Pruritus

Met primary endpoint with 68% reduction in worst itching scores versus placebo after eight-week treatment period (p<0.0019)

Met secondary endpoint in quality of life domains versus placebo after eight-week treatment period (p<0.0007)    

I.V. CR845 well tolerated after eight weeks of treatment    

Conference call today at 8:30 a.m. EDT to review results and next steps  

Cara Therapeutics, Inc. (CARA), a biopharmaceutical company focused on developing and commercializing new chemical entities designed to alleviate pain and pruritus by selectively targeting peripheral kappa opioid receptors, today announced positive top-line results from Part A of its Phase 2/3 trial showing that I.V. CR845 met both primary and secondary endpoints for efficacy (reduced itching and improved quality of life, respectively) in patients with uremic pruritus (UP) with statistical significance. UP is an intractable and debilitating systemic itch condition with a high prevalence in patients with chronic kidney disease (CKD), for which there are no approved therapies in the United States.

“We are extremely pleased with these results, where I.V. CR845 demonstrated sustained clinical and quality of life benefits in dialysis patients suffering from UP and supports the viability of this therapeutic approach for the long-term treatment of this unmet medical need,” said Derek Chalmers, Ph.D., D.Sc., President and Chief Executive Officer of Cara Therapeutics. “As a next step, we plan to meet with the FDA to finalize the trial design of Part B of this Phase 2/3 study and to initiate patient recruitment later this year.”

“These exciting results underscore I.V. CR845’s potential, if successfully developed, to become an approved therapy in the U.S. for CKD patients suffering from UP,” said Gil Yosipovitch, M.D., Professor of Dermatology, Miller School of Medicine, and Director of the Miami Itch Center at the University of Miami. “There is an unmet medical need for an effective long-term therapy for treating this intractable pruritus and providing meaningful improvement in the quality of life of these patients under dialysis treatment.”

“This study demonstrated encouraging, statistically significant improvements across quality of life measures for hemodialysis patients with this condition,” said Mark Unruh, M.D., Chair of the Department of Internal Medicine at the University of New Mexico School of Medicine. “Importantly, these improvements persisted for the entire eight-week treatment period, with the anti-itch effect apparently sustained over time, suggesting that CR845 has the potential to be an effective treatment for this difficult condition, if successfully developed and approved.”

I.V. CR845 Phase 2/3 UP Trial Design and Top-line Results

Part A of the Phase 2/3 UP trial was a randomized, double-blind, placebo-controlled trial of three doses of I.V. CR845 (0.5 ug/kg, 1.0 ug/kg, and 1.5 ug/kg) administered three times per week after dialysis over an eight-week treatment period in 174 patients with moderate-to-severe UP.

The primary endpoint was the change from baseline of the mean worst itching score for week eight (days 51-57) based on a validated 0-10 Numeric Rating Scale (NRS). Patients receiving I.V. CR845 experienced a 68 percent greater reduction from baseline in worst itch scores than those receiving placebo (p-value<0.0019).

The secondary endpoint focused on quality of life measures associated with pruritus using the Skindex-10 score, a validated self-assessment scale with higher scores indicating worse quality of life. Patients receiving I.V. CR845 experienced a 100 percent greater reduction from baseline in the average total Skindex-10 score at week eight than those receiving placebo (p-value<0.0007). The total average Skindex-10 score reflected statistically significant reductions in each of the three Skindex-10 domains; disease (p-value=0.0001), mood/emotional distress (p-value=0.01), and social functioning (p-value=0.009).

Overall, I.V. CR845 was well tolerated over the eight-week treatment period and the unblinded Drug Safety Monitoring Board did not report any significant drug-related events during the course of the trial. The most common adverse events were transient paresthesia (primarily mid-facial tingling or numbness) and dizziness, as reported in previous clinical studies of I.V. CR845.

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Form 10-K for CARA THERAPEUTICS, INC.


10-Mar-2017

Annual Report

Item 7. Management’s Discussion and Analysis of Financial Condition and Results of Operations.You should read the following discussion and analysis of our financial condition and results of operations together with our financial statements and the related notes appearing at the end of this Annual Report on Form 10-K. Some of the information contained in this discussion and analysis or set forth elsewhere in this Annual Report on Form 10-K, including information with respect to our plans and strategy for our business and related financing, includes forward-looking statements that involve risks and uncertainties. You should read “Cautionary Note Regarding Forward-Looking Statements” and Item 1A. Risk Factors of this Annual Report on Form 10-K for a discussion of important factors that could cause actual results to differ materially from the results described in or implied by the forward-looking statements contained in the following discussion and analysis.

Overview

Introduction

We are a clinical-stage biopharmaceutical company focused on developing and commercializing new chemical entities designed to alleviate pain and pruritus by selectively targeting kappa opioid receptors. We are developing a novel and proprietary class of product candidates that target the body’s peripheral nervous system.

We commenced operations in 2004, and our primary activities to date have been organizing and staffing our company, developing our product candidates, including conducting preclinical studies and clinical trials of CR845-based product candidates, and raising capital. To date, we have financed our operations primarily through sales of our equity and debt securities and payments from license agreements. We have no products currently available for sale, and substantially all of our revenue to date has been revenue from license agreements, although we have received nominal amounts of revenue under research grants.

Product Development Pipeline

The current status of the development of our product candidates is as follows:

I.V. CR845 for Treatment of Acute Postoperative Pain

Our most advanced product candidate, I.V. CR845, demonstrated significant pain relief and a favorable safety and tolerability profile in three randomized, double-blind, placebo-controlled Phase 2 clinical trials in patients with acute postoperative pain, without inducing many of the undesirable side effects typically associated with currently available pain therapeutics. In addition, in the fourth quarter of 2014, we successfully completed a Human Abuse Liability, or HAL, trial of I.V. CR845 in which I.V. CR845 met the primary endpoint of demonstrating statistically significant lower “drug liking” scores as compared to the approved schedule IV opioid, pentazocine. We believe that the totality of results from the HAL trial are supportive of the potential for CR845 to be the first non-scheduled or low (Schedule V) scheduled peripheral opioid for acute pain.

In September 2015, we initiated our Phase 3 clinical trial program for I.V. CR845 in postoperative pain with the dosing of the first subjects in an adaptive pivotal trial in patients undergoing a range of abdominal surgeries. This trial is a multi-center, randomized, double-blind, placebo-controlled, parallel-group adaptive design trial with repeated doses of I.V. CR845 or placebo administered both prior to and following abdominal surgery in male and female patients. The trial protocol initially included three dose levels of I.V. CR845 (1.0 ug/kg, 2.0 ug/kg and 5.0 ug/kg), which were compared to placebo with an interim conditional power assessment to identify optimal doses to be used to complete the enrollment of this trial.

In June 2016, we modified the trial protocol and resumed the trial as a three-arm trial, testing two doses of CR845 (1.0 ug/kg and 0.5 ug/kg) versus placebo, based on a safety review by us, the trial’s Independent Data Monitoring Committee and the FDA of unblinded safety data from the first 90 patients dosed. The safety review was conducted in response to a clinical hold that the FDA placed on the trial in February 2016 and removed in April 2016 following the safety review. The clinical hold was based on a pre-specified stopping rule related to elevated serum sodium levels of greater than 150 mmol/L that was included in the clinical trial protocol.


Table of Contents
The revised trial is enrolling up to 450 patients undergoing various abdominal surgeries, all of which are associated with moderate-to-severe postoperative pain, within the United States. The primary efficacy measure is the Change in Pain Intensity over the 24-hour postoperative period using a common measurement method known as area under the curve, or AUC, using the patient-reported Numeric Rating Scale, or NRS, score collected at pre-specified time points through 24 hours. Postoperative nausea and vomiting is also being evaluated as a secondary efficacy measure. The impact of I.V. CR845 treatment on inflammatory biomarkers is also being explored. An interim conditional power analysis of our adaptive Phase 3 trial of I.V. CR845 for postoperative pain is expected in the second quarter of 2017.

Based on previous guidance from the FDA, we believe we will require 1,500 total exposures to I.V. CR845, including all Phase 1, Phase 2 and Phase 3 trials, prior to submitting a new drug application, or NDA. We believe our planned clinical trials and our clinical trials completed to date will result in a sufficient number of drug exposures to support an NDA.

Oral CR845 for Treatment of Osteoarthritis

We are also developing an oral version of CR845, or Oral CR845, for acute and chronic pain. In August 2015, we advanced our tablet formulation of Oral CR845 into a Phase 2a clinical trial in patients with osteoarthritis, or OA, of the knee or hip. The Phase 2a trial was a single-blind, randomized, multiple ascending dose trial designed to evaluate the safety, pharmacokinetics, or PK, and effectiveness of oral CR845 tablets dosed over a two-week treatment period in OA patients experiencing moderate-to-severe pain, defined as >4 on an 11-point NRS at baseline.

In December 2015, we announced positive top-line results from this Phase 2a trial. The results showed a dose-related reduction in mean baseline pain score up to 34% after two weeks, with statistically significant reduction in mean rescue medication for the top 5.0 mg dose group of approximately 80 percent. In this trial, all four tablet strengths were observed to be safe and well tolerated.

The Phase 2a trial established therapeutic doses and a dosing regimen for a larger randomized, double-blind, placebo-controlled Phase 2b trial, which we initiated during the third quarter of 2016. The Phase 2b trial is a trial of three tablet strengths of CR845, 1.0 mg, 2.5 mg and 5.0 mg, dosed twice-daily over an eight-week treatment period in approximately 330 OA patients experiencing moderate-to-severe pain across the United States. The primary efficacy endpoint is the change from baseline at week eight, with respect to the weekly mean of the daily pain intensity score using an NRS. Secondary endpoints include change from baseline in the WOMAC, the Patient Global Impression of Change, or PGIC, and amount of rescue medication used. We expect to report top-line data in the second quarter of 2017.

I.V. CR845 for Treatment of Uremic (Chronic Kidney Disease-Associated) Pruritus

CR845 has exhibited anti-pruritic, or anti-itch, potency in standard preclinical models. In July 2015, we reported positive top-line efficacy results from a Phase 2 proof-of-concept trial of I.V. CR845 for the treatment of uremic pruritus, a systemic condition with high prevalence in dialysis patients, for which there are no approved therapeutics in the United States. We observed that I.V. CR845 demonstrated statistically significant results on the primary endpoint of reducing worst itch intensity as well as the secondary endpoint of quality of life improvements. We also observed I.V. CR845 to have a favorable safety and tolerability profile in the trial.

In June 2016, we initiated a two-part Phase 2/3 adaptive design trial of I.V. CR845 in dialysis patients suffering from moderate-to-severe uremic pruritus. Part A of the trial, is a randomized, double-blind, placebo-controlled trial in 160 patients of three doses of I.V. CR845 (0.5ug/kg, 1.0 ug/kg and 1.5 ug/kg) administered three times per week after dialysis over an 8-week period. Part B will be a randomized double-blind placebo-controlled trial in up to 240 patients of one optimized dose of I.V. CR845 administered three times per week after dialysis over a 12-week treatment period. The primary endpoint will be reduction in worst itching scores from baseline values measured on a standard NRS alongside secondary quantitative quality of life endpoints. We expect to report top-line data from Part A of this trial in the first quarter of 2017.


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We have also initiated a pharmacokinetic safety trial of multiple doses of Oral CR845 in hemodialysis patients to define bioequivalent tablet strengths to inform our ability to develop an oral tablet formulation for moderate-to-severe uremic pruritus. We expect to complete this trial in the first quarter of 2017, with data readout expected in the second quarter of 2017.

See Part I, Item 1, Business – Our Product Candidates in this Annual Report on Form 10-K for a more detailed discussion of our clinical trials.

Collaborations with Maruishi and CKD

To date, we have entered into two license agreements relating to the development of CR845.

In April 2013, we entered into a license agreement with Maruishi Pharmaceutical Co., Ltd., or Maruishi, in Japan, under which we granted Maruishi an exclusive license, or the Maruishi Agreement, to develop, manufacture and commercialize drug products containing CR845 in Japan in the acute pain and uremic pruritus fields. We and Maruishi are each required to use commercially reasonable efforts, at our respective expense, to develop, obtain regulatory approval for and commercialize CR845 in the United States and Japan, respectively. In addition, we have provided Maruishi specific clinical development services for CR845 in Maruishi’s field of use.

Under the terms of the Maruishi Agreement, we received a non-refundable and non-creditable upfront license fee of $15.0 million and are eligible to receive up to an aggregate of $6.0 million in clinical development milestones and $4.5 million in regulatory milestones. In August 2014, we received a clinical development milestone payment of $0.5 million upon completion by Maruishi of a Phase 1 clinical trial in Japan related to CR845 in acute post-operative pain. In October 2015, we received a $1.7 million milestone payment (net of contractual foreign currency exchange adjustments of $0.3 million) related to the initiation by Maruishi of a Phase 2 clinical trial of CR845 in Japan for uremic pruritus. We are also eligible to receive tiered royalties, with percentages ranging from the low double digits to the low twenties, based on net sales of products containing CR845 in Japan, if any, and share in any sub-license fees. In addition, in connection with the Maruishi Agreement, Maruishi purchased 2,105,263 shares of our Junior A Preferred Stock for $3.80 per share, for an aggregate purchase price of $8.0 million, which shares were automatically converted into 842,105 shares of common stock upon the closing of our initial public offering in 2014.

In April 2012, we entered into a license agreement with Chong Kun Dang Pharmaceutical Corporation, or CKD, in South Korea, under which we granted CKD an exclusive license, or the CKD Agreement, to develop, manufacture and commercialize drug products containing CR845 in South Korea. We and CKD are each required to use commercially reasonable efforts, at our respective expense, to develop, obtain regulatory approval for and commercialize CR845 in the United States and South Korea, respectively.

Under the terms of the CKD Agreement, we received a non-refundable and non-creditable upfront license fee of $0.6 million and are eligible to receive up to an aggregate of $2.3 million in clinical development milestones and $1.5 million in regulatory milestones. We also issued 173,611 shares of our Junior Preferred Stock to CKD in consideration for $0.4 million, which shares were automatically converted into 69,444 shares of common stock upon the closing of our initial public offering in 2014. During 2012, we received $0.6 million, net of foreign taxes, from CKD upon the achievement of clinical development milestones under the CKD Agreement. During the year ended December 31, 2015, we met the milestone criteria, as set forth in the CKD Agreement, for completion of a Phase 1b trial of Oral CR845 in the United States and for completion of a Phase 2 trial of CR845 in uremic pruritus patients in the United States, respectively. As a result, we received milestone payments totaling $0.6 million (net of South Korean withholding tax) from CKD. We are also eligible to receive tiered royalties with percentages ranging from the high single digits to the high teens, based on net sales of products containing CR845 in South Korea, if any, and share in any sub-license fees.

Components of Operating Results

Revenue

To date, we have not generated any revenue from product sales and do not expect to generate any revenue from the sale of products in the near future. Substantially all of our revenue recognized to date has consisted of upfront payments under license


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agreements with Maruishi and CKD for CR845, a portion of which was deferred upon receipt, as well as license agreements for CR665, our first-generation drug program for which development efforts have ceased. To date, we have earned a total of $3.5 million in clinical development or regulatory milestone payments, net of contractual foreign currency adjustments and South Korean withholding taxes, but have not received any royalties, under these collaborations.

Research and Development (R&D)

To date, our R&D expenses have related primarily to the development of CR845. R&D expenses consist of expenses incurred in performing R&D activities, including compensation and benefits for full-time R&D employees, facilities expenses, including laboratory build-out costs, overhead expenses, cost of laboratory supplies, clinical trial and related clinical manufacturing expenses, third-party formulation expenses, fees paid to contract research organizations, or CROs, and other consultants, stock-based compensation for R&D employees and non-employee consultants and other outside expenses. Our R&D expenses also include expenses related to preclinical activities, such as drug discovery, target validation and lead optimization for CR845 and our other, earlier stage programs.

R&D costs are expensed as incurred. Non-refundable advance payments for goods or services to be received in the future for use in R&D activities are deferred and capitalized. The capitalized amounts are expensed as the related goods are delivered or the services are performed. Most of our R&D costs have been external costs, which we track on a program-by program basis. Our internal R&D costs are primarily compensation expenses for our full-time R&D employees. We do not track internal R&D costs on a program-by-program basis.

R&D activities are central to our business model. Product candidates in later stages of clinical development generally have higher development costs than those in earlier stages of clinical development, primarily due to the increased size and duration of later-stage clinical trials. Based on our current development plans, we presently expect that our R&D expenses will continue near their current level through 2017. However, it is difficult to determine with certainty the duration and completion costs of our current or future preclinical programs and clinical trials of our product candidates, or if, when or to what extent we will generate revenues from the commercialization and sale of any of our product candidates that obtain regulatory approval. We may never succeed in achieving regulatory approval for any of our product candidates.

The duration, costs and timing of clinical trials and development of our product candidates will depend on a variety of factors including:

� per patient trial costs;

� the number of patients that participate in the trials;

� the number of sites included in the trials;

� the countries in which the trial is conducted;

� the length of time required to enroll eligible patients;

� the number of doses that patients receive;

� the drop-out or discontinuation rates of patients;

� potential additional safety monitoring or other studies requested by regulatory agencies;

� the duration of patient follow-up; and

� the efficacy and safety profile of the product candidate.

In addition, the probability of success for each product candidate will depend on numerous factors, including competition, manufacturing capability and commercial viability. We will determine which programs to pursue and how much to fund each program in response to the scientific and clinical success of each product candidate, as well as an assessment of each product candidate’s commercial potential.

General and Administrative

General and administrative expenses consist primarily of salaries and other related costs, including stock-based compensation, for personnel in executive, finance, accounting, business development and human resources functions. Other significant costs include facility costs not otherwise included in R&D expenses, legal fees, insurance costs and fees for accounting and consulting services.


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We anticipate that our general and administrative expenses will increase in the future to support our continued R&D activities and potential commercialization of our product candidates. These increases will likely include increased costs related to the hiring of additional personnel and fees to outside consultants, lawyers and accountants and investor relations costs. In addition, if I.V. CR845 or any future product candidate obtains regulatory approval for marketing, we expect to incur expenses associated with building a sales and marketing team.

Other Income

Other income consists of interest and dividend income earned on our cash, cash equivalents, marketable securities and restricted cash and realized gains and losses on the sale of marketable securities.

Benefit from Income Taxes

The benefit from income taxes relates to state R&D tax credits exchanged for cash pursuant to the Connecticut R&D Tax Credit Exchange Program, which permits qualified small businesses engaged in R&D activities within Connecticut to exchange their unused R&D tax credits for a cash amount equal to 65% of the value of the exchanged credits.

Results of Operations

Comparison of the years ended December 31, 2016, 2015 and 2014

                                                                 Year Ended December 31,
                                              2016                           2015                        2014
                                                                Dollar amounts in thousands
                                                          % change                       % change
License and milestone fee revenue          $       -           -100 %      $  1,710            466 %    $   302
Collaborative revenue                              -           -100 %         2,093             -5 %      2,201
Clinical compound revenue                          86           100 %            -            -100 %        674

Total revenue                              $       86           -98 %      $  3,803             20 %    $ 3,177

License and milestone fee revenue

License and milestone fee revenue consists of (1) for the year ended December 31, 2015, $1.1 million of the $1.7 million milestone payment earned in September 2015 under the Maruishi Agreement, which was attributable to the previously delivered license, and $0.6 million from the two milestone payments earned by us under the CKD Agreement in July and September 2015 and (2) for the year ended December 31, 2014, $0.3 million of the $0.5 million milestone achieved under the Maruishi Agreement, which was attributable to the previously delivered license.

Collaborative revenue

Collaborative revenue for the year ended December 31, 2015 consists of $0.6 million of the $1.7 million milestone payment earned in September 2015 under the Maruishi Agreement, which was attributable to the fully-delivered R&D services deliverable, and $1.5 million of revenue that had been deferred upon entry into the Maruishi Agreement. Collaborative revenue for the year ended December 31, 2014 includes $2.2 million of revenue that had been deferred upon entry into the Maruishi Agreement.


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Clinical compound revenue

Clinical compound revenue for the years ended December 31, 2016 and 2014 includes $86 thousand and $674 thousand, respectively, from the sale of clinical compound to Maruishi.

Research and Development Expense



                                                              Year Ended December 31,
                                            2016                        2015                        2014
                                                            Dollar amounts in thousands
                                                       % change                    % change
Direct clinical trial costs               $ 37,257           175 %    $ 13,560            34 %    $ 10,099
Consultant services in support of
clinical trials                              1,860            86 %         999            -8 %       1,091
Stock-based compensation                     1,301            21 %       1,073           208 %         349
Depreciation and amortization                  839            88 %         447             6 %         422
Other R&D operating expenses                 7,996            56 %       5,142            65 %       3,107

Total R&D expense                         $ 49,253           132 %    $ 21,221            41 %    $ 15,068

For the year ended December 31, 2016 compared to the year ended December 31, 2015, the net increase in direct clinical trial costs and related consultant costs primarily resulted from increases totaling $22.3 million resulting from the Phase 2/3 I.V. CR845 clinical trial in patients with uremic pruritus, the Phase 2b clinical trial of Oral CR845 in OA patients, the Phase 3 I.V. CR845 adaptive pivotal clinical trial and the Phase 1 trial of Oral CR845 in hemodialysis patients, coupled with a net increase of $2.7 million of CR845 drug manufacturing costs and a net increase of $4.0 million for toxicology studies. Those costs were partially offset by decreases totaling $4.4 million in clinical trial costs primarily in connection with the completion of the Phase 2a Oral CR845 clinical trial in patients with OA, in the fourth quarter of 2015, and the completion of the Phase 2a I.V. CR845 proof-of-concept trial in patients with uremic pruritus, in the third quarter of 2015. The increase in stock-based compensation expense relates primarily to increased employee headcount, partially offset by a decrease in expense related to stock option awards granted to non-employee consultants, which are marked to market each quarter, due to the decrease in the market price of our common stock. The increase in depreciation and amortization expense reflects the acceleration of amortization of the leasehold improvements at our Shelton, Connecticut facility related to research and development activities prior to the relocation of our corporate headquarters (see Note 19 of Notes to Financial Statements in this Annual Report on Form 10-K). The increase in other R&D operating expenses was primarily the result of an increase in payroll and related costs associated with R&D personnel and rent, which includes recognition of all of the remaining rent expense allocable to research and development activities due during the remaining term of the Shelton operating lease (see Note 19 of Notes to Financial Statements in this Annual Report on Form 10-K).

For the year ended December 31, 2015 compared to the year ended December 31, 2014, the net increase in direct clinical trial costs and related consultant costs primarily resulted from increases totaling $5.4 million resulting from the I.V. CR845 Phase 2/3 adaptive study in patients with uremic pruritus and the Phase 2a Oral CR845 study in patients with OA, as well as a net increase of $1.4 million of CR845 drug manufacturing costs. Those costs were partially offset by decreases totaling $4.0 million in clinical trial costs in connection with the I.V. CR845 HAL trial and the Oral CR845 Phase 1a/1b trials, which were completed in 2014. There was also a net increase of $0.6 million for toxicology studies. The increase in stock-based compensation expense mostly reflects an increase in the number of option grants, in part as a result of growth in employee headcount. The increase in other R&D operating expenses was primarily the result of an increase in payroll and related costs associated with R&D personnel, recruiting costs and the cost of meetings and travel.


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The following table summarizes our R&D expenses by product candidate for the years ended December 31, 2016, 2015 and 2014:

                                                                  Year Ended December 31,
                                                2016                        2015                        2014
                                                                Dollar amounts in thousands
                                                           % change                    % change
External research and development expenses:
I.V. CR845                                    $ 23,244           155 %    $  9,149            24 %    $  7,369
Oral CR845                                      15,873           194 %       5,402            24 %       4,371
Internal research and development expenses      10,136            52 %       6,670           100 %       3,328

Total research and development expenses       $ 49,253           132 %    $ 21,221            41 %    $ 15,068

General and Administrative Expense



                                                                Year Ended December 31,
                                             2016                        2015                        2014
                                                              Dollar amounts in thousands
                                                         % change                    % change
Professional fees and public/investor
relations                                   $ 2,032              8 %    $ 1,883              6 %    $ 1,773
Stock-based compensation                      1,499              4 %      1,441             41 %      1,022
Depreciation and amortization                   626             60 %        392              9 %        361
Other G&A operating expenses                  5,076             25 %      4,054             34 %      3,025
. . .

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marijuana stocks

Cara Therapeutics to Announce Fourth Quarter and Full Year 2016 Financial Results on March 9, 2017

Cara Therapeutics, Inc. (CARA), a biotechnology company focused on developing and commercializing new chemical entities designed to alleviate pain and pruritus by selectively targeting peripheral kappa opioid receptors, today announced that the Company will host a conference call and live audio webcast on Thursday, March 9, 2017, at 4:30 p.m. ET to report fourth quarter and full year 2016 financial results and provide a corporate update.

To participate in the conference call, please dial 855-445-2816 (domestic) or 484-756-4300 (international) and refer to conference ID 70053458. A live webcast of the call can be accessed under “Events and Presentations” in the News & Investors section of the Company’s website at www.CaraTherapeutics.com.

An archived webcast recording will be available on the Cara website beginning approximately two hours after the call.

About Cara Therapeutics

Cara Therapeutics is a clinical-stage biotechnology company focused on developing and commercializing new chemical entities designed to alleviate pain and pruritus by selectively targeting peripheral kappa opioid receptors. Cara is developing a novel and proprietary class of product candidates that target the body’s peripheral nervous system and have demonstrated initial efficacy in patients with moderate-to-severe pain without inducing many of the undesirable side effects typically associated with currently available pain therapeutics.

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