Cara Therapeutics Initiates Enrollment in Phase 2b Trial of Peripherally Acting Kappa Opioid Agonist, Oral CR845, in Chronic Pain Patients

Trial to evaluate three tablet strengths of CR845 versus placebo in approximately 330 osteoarthritis patients

Top-line data expected in first half of 2017

STAMFORD, Conn., Sept. 15, 2016 -- Cara Therapeutics, Inc. (Nasdaq: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 the initiation of patient enrollment in a Phase 2b trial of an oral tablet formulation of its peripherally selective kappa opioid agonist, CR845, for the treatment of pain associated with osteoarthritis (OA). The Company expects to report top-line data from this trial during the first half of 2017.

“The initiation of this osteoarthritis trial is an important step in establishing the potential clinical utility of CR845 in the treatment of chronic inflammatory pain,” said Joseph Stauffer, D.O., M.B.A., Chief Medical Officer of Cara Therapeutics. “The biggest challenge in analgesic development today centers on providing effective medications that lack the abuse burden of traditional pain drugs, and it appears from our previous preclinical and human abuse liability data that CR845 could represent a novel, non-addicting approach to the treatment of chronic pain.”

The Phase 2b trial is a randomized, double-blind, placebo-controlled trial of three tablet strengths of CR845, 1.0 mg, 2.5 mg and 5.0 mg, dosed twice a day (BID) over an eight-week treatment period in approximately 330 osteoarthritis patients experiencing moderate-to-severe pain. The primary efficacy endpoint will be change from baseline at week eight, with respect to the weekly mean of the daily pain intensity score using a numerical rating scale (NRS). Secondary endpoints will include: change from baseline in the Western Ontario and McMaster Osteoarthritis Index (WOMAC), the Patient Global Impression of Change (PGIC) and amount of rescue medication used.

About Oral CR845 Phase 2a Osteoarthritis Data

The Phase 2a trial, which reported top-line data in December 2015, was a single‐blind, randomized, multiple ascending dose trial designed to evaluate the safety, pharmacokinetics (PK) and effectiveness of oral CR845 tablets dosed over a two-week treatment period in OA patients experiencing moderate-to-severe pain. Four tablet strengths (0.25 mg, 0.5 mg, 1.0 mg and 5.0 mg) were administered twice a day (BID) over a two-week treatment period in a total of 80 OA patients enrolled at five sites in the U.S. Results of this trial indicated:

• The mean joint pain score (NRS score) exhibited a dose-related reduction from baseline to the end of the two-week treatment period, ranging from -25 percent at the lowest (0.25 mg) tablet strength up to -34 percent for the highest (5.0 mg) tablet strength.
• 50 percent of the patients in the 5.0 mg dose group reported at least a 30% reduction in their pain score at the end of the treatment period.
• Integrated AUC analysis of the overall NRS score for the entire treatment period indicated a statistically significant reduction in the 5.0 mg dose group compared to the three lower doses used in the trial.
• The reduction in pain score in the 5.0 mg dose group was accompanied by a statistically significant reduction in mean rescue medication of approximately 80 percent.
• 59 percent of patients in the 5.0 mg dose group used no rescue medication in week two of the trial.
• The effectiveness of the 5.0 mg dose was further supported by statistically significant, dose-related increases in the proportion of patients whose OA was “very much improved” or “much improved,” as indicated by patient global assessment (Cochran-Mantel-Haenszel test, p=0.02, 2-sided).

About I.V. CR845 Human Abuse Liability (HAL) Data

The HAL trial was a double-blind, randomized, active- and placebo-controlled four-way crossover trial that evaluated the abuse potential of I.V. CR845 in 40 non-dependent, recreational polydrug users with lifetime and recent hallucinogenic drug use. The primary objective of the trial was to measure the relative abuse potential of both a therapeutic and supratherapeutic dose of CR845, compared to an intravenous dose of pentazocine. Pentazocine is a mixed-action kappa and mu opioid receptor agonist used clinically in the treatment of moderate-to-severe pain and is classified by the Drug Enforcement Agency (DEA) as a Schedule IV drug, indicative of reduced abuse liability compared to most other opioids.

Top-line results announced in October 2014 showed that therapeutic and supratherapeutic doses of I.V. CR845 met the trial’s primary endpoint by demonstrating highly statistically significant lower “drug liking” scores as measured by visual analog scale (VAS) Emax (p <0.0001) when compared to I.V. pentazocine, a Schedule IV opioid receptor agonist. I.V. CR845 also demonstrated highly statistically significant lower “feeling high” and “overall liking” scores (p <0.0001) as compared to pentazocine. Additionally, both doses of I.V. CR845 were rated equivalent to placebo on “overall drug liking” and “take drug again” measures. “Drug liking,” “feeling high,”  “overall liking” and “take drug again” scores are standard subjective measures recommended by the U.S. Food and Drug Administration (FDA) to assess a drug’s abuse liability, both for recommended scheduling, as well as labeling.

About Prescription Opioid Overdose

According to the Centers for Disease Control and Prevention (CDC), deaths in the U.S. due to prescription opioids have quadrupled since 1999, with more than 19,000 deaths attributed to prescription opioid abuse or misuse in 2014, the equivalent of 52 deaths per day for that year. Statistics compiled by the National Institute on Drug Abuse (NIDA) indicate that young adults (age 18 to 25) are the most frequent abusers of prescription opioid pain relievers. In 2010, almost 3,000 young adults died from prescription drug (mainly opioid) overdoses, with many more requiring emergency treatment. This outnumbers deaths from overdoses of any other drug, including heroin and cocaine combined.

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 efficacy in patients with moderate-to-severe pain without inducing many of the undesirable side effects typically associated with currently available 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 for expected timing of reporting top-line results of the Company's Phase 2b trial of Oral CR845, and Oral CR845’s potential to provide a non-addictive approach to the treatment of chronic pain. 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 Annual Report on Form 10-K for the year ended December 31, 2015 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.

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