It's too early to say whether Cara Therapeutics Inc.'s delay of its phase III adaptive pivotal trial with intravenous (I.V.) CR845 for postoperative pain will provide an edge for competitor Trevena Inc. with oliceridine (TRV130), but the FDA's protocol hold was triggered by a pre-specified, conservative measure of previously seen sodium levels and could be dispatched within a few months.

Shares of Shelton, Conn.-based Cara (NASDAQ:CARA) fell 31 percent, or $2.15, to close Friday at $4.76 after the company said the stopping rule built into the protocol, based on elevated serum sodium levels greater than 150 mmol/L (normal is 135 to 146), was met during the first phase of the study. The effect turned up in four patients, two of whom counted as protocol violations.

Cara and the independent data monitoring committee have begun a review of unblinded safety data, which will be discussed with U.S. regulators. CR845 is a peripherally acting kappa opioid receptor agonist in development for acute and chronic pain and pruritus.

Chief Medical Officer (CMO) Joseph Stauffer told investors during a conference call that no serious adverse events have been recorded in the trial, and the four patients with high sodium, or hypernatremia – one with 154 mmol/L, two with 151, one with 150 – had no symptoms and the condition of each was resolved within 24 hours. All were getting the highest dose tested, 5 mcg/kg. (Other arms are trying 1 mcg/kg and 2 mcg/kg.) "We know from the past [trials] it happens," he said. "That's why we put it in the protocol as part of a pre-specified rule to look at."

CEO Derek Chalmers said transient sodium hikes "generally [have been] labeled as clinically insignificant" in other studies.

Specifically, CLIN3001 is a multicenter, randomized, double-blind, placebo-controlled, parallel-group adaptive design experiment with repeated doses of I.V. CR845 or placebo given prior to and following abdominal surgery in male and female patients. The trial is enrolling up to 600 patients undergoing hysterectomy, prostatectomy, hemi-colectomy or ventral hernia repair at 30 sites in the U.S. The primary efficacy measure is the change in pain intensity over the 24-hour postoperative period using the patient-reported Numeric Rating Scale score, collected at pre-specified time points through 24 hours. Nausea and vomiting, reduced in previous trials, are being evaluated as a secondary efficacy measure. Based on ex vivo reductions in inflammatory biomarkers in synovial joint cells from patients with inflammatory disease, the impact of CR845 on those biomarkers is being explored as well.

'TEMPORARY SETBACK,' ANALYST SAYS

"We believe we can tolerate grade 1 hypernatremia," measured as the upper limit of normal to 150 mmol/L, CMO Stauffer said. The four patients in question landed in the grade 2 category: greater than 150 to 155. Grade 3 is 155 to 160, and grade 4 is anything above 160. Of the two protocol slips, one was allowed to enter with a high baseline sodium level. "That was a violation right there and shouldn't have been allowed into the trial," he said. "The other patient was just given too much I.V. [saline-containing] fluid postoperatively," which probably skewed the levels without causing symptoms.

Asked about respiratory depression, a side effect with other opiate pain drugs, Stauffer said the problem doesn't exist. "In this trial, like all of the previous trials, the drug has always been given to people while they're wide awake, prior to surgery, so respiratory depression never even enters into the conversation here. It's just not part of the pharmacology."

CEO Chalmers said the company hopes to be in a position by the end of March to ask for a type A meeting with the FDA, which will review all of the findings and recommend the next steps.

Jefferies analyst Biren Amin said in a research report that the clinical hold "bodes well for Trevena's postoperative pain program, even if CLIN3001 is only delayed," since the latest action could mean a stall of two to six months as well as possibly holding off a second phase III trial with CR845. King of Prussia, Pa.-based Trevena's pain therapy, self-administered by way of a patient-controlled analgesia device, is a biased mu opioid receptor ligand/opioid receptor modulator. Trevena "remains on track and expects that it will have its end-of-phase II meeting with the FDA later this quarter," he said. "The phase III pivotal trials will enroll 300-600 patients, and Trevena will likely propose bunionectomy and abdominoplasty surgery models to the FDA for their hard- and soft-tissue models, respectively." CR845 also has been tested in bunionectomy patients. Shares of Trevena (NASDAQ:TRVN) closed Friday at $9.18, up 16 cents. (See BioWorld Today, Sept. 2, 2015.)

Piper Jaffray analyst Charles Duncan said the Cara sell-off amounted to an overreaction for three reasons. "First, the hold is based on pre-specified pharmacovigilance on hypernatremia in just the high-dose arm, with no clinical sequelae," he wrote in a research report. "Second, with no other safety issues observed in CLIN3001, CR845 continues to exhibit a superior side effect profile to mu-opioids at all dose levels. Third, management expects the analyses will delay CLIN3001 only about three months, and we don't see the hold as impairing the use of CLIN3001 data. In advance of FDA review and recommencement of CLIN3001, with an interim [data report] now around the second half of 2016, we view this as a temporary setback."