A Bump in the Road Ahead for CARA? A Look Ahead At The Next Catalyst – Acute Pain

Later this year, CARA is expected to complete a phase 3 trial of its lead drug candidate, CR845, for the treatment of acute pain. We think there is a lot of uncertainty around this trial and aim to highlight the reasoning below.


Cara Therapeutics (“Cara”) is an early stage biopharmaceutical company focused on developing and commercializing new chemical entities designed to alleviate pain and pruritus by selectively targeting kappa opioid receptors located in the peripheral nervous system. The company is attempting to capitalize on their unique compound that avoids any CNS entry. Through avoiding CNS entry, CR845 should minimize kappa receptor associated psychiatric symptoms. In addition, by avoiding mu receptors, CR845 differentiate itself from the opioids on the market today. Mu receptor agonists often cause side effects including nausea, vomiting, addiction and respiratory depression.

Cara is expected to announce data for its adaptive pivotal clinical 3001 trial of I.V CR845 in post-operative pain later this year. The trial is a multi-center, randomized, double-blind study that will primarily look at differences in Pain Intensity Numeric Rating Scale scores, and secondarily look at nausea, vomiting, and need for rescue medication (IV morphine and ondansetron, for pain and nausea respectively). Their data needs to prove that CR845 can significantly reduce pain, and secondarily CARA will be looking to reduce morphine use in a clinically significant way, and to decrease nausea and vomiting. From a longer-term perspective, if this drug is to be effective in the marketplace if it is eventually approved, the overall patient experience must improve such that the decrease in nausea and vomiting outweighs the troubles of any other adverse events (e.g. facial tingling, electrolyte imbalances). If CR845 can significantly reduce the reliance on mu opioid agonists such as morphine, then providers will also rely on it heavily when concerned about respiratory depression in high risk patients or former opioid addicts. It is important to note that adding CR845 for acute pain does not address the chronic opioid abuse issue because short term opioid use in the hospital is vastly different than its use in the outpatient setting for chronic pain.


Cara currently has $112.4M of cash according to it’s latest 10Q. This includes the latest offering from April that amounted to $86.5M. On the latest earnings call, the management team stated that they expect to keep expenses flat. The company projects that they have enough cash to fund operations until 2019.

IV CR845 Phase 2 Trials in Acute Pain

CR845 trial results in acute pain thus far, have been mixed. Two of these trials were in patients undergoing a laparoscopic hysterectomy, a soft tissue surgical procedure, and a third trial was in patients undergoing a bunionectomy, a hard tissue surgical procedure.

CR845 efficacy data in their first phase 2 trial (CLIN2001) in hysterectomy patients showed that with one postoperative bolus dose of CR845 at 40 ug/kg, only 1/20 respondents met its primary endpoint of more than 40% reduction in pain intensity. However, morphine use was reduced at several time points measured, for example from mean values (standard deviation) of 5.9 (4.56) mg to 2.9 (2.63) mg at the 4-8 hour time period following postoperative study drug treatment, which was statistically significant.

CLIN2002 was performed with patients receiving either placebo or 40 ug/kg both preoperatively and postoperatively, which resulted in 4 different arms for the trial. For the primary endpoint, patients in the placebo arm received 21.9 mg of morphine (SD 1.89), whereas patients in the CR845 pre and postoperative treatment group received 13.9 mg (SD 2.20), which means patients saw a reduction in morphine use by 37% (p-value<0.05). For the secondary endpoint, the Sum of Pain Intensity Differences (SPID) score at 0-24 hours was -833.1 (SD 124.8) in the CR845 pre and post-operative arm, an improvement over the -413.7 (SD 67.8) in the placebo arm, which was statistically signficant. In addition, CLIN2002 showed statistically significant reduction in morphine use during hours 2-24 (“post-PACU”), improved total pain relief (TOTPAR) scores at 0-2h, and reduced nausea and vomiting. However, 7/20 patients suffered from high serum sodium levels in the CR845 pre and post-operative arm, and one of these patients was categorized as having a serious adverse event.

Finally, a phase 2 study done in patients receiving a bunionectomy (CLIN2003) had an active arm in which patients received 5 ug/kg IV bolus upon reaching a qualifying pain intensity score, additional doses on an as-needed basis 30-60 minutes later, and then no more frequently than every 8 hours through a 48 hour dosing period. The study showed a statistically significant decrease in SPID scores for patients who received the drug at 24, 36, and 48 hours. However, 8/34 of the patients dropped out (~24%, 6 were due to efficacy). CLIN2003 did not show a difference in mean fentanyl use (rescue pain medication) between placebo and CR845 groups, but the incidence of nausea and vomiting was reduced by 60% and 80% respectively. The most frequent adverse events observed were facial tingling and drowsiness (ie. somnolence) (both were >10%). The mean plasma sodium concentration in treated patients increased by approximately 3% over 24 hours from baseline levels. These increased levels were not found to be clinically significant, but this low rise was attributed to the lower dose of CR845 and the replacement of fluid loss with oral water or sodium-free IV fluid.

In September 2015, CARA initiated its 3001 Phase 3 IV CR845 trial in patients undergoing a range of abdominal surgeries. The trial was halted in February 2016 based on a stopping rule related to elevated serum sodium levels of greater than 150 mmol/L. In June 2016, based on the safety review and analysis of interim efficacy signals for pain, supplemental opioid use, and opioid side effects by an external review committee, Cara decided to move forward with the study to test dosing at 0.5 and 1.0 ug/kg. Based on the Q2 2017 earnings call, it seems that management’s decision to move forward was based more on reassurance of safety rather than clear efficacy signals.

The original dosing at the beginning of the phase 3, 3001 trial was at 1.0, 2.0, and 5.0 ug/kg. For the restarted trial, CR845 IV 0.5 or 1.0 ug/kg is being administered as an IV bolus 2x loading dose one hour prior to anesthetic induction for surgery, then within 30 minutes of the patient being considered stable in the post operative recovery room. Subsequent dosing is being administered at 6, 12 and 18 hours. It is important to note that the half-life of the drug is approximately 2 hours.1 Anti-nausea rescue medication (ondansetron 4 mg IV) may be requested, as well as analgesic rescue medication (morphine 5mg IV), post surgery, as needed. Saline infusion (IV 0.45%) for fluid replenishment is being provided. 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. This measurement method is different than the VAS and SPID approach used in earlier phase 2 trials. Postoperative nausea and vomiting is also being evaluated as a secondary efficacy measure.

From an investment perspective, a key takeaway is that there is a lot of uncertainty in whether CR845 will pass this current phase 3 trial. The safety and tolerability of CR845 in the phase 3 trial is not overly concerning because the doses are lower than previously studied doses in this indication. It is worth noting that the same doses have been used in the uremic pruritus trials, though they were spread out into administration three times a week. However, much uncertainty remains about whether efficacy will be proven at these low doses that are spread out more frequently than the previous trials. In fact, the dosing, frequency of doses, and endpoints are all different than prior trials testing CR845 in acute pain.

This article was written to highlight that this is not a phase 3 trial in acute pain that is being done to reconfirm a highly effective phase 2 trial, but rather a very risky phase 3 trial different from its previous phase 2 trials in dosing and primary endpoint, with an unpredictable probability of success. The questions remain, to what extent missing the primary endpoint would affect stock price, and how mixed results (e.g. missing the primary pain endpoint, but meeting a secondary endpoint such as reduced nausea) would affect stock price. Based on your tolerance for risk and your long-term view of CR845 in uremic pruritus, you should consider the uncertainty of positive readouts in the current phase 3 chronic pain trial in your investment strategy for CARA.

In our hypothetical model portfolio at Amp, we have a relatively small position in CARA that we plan to hold through these results with the possibility of increasing our stake if the results should drive the stock lower to a better entry point. We plan to continue to monitor CARA based on further data related to uremic pruritis and possible future trials on chronic and/or acute pain where results are more predictable based on the additional data from this year.


1 Jahr, Jonathan. The Essence of Analgesia and Analgesics. By Raymond Sinatra. N.p.: n.p., n.d. 490-91.


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