Cara Therapeutics: Scratching at Multiple Indications in 2020
#CARA #Pruritus
Summary
2020 is a big year for oral Korsuva.
CARA took a big hit in late 2019 from oral phase 2 data.
The second phase 3 readout for IV Korsuva, KALM-II, is set to report out in Q2 ‘20.
Overview
Cara Therapeutics focuses on developing therapies to treat itching, called pruritus, which is an unfortunate side effect for a lot of diseases. Cara’s late stage candidate, CR845 (Korsuva), initially targeted post-op pain. The company made the switch from focusing on pain to targeting pruritus after more promising data on the latter indication led the way. Cara initially focused on treating itching associated with kidney disease, but are now branching out into itching associated with other indications with their oral formulation.
Cara’s lead and only clinical stage asset is CR845, also known as Korsuva. CR845 is administered either orally or intravenously (IV). CR845 IV is the most advanced asset targeting itching associated with chronic kidney disease in hemodialysis patients, referred to as pruritus CKD-HD. The oral formulation targets pruritus associated with kidney disease (CKD), liver disease (CLD), and atopic dermatitis (AD). CR845 IV treating post operative pain is currently on hold, and based on sub-par data may continue to idle unless a partner or some other opportunity can be found for it. See Cara’s up-to-date pipeline below at Amp Bioresearch.
Cara Pipeline:
CR845 is a kappa opioid receptor agonist (KORA), which seems to have the potential to work without some of the other side effects characteristic of typical opioids. CR845 shows poor penetration across the blood-brain barrier and therefore produces little or no CNS-related side effects which are typical pitfalls of other opioids. For instance, morphine acts primarily by activating mu opioid receptors located in the CNS. As outlined in the slide below you can see how selective CR845 is at activating kappa opioid receptors as compared to morphine and fentanyl.
CR845 Kappa Receptor Opioid Profile
(Source: Cara Corporate Presentation)
Right now Cara stock is sitting near a twelve month low following the results of the phase 2 dose finding study of oral CR845 in pruritus associated with CKD stages 3-5. The market reacted to the data with a 35% pull back. Going into the data the stock ran up almost 50%, so the market was expecting cleaner positive results from a first glance at oral efficacy. KALM-1, the first robust trial for IV CR845 in pruritus associated with CKD-HD read out positively in Q2 of last year. Below is an annotated chart from a one year period.
Cara 1 Year Stock Chart
Upcoming Catalyst Landscape
2020 is a hectic year for Cara in terms of catalysts, both the IV and oral CR845 have readouts. Going into 2020 they had the phase 2 readout for oral CR845 in CKD, in the second quarter of 2020 we can expect top-line results from KALM-2 the global phase 3 for IV CR845 in pruritus associated with CKD-HD, as well as interim results for phase 2 treating AD-aP. In the second half of 2020 we can expect top-line results from phase 2 oral in both AD-aP and CLD-aP, as well as the planned NDA submission for IV CR845 (Korsuva) in pruritus associated with CKD-HD.
CR845 IV is sitting in a pretty good place for Cara at the moment. Leapfrogging from an ex-US licensing deal with one of the leaders in dialysis clinics (see below), to positive phase 3 data, and then the expected global phase 3 data coming soon. The partnership was with Vifor Fresenius Medical Care Renal Pharma (VFMCRP) for an ex-US licensing agreement that included $70M in upfront payment (cash and equity), up to $470M in regulatory and commercial milestones, and a tiered double-digit royalty. Although there is a U.S. co-marketing component as well, Cara retains the rights to profits in non-Fresenius US dialysis clinics, and a profit share in US Fresenius dialysis clinics. The details of the agreements are seen below.
Cara Fresenius Deal
(Source: Cara Corporate Presentation)
The KALM-1 data that was released in Q2 ‘19 looked very clean, and quick acting. The primary endpoint was proportion of subjects achieving ≥3 point improvement from baseline in weekly mean of daily worst itching intensity NRS (WI-NRS) at week 12. Secondary endpoints were the proportion of subjects achieving ≥4 point improvement in WI-NRS at week 12, and Change from baseline in itch-related Quality of Life as measured by 5-D Itch and Skindex-10 questionnaires as week 12. The results from KALM-1 for the primary endpoint were 28% vs. 51% for placebo and Korsuva (CR845) respectively, with a p-value of 0.000019 (See graph below). The secondary endpoints also were statistically significant as well. The trial had a 1 week run-in period and a 12 week treatment period, with the opportunity to continue into a 52 week open label ongoing expansion study. The KALM-2 trial design is the same but global, including centers in US, Europe, and Asia Pac regions. Although there is more risk in KALM-2 than there was in KALM-1, there is still a high chance of success. It is noteworthy regarding the KALM-2 trial that CARA announced in October 2019 that the target enrollment was increased from 350 patients, the initial target and the number of subjects in the KALM-1 trial, to 430 patients to maintain similar statistical power to the KALM-1 US trial (Cara Press Release). Thus, results from the KALM-2 trial are likely not as clean as the KALM-1 trial. The hope is that given the very high statistical significance of the KALM-1 trial for the primary endpoint, even if results from the KALM-2 trial are not as clean, they will at least reach a p value of less than 0.05, and hopefully even better given the increased subject numbers.
KALM-I Primary Endpoint
(Source: KALM-I Results Slide Deck)
The second expected catalyst in the second quarter of 2020 for Cara is the interim analysis for the phase 2 oral CR845 study in AD-aP. This is the first time the company will report results for CR845 in AD-aP patients and only the second readout with efficacy and safety for oral CR845. These uncertainties leave some clear risk in this readout, even when drawing some conclusions between oral trials. However, the trial is similar to the phase 2 oral CKD trial that read out late last year, although it has some differences. The atopic dermatitis trial is testing three doses, 0.25, 0.5, and 1mg BID vs. placebo over a 12 week treatment period. The possible addressable markets for these oral CR845 indications such as AD seem exciting, with the company noting a fair amount of pruritus experienced with the current indications being targeted.
Rates of Pruritus Experienced
(Source: Cara Company Presentation Jan 2020)
Deeper Look at Oral Phase 2 [AMP Exclusive]
Let’s take a closer look at the results of the dose finding phase 2 readout for oral CR845 treating stage 3-5 CKD-aP (See oral phase 2 press release). We italicize dose finding to draw attention to the fact this was the first time we saw efficacy data for oral CR845 in humans. The market may have been expecting clean data based on the IV CR845 data, but without a controlled trial, those expectations were just too high. This could have been a major factor in the stocks runup of almost 50% into the data results. These assumptions can also be based on the phase 1 oral CR845 results noting the plasma levels reached for the 1.0 mg tablet levels were similar to those reached with 1.0 mcg/kg IV (Cara oral phase 1 press release). It is interesting to note that Cara had a 2.5 mg dose tablet in phase 1, which they did not include in the phase 2 study.
The phase 2 study for oral Korsuva (CR845) treating CKD-aP was a 12 week trial with a 1 week run-in period. The primary endpoint was change from baseline in weekly mean of daily Worst Itching Intensity NRS (WI-NRS) score at week 12. For secondary endpoints refer to the trial design slide below. The 269 enrolled patients were randomized 1:1:1:1 to either once-daily oral Korsuva 0.25 mg, 0.5 mg, 1.0 mg, or placebo.
Oral Phase 2 CKD-aP Trial Design
(Source: Cara Results Slide Deck)
It is noteworthy regarding baseline demographics, that around 60% of patients for each arm were stage 3 CKD non-dialysis patients. Patients at this stage do have more kidney function than stage 4 or 5 patients, which could have an impact on drug clearance. The phase 1 study noted above enrolled CKD patients on hemodialysis, not stages 3-5.
Oral Phase 2 CKD-aP Baseline Characteristics
(source: Cara Oral Phase 2 Results Slide Deck)
Let’s dive in and take a closer look at the oral phase 2 data, and how it compares to the IV phase 3 data, noting the risks and uncertainties when comparing across trials. Below is a table noting the baseline demographics and results for the oral phase 2 and IV phase 3 studies. The baseline WI-NRS, 5-D itch scale, and Skindex-10 scores were comparable between the two trials. It is noteworthy that patients responded better overall to both drug and placebo in the phase 2 oral study vs. the phase 3 IV KALM-I study. However, the most striking difference between the trials is in the placebo group: 58% of the placebo group achieved at least a 3 point improvement in the WI-NRS endpoint in the oral phase 2 study, whereas only 28% hit that endpoint in the Phase 3 IV study. Similarly, the placebo group achieved a 3.3 point reduction in the WI-NRS score in the phase 2 oral study, but only a 1.9 point reduction in the phase 3 IV study.
Phase 2 Oral and Phase 3 IV Baseline Table
Phase 2 Oral and Phase 3 IV Results Table
Despite the high placebo effect, the data from the phase 2 trial establishes human proof of concept for oral CR845 in CKD and bodes well for the phase 3 trial. Although it was only statistically significant at 12 weeks for the reduction in WI-NRS endpoint (the primary endpoint in the phase 2, but not the IV phase 3 trial), the 1.0mg oral dose in the phase 2 study performed better than the placebo group despite the high placebo effect. Furthermore, the weekly WI-NRS score showed the 1.0 mg group consistently outperforming placebo (see graph immediately below). Finally, more recent data provided by CARA for an NRS complete responder analysis is even more convincing at all doses, although further statistical manipulation was performed (See NRS Complete Responder Graph Below).
Source – CARA Phase 2 data readout deck
(Source: Cara Company Presentation Jan 2020)
The adverse events (AE) profile of oral CR845 in the phase 2 CKD appeared worse than placebo, but well within an acceptable level for regulatory and possible future commercial success. There appeared to be a slight elevation in some AEs such as dizziness, constipation, diarrhea, and fatigue, with the 1.0 mg dose of CR845 compared to placebo, although remaining in the low to mid-single digits. Furthermore, about 13% vs. 8% of patients in the 3 CR845 vs. placebo treatment groups experienced at least one serious treatment emergent AE. It would have been interesting to see how the 2.5 mg dose performed. However, in this chronic treatment setting where there are over-the-counter and generic off-label options, patients might be less willing to accept an AE much worse than that demonstrated for the 1 mg group. The discontinuation rates looked similar to placebo for CR845 with 7.5%, 2.9%, 7.6%, and 13.4% for placebo, 0.25mg tablet, 0.5mg tablet, and 1.0mg tablet respectively.
The big question out of the phase 2 CR 845 trial is what caused such a high placebo effect. First, a high placebo effect is a major challenge for patient reporting outcomes trials such as pruritus trials. Second, the company noted on their conference call reporting the data that many of the sites for the phase 2 oral trial were sites for the KALM-1 trial, and therefore might have been favorably biased. Finally, the company noted that for phase 3, they would increase the number of subjects receiving the 1.0 mg CR 845 dose such that even if the same results were obtained as in phase 2, they would be statistically significant. We wonder whether further trial design changes could be made that take advantage of some of the trial designs for depressions that try to better deal with a high placebo effect. Regardless, it is likely that CARA will use their usual trial design where they wisely in our view, do an interim powering analysis that allows them to increase the number of subjects, before completing enrollment in a trial. In summary, we feel that there will likely be a good chance of success for CARA in its future oral CR845 CKD trial, pending CARA’s announcement of trial details after their upcoming end of phase 2 FDA meeting.
Finally, let’s take a look at the upcoming interim analysis for the phase 2 oral AD-aP readout coming in the second quarter of this year, and see how the trial design compares to the oral CKD phase 2. The first major difference is the dose, which for the phase 2 oral CKD was once daily, but for AD-aP is BID (twice daily). This means patients are getting double the drug, which could have some effect on efficacy and safety. Apart from that the trials are fairly identical with the 1 week run-in period, 12 week treatment period, and change in WI-NRS as the primary endpoint. The only other differences are in the secondary endpoints. The topline results for AD-aP and CLD-aP are expected in the second half of 2020. Of course, as the first readout for CR845 outside of CKD, there is significant risk in these trials. If you have any thoughts, comments, or insights about the chances of success in AD or CLD compared to CKD, let us know in the comments below.
Pruritus Competitive Landscape
There are two other clinical stage drugs targeting pruritus that have readouts coming this year. Serlopitant from Menlo Therapeutics, and KPL-716 from Kiniksa Pharmaceuticals. Serlopitant has a phase 3 readout in prurigo nodularis itch in March or April of 2020, and a phase 2 readout for chronic pruritus of unknown origin in late Feb of 2020. KPL-716 also has two readouts this year, first a phase 2 trial in prurigo nodularis itch and a phase 2 in chronic pruritus, both coming in the first half of 2020. It is noteworthy that none of these trials appear to target exactly the same indications as CARA is targeting with CR845, but there may be some overlap. Diving into these drugs is beyond the scope of this article, but if you would like us to post prior date in our Amp prior trial database, or an update with more details, leave a comment below and let us know.
CARA Financials
Cara ended the 3rd quarter of 2020 with $193M in cash and cash equivalents. With a burn rate of around $33M/quarter, that leaves CARA about 1.5 years of cash at the current burn rate. It is noteworthy that CARA’s burn rate is likely to increase as IV Korsuva gets closer to commercialization. Despite this, the company still appears to have at least one year of cash. To learn more about cash targets for public pre-commercial biopharma companies, watch our Amp Biopharma Quick-Ed educational video on this topic. With less than 2 years of cash, it is likely that CARA will do another cash raise if one of their readouts in 2020 is a positive and gives their stock price a nice boost.
Amp Final Thoughts
It’s clear that the pruritus space is a large one, with few approved targeted treatment options available. The phase 2 oral data for CR845 was not as clean as the market was expecting given the high placebo effect, but it was strong enough to give us excitement about their future phase 3. 2020 is a packed year for Cara in terms of major catalyst events, and the major stock price pullback from the phase 2 oral data late in 2019 may offer an opportunity to accumulate a position at a good value. CARA’s lucrative collaboration agreement with Fresenius and the growing body of positive human clinical data from CR845 in pruritus makes CARA an interesting biopharma company for investors in this space.