KORSUVA: The Decisions Cara Therapeutics INC. made to Potentially Revolutionize Pain and Pruritus Relief
By: Luka Mihailovic
When the creative team of Dr. Derek Chalmers, Dr. Frederique Menzaghi and Dr. Michael Lewis founded Cara Therapeutics Inc. in Stamford, Connecticut, in 2004, they created a company that would eventually be amongst some of the most promising young biotech firms of the early 21st century . They centered this company on the development of a novel opioid-receptor acting painkiller that had the potential to provide the benefits of conventional opioids, without the risk of negative side effects and the possibility of abuse and addiction. This drug was developed as CR845 with the trade name KORSUVA and in 2018 it was in different phases of clinical trials in three main sectors; acute pain relief, chronic pain relief, and pruritus (severe itching) (Figure 1). The results of these trials have shaped the decisions Cara has had to make moving forward in terms of which routes to take with KORSUVA, boiling down to which pipelines should they have continued to fund. Only over the past couple years, in 2017 and 2018, Cara has been forced to execute these critical decisions. Which of these sectors should Cara have devoted most of their focus to? Which areas should they have ignored altogether? And finally, were there alternative routes, such as potential partnerships Cara could have taken to improve the development of their drugs?
Significance of KORSUVA
Optimizing Pain relief was one of the bigger challenges facing the field of medicine over the last couple decades. This is due to the fact that although we had effective drugs to treat pain, many of them belonged to the opioid family and thus came with a high risk of addiction as well as a variety of negative side effects. These drugs, such as morphine, codeine and oxycodone, were commonly prescribed to treat pain, mainly acute or temporary pain associated with soft tissue damage. This often occurs after surgery or through injuries and disease. They could also be used to treat chronic pain however they were used cautiously due to the fact that the benefits they could provide were outweighed by a number of harmful side effects. These included nausea, vomiting, sedation, constipation, and drowsiness . In some cases respiratory problems occured, as well as analgesia, which is an increased sensitivity to pain. However, one of the larger issues associated with opioids was the possibility of addiction and dependence. The National Institute on Drug abuse had projected that somewhere between 26 and 36 million people abuse opioids worldwide in 2017. In the U.S. alone this was around 2.6 million people . One might think that illegal drugs like heroin would make up the majority of this statistic, but the same article noted that an estimated 450,000 people in the United States were addicted to heroin to contribute, while 2.1 million cases involved prescription drug abuse. There were more than double the amount of deaths from opioid abuse annually in 2017 than in 2002  (Figure 2). This was clearly a major global issue that was only becoming worse with time. Steps were being taken to find better alternatives but there were also approaches targeting the way these drugs act. What if there was a drug that could alter how these opioids affected our bodies?
These opioids function through interactions with 3 main opioid receptors. The opioids used today target Mu receptors that are located in the central nervous system, such as in the spinal cord and brain. This is what was believed to cause the negative side effects associated with these drugs, but was also the probable cause of addition development. There are however, other receptors located in the peripheral nervous system called kappa receptors that can potentially induce pain relief without these negative effects . KORSUVA was developed by Cara as the first kappa opioid receptor agonist (KORA). This drug has high affinity towards these kappa receptors while ignoring the Mu receptors found in the central nervous system. This was attributed in part to the fact that KORSUVA is very poor at penetrating the blood-brain barrier. Thus KORSUVA has the potential to provide the benefits of traditional opioids such as acute and chronic pain relief, and anti-pruritus, without the myriad of negative side effects that usually come with these drugs.
As of January 2018, Cara had not generated any profits from the direct sale of its products, and had been in a consistent state of research and development through clinical trials. Cara themselves have stated in a 2017 financial report, that they do not expect to generate revenue in the next several years. The only revenue they had generated to date had come from upfront licensing fees to other companies as well as milestone payments from these companies such as through completion of different phases of clinical trials of their licensed drugs. One of these companies was Maruishi Pharmaceutical Co., Ltd, that had paid a license fee of $15 million to research and develop KORSUVA in Japan as well as providing the possibility of up to $10.5 million in regulatory and clinical milestones. As of February 2018, Cara had received $3 million in these milestone payments. As part of this agreement Maruishi had also obtained 842,105 shares of Cara for another $8 million. Another company called Chong Kun Dang Pharmaceutical Corporation (CKDPC) had a similar agreement with Cara paying a $600,000 upfront license fee, up to $3.8 million in milestones, and purchasing 69,444 shares for $400,000. These collaborations had contributed to Cara’s total revenue as of February 2018 of $5.2 million .
Like most drug companies in clinical trial stages, Cara was in a state of consistent net loss. In the end-of-year financial report released in January 2018, they reported a net loss of $57.3 million in 2016 and $58.1 million in 2017  (Figure 3). This was due to the fact that they were still in the phases of research and development of their products. Research and development contributed $48.6 million in expenses for 2017 (Figure 4). In total they had reached a deficit of $220.3 million. This was typical of a starting drug development company and the share price of 11.89 USD in March 2018 was relatively the same as it was in 2014 (12.9 USD). However these shareholders would eventually need to see a return on their investments and a shift in this direction would be reflected by positive data from clinical trials. Cara could not continue to fund all of their pipelines for KORSUVA using investor money on their own and they needed to make critical decisions about the future focus of their company. This involved careful analysis of the markets and efficiency of their pipelines for KORSUVA in terms of acute and chronic pain and pruritus treatment to determine which of these to continue funding and which to discontinue.
Pain Relief Pipeline
The treatment for pain management was generally linked to the intensity of pain the patient was suffering from. Mild to moderate pain was treated mainly through the use of non-steroidal anti-inflammatory drugs (NSAIDS) such as Advil or Tylenol. Mu opioids such as Oxycodone were only prescribed in patients suffering from moderate to severe pain, however in this area they were the only effective drugs to treat these conditions. This resulted in Mu opioids making up a huge portion of total prescription drug classes in 2017. IQVIA, a company devoted to providing medical data to companies involved with healthcare, stated that in 2017, the total market in the United States for analgesics (pain relief drugs) was $45.5 billion which translated to 406 million prescriptions written in just that year. Opioids were a part of 53% of these cases and contributed to $6.9 billion in sales of 2017  (Figure 5). These cases are made up of acute pain, usually following surgery or injury and chronic pain.
The International Association for the Study of Pain reported in 2017 that there were approximately 53 million outpatient surgeries, meaning immediate release after procedures, and 46 million inpatient surgeries, requiring overnight postoperative care. These cases involved 234.3 doses of IV injections of opioids including morphine, fentanyl and hydromorphone. This was a huge market that was dominated by a competitor with known flaws that potentially did not exist in KORSUVA. Those conventional opioids contributed in large part to 2 main postoperative symptoms that developed in patients that were given IV and oral Mu opioids. One was postoperative opioid-induced respiratory depression (POIRD) and the other was postoperative nausea and vomiting (PONV). The Journal of Anesthesiology News had reported that POIRD can occur in 29% of patients even if they show no other signs of ongoing symptoms. Another journal called the Best Practice & Research Clinical Anaesthesiology had reported that PONV can occur in 33% of patients given Mu opioids . Both of these conditions were not only detrimental to the patients that experienced them, but also resulted in lengthened postoperative care and therefore increased hospital expenses. PONV was attributed to approximately $1 billion in postoperative healthcare costs. This again, represented how much expenses could be saved through the use of KORSUVA.
Now, the market for acute pain was huge, and KORSUVA had the potential to introduce itself as a serious competitor to conventional opioid analgesics, however in order to determine whether it was worth continuing funding of this postoperative pain management route, the efficacy of KORUSVA as well as its addition potential had to be evaluated. KORSUVA proved highly effective in pain management in phase 1 and phase 2 clinical trials of 970 patients. Patients noted increased pain relief without any significant negative side effects other than increased urine output and slight facial tingling in some patients. This led to the initiation of phase 3 clinical trials of IV KORSUVA as analgesic in postoperative patients who underwent a variety of different abdominal surgeries in June 2017. 450 Patients were given two different does of KORSUVA (1.0 ug/kg and 0.5 μg/kg I.V.), as well as a placebo and were monitored and asked to score their levels of pain relief. This study is still going on and results were expected to be released in 2018 during the second quarter. The results of this study were critical. The U.S. Food and Drug Administration (FDA) had granted KORSUVA in IV form “breakthrough designation”. This means that if these phase 3 trials proved to be effective, the FDA would improve and speed up the chances for approval. The FDA was notorious for strict regulation and analysis before they approved a potential drug. Tufts Center for the Study of Drug Development had estimated that the average cost of getting a new drug approved by the FDA was around $2.6 billion  (Figure 6). This was still much higher than the approximate $350 million Cara had spent so far on developing KORSUVA in all of its pipelines. Granted, they still needed funding for the completion of phase 3 trials before approval, but this was still much lower than the average cost. Therefore Dr. Derek Chalmers and his board of directors decided that this pipeline, using KORSUVA in IV form to treat postoperative pain was the main sector the company should devote its focus to.
An increase in funding of $12.1 million was devoted to this phase 3 trial as well as additional funding for a human abuse liability (HLA) trial to demonstrate the absence of abuse potential in patients given KORSUVA. Patients undergoing postoperative care were given KORSUVA and others were given the opioid pentacozine. Pentacozine is a Schedule IV drug that is much less addictive than common opioids such as morphine. Patients were asked to score the 2 drugs in sections such as “over liking of the drug”, “feeling high”, and “possibilities of continual use”. The study found that KORSUVA ranked much lower than this already less addictive drug. This study helped to launch KORSUVA into phase 3 trials, put it into the FDA radar, and increase the focus of the company into this area . The company also decided that they would implement a sales team to market KORSUVA to hospitals across the U.S. following FDA approval. They have set the size of this team to 80 individuals to extend to a major portion of the physicians. They have also stated that they plan to organize a group of medical liaison officers and an underlying infrastructure as a foundation for marketing of KORSUVA.
Another potential target market for KORSUVA was as a chronic pain management analgesic. Long-term pain was mainly caused from injuries through accidents and the majority of cases involved lower back pain. These cases are usually treated with long-acting opioids such as oxycodone (Oxycontin) and hydrocodone or drugs that combine these opioids with NSAIDS such as Percocet and Vicodin. These drugs were usually taken by patients outside of the hospital setting and therefore oral formulations were more feasible than IVs. These NSAIDS were gradually being replaced by standalone Mu opioid agonists due to increased public awareness of liver toxicity issues associated with the common NSAID acetaminophen (Paracetamol), as well as FDA placing a requirement of warnings of possible cardiovascular complications on NSAID packaging in July 2005. However, similar to the cases of acute pain management, albeit to a greater degree due to long-term use, these Mu opioids still carried the potential for adverse negative side effects and the development of addiction. In addition to this, long-term use of these drugs could lead to the development of tolerance and therefore the need for continual increased doses and an amplification of those detrimental properties. In 2013, the FDA announced the implication of a brand new set of safety labeling on opioid products as well the requirements of safety studies after drugs have been placed on the market in addition to before . The DEA also regulates the security and distribution of most of these Mu opioids through the Controlled Substances Act. Therefore, if KORSUVA gained FDA approval for chronic pain treatment as well, and can bypass these regulations by proving the absence of the negative properties associated with Mu opioids, it would establish itself as a major player in chronic pain management.
This led to the development of an oral formulation of KORVUSA in a pipeline for chronic pain treatment, specifically running clinical trials in patients suffering from osteoarthritis that was expected to show huge promise. A Phase 2b trial was conducted in 2016 in which 476 patients with osteoarthritis in their hips and/or knees were given varying doses of KORVUSA in tablet form (1.0 mg, 2.5 mg and 5.0 mg) and asked to evaluate their pain relief. This trial however, generated the first negative results for KORVUSA as a pain medication. Only patients suffering from hip osteoarthritis (OA) and only those who received the strongest 5 mg doses noted a significant increase in pain relief. This resulted in a decrease of Cara Therapeutics stock by 40% on the day the trial data was announced. However this data showed that KORVUSA may still have potential to treat OA of the hip, but a new Phase 2b trial must be conducted with new dosage parameters and a focus on patients suffering chronic hip pain only.
Even though this oral KORVUSA pipeline to treat chronic pain has the potential to generate the most revenue post-commercialization, Cara came to the conclusion that they could not afford to devote more time and resources into this area on their own. They announced in the financial report for the 2017 fiscal year that they plan to seek partnerships with companies revolving around the chronic pain market in order to finance further pursuit into this sector. They would instead focus on the acute pain management pipeline if the Phase 3 clinical trials proved successful, as well as the thirds potential market, for anti-pruritic medication.
The final pipeline Cara was involved with was in the field of anti-pruritics. These drugs were designed to alleviate intense itching that comes as a symptom of a variety of diseases. Itching was known to come from the release of substances called pruritogens from various peripheral cells of the body including some immune and nerve cells. Interestingly, it seemed that these cells regulated the release of these compounds through the same opioid receptors responsible for pain relief in traditional opioids; the mu opioid receptors. This was why prolonged opioid use such as through heroin addiction often led to increased itching in individuals. Now, the activation of kappa receptors through a drug like KURSOVA could counteract the effects of Mu receptor activation to relieve itching sensations.
According to IQVIA approximately 45 million Americans were diagnosed with an illness that pruritus as a symptom in 2013. Some form of treatment designed to act against pruritus was prescribed to 47% of these people. This added up to about 21 million prescriptions. There were also cases of uremic pruritus coming from patients on dialysis from diseases such as chronic kidney disease. Fresenius Medical Care, a healthcare company devoted to patients on dialysis projected that, in 2016, around 3 million people around the world were on some form of dialysis treatment and approximately 70% of them experienced renal or uremic pruritus . Therefore these numbers showed Cara that this was obviously not as big a market as that for analgesics, but it was still a sizeable number of potential consumers. There were also no FDA approved drugs to treatment this condition and management was done through attempts to alleviate symptoms. There was also only one truly viable competitor (although this competitor was also not FDA approved) made by a company called Toray Industries called Remitch, however it was both a kappa receptor agonist and a mu receptor agonist. It therefore had the potential to reduce itching in some areas and trigger it in others. It was also known to have the ability to cross the blood brain barrier and induce other negative side effects. Other treatments of pruritus included anti-depressants, anti-histamines and corticosteroids, but these too varied in their actual effectiveness from patient to patient. Cara had to examine effective was KORSUVA at treating these patients. Would it show the same huge promise as in acute postoperative pain management, or would it fail as the oral chronic pain form did?
KORVUSA had a very successful phase 2 trial in June 2016. Patients suffering from uremic pruritus were given KORSUVA injections as well as placebo and asked to rank their scores in terms of reduction of itching. These 174 patients actually experienced on average, a 68% reduction in overall itching. When given IV KORSUVA there was a 100% greater reduction in itching . These results were very promising and led to the initiation of a phase 3 clinical trial in January 2018. 350 patients on hemodialysis as a result of being diagnosed with chronic kidney disease will be monitored over a 12 week period of treatment to evaluate the efficacy of KORSUVA . These results will determine the steps Cara will take going forward in the anti-pruritic market and the expectations are very high.
Final Decisions Going Forward
There were many ups and downs on the road Cara took to establish itself in the anti-pruritic and pain relief market. They recognized that although their breakthrough drug KORSUVA had the potential to treat a variety of cases through different pipelines, as a young company they did not have the foothold and finances to back every single one. They had to make key decisions about how to handle each of their pipelines. Cara recognized that the market for pain management was massive and they had a product that had something every possible one of its competitors did not. They had a drug that could alleviate pain, without possible negative side effects or addiction potential. Initially this was the main focus after the discovery of KORSUVA. They run the drug through clinical trials for both acute pain and chronic pain management, however they could not afford to continue both after their chronic pain pipeline proved that it needed further modification to continue. To address this, Cara will be seeking further partnerships or to license out their products for further testing by other companies such as Maruishi. This will allow them to focus on their successful acute pain pipeline on their own, a path that is currently under phase 3 trials and is generating high expectation. However, because their drug also functioned as an opioid, even if it passed every clinical trial and moved on to commercialization, it would still most likely be under strict FDA regulation. They could not afford to devote all their resources into pain management and found that KORSUVA can actually act on kappa receptors to act as an anti-pruritic. This led to even further pursuit into this new direction. Cara finally decided to devote the majority of its time and resources to two major sectors; using KORSUVA an analgesic for postoperative care and as an anti-pruritic in patients suffering from chronic kidney disease and on dialysis. They did this through careful analysis of both the markets in these sectors as well as the efficacy on their drugs. Cara Therapeutics has huge potential to assert itself in these markets as a provider of the first solely kappa opioid receptor agonist to provide a revolutionized form of pain relief without detrimental effects.
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