CARA: Cara Therapeutics Analysis and Research Report
2018-05-09 - by Asif , Contributing Analyst - 428 views
Cara Therapeutics is a clinical-stage biopharmaceutical company focused on developing and commercializing new chemical entities designed to alleviate pruritus and pain by selectively targeting kappa opioid receptors. Cara Therapeutics is developing a novel and proprietary class of product candidates, led by KORSUVA (CR845/difelikefalin), that target the body’s peripheral nervous system and certain immune cells. The U.S. Food and Drug Administration, or FDA, has conditionally accepted KORSUVA as the trade name for CR845/difelikefalin injection, an investigational drug product for the treatment of itch, whose safety and efficacy have not been fully evaluated by any regulatory authority. In Phase 2 trials, KORSUVA (CR845/difelikefalin) has demonstrated statistically significant reductions in itch intensity and concomitant improvement in quality of life measures in hemodialysis patients with moderate-to-severe chronic kidney disease-associated pruritus, or CKD-aP, and is currently being investigated in Phase 3 trials in hemodialysis patients with CKD-aP. In addition, CR845/difelikefalin has also demonstrated initial signs of efficacy in patients with moderate-to-severe pain without inducing many of the undesirable side effects typically associated with currently available pain therapeutics.
The company commenced operations in 2004, and its primary activities to date have been organizing and staffing its company, developing its product candidates, including conducting preclinical studies and clinical trials of CR845/difelikefalin-based product candidates, and raising capital. To date, Cara Therapeutics has financed its operations primarily through sales of its equity and debt securities and payments from license agreements. Cara Therapeutics has no products currently available for sale, and substantially all of its revenue to date has been revenue from license agreements, although Cara Therapeutics has received nominal amounts of revenue under research grants.
The Market Opportunity – Pruritus
Pruritus, or itch, is defined as an unpleasant sensation that provokes the desire to scratch. Certain systemic diseases have been known to cause pruritus that ranges in intensity from a mild annoyance to an intractable, disabling condition. Itch originates in the epidermis and dermal–epidermal junction and is transmitted by itch-selective sensory neuron C fibers, or pruriceptors. Some of these fibers are sensitive to histamine while others are not, and there is evidence for histamine-insensitive C fibers that are activated by numerous itch-inducing substances or pruritogens, many of which initiate signals through interaction with specific G-protein-coupled receptors. In addition, there is increasing evidence for the differential involvement of these systems in various forms of itch which may involve disease-specific pruritogens. As an example, chronic pruritus associated with kidney failure and dialysis is thought to involve complex interactions among peripheral cells (T cells, mast cells, neutrophils, eosinophils, and keratinocytes) and histamine-insensitive nerve fibers, involving increased release of cytokines, proteases, and neuropeptides, interacting with multiple receptors that lead to exacerbation of itch. These different peripheral cell types express kappa opioid receptors, which can regulate the release of these pruritogenic substances, while the kappa opioid receptors on C fibers are thought to regulate their response to these pruritogens. Because kappa opioid receptors are expressed in peripheral tissues, there appears to be no need for a centrally-acting kappa opioid to modulate itch signals. The itch-sensitive sensory nerve fibers transmit signals to the cell bodies in the dorsal root ganglia (that also have kappa opioid receptors), which send fibers to enter the spinal cord. Itch signals then ascend via the spinothalamic tract to multiple brain areas for sensory processing and interactions with cognitive and other systems.
Additionally, the activation of kappa receptors via an agonist is thought to reduce itching by functionally counteracting increased mu opioid receptor activity which is suggested to be associated with some chronic forms of pruritus. Activation of the mu opioid receptor in the brain and in the peripheral nerve endings results in itching while unselective mu opioid antagonists can inhibit itching. Kappa opioid receptor stimulation inhibits the effects of mu receptor activation both centrally and peripherally.
Pruritus may be classified into the following categories on the basis of the underlying causative disease: renal or uremic pruritus, cholestatic pruritus, dermatological pruritus, hematologic pruritus, endocrine pruritus, pruritus related to malignancy and idiopathic generalized pruritus. According to a study Cara conducted with IMS Health (now IQVIA) utilizing medical claims data from 2013, nearly 45 million patients have been diagnosed with diseases known to trigger pruritus in the United States alone. Of those patients, nearly half (47%), or 21 million, received a prescription for an anti-pruritic agent such as corticosteroids, antihistamines, select antidepressants, counterirritants, bile acid sequestrants, rifampin, narcotic antagonists and partial agonists, topical immunomodulators (Elidel, Protopic) or gabapentin.
Chronic Kidney Disease-Associated Pruritus (CKD-aP)
CKD-aP (also known as uremic pruritus) can occur in patients with chronic renal failure and is most often seen in patients receiving hemodialysis. According to Fresenius Medical Care, a world leading provider of products and medical care for dialysis patients, there were approximately 3 million patients globally undergoing dialysis in 2016. It is estimated that nearly 70% of these patients suffer from some renal or uremic pruritus with over 50% of these patients experiencing moderate to severe pruritus according to a study of dialysis patients.
Currently, there are no approved products in the United States to treat CKD-aP. Patients are generally managed with a multitude of products including corticosteroids, gabapentin, antihistamines, antidepressants and others with varying degrees of success. There is one product, nalfurafine (Remitch®) marketed by Toray Industries, approved to treat CKD-aP in Japan. Nalfurafine is a kappa opioid receptor agonist, but it also has partial mu-opioid receptor activity. Mu agonists, like morphine, are known to cause itch. Kappa agonists that cross the blood brain barrier, like nalfurafine, are also known to cause CNS-related adverse events resulting in high rates of discontinuation. The limited efficacy in light of concerns about adverse events caused European Medicines Agency not to approve nalfurafine for the treatment of uremic pruritus in 2013.
Other Causes of Pruritus
There are many other systemic diseases that can trigger pruritus in patients. They include cholestatic liver disease, endocrinologic disease (e.g. hyperthyroidism), malignancy (e.g. Hodgkin lymphoma), hematologic disease (e.g. polycythemia vera), atopic dermatitis, eczema, psoriasis, hives/urticarial, and lice/scabies. Data from a Cara-sponsored IMS Health (now IQVIA) study, utilizing medical claims data from 2013, indicate that over 20 million patients suffer from some level of pruritus in the United States. Many of these patients are sub-optimally treated for their pruritus with products not approved to treat their condition.
The Market Opportunity – Pain Management
Pain is generally categorized by its duration as either acute or chronic, by its severity, as either mild, moderate or severe, and its type and/or causality, such as postoperative or neuropathic. Acute pain is typically caused by an injury resulting in nerve, tissue or bone damage and is expected to subside in severity when the injury heals. Postoperative pain is a subset of the acute pain market. Chronic pain, on the other hand, is prolonged, and can be the long-term result of an acute injury or an ongoing disease condition, such as neuropathic pain associated with diabetes. According to a recent Institute of Medicine report, chronic pain affects approximately 100 million U.S. adults, while millions of others experience acute pain caused by events such as surgery, injury, childbirth and illness.
The severity of pain is the key factor in determining the appropriate therapy. Mild or mild-to-moderate pain is generally treated with non-opioid products, such as oral formulations of nonsteroidal anti-inflammatory drugs, or NSAIDs (e.g., ibuprofen, naproxen), aspirin, and acetaminophen. Moderate-to-severe pain, on the other hand, is typically treated with products containing traditional mu opioids. Mu opioid analgesics are effective to some degree for many patients, but have poor side effect and abuse liability profiles, which limits or precludes their use in treating less severe pain. For many people with moderate-to-severe pain, opioid analgesics are the only effective method of treating pain. As a result, these opioid analgesics are among the largest prescription drug classes in the United States. According to IQVIA, the total U.S. market for pain management pharmaceuticals was $45.5 billion in 2017. The prescription pain management market in the United States is dominated by opioid analgesics, which, according to IQVIA data, represented 53% of the 406 million analgesic prescriptions written in 2017 and accounted for sales of $6.9 billion in that year. In 2016, according to Visiongain, an independent industry research company, total sales for pain therapies worldwide, exceeded $67.8 billion.
Opioid analgesics decrease the perception of pain by stimulating mu, delta and/or kappa opioid receptors. All of these receptors are involved in modulating pain signals. The most widely used opioid analgesics, including hydrocodone, oxycodone, morphine, and fentanyl, act primarily through the activation of mu opioid receptors in the central nervous system, or CNS. However, because of the wide distribution of mu opioid receptors throughout the brain, morphine and other mu opioid analgesics also trigger a characteristic pattern of adverse “central” side effects, including nausea and vomiting, itching and respiratory depression. Mu opioids are also known to cause euphoria, which can lead to misuse, abuse and addiction issues.
Postoperative Pain Market
Postoperative pain represents a substantial part of the overall acute pain market. According to the International Association for the Study of Pain, more than 46 million inpatient and 53 million outpatient surgeries are performed annually in the United States. Moderate-to-severe pain in a hospital or other medical setting is most often treated with injectable analgesics. The United States I.V./injectable analgesic therapy market primarily consists of mu opioid agonists, such as morphine, hydromorphone and fentanyl, and certain non-opioid analgesics, such as Toradol® (and related generic I.V. ketorolac products), Caldolor® (I.V. ibuprofen), Dyloject® (I.V. diclofenac sodium) and Ofirmev® (I.V. acetaminophen). In 2014, there were 234.3 million doses of injectable opioid analgesics used in United States according to the IMS Health (now IQVIA) NSP Audit.
According to Practice Guidelines developed by the American Society of Anesthesiologists, the standard of care for treating acute postoperative pain is multimodal analgesia, which includes the administration of two or more drugs that act by different mechanisms for providing analgesia in a manner that will minimize the occurrence of adverse events. When patients are ready for discharge, a transition is typically made to a prescription oral pain medication, allowing patients to self-administer relatively strong analgesics after being discharged home. This transition from an I.V. pain medication to an oral pain medication is commonly referred to as I.V.-to-oral transition, or “step-down” therapy.
Strong mu opioid analgesics, such as morphine, fentanyl, and hydromorphone, are mainstays of pain treatment in the immediate postoperative period and are used as part of a multimodal analgesic approach. However, the use of strong mu opioid analgesics is associated with an array of unwanted and serious side effects, including postoperative opioid-induced respiratory depression, or POIRD, postoperative nausea and vomiting, or PONV, and opioid-induced bowel dysfunction, which contributes to the severity of postoperative ileus. According to Anesthesiology News, a trade journal, the incidence of POIRD may be as high as 29%, can occur unexpectedly in even the healthiest of patients, and exerts a disproportionately high toll on length of stay and hospital costs due to the significant expenses associated with the treatment of POIRD. According to an article published in Best Practice & Research Clinical Anaesthesiology, a trade journal, PONV occurs in approximately one-third of surgical patients overall and is one of the most important factors in determining length of stay after surgery, resulting in estimated annual costs in the U.S. in the range of $1 billion. These mu opioid-related adverse events not only significantly increase the cost of care, but also reduce a patient’s quality of care and lead to sub-optimal recovery.
Nonopioid analgesics formulated for injection or infusion, including I.V. acetaminophen and NSAIDs, such as I.V. ibuprofen, are available as alternatives to mu opioids to relieve acute pain, but their use is limited in a postoperative care setting as a result of their limited efficacy. I.V. acetaminophen and NSAIDs also have side effects that limit their use at higher, more efficacious doses. Acetaminophen is associated with risk of liver toxicity, which can be fatal, and NSAIDs are associated with risks of bleeding, serious gastrointestinal side effects including ulcers, kidney damage, and serious cardiovascular thrombotic events such as stroke and heart attack, which can be fatal.
Chronic Pain Market
The most common causes of moderate-to-severe chronic pain are musculoskeletal problems and inflammatory conditions. Injuries from accidents resulting in fractures, dislocations or soft tissue injury, as well as lower back pain, are the most frequent causes of musculoskeletal pain. Although these injuries are mostly non-fatal, the cost in terms of long-term disability, medical expense and lost productivity is large. Moderate-to-severe chronic pain is typically treated with prescription products including immediate release and long-acting opioids, such as the branded products OxyContin® (oxycodone), NUCYNTA® ER (tapentadol) and Opana® ER (oxymorphone), and combination products that include an opioid combined with an NSAID or acetaminophen, such as the branded products Vicodin® (hydrocodone and acetaminophen) and Percocet® (oxycodone and acetaminophen). Prescription products for chronic pain are usually in oral tablet or capsule form because the vast majority of these patients are taking these medications outside of the hospital setting.
On April 7, 2005, the FDA announced a decision to require boxed warnings of potential cardiovascular risk for all NSAIDs. The 2005 FDA warning related to cardiovascular adverse events associated with NSAIDs and the increased awareness of the risk of liver toxicity associated with high doses of acetaminophen have led to increased use of mu opioid analgesics for the treatment of chronic pain. However, the use of mu opioid analgesics carries significant additional risks. Chronic opioid use causes patients to develop tolerance for the opioid, which results in the patient needing increasing opioid doses to achieve the same level of pain relief. For the most commonly prescribed analgesic combination products, the need for increasing doses to achieve the same level of pain relief means exposure to increasing amounts of NSAIDs or acetaminophen, which carry the risks attendant to these therapeutics. Moreover, due to their CNS activity, mu opioids produce feelings of euphoria, which can give rise to abuse and addiction. Underlining the severity of this issue, in September 2013, the FDA announced class-wide safety labeling changes and new post-market study requirements for all extended-release and long-acting mu opioid analgesics intended to treat pain. In support of this action, the FDA Commissioner stated that “[t]he FDA is invoking its authority to require safety labeling changes and post-market studies to combat the crisis of misuse, abuse, addiction, overdose, and death from these potent drugs that have harmed too many patients and devastated too many families and communities.” In addition, as a result of their potential for misuse, abuse and addiction, currently approved mu opioids are strictly regulated by the DEA under the Controlled Substances Act, which imposes strict registration, record keeping and reporting requirements, security control and restrictions on prescriptions, all of which significantly increase the costs and the liability attendant to prescription opioid analgesics.
The Unmet Need in Pain Management
Despite the size of the pain management market, there has been little innovation in the development of new analgesics, with nearly all recent new drug approvals limited to reformulations and improved methods of delivery of existing therapeutics. Mu opioids continue to be the most prescribed drugs for pain management, despite their side effects and the potential for misuse, abuse and addiction. These concerns often cause healthcare providers to administer or prescribe less than optimal doses of mu opioids, or patients to take lower than prescribed doses, resulting in inadequate pain relief. Consequently, the company believe that the pain market represents a therapeutic area with substantial unmet needs for patients in pain, for physicians who must balance pain control with risks of causing severe adverse events, and for healthcare organizations that bear the costs of managing the consequences of undertreated pain and drug-related adverse events. The company believe that CR845/difelikefalin, with its novel mechanism of action, will be attractive to patients and physicians, as well as hospitals and payers, as a treatment for moderate-to-severe pain because of its ability to provide pain relief without opioid-related adverse events or abuse and addiction issues associated with currently approved mu opioid analgesics.
The company's strategy is to develop and commercialize a novel and first-in-class portfolio of peripherally-acting kappa opioid receptor agonists, with KORSUVA (CR845/difelikefalin) injection and Oral KORSUVA (CR845/difelikefalin) as its lead candidates. Cara Therapeutics has designed and are developing product candidates which have clearly defined clinical development programs and target significant commercial market opportunities. The key elements of its strategy are as follows:
Advance KORSUVA (CR845/difelikefalin) injection for the treatment of moderate-to-severe CKD-aP in patients undergoing hemodialysis to support regulatory approval. In January 2018, based on positive data from its earlier Phase 2 studies, the company initiated the first pivotal Phase 3 trial of KORSUVA (CR845/difelikefalin) injection in hemodialysis, or HD, patients suffering from moderate to severe CKD-aP. The company also expect to initiate an international Phase 3 study with KORSUVA (CR845/difelikefalin) injection in multiple countries later this year. These studies will support filings for regulatory approval in the United States and other non-U.S. markets. In June, 2017, the FDA granted Breakthrough Therapy Designation to KORSUVA (CR845/difelikefalin) injection for the treatment of CKD-aP in HD patients, for which there are currently no approved therapies in the United States. The Breakthrough Therapy Designation was in part supported by positive data from its previous Phase 2 efficacy studies. In March 2017, the company reported positive data from a Phase 2/3 trial of KORSUVA (CR845/difelikefalin) injection in HD patients with CKD-aP where patients receiving KORSUVA (CR845/difelikefalin) experienced a highly statistically significant reduction in worst itch scores as well as statistically significant improvement in quality of life measures versus placebo after eight weeks of treatment. KORSUVA (CR845/difelikefalin) was observed to be well tolerated, with no significant drug-related events. Earlier, in July 2015, the company reported similar positive top-line safety and efficacy results from a smaller Phase 2 trial in HD patients with CKD-aP after two weeks of treatment.
Build a specialty sales and marketing organization to commercialize KORSUVA (CR845/ difelikefalin) injection for the treatment of CKD-aP in HD patients in the United States, if approved. If KORSUVA (CR845/ difelikefalin) injection is approved by the FDA for the treatment of CKD-aP in HD patients, the company expect to establish a sales force to market to nephrologists in dialysis centers across the United States. The company also intend to build a supportive commercialization organization as well as establish a reimbursement strategy and infrastructure to support its sales and marketing efforts. The company do not intend to commercialize KORSUVA (CR845/difelikefalin) injection for CKD-aP in HD patients on its own outside the United States and expect to seek one or more global development and commercialization partner(s). The company already have development and commercialization agreements with Maruishi and with CKDP for development of KORSUVA (CR845/difelikefalin) for the Japanese and South Korean markets, respectively.
Expand the use of Oral KORSUVA (CR845/difelikefalin) in other pruritic indications by establishing proof-of-concept in clinical conditions such as non-dialysis stage III-V CKD-aP, chronic liver disease associated pruritus (CLD-aP) and certain dermatologic conditions. Based on potent anti-pruritic (anti-itch) effect the company observed with KORSUVA (CR845/difelikefalin) injection in CKD-aP in hemodialysis patients as well as the data the company and others have generated in preclinical models of itch, Cara Therapeutics has initiated Phase 1 safety and pharmacokinetic, or PK, studies with Oral KORSUVA (CR845/difelikefalin) in different patient populations where pruritus continues to be a major unmet medical need. In the fourth quarter of 2017, the company initiated a Phase 1 study with Oral KORSUVA (CR845/difelikefalin) in patients with CKD to determine drug exposure to inform dose selection for a Phase 2 study in patients with CKD-aP, which the company expect to initiate in the first half of 2018. Cara Therapeutics is also conducting a Phase 1 safety/ tolerability and PK study in patients with CLD due to various underlying etiologies to support an efficacy proof-of-concept Phase 2 study in similar patients with CLD-aP.
Continue to advance I.V. CR845/difelikefalin for the treatment of moderate-to-severe acute pain in acute care settings in the United States. Cara Therapeutics is conducting an adaptive Phase 3 trial of I.V. CR845/difelikefalin for postoperative pain. An interim conditional power analysis of its adaptive Phase 3 trial of I.V. CR845/difelikefalin for postoperative pain was conducted in the second quarter of 2017 and the study continues to test two doses of I.V. CR845/difelikefalin (0.5 ug/kg and 1 ug/kg). Based on guidance from the FDA, the company believe the company will require at least 500 total exposures to CR845/difelikefalin at the highest to-be-marketed dose, including all Phase 1, Phase 2 and Phase 3 trials, prior to submitting a new drug application, or NDA, to the FDA for this indication.
Build a sales and marketing organization to commercialize I.V. CR845/difelikefalin for acute pain in the acute care setting in the United States, if approved. Cara Therapeutics is planning to establish a hospital-based sales force to market I.V. CR845/difelikefalin to physicians in the United States, if approved. The company believe that a sales force of approximately 80 sales professionals will be able to reach a large majority of its target market. The company also intend to build a medical liaison organization as well as a reimbursement infrastructure to support its sales and marketing efforts.
Establish partnerships for further development and commercialization of CR845/difelikefalin for chronic pain indications. The company do not intend to further develop and commercialize Oral CR845/difelikefalin on its own and will seek partnerships and collaborations with companies that have development and commercialization expertise in chronic pain. In June 2017, the company announced top-line results of Oral CR845/difelikefalin from the Phase 2b double blind placebo-controlled trial where three different doses (1, 2.5 and 5 mg twice daily) of CR845/difelikefalin were evaluated in patients with moderate to severe osteoarthritis, or OA, of the hip or knee over an eight-week treatment period. While the study did not meet statistical significance in reduction in pain scores across all OA patients (OA of hip and knee), at the 5 mg twice daily dose, patients with OA of the hip experienced statistically significant reduction in mean weekly pain score.
The company's product candidate, CR845/difelikefalin, is a new chemical entity, which is designed to selectively stimulate kappa, rather than mu, opioid receptors outside of the CNS. CR845/difelikefalin has been designed with specific chemical characteristics to restrict its entry into the CNS and further limit its mechanism of action to kappa opioid receptors in the peripheral nervous system, or nerves outside of the brain and spinal cord. In addition to the side effects associated with activation of mu opioid receptors in the CNS, activation of kappa receptors in the CNS is also known to result in some undesirable effects, including acute psychiatric disorders. CR845/difelikefalin specifically targets peripheral nervous system and certain immune cells that results in modulation of pain signals as well as relief from pruritus or itch associated with certain chronic diseases. Since CR845/difelikefalin is designed to modulate signals peripherally without any significant activation of mu or kappa opioid receptors in the CNS, it is generally not expected to produce the CNS-related side effects of mu opioids or the psychiatric side effects associated with centrally-active kappa opioids. CR845/difelikefalin has been administered to more than 1,800 human subjects in Phase 1, Phase 2, Phase 2/3 and Phase 3 clinical trials as an I.V. infusion, rapid intravenous injection or oral capsule or tablet, and thus far has been observed to be well tolerated in these clinical trials.
Based on the clinical trials and preclinical studies Cara Therapeutics has completed to date, the company believe that CR845/difelikefalin, if approved, will be attractive to both patients and physicians as a treatment for moderate-to-severe pain and pruritus associated with certain diseases such as Chronic Kidney Disease-associated pruritus, or CKD-aP, Chronic Liver Disease associated pruritus, or CLD-aP and others due to the following attributes:
- novel, peripherally-acting, kappa opioid receptor agonist mechanism of action;
- evidence of efficacy in completed clinical trials of pain and pruritus;
- potential for reducing mu opioid use and opioid-related adverse events, or AEs, such as nausea and vomiting;
- avoidance of mu opioid-related CNS side effects, such as respiratory depression and euphoria;
- absence of euphoria which lowers addiction or abuse potential;
- avoidance of interactions with other drugs because, as a peptide composed of four non-natural D-amino acids that is not metabolized in the liver, CR845/difelikefalin does not interact with the liver enzymes responsible for the metabolism of most commonly used classes of drugs; and
- availability in injectable form for acute pain treatment as well as for treatment of pruritus in CKD patients undergoing hemodialysis in the hospital setting and oral form for treatment of chronic pain or pruritus conditions in the outpatient setting.
The company's current product candidate pipeline is summarized in the table below:
|Program||Product Candidate||Primary Indication||Status||Commercialization Rights|
|Pruritus||KORSUVA (CR845/ difelikefalin) Injection||Pruritus Chronic Kidney Disease- Hemodialysis (CKD-HD)||• Phase 3 U.S. efficacy trial ongoing; Phase 3 long term safety trial ongoing||Cara (Worldwide, other than Japan and South Korea); Maruishi (Japan); CKDP (South Korea)|
|• Phase 2/3 adaptive trial completed (data released); end of Phase 2 meeting with FDA completed|
|• Breakthrough Therapy Designation granted by FDA in June 2017|
|Oral KORSUVA (CR845/difelikefalin)||Pruritus Chronic Kidney Disease- Hemodialysis (CKD-HD)||• Phase 1 safety and PK study completed||Cara (Worldwide, other than Japan and South Korea); Maruishi (Japan); CKDP (South Korea)|
|Oral KORSUVA (CR845/difelikefalin)||Pruritus CKD (Stage III - V) (non-hemodialysis)||• Phase 1 safety and PK study in patients with Stage III-V CKD ongoing||Cara (Worldwide, other than Japan and South Korea); Maruishi (Japan); CKDP (South Korea)|
|Oral KORSUVA (CR845/difelikefalin)||Pruritus Chronic Liver Disease (CLD)||• IND filed in 4Q 2017||Cara (Worldwide, other than South Korea); CKDP (South Korea)|
|• Phase 1 safety and PK trial initiated in 1Q 2018|
|Pain||CR845/difelikefalin Injection||Acute Post Operative Pain||• Phase 3 Adaptive trial ongoing; Interim conditional power analysis completed. Data expected in 2Q 2018||Cara (Worldwide, other than Japan and South Korea); Maruishi (Japan); CKDP (South Korea)|
|Oral CR845/difelikefalin||Chronic Pain||• Phase 2b osteoarthritis, or OA, clinical trial completed. Top-line data released||Cara (Worldwide, other than South Korea); CKDP (South Korea)|
|CR701||Chronic Pain||• Preclinical||Cara (Worldwide)|
KORSUVA (CR845/Difelikefalin) Injection for Treatment of Chronic Kidney Disease-Associated Pruritus (CKD-aP)
Pruritus, or itch, is associated with certain chronic conditions such as chronic kidney disease, or CKD, as well as with diseases such as atopic dermatitis, eczema, cholestatic liver disease and psoriasis. Based on KORSUVA (CR845/difelikefalin)’s effect on the peripheral nervous system and immune cells as well as KORSUVA (CR845/difelikefalin)’s anti-pruritic potency in preclinical models, the company believe KORSUVA (CR845/difelikefalin) has the potential to treat pruritus across multiple medical conditions.
Uremic pruritus, also known as CKD-associated pruritus, or CKD-aP, is an intractable systemic itch condition with high prevalence in patients with CKD undergoing dialysis for which there are no approved therapeutics in the United States.
In the first quarter of 2018, the company initiated the first pivotal Phase 3 efficacy trial of KORSUVA (CR845/difelikefalin) injection in the United States for the treatment of CKD-aP in patients undergoing hemodialysis. The company also expect to initiate an international Phase 3 efficacy trial of KORSUVA (CR845/difelikefalin) injection in 2018. In addition to the efficacy trials, Cara Therapeutics is also conducting a 52-week Phase 3 safety study of KORSUVA (CR845/difelikefalin) injection in patients undergoing hemodialysis with CKD-aP.
In June 2017, the FDA granted breakthrough therapy designation for KORSUVA (CR845/difelikefalin) injection for the treatment of moderate-to-severe uremic pruritus in patients with CKD undergoing hemodialysis. This regulatory decision was supported by positive top-line results from the Phase 2 clinical trial of KORSUVA (CR845/difelikefalin) injection in patients with CKD-aP. Breakthrough therapy designation is granted to expedite the development and review process for new therapies addressing serious or life-threatening conditions, where preliminary clinical evidence indicates that the drug candidate may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints.
KALM-1 Phase 3 Efficacy Trial of KORSUVA (CR845/Difelikefalin) Injection
In January, 2018 the company initiated the first Phase 3 efficacy trial to support regulatory filings for the approval of KORSUVA (CR845/difelikefalin) injection. This U.S study is a multicenter, randomized, double-blind, placebo-controlled 12-week treatment trial (with a 52-week open label extension phase) that is designed to evaluate the safety and efficacy of 0.5 ug/kg of KORSUVA(CR845/difelikefalin) injection to be administered three times per week after dialysis in 350 hemodialysis patients with moderate-to-severe pruritus, with a pre-specified interim analysis that allows for expansion of the study to up to 500 patients, if needed. The primary efficacy endpoint is the proportion of patients achieving at least a 3‑point improvement from baseline with respect to the weekly mean of the daily 24‑hour worst itching intensity numeric rating scale, or NRS, score at week 12. Secondary endpoints of the Phase 3 trial include assessment of itch-related quality of life changes measured using validated self-assessment 5-D Itch and Skindex-10 scales, as well as the proportion of patients achieving at least 4-point improvement from baseline in weekly mean of the daily 24-hour worst itching NRS score at week 12.
Phase 3 Safety Trial of KORSUVA (CR845/Difelikefalin) Injection
In the second quarter of 2017, the company initiated a 52-week Phase 3 safety trial that is expected to enroll up to 240 hemodialysis patients with CKD-aP who completed one of its prior Phase 2/3 trials of KORSUVA (CR845/difelikefalin) injection (CR845-CLIN2101 Part A or CR845-CLIN2005 Part B) as well as patients who have not been previously exposed to CR845/difelikefalin. This open-label trial is evaluating the long-term safety of KORSUVA (CR845/difelikefalin) injection at the dose of 0.5ug/kg.
The design and dose selection for its Phase 3 trials are based on results of the previously completed Phase 2 trials of KORSUVA (CR845/difelikefalin) injection in hemodialysis patients with CKD-aP in consultation with the FDA as part of its End of Phase 2 meeting with the FDA that was held in September 2017.
Phase 2/3 Adaptive Design Trial of KORSUVA (CR845/Difelikefalin) Injection in Dialysis Patients
In June 2016, the company initiated a two-part Phase 2/3 adaptive design trial of KORSUVA (CR845/difelikefalin) injection in dialysis patients suffering from moderate-to-severe uremic pruritus. In March 2017, the company announced top-line data from the Phase 2 trial, which was a randomized, double-blind, placebo-controlled trial of three doses of intravenous KORSUVA (CR845/difelikefalin) injection (0.5ug/kg, 1.0 ug/kg and 1.5 ug/kg) administered three times per week after dialysis over an eight-week treatment period in 174 patients with moderate-to-severe uremic pruritus.
The primary endpoint of this trial was the change from baseline of the mean worst itching score for week eight measured on a standard NRS for itch. Patients receiving KORSUVA (CR845/difelikefalin) injection experienced a 68% greater reduction from baseline in worst itch scores than those receiving placebo (p<0.0019). The secondary endpoint of this trial focused on quality of life measures associated with pruritus using the Skindex-10 score, a validated self-assessment scale with higher scores indicating worse quality of life. Patients receiving I.V. CR845 experienced a 100% greater reduction from baseline in the average total Skindex-10 score at week eight versus those receiving placebo (p<0.0007). The total average Skindex-10 score reflected statistically significant reductions in each of the three Skindex-10 domains: disease (p<=0.0001), mood/emotional distress (p=0.01) and social functioning (p=0.009). In a post-hoc analysis, (1) 64% of the patients treated at the 0.5 ug/kg dose experienced at least a 3‑point improvement from baseline with respect to the weekly mean NRS score versus 29% of patients on placebo (p<0.01), and (2) 51% of the patients treated at the 0.5 ug/kg dose experienced at least a 4‑point improvement from baseline with respect to the weekly mean NRS score versus 24% of patients on placebo (p<0.05).
Overall, KORSUVA (CR845/difelikefalin) was observed to be well tolerated over the eight-week treatment period and the unblinded Drug Safety Monitoring Board did not raise any safety concerns during the course of the trial. The most common adverse events were transient paresthesia (i.e., primarily mid-facial tingling or numbness), somnolence and dizziness, as reported in previous clinical studies of KORSUVA (CR845/difelikefalin). Full results of this trial were presented at Kidney Week 2017, the American Society of Nephrology's Annual Meeting on November 2-4, 2017.
Phase 2 Efficacy Trial in Dialysis Patients (Part B)
Part B of the CLIN2005 study was a randomized, double-blind, placebo-controlled Phase 2 proof-of-concept trial, which measured the efficacy of KORSUVA (CR845/difelikefalin) injection compared to placebo in reducing the intensity of itch in dialysis patients with uremic pruritus over a two-week dosing period, who had baseline "worst itching" scores of greater than 40% on a visual analog scale, or VAS. The primary endpoint of the study was the change from baseline in the average "worst itching" scores during the second week of treatment, as recorded on a VAS. Secondary endpoints focused on quality of life measures associated with pruritus burden using a series of validated self-assessment scales. The study enrolled a total of 65 dialysis patients in the United States. In July 2015, the company reported positive top-line efficacy results from this trial, in which the company observed that KORSUVA (CR845/difelikefalin) injection demonstrated statistically significant reduction in worst itch intensity, the primary endpoint of the trial, as well as statistically significant improvement in quality of life measures such as Skindex-10, the trial’s secondary endpoint. The overall safety and tolerability profile was favorable.
Phase 1b Safety and Pharmacokinetic Trial in Dialysis Patients (Part A)
In 2014, the company conducted a Phase 1b clinical trial, which was part A of CLIN2005, a Phase 2 proof-of-concept trial of KORSUVA (CR845/difelikefalin) injection for the treatment of uremic pruritus. Part A was a double‐blind, randomized, placebo‐controlled trial designed to evaluate the safety and PK of KORSUVA (CR845/difelikefalin) injection in 24 hemodialysis patients. KORSUVA (CR845/difelikefalin) was administered in the form of intravenous bolus injection at doses ranging from 0.5 ug/kg to 2.5 ug/kg after each dialysis session up to three times per week. Pharmacokinetic analysis indicated that KORSUVA (CR845/difelikefalin) injection exhibited dose linear increases in maximum serum concentration and total KORSUVA (CR845/difelikefalin) exposure measured by AUC, with an approximate 10-fold increase in AUC across doses in these dialysis patients compared to normal subjects. KORSUVA (CR845/difelikefalin) injection was observed to be safe and well tolerated over the one-week dosing period. The most common AEs were transient facial tingling and headache. No serious AEs were reported. Although uremic pruritus was not an inclusion criterion for randomization, three subjects entered the trial with "worst itching" baseline scores in the moderate-to-severe range, > 4.0 on a 10.0-point VAS. All three of these subjects received dosing of KORSUVA (CR845/difelikefalin) injection up to three times per week (with two subjects receiving 1 ug/kg and one receiving 2.5 ug/kg) and ended the one-week dosing period with reported "worst itching" scores of 1.0 or less on a VAS.
Oral KORSUVA (CR845/Difelikefalin) for Treatment of Chronic Kidney Disease-Associated Pruritus
In mid-2017, the company announced top-line results from a Phase 1 safety and PK study of multiple doses of Oral KORSUVA (CR845/difelikefalin) in patients with CKD undergoing hemodialysis to define tablet strengths to inform its ability to develop an oral tablet formulation for the treatment of moderate-to-severe uremic pruritus. The Phase 1 results showed that all four tablet strengths of Oral KORSUVA (CR845/difelikefalin) (0.25, 0.5, 1.0 and 2.5 mg) were generally well-tolerated when administered either daily or after each dialysis session three times per week. Top-line PK analysis indicated that plasma levels of KORSUVA (CR845/difelikefalin) attained after oral administration of doses up to 2.5 mg were comparable to or exceeded those attained with clinically efficacious doses of KORSUVA (CR845/difelikefalin) injection for the treatment of moderate-to-severe CKD-aP in patients undergoing hemodialysis. The plasma levels of KORSUVA (CR845/difelikefalin) attained after oral administration of the 1.0 mg tablet strength approximated those attained with the 1.0 ug/kg KORSUVA (CR845/difelikefalin) injection dose, which demonstrated significant clinical benefit in its Phase 2/3 trial in patients undergoing hemodialysis with CKD-aP.
Overall, the frequency of treatment emergent adverse events, or TEAEs, in Oral KORSUVA (CR845/difelikefalin)-treated patients was similar to the group administered placebo. All TEAEs were generally mild and comparable to those reported in its Phase 2/3 trial after KORSUVA (CR845/difelikefalin) injection administration in CKD-aP patients undergoing hemodialysis. Absolute oral bioavailability of the 1.0 mg tablet strength was determined to be similar in CKD patients undergoing hemodialysis to that obtained in non-CKD patients.
In October 2017, the company initiated a Phase 1 trial of Oral KORSUVA (CR845/difelikefalin) in patients with Stage III - V CKD (non-hemodialysis). The Phase 1 trial is designed to examine the PK and safety of up to four tablet strengths of Oral KORSUVA (CR845/difelikefalin) (0.25 mg, 0.5 mg, 1.0 mg and 2.5 mg), dosed daily over a one-week treatment period in up to 80 patients with stage III-V CKD (non-hemodialysis). Data from this trial will inform dose selection and design of a planned placebo-controlled Phase 2 trial of Oral KORSUVA (CR845/difelikefalin) in patients with stage III-V CKD (non-hemodialysis) and hemodialysis patients with moderate-to-severe pruritus, which the company plan to initiate in the first half of 2018.
Oral KORSUVA (CR845/Difelikefalin) for Treatment of Chronic Liver Disease-Associated Pruritus
CLD-aP manifests as “cholestasis” symptoms causing severe whole-body itch. It is an intense, intractable, debilitating condition that significantly disrupts patients’ daily activities and sleep, and consequently impairs their quality of life. Although the pathophysiology is not well understood, it is likely multi-factorial, involving immune system dysregulation (including elevated pro-inflammatory activity) and imbalance in the endogenous opioid system. Consequently, the use of selective kappa-opioid receptor agonists has been suggested for the treatment of pruritus in patients with CLD.
In the fourth quarter of 2017, the company submitted an investigational new drug application, or IND, to the FDA for Oral KORSUVA (CR845/difelikefalin) for symptomatic relief of CLD-aP and initiated a Phase 1 safety and PK clinical trial of Oral KORSUVA (CR845/difelikefalin) in patients with chronic liver disease in the first quarter of 2018. The company aim to initiate a Phase 2 trial of Oral KORSUVA for the treatment of CLD-aP later this year.
Intravenous CR845/Difelikefalin for Treatment of Acute Postoperative Pain
Cara Therapeutics is also investigating CR845/difelikefalin for the treatment of pain in an acute care setting. CR845/difelikefalin is designed to provide pain relief without stimulating mu opioid receptors and therefore potentially without mu opioid-related side effects, such as nausea, vomiting, respiratory depression and euphoria.
Phase 2/3 Efficacy and Safety Trial of CR845/Difelikefalin Injection in Patients Undergoing Abdominal Surgery
In September 2015, the company initiated its Phase 3 clinical trial program for CR845/difelikefalin injection in postoperative pain in an adaptive trial in patients undergoing a range of abdominal surgeries. This trial is a multi-center, randomized, double-blind, placebo-controlled, parallel-group adaptive design trial with repeated doses of CR845/difelikefalin injection or placebo administered both prior to and following abdominal surgery. The trial protocol initially included three dose levels of CR845/difelikefalin injection (1.0 ug/kg, 2.0 ug/kg and 5.0 ug/kg), which were compared to placebo with an interim conditional power assessment to identify optimal doses to be used to complete the enrollment of this trial.
In June 2016, the company modified the trial protocol and resumed the trial as a three-arm trial, testing two doses of I.V. CR845/difelikefalin (1.0 ug/kg and 0.5 ug/kg) versus placebo, based on a safety review by it, the trial’s Independent Data Monitoring Committee, or IDMC, and the FDA, of unblinded safety data from the first 90 patients dosed. The safety review was conducted in response to a clinical hold that the FDA placed on the trial in February 2016 and removed in April 2016 following the safety review. The clinical hold was based on a pre-specified stopping rule related to elevated serum sodium levels of greater than 150 mmol/L that was included in the clinical trial protocol.
The revised trial is enrolling up to 450 patients within the United States undergoing abdominal surgeries, all of which are associated with moderate-to-severe postoperative pain. The primary efficacy endpoint 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 NRS score collected at pre-specified time points through 24 hours post-surgery. Postoperative nausea and vomiting is also being evaluated as a secondary efficacy endpoint.
In June 2017, the company announced the completion of a prespecified interim conditional power analysis of its adaptive Phase 3 trial of CR845/difelikefalin injection. Based on the guidance of the IDMC, the trial is continuing in accordance with its current protocol, testing two doses of CR845/difelikefalin injection (1.0 ug/kg and 0.5 μg/kg I.V.) versus placebo in up to 450 patients undergoing abdominal surgery. The IDMC also reviewed the available safety information, including serum sodium levels, and confirmed that both doses of CR845/difelikefalin injection were observed to be well tolerated with no significant changes in the monitored safety parameters. The company expect data from this trial in the second quarter of 2018.
Phase 1 and 2 Acute Pain Clinical Trials (Post-Surgery) of CR845/Difelikefalin Injection
Previously, in three different randomized, double-blind, placebo-controlled Phase 2 clinical trials, CR845/difelikefalin injection has been shown to be well tolerated and demonstrated efficacy of pain relief. Two of these trials were conducted in patients undergoing laparoscopic hysterectomy, a soft tissue surgical procedure, and a third trial was in patients undergoing bunionectomy, a hard tissue surgical procedure. Intravenous administration of CR845/difelikefalin resulted in statistically significant reductions in pain intensity, as measured by the sum of pain intensity difference. In addition, in both surgical models, CR845/difelikefalin injection exhibited an ability to decrease the opioid-related adverse events, or AEs, of nausea and vomiting associated with current therapies, along with no evidence of drug-related respiratory depression. According to research conducted at Duke University, post-operative AEs, such as nausea and vomiting associated with currently approved opioids, increase the length of time that a patient spends in the hospital and increases the cost of caring for those patients. Therefore, the company believe that if successful, CR845/difelikefalin injection administered in a post-surgical setting has the potential to significantly reduce the length of hospital stays, thereby reducing overall healthcare costs.
The safety profile of CR845/difelikefalin injection has been demonstrated in six Phase 1 and three Phase 2 acute pain studies. In these trials, CR845/difelikefalin injection was administered to approximately 970 human subjects at single or repeat doses ranging from 1ug/kg to 40 ug/kg up to a 1-week period, in the form of intravenous infusion or bolus injection. CR845/difelikefalin injection was considered to be generally safe and well tolerated in all of these clinical trials. The most common treatment-emergent adverse events, or TEAEs, across evaluated populations in acute pain trials were transient facial tingling or numbness, dizziness and fatigue. In addition, a transient increase in urine output in the absence of electrolyte loss, otherwise known as aquaresis, was also observed, which in some subjects in acute pain trials was accompanied by asymptomatic elevations in plasma sodium that were generally considered to be clinically unimportant. No clinically significant changes in electrocardiogram characteristics have been observed in any of these studies. Importantly, there appeared to be no cases of the characteristic CNS-related adverse events, such as acute psychiatric side effects, typically observed with prior-generation CNS-active kappa agonists.
Human Abuse Liability Trial of CR845/Difelikefalin Injection
In the fourth quarter of 2014, the company successfully completed a Human Abuse Liability, or HAL, trial of CR845/difelikefalin injection. The results from this HAL trial indicate that CR845/difelikefalin injection met the trial’s primary endpoint by demonstrating highly statistically significant lower “drug liking” scores as measured by VAS Emax (p <0.0001) when compared to pentazocine, an approved Schedule IV opioid receptor agonist. I.V. CR845 also demonstrated highly statistically significant lower “feeling high,” “overall liking,” and “take drug again” scores (p <0.0001) as compared to pentazocine. Additionally, CR845/difelikefalin injection showed no “drug liking” dose response as both doses of CR845/difelikefalin injection were the same. Those scores represent standard subjective measures recommended by the FDA to assess a drug’s abuse liability. The company believe that the totality of the results from the HAL trial are supportive of the potential for CR845/difelikefalin to be the first non-scheduled or low (Schedule V) scheduled peripheral opioid for acute pain or pruritus. Data from this trial were also presented at PAINWEEK in September 2015 in Las Vegas, Nevada.
Respiratory Safety Phase 1 Trial of CR845/Difelikefalin Injection
In April 2017, the company announced summary results from its quantitative Phase 1 trial evaluating respiratory safety of CR845/difelikefalin injection. Respiratory depression remains the most life-threatening side effect of traditional, centrally acting, opioid analgesics, the most commonly used drug class for current treatment of postoperative pain in the United States. The Phase 1 trial was a randomized, double-blind, placebo-controlled, three-way crossover trial of two doses of CR845/difelikefalin injection versus placebo on three measures of respiratory drive in 15 healthy volunteers. Each subject was randomized to one of three treatment sequences and was administered I.V. bolus placebo, I.V. CR845/difelikefalin (1.0 ug/kg) and I.V. CR845/difelikefalin (5.0 ug/kg) on sequential 24-hour periods, with I.V. CR845/difelikefalin (5.0 ug/kg) representing a projected five-fold supra-therapeutic dose. After each administration, and continuing through four hours post-dosing, end-tidal CO2, or ETCO2, oxygen saturation, or SpO2, and respiratory rate were continuously monitored. The primary safety endpoints were: a >10 mmHg sustained (>30 seconds duration) increase in ETCO2 above baseline or to >50 mmHg, and a sustained reduction in SpO2 to <92 percent.
There were no statistically significant differences in any respiratory measures observed between groups throughout the four-hour observation period post-dosing and no individual subject met the threshold for a respiratory safety event. Additionally, all treatment-emergent adverse events were previously reported with CR845/difelikefalin administration and were mild, resolving without intervention. Full data from this study were also presented at the American Society of Anesthesiologists’ annual meeting in Boston in October, 2017.
Oral CR845/Difelikefalin for Treatment of Osteoarthritis
The company also investigated an oral version of CR845/difelikefalin, or Oral CR845/difelikefalin for pain relief, which the company believe could be used to provide pain relief to patients with acute or chronic pain in an outpatient setting and also as an I.V.-to-oral transition, or step-down, therapy for hospital patients being prepared for discharge. The company believe Oral CR845/difelikefalin can potentially address a significant unmet medical need for a safer alternative to opioids, NSAIDs or CNS anticonvulsant agents for the treatment of moderate-to-severe acute and chronic pain. In addition to the efficacy benefits that CR845/difelikefalin has previously demonstrated, the company believe, if successful, a significant benefit of Oral CR845/difelikefalin in the acute and chronic pain market could be its lack of CNS side effects, including euphoria, which should preclude the misuse, abuse and addiction risks associated with currently approved mu opioids.
Phase 2b Trial of Oral CR845/Difelikefalin
In the third quarter of 2016 the company initiated a Phase 2b trial with Oral CR845/difelikefalin, which was designed to evaluate three tablet strengths (1.0 mg, 2.5 mg and 5.0 mg), dosed twice-daily over an eight-week treatment period in 476 patients with OA of the knee or hip experiencing moderate-to-severe pain across the United States. The primary efficacy endpoint was the change from baseline at week eight, with respect to the weekly mean of the daily pain intensity score using an NRS score. Secondary endpoints included overall Patient Global Assessment, or PGA, score, and overall improvement in Western Ontario and McMaster Osteoarthritis Index, or WOMAC, scores, two commonly used patient-reported outcome measures, as well as mean reduction in rescue medication.
In June 2017, the company announced top-line results from the Phase 2b trial. The results of the primary efficacy analysis of change from baseline in pain intensity NRS score comparing Oral CR845/difelikefalin (all doses) vs. placebo were not statistically significant across all patients (OA of the knee or hip). However, patients with OA of the hip maintained on the 5.0 mg dose to the end of the eight-week treatment period exhibited a statistically significant 39% reduction in mean joint pain score versus placebo (p=0.043); all patients (OA of the knee or hip) maintained on the 5.0 mg dose to the end of the eight-week treatment period exhibited a 35% reduction in mean joint pain score versus placebo, which did not reach statistical significance (p=0.111). For patients maintained on the 5.0 mg dose, there was a statistically significant increase in the proportion of patients whose OA pain was “very much improved” or “much improved” as indicated by PGA score in both the total patient group (p <0.005 vs. placebo) and in patients with primary OA of the hip (p<0.006 vs. placebo). The reduction in pain score in the 5.0 mg dose group in hip patients was accompanied by a reduction in mean rescue medication of 41% at week eight versus placebo. Patients maintained on the 1.0 mg and 2.5 mg tablet strengths did not exhibit significant reductions in mean joint pain scores compared to placebo. All tablet strengths were generally well tolerated with no drug-related serious adverse events. For the 5.0 mg dose, the most common adverse events reported at the >5 percent incidence level were dry mouth (6%) and constipation (12%). There were no clinically significant changes in serum sodium levels observed during the eight-week treatment period for any dose group. Full results from this trial were presented at the American College of Rheumatology’s Annual Meeting held in November 2017.
Phase 2a Trial of Oral CR845/Difelikefalin
In August 2015, the company advanced its tablet formulation of Oral CR845/difelikefalin into a Phase 2a clinical trial in patients with osteoarthritis, or OA, of the knee or hip. The Phase 2a trial was a single-blind, randomized, multiple ascending dose trial designed to evaluate the safety, PK and effectiveness of Oral CR845/difelikefalin tablets dosed over a two-week treatment period in OA patients experiencing moderate-to-severe pain. Patients discontinued current pain medications five days prior to baseline measurements. Four tablet strengths (0.25 mg, 0.5 mg, 1.0 mg and 5.0 mg) were administered twice a day over a two-week treatment period in a total of 80 OA patients. In addition to safety and PK observations, CR845/difelikefalin 's effectiveness was assessed by: change from baseline in joint pain using the NRS score, change from baseline in the Western Ontario and McMaster Osteoarthritis Index, or WOMAC, change from baseline in rescue medication use, and Patient Global Assessment, or PGA. Acetaminophen was the only allowable rescue medication. PK analyses indicated dose-proportional exposure of CR845/difelikefalin after oral administration, with the 5.0 mg dose group exhibiting an approximately five-fold increased mean AUC value compared to the 1.0 mg dose group.
In December 2015, the company announced positive top-line results from this Phase 2a trial. The results showed a dose-related reduction in mean joint pain score after two weeks of treatment (from baseline) ranging from 25% reduction at the lowest dose (0.25 mg) to up to 34% reduction for the highest (5.0 mg) dose. Additionally, a post-hoc analysis also showed that 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% (p= 0.02, for 5.0 mg vs lower dose groups). 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 (p=0.02). In this trial, all four tablet strengths were observed to be safe and well tolerated.
The company do not intend to develop Oral CR845/difelikefalin in pain associated with OA on its own and will likely seek one or more potential partner(s) for further development of Oral CR845/difelikefalin in this indication.
In addition to its CR845/difelikefalin family of peripheral kappa agonists, Cara Therapeutics has discovered lead molecules that selectively modulate peripheral cannabinoid receptors. Studies on the effects of cannabis have led to the discovery of an endogenous system of ligands in humans involved in a number of physiological processes, including pain and inflammation. The main naturall y-occurring ligands for this system, anandamide and 2-arachidonoylglycerol (2-AG), activate a number of cannabinoid receptors, including CB1 and CB2 receptors. Like opioid receptors, CB1 and CB2 receptors are members of the G protein-coupled receptor superfamily. CB1 receptors and associated ligands are mainly localized in the brain, whereas CB2 receptors are found mainly in peripheral tissues, particularly immune cells such as leukocytes and mast cells, which have been shown to be involved in pain and inflammatory responses. Cara Therapeutics is developing lead molecules that selectively modulate peripheral CB receptors without targeting CNS cannabinoid receptors.
The company's most advanced CB compound, CR701, is a peripherally-restricted, mixed-CB1/CB2 receptor agonist that selectively interacts with these cannabinoid receptor subtypes, with no off-target activities. The compound is orally bioavailable, active in preclinical models of inflammatory and neuropathic pain, and does not produce the side effects characteristic of centrally-active cannabinoids, such as sedation and hypothermia. Accordingly, CR701 would be expected to have substantially less abuse potential than centrally-active cannabinoids, but retain activity against therapeutically valuable peripheral targets, similar in principle to CR845/difelikefalin.
Cara Therapeutics has completed pre-GLP safety studies with CR701 and are exploring the option of conducting the necessary GLP studies (safety studies conducted under the regulatory standard of Good Laboratory Practices) necessary to file an IND with the FDA to initiate a Phase 1 ascending single-dose tolerance and PK study in healthy human subjects.
Maruishi Pharmaceutical Co., Ltd.
In April 2013, the company entered into a license agreement with Maruishi, or the Maruishi Agreement, under which the company granted Maruishi an exclusive license to develop, manufacture and commercialize drug products containing CR845/difelikefalin in Japan in the acute pain and uremic pruritus fields. Maruishi has a right of first negotiation for any other indications for which the company develop CR845/difelikefalin and, under certain conditions, Maruishi may substitute another pruritus indication for the uremic pruritus indication originally included in its license from it. If the company abandon development of CR845/difelikefalin and begin development of another kappa opioid receptor agonist that is covered by the claims of the patents the company licensed to Maruishi, such other agonist will automatically be included in the license to Maruishi. Maruishi is required to use commercially reasonable efforts, at its expense, to develop, obtain regulatory approval for and commercialize CR845/difelikefalin in Japan. Cara Therapeutics is required to use commercially reasonable efforts, at its expense, to develop, obtain regulatory approval for and commercialize CR845/difelikefalin in the United States.
Under the terms of the Maruishi Agreement, the company received a non-refundable and non-creditable upfront license fee of $15.0 million and are eligible to receive up to an aggregate of $10.5 million in clinical development and regulatory milestones. In August 2014, the company received a milestone payment of $0.5 million upon the completion by Maruishi of a Phase 1 clinical trial in Japan related to CR845/difelikefalin in acute post-operative pain. In September 2015, Maruishi initiated a Phase 2 clinical trial of CR845/difelikefalin in Japan for uremic pruritus, which triggered a $1.7 million milestone payment (net of contractual foreign currency exchange adjustments of $0.3 million) to it. In March 2017, the company received a payment of $0.8 million from Maruishi when it entered into a sub-license agreement related to CR845/difelikefalin. Cara Therapeutics is also eligible to receive a one-time sales milestone of one billion Yen (approximately $9.4 million based on the U.S. Dollar/Yen exchange rate as of March 8, 2018) when a certain sales level is attained. The company also receive a mid-double-digit percentage of all non-royalty payments received by Maruishi from its sublicensees, if any. Cara Therapeutics is also eligible to receive tiered royalties based on net sales, if any, with minimum royalty rates in the low double digits and maximum royalty rates in the low twenties. Maruishi’s obligation to pay it royalties continues, on a product-by-product basis, until the expiration of the last-to-expire licensed patent covering such product or the later expiration of any market exclusivity period. The Maruishi Agreement continues until terminated. Either the company or Maruishi may terminate the Maruishi Agreement for the other party’s breach of the agreement or bankruptcy. Maruishi may terminate the agreement at any time at will. The company may terminate the agreement as a whole if Maruishi challenges the licensed patent rights, and the company may terminate the agreement with respect to any indication if Maruishi discontinues its development activities. In addition, in connection with the license agreement, Maruishi made an $8.0 million equity investment in its company.
Chong Kun Dang Pharmaceutical Corporation
In April 2012, the company entered into a license agreement with CKDP, or the CKDP Agreement, under which the company granted CKDP an exclusive license to develop, manufacture and commercialize drug products containing CR845/difelikefalin in South Korea. CKDP is required to use commercially reasonable efforts, at its expense, to develop, obtain regulatory approval for and commercialize CR845/difelikefalin in South Korea. Cara Therapeutics is required to use commercially reasonable efforts, at its expense, to develop, obtain regulatory approval for and commercialize CR845/difelikefalin in the United States.
Under the terms of the CKDP Agreement, the company received a non-refundable and non-creditable $0.6 million upfront payment and are eligible to earn up to an aggregate of $3.8 million in development and regulatory milestones. In addition, in connection with the CKDP Agreement, CKDP made a $0.4 million equity investment in its company. The company will also receive a mid-double-digit percentage of all non-royalty payments received by CKDP from its sublicensees, if any. Cara Therapeutics is also eligible to receive tiered royalties ranging from the high single digits to the high teens based on net sales, if any. CKDP’s obligation to pay it royalties continues, on a product-by-product basis, until the expiration of the last-to-expire licensed patent covering such product or the later expiration of any market exclusivity period.
During 2012, the company received an additional $0.6 million, net of foreign taxes, from CKDP upon the achievement of two clinical development milestones under the CKDP Agreement. During 2015, the company received a total of $0.6 million, net of foreign taxes, from CKDP upon the achievement of two clinical development milestones under the CKDP Agreement. The CKDP Agreement continues until CKDP no longer has any obligation to pay it royalties on any product. Either the company or CKDP may terminate the CKDP Agreement for the other party’s breach of the CKDP Agreement or bankruptcy. CKDP may terminate the CKDP Agreement if any of the licensed patent rights is invalid, unenforceable, is narrowed in scope or is deemed unpatentable, except as a result of a challenge by CKDP, or a third party commercializes a product containing a compound identical to CR845/difelikefalin without infringing any of the licensed patent rights in South Korea. The company may terminate the CKDP Agreement if CKDP challenges the licensed patent rights or if a third party in South Korea owns an issued patent that claims CR845/difelikefalin and CKDP’s sale of products would infringe that patent.
Sales and Marketing
In executing its strategy, its goal is to have significant control over the development process and commercial execution for CR845/difelikefalin in the United States, if approved.
The company anticipate developing a distribution capability and commercial organization in the United States to market and sell KORSUVA (CR845/difelikefalin) injection, if approved, in the dialysis setting, while out-licensing commercialization rights in certain geographical territories outside of the United States. For Oral KORSUVA (CR845/difelikefalin), the company plan to develop and commercialize its drug candidate in pruritus indications, such as CKD-aP, CLD-aP and potentially others, on its own in the United States, while exploring partnerships for development and commercialization in geographical territories outside the United States.
In 2015, the company commissioned a qualitative market research study of nephrologists to evaluate the commercial potential of KORSUVA (CR845/difelikefalin) for CKD-aP. The study suggests KORSUVA (CR845/difelikefalin) would be well received by nephrologists, if approved. The key findings from the study were:
- There is a clear unmet need to manage CKD-aP among dialysis patients.
- Currently, there are no effective options for severe CKD-aP.
- CR845/difelikefalin demonstrates impressive efficacy for CKD-aP.
- Physicians were impressed with placebo-like adverse event profile.
- KORSUVA (CR845/difelikefalin) injection can easily be incorporated into dialysis sessions.
As a result, the company believe that, if successful, KORSUVA (CR845/difelikefalin) is well positioned to address the unmet needs for hemodialysis patients suffering from CKD-aP.
The company had also commissioned market research for I.V. CR845/difelikefalin for the treatment of postoperative pain that suggests it would be well received by physicians, if approved. This research indicated that in addition to providing pain relief, reducing side effects such as nausea and vomiting, were among the highest unmet needs in the postoperative setting. In its three Phase 2 trials, I.V. CR845/difelikefalin demonstrated statistically significant pain relief and statistically significant reductions in nausea and vomiting. As a result, the company believe that, if successful, I.V. CR845/difelikefalin is well positioned to address unmet needs in the postoperative pain market.
The company strive to protect the proprietary technologies that the company believe are important to its business, including seeking and maintaining patent protection intended to cover the composition of matter of its product candidates, their methods of use, related technology and other inventions that are important to its business. As more fully described below, patent applications have been filed covering compositions of matter for and methods of using CR845/difelikefalin. Ten U.S. patents directed to CR845/difelikefalin and its uses have been issued, which are expected to expire no earlier than 2027. The company also rely on trade secrets and careful monitoring of its proprietary information to protect aspects of its business that are not amenable to, or that the company do not consider appropriate for, patent protection.
The company's success will depend significantly on its ability to obtain and maintain patent and other proprietary protection for commercially important technology, inventions and know-how related to its business, defend and enforce its patents, maintain its licenses to use intellectual property owned by third parties, preserve the confidentiality of its trade secrets and operate without infringing valid and enforceable patents and other proprietary rights of third parties. The company also rely on know-how, and continuing technological innovation to develop, strengthen, and maintain its proprietary position in the field of peripheral analgesia and treatment of pruritus.
A third party may hold intellectual property, including patent rights, which are important or necessary to the development of its products. It may be necessary for it to use the patented or proprietary technology of third parties to commercialize its products, in which case the company would be required to obtain a license from these third parties on commercially reasonable terms, or its business could be harmed, possibly materially. If the company were not able to obtain a license or were not able to obtain a license on commercially reasonable terms, its business could be harmed, possibly materially.
The company plan to continue to expand its intellectual property estate by filing patent applications directed to novel peripheral analgesics and novel uses of its proprietary compounds. The company anticipate seeking patent protection in the United States and internationally for the chemistries and processes for manufacturing these compounds and the use of these compounds in a variety of therapies.
The patent positions of biopharmaceutical companies like it are generally uncertain and involve complex legal, scientific and factual questions. In addition, the coverage claimed in a patent application can be significantly reduced before the patent is issued, and the patent’s scope can be modified after issuance by later judicial decisions. Consequently, the company do not know whether any of its product candidates will be adequately protectable or remain protected by enforceable patents. The company cannot predict whether the patent applications Cara Therapeutics is currently pursuing will issue as patents in any particular jurisdiction or whether the claims of any issued patents will provide sufficient proprietary protection from competitors. Any patents that the company hold may be challenged, circumvented or invalidated by third parties.
Because patent applications in the United States and certain other jurisdictions are maintained in secrecy for up to 18 months, and since publication of discoveries in the scientific or patent literature often lags behind actual discoveries, the company cannot be certain of its entitlement to the inventions covered by pending patent applications. Moreover, the company may have to participate in interference proceedings declared by the United States Patent and Trademark Office, or USPTO, to determine priority of invention, or in post-grant challenge proceedings in the USPTO or a foreign patent office such as oppositions, inter-partes review, post grant review, or a derivation proceeding, that challenge its entitlement to an invention or the patentability of one or more claims in its patent applications or issued patents. Such proceedings could result in substantial cost, even if the eventual outcome is favorable to it.
The patent portfolios for its most advanced programs are summarized below.
The company's synthetic peptide amide kappa opioid agonist patent portfolio is wholly owned by it. The portfolio includes thirteen issued U.S. patents (U.S. Patent Nos. 7,402,564; 7,713,937; 7,727,963; 7,842,662; 8,217,007; 8,236,766; 8,486,894, 8,536,131, 8,906,859, 8,951,970, 9,321,810, 9,334,305 and 9,359,399) with claims to compositions of a wide range of synthetic peptide amide kappa opioid agonists, including CR845/difelikefalin and related molecules, as well as methods of using these compounds. U.S. Patent No. 7,402,564, which is the earliest issued U.S. patent claiming CR845/difelikefalin compositions is due to expire November 12, 2027, although under certain circumstances the patent term may be extended for up to a further five (5) years based upon the Hatch-Waxman Act. The CR845/difelikefalin patent portfolio also includes pending U.S. patent applications which claim additional uses and methods of administering CR845/difelikefalin. Related foreign applications were filed in more than 40 other countries. National patents have been granted in 31 European countries, as well as in Australia, Canada, China, Hong Kong, Israel, Japan, Malaysia, Mexico, New Zealand, Russia, Singapore, South Africa and South Korea. These granted foreign patents with claims to CR845/difelikefalin are due expire no earlier than November 12, 2027. Patent applications claiming CR845/difelikefalin are pending in Brazil and India.
The company's imidazoheterocycle cannabinoid compound patent portfolio, which is wholly owned by it, includes U.S. Patent Nos. 7,517,874, 8,431,565 and 8,859,538. These U.S. patents are due to expire no earlier than June 20, 2028. A related international PCT application was filed and sixteen national patent applications and a European regional patent application has been filed based on the international patent application. The European regional patent has been granted as have national patents in Australia, Canada, Hong Kong, Israel, Japan, Malaysia, Mexico, New Zealand, Philippines, Singapore, Russia and South Africa. These and any other patents resulting from the pending national patent applications, if issued, expire no earlier than June 20, 2028. Patent applications claiming CR701 are pending in Brazil, China, India and South Korea.
Other Cara Patents and Patent Applications
The company also own several other U.S. Patents including U.S. Patent Nos. 7,741,350; 7,960,376; 7,960,377 and 8,211,926 with claims to other cannabinoid compounds and U.S. Patent No. 8,217,000 with claims to regulation of prolactin in mammals including humans.
In addition, its kappa receptor opioid peptide international patent portfolio, which is wholly owned by it, includes claims to CR665, its first-generation kappa opioid receptor agonist, related compounds, and methods of using these compounds. The international PCT patent application PCT/US98/27282 was filed and progeny national patent applications have been granted in over 40 other countries. Granted patents with claims to CR665 have been maintained in Brazil, Canada, China, France, Germany, India, Italy, Russia, Spain and the U.K. and are due to expire on December 22, 2018, except for the Brazilian patent, the term of which has been extended to October 21, 2024 to compensate for patent office delays.
The term of individual patents depends upon the legal term of the patents in the countries in which they are obtained. In most countries in which the company file, the patent term is 20 years from the earliest date of filing a PCT application or a non-provisional patent application. The term of a patent in the United States can be adjusted and extended due to the failure of the United States Patent and Trademark Office following certain statutory and regulation deadlines for progressing prosecution and issuing a patent.
In the United States, the patent term of a patent that covers an FDA-approved drug may also be eligible for patent term extension, which permits patent term restoration as compensation for a portion of the patent term lost during the FDA regulatory review process. The Hatch-Waxman Act permits a patent term extension of up to five years beyond the expiration of the patent. The length of the patent term extension is related to the length of time the drug is under regulatory review. Patent extension cannot extend the remaining term of a patent beyond a total of 14 years from the date of product approval and only one patent applicable to an approved drug may be extended. Similar provisions are available in Europe and other non-United States jurisdictions to extend the term of a patent that covers an approved drug. In the future, if and when its pharmaceutical products receive FDA approval, the company expect to apply for patent term extensions on patents covering those products. Although the company intend to seek patent term extensions to any of its issued patents in any jurisdiction where these are available there is no guarantee that the applicable authorities, including the FDA in the United States, will agree with its assessment of whether such extensions should be granted, and even if granted, the length of such extensions.
The company also rely on trade secret protection for its confidential and proprietary information. Although the company take steps to protect its proprietary information and trade secrets, including through contractual means with its employees and consultants, third parties may independently develop substantially equivalent proprietary information and techniques or otherwise gain access to its trade secrets or disclose its technology. Thus, the company may not be able to meaningfully protect its trade secrets. It is its policy to require its employees, consultants, outside scientific collaborators, sponsored researchers and other advisors to execute confidentiality agreements upon the commencement of employment or consulting relationships with it. These agreements provide that all confidential information concerning its business or financial affairs developed or made known to the individual during the course of the individual’s relationship with it is to be kept confidential and not disclosed to third parties except in specific circumstances. In the case of employees, the agreements provide that all inventions conceived by the individual, and which are related to its current or planned business or research and development, or R&D, or made during normal working hours, on its premises or using its equipment or proprietary information, are its exclusive property.