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Cebranopadol, a Novel First-In-Class Analgesic Drug Candidate: First Experience with Cancer-Related Pain for up to 26 Weeks E

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Cebranopadol, a Novel First-In-Class Analgesic Drug Candidate: First Experience with Cancer-Related Pain for up to 26 Weeks E 390 Journal of Pain and Symptom Management Vol. 58 No. 3 September 2019 Original Article Cebranopadol, a Novel First-in-Class Analgesic Drug Candidate: First Experience With Cancer-Related Pain for up to 26 Weeks E. Dietlind Koch, MD, Sofia Kapanadze, MD, Marie-Henriette Eerdekens, MD, MBA, Georg Kralidis, PhD, Jirı´Letal, PhD, Ingo Sabatschus, MD, and Sam H. Ahmedzai, MD Innovation Unit Pain, Clinical Science (E.D.K., S.K., M.-H.E.); Data SciencesdStatistics (G.K., J.L.); Global Drug Safety (I.S.), Grunenthal€ GmbH, Aachen, Germany; and Department of Oncology (S.H.A.), University of Sheffield, Sheffield, UK Abstract Context. Pain is one of the most prevalent symptoms associated with cancer. Strong opioids are commonly used in the analgesic management of the disease, but carry the risk of severe side effects. Cebranopadol is a first-in-class drug candidate, combining nociceptin/orphanin FQ peptide and opioid peptide receptor agonism. For cancer patients, frequently experiencing multimorbidities and often exposed to polypharmacy, cebranopadol is easy to handle given its once-daily dosing, the small tablet size that enables swallowing, and the option to flexibly titrate to an effective dose. Objectives. We assessed the safety and tolerability of prolonged treatment with oral cebranopadol for up to 26 weeks in patients suffering from chronic moderate-to-severe cancer-related pain. Methods. This was a non-randomized, multi-site, open-label, single-arm clinical trial with patients who had completed a double-blind trial comparing morphine prolonged release with cebranopadol. In this extension trial, patients were treated with oral cebranopadol for up to 26 weeks. Results. Cebranopadol was safe and well tolerated in patients with chronic moderate-to-severe pain related to cancer in the dose range tested (200e1000 mg once daily). The median and mean pain levels remained in the range of mild pain during the treatment period. Conclusion. Our data suggest that cebranopadol was safe and well tolerated when administered for up to 26 weeks in patients with chronic cancer-related pain who were previously treated with cebranopadol or morphine prolonged release. J Pain Symptom Manage 2019;58:390e399. Ó 2019 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved. Key Words Cebranopadol, cancer pain, open-label, prolonged treatment, nociceptin/orphanin FQ peptide Introduction increased the number of patients living with progres- sive cancer2 and the symptoms thereof, which include Cancer has become a major cause of morbidity and pain arising from the primary cancer and/or resulting mortality worldwide. Based on current trends, an in- from anticancer treatments. crease in incidence can be expected from 12.7 million Pain is one of the most common symptoms associ- new cases in 2008 to 22.2 million by 2030.1 Although ated with malignant tumors, occurring in 59% of cancer still constitutes a major public health threat, patients undergoing anticancer treatment and significant progress has recently been made in its approximately 75% of patients with advanced dis- treatment. This has led to a longer survival and ease.3,4 In addition, unrelieved pain denies patients Address correspondence to: E. Dietlind Koch, MD, Clinical Sci- Accepted for publication: May 23, 2019. ence, Grunenthal€ GmbH, Zieglerstraße 6, 52078 Aachen, Germany. E-mail: [email protected] Ó 2019 American Academy of Hospice and Palliative Medicine. 0885-3924/$ - see front matter Published by Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.jpainsymman.2019.05.012 Vol. 58 No. 3 September 2019 Cebranopadol: Prolonged Use for Cancer Pain 391 comfort and greatly impacts their activities, emotions, Methods motivation, and overall quality of life in addition to 3,5 Trial Setting, Ethics, and Consent the burden of having a life-threatening disease. We conducted a non-randomized, multi-site, open- Furthermore, 5% to 56% of long-term cancer survivors label, single-arm extension trial to describe the safety experience persistent pain from diverse etiologies and tolerability of prolonged treatment with oral ce- (e.g., postsurgical and radiotherapy-, or branopadol for up to 26 weeks in patients suffering chemotherapy-induced pain), despite the availability 6,7 from moderate-to-severe cancer-related pain, who of various analgesics. This indicates the need for had previously just completed a double-blind trial further improvements in pain therapy, both in pa- comparing morphine prolonged release (PR) twice tients living with cancer and in cancer survivors. daily with cebranopadol once daily for six weeks Chronic cancer-related pain, that is, pain caused by (NCT01964378).20 The current trial started on the tumor itself as well as resulting from anticancer December 18, 2013 with the enrollment of the first pa- treatments, may have different underlying pathophys- tient and was completed on May 3, 2016 when the last iologies with nociceptive and neuropathic compo- 3 patient completed the last follow-up examination. A nents, and can be considered as mixed pain. The total of 22 sites in 10 countries enrolled patients. established approach to this complex form of pain The clinical trial protocol, amendments, and has relied heavily on the use of so-called ‘‘strong opi- informed consent forms were approved by the rele- oids,’’ of which morphine, oxycodone, hydromor- 8 vant regulatory authorities and ethical committees, phone, and fentanyl are representatives. However, and all patients provided written informed consent the archetypal opioid morphine has a weak evidence before entry in the trial. The EudraCT trial number base for its use in cancer-related pain and is associated 9,10 is 2013-001877-26 and the ClinicalTrials.gov identifier with a significant side-effect profile. is NCT02031432. Cebranopadol is a novel, first-in-class, small-mole- cule analgesic, characterized by its high nociceptin/ orphanin FQ peptide (NOP) and opioid receptor Trial Design e agonistic activity11 13. As NOP and opioid receptor ag- A flow diagram of the trial is provided in Fig. 1. The onists modulate pain via distinct yet related targets, a first visit took place on the day of treatment comple- combined agonistic activity may be particularly suited tion of the preceding double-blind trial. Open-label to provide potent analgesia with a better tolerability oral cebranopadol was initially titrated to an optimal profile than classical opioids.11 Although strong opi- individual beneficial dose (defined as a balance be- oids induce potent analgesia, the fact that their use tween self-reported analgesia and side effects) in an may lead to the development of tolerance and physical approximately two-week titration phase. Patients dependence can limit their clinical utility. Impor- were started on cebranopadol 200 mg daily (i.e., the tantly, NOP receptor activation has been associated lowest-allowed dose level). However, if patients were with reduced development of tolerance,14 addiction,15 treated with either of the two highest dose levels in and physical dependence.16 the maintenance phase of the preceding trial (i.e., ce- Cebranopadol is in clinical development. It has branopadol 800 or 1000 mg daily, or morphine PR 120 shown an improved profile regarding respiratory or 150 mg daily), titration in the current trial could be safety17 and a lower abuse potential18 compared with started at cebranopadol 400 mg daily, if considered classical opioids, which may be of relevance in chronic suitable by the investigator. These options allowed a pain management. Its analgesic efficacy has been smooth transition from one trial to the other while e shown in acute and chronic pain conditions.19 21 maintaining the blind of the preceding trial. The pharmacokinetic properties of cebranopadol The dose selected by the end of the titration phase allow for once-daily administration22 and its small was continued during a 24-week maintenance phase tablet size facilitates easy swallowing. This decreases with possibility for further dose adjustments. Available the medication burden for patients receiving anti- dose levels were cebranopadol 200, 400, 600, 800, or cancer treatments, with progressive illness, or with co- 1000 mg daily. morbidities often requiring several concomitant Cebranopadol could be taken with or without food, medications, and thus may contribute to improving once daily in the morning. In addition, at any time quality of life and treatment adherence. during the trial, the dose could be discontinued for So far, most data on long-term use of strong analge- a certain period (e.g., because of adverse events sics have been collected in non-cancer populations, [AEs]) depending on the patients’ needs. During with only limited data available for cancer popula- both the titration phase and the maintenance phase, tions. The current trial investigated prolonged treat- all patients were allowed to receive on-demand anal- ment with oral cebranopadol for up to 26 weeks in gesic treatment (e.g., immediate release opioids), patients suffering from cancer-related pain. for unbearable breakthrough pain, as prescribed by 392 Koch et al. Vol. 58 No. 3 September 2019 Titraon Phase Maintenance Phase Follow-up Visit Visit number 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 (S = site; T = telephone) (S) (T) (S) (T) (T) (S) (T) (S) (S) (S) (S) (S) (S) (S) (S) Day 1 371115 17 24 31 45 73 101 129 157 185 199 Fig. 1. Flow diagram of the extension trial. the investigator. The average use of such on-demand (e.g., new medication) of TEAEs; time to discontin- medication during the previous day (for the first uation from treatment due to TEAEs; time to treatment visit) and during the last three days (for discontinuation from treatment due to TEAEs all other visits) was collected. The recommended judged as at least possibly related to cebranopadol maximum daily dose of on-demand opioid medica- by the investigator; clinically relevant changes from tion was not to exceed 90 mg of an oral morphine baseline in vital signs assessments, weight, laboratory equivalent.
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