Date: 2014-06-19
Type of information: Publication of results in a medical journal
phase: 3
Announcement: publication of results in The New England Journal Of Medicine
Company: AstraZeneca (UK)
Product: naloxegol
Action
mechanism: Naloxegol is a peripherally-acting mu-opioid receptor antagonist being investigated for the treatment of constipation (opioid-induced constipation or OIC) as a side effect of prescription opioid pain medicines. Naloxegol is part of the exclusive worldwide license agreement announced on 21 September 2009 between AstraZeneca and Nektar Therapeutics. It was developed using Nektar’s oral small molecule polymer conjugate technology.
Disease: non-cancer related pain and opioid-induced constipation
Therapeutic area: Digestive diseases - Cancer -Oncology
Country:
Trial
details: The core Phase III KODIAC programme for naloxegol is comprised of four clinical trials which are designed to investigate the safety and efficacy of naloxegol for the treatment of OIC in patients with non-cancer related pain. The full data from these trials will be submitted for presentation at future medical meetings.
The three trials reporting top-line results on November 2012 include KODIAC-04, -05, and -07. KODIAC-04 and -05 are replicate pivotal 12-week efficacy and safety trials, while KODIAC-07 is a 12-week safety extension of KODIAC-04. After initial locking of the database for KODIAC-05, data associated with one patient that was previously assessed as non-retrievable was found to be retrievable. These data were added to the database and the database was again locked and underwent a final analysis. All three trials were conducted in patients with non-cancer pain and documented OIC, who require daily opioid therapy. Enrolment is complete for the open-label, randomized, 52-week long-term safety trial (KODIAC-08) and the trial is expected to be completed by Q1 2013.
KODIAC-04 and -05 are both multicenter, randomized, double-blind, placebo-controlled pivotal trials of 12 weeks duration evaluating 12.5 mg and 25 mg naloxegol administered once-daily. The primary endpoint in both trials was percentage of OIC responders versus placebo over 12 weeks of treatment where a responder was defined as having at least three Spontaneous Bowel Movements (SBM) per week, with at least one SBM per week increase over baseline, for at least nine out of 12 weeks, and at least three out of the last four weeks. Under the design of both trials, statistical significance for the primary endpoint would be achieved if at least one of the two naloxegol doses had a p-value Full results from KODIAC-04 and -05 will be presented at Digestive Disease Week (DDW), 18-21 May, 2013. Full results from KODIAC-07, along with KODIAC-08, will be presented at a scientific meeting later in 2013.
Latest
news: * On June 19, 2014, AstraZeneca announced that the New England Journal of Medicine (NEJM) has published results of two pivotal Phase III studies – KODIAC-4 and KODIAC-5 of naloxegol. Primary endpoint data from the KODIAC-4 and -5 studies showed that more OIC patients treated with naloxegol 25 mg had a consistent response of increased spontaneous bowel movements (SBMs) through 12 weeks of treatment compared to placebo [44% vs. 29% (p=0.001 KODIAC-4) and 40% vs. 29% (p=0.021 KODIAC-5)]. The 12.5 mg dose in KODIAC-5 did not show statistical significance for the primary endpoint.The 25 mg dose also demonstrated a higher response rate through 12 weeks of treatment compared to placebo in patients with laxative inadequate response (LIR), a secondary endpoint. Results for an additional secondary endpoint showed that patients taking naloxegol 25 mg in the KODIAC-4 and KODIAC-5 studies were likely to have a first post-dose spontaneous bowel movement 25-30 hours sooner than placebo, respectively (median six and 12 hours for naloxegol 25 mg compared to 36 and 37 hours for placebo, in studies KODIAC-4 and -5, respectively). The Phase III studies, KODIAC-4 (n=652) and KODIAC-5 (n=700), were 12-week, multicenter, randomised, double blind, placebo-controlled pivotal trials that evaluated 12.5 mg and 25 mg doses of naloxegol, administered once-daily. Additional results from the KODIAC-4 and KODIAC -5 clinical trials published in NEJM included: The number of SBMs per week increased with naloxegol 25 mg treatment over 12 weeks, with both studies showing an improvement in treatment effect versus placebo - Improvements in straining, stool consistency, and frequency of days with complete SBMs were observed with naloxegol 25 mg (both studies). The most commonly reported adverse effects with naloxegol were gastrointestinal in origin (abdominal pain, diarrhea, nausea, vomiting, flatulence) and appeared to be dose-ordered, occurring more commonly in the 25 mg group. Most adverse events were mild to moderate in severity and occurred shortly after initiation of naloxegol. There was 1 major adverse cardiovascular event (MACE) in the 25 mg treatment arm, 1 in the 12.5 mg treatment arm and 2 in the placebo arm. * On February 26, 2013, AstraZeneca has announced high-level results from KODIAC-08, an open-label, randomised, 52-week, long-term safety trial of naloxegol versus usual care (UC) in patients with non-cancer related pain and opioid-induced constipation (OIC). UC was defined as the investigator’s choice of an existing laxative treatment regimen for OIC. This is the fourth trial in the naloxegol Phase III development programme, and was designed to evaluate the long-term safety and adverse event (AE) profile of naloxegol in patients taking 25 mg once daily, as compared to UC. In the trial, a total of 534 patients received naloxegol once daily for up to 52 weeks, while 270 patients received UC for OIC during the same treatment period. The most commonly reported AEs occurring more frequently on naloxegol than on usual care included abdominal pain, diarrhoea, nausea and headache. The trial reported no imbalances in serious adverse events (SAEs). In addition, there were a low number of major adverse cardiovascular events (MACE), as adjudicated by an independent external committee, and there was no imbalance of these events across naloxegol and UC arms. There were no increases from baseline levels in mean daily pain scores or mean total daily opioid dose in either the naloxegol or the UC arm. Additionally, there were no reports of opioid withdrawal AEs which could be attributed to naloxegol. A full assessment of the safety and tolerability findings is ongoing.
The core phase III programme is now completed and submissions of a New Drug Application (NDA) filing in the US and a Marketing Authorisation Application (MAA) filing in the EU are planned for the third quarter of 2013, pending AstraZeneca’s final preparation of the registration package and a pre-NDA meeting with the FDA.
* On November 12, 2012, AstraZeneca has announced positive top-line results from two Phase III trials and one safety extension trial in patients with non-cancer related pain and opioid-induced constipation (OIC). These Phase III KODIAC trials evaluated the safety and efficacy of naloxegol, an oral peripherally-acting, mu-opioid receptor antagonist for the treatment of OIC, a common side effect of prescription opioids.
Analysis of the data indicates that in KODIAC-04 both naloxegol doses (12.5 mg and 25 mg) demonstrated statistically significant results for the primary endpoint. P-values were 0.015 and 0.001 respectively.
In KODIAC-05, the 25 mg dose demonstrated a statistically significant result for the primary endpoint but the 12.5 mg dose did not. P-values were 0.202 for 12.5 mg and 0.021 for 25 mg.
The analyses also showed no clinically relevant imbalances in serious adverse events (SAEs), including externally adjudicated major cardiovascular events, across the three treatment arms in KODIAC-04, -05 and -07. The most common adverse events (AEs) in the naloxegol treatment arms in both trials were abdominal pain, diarrhea and nausea. In KODIAC-07, (the safety extension of KODIAC-04) the occurrence of AEs and SAEs was lower than in KODIAC-04 and -05. Among non serious adverse events, arthralgia was the most common and was reported only in patients in the naloxegol 25 mg arm. All other common AEs were distributed similarly across the three treatment arms. In KODIAC-04 and -05 for either naloxegol dose, compared to placebo, there were no significant differences in change from baseline in mean daily pain scores or mean total daily opioid dose. A full assessment of the safety and tolerability findings of all three studies is ongoing.
