Date: 2014-01-07
Type of information: Initiation of development program
phase: 3
Announcement: update
Company: Alkermes (Ireland)
Product: ALKS 5461
Action
mechanism: ALKS 5461 is the combination of ALKS 33 and buprenorphine and is designed to be a non-addictive opioid modulator. ALKS 33 is an oral opioid modulator that builds on Alkermes’ scientific expertise in opioid biology and pharmacology, as well as the company’s clinical and commercial knowledge in the field of addiction and central nervous system disorders. ALKS 5461 is also in clinical development for the treatment of cocaine addiction, which is being funded through a grant from the National Institute on Drug Abuse (NIDA). In October 2013 , the FDA has granted Fast Track status for ALKS 5461 for the adjunctive treatment of MDD in patients with an inadequate response to standard therapies.
Disease: major depressive disorder (MDD)
Therapeutic area: CNS diseases - Mental diseases
Country:
Trial
details: The phase 2, randomized, double-blind, multicenter, placebo-controlled study assessed the efficacy and safety of two doses of ALKS 5461 when administered once daily for four weeks as adjunctive treatment in 142 patients with MDD who had an inadequate response to a stable dose of either a selective serotonin reuptake inhibitor (SSRI) or a serotonin-norepinephrine reuptake inhibitor (SNRI). Patients received one of two dosing regimens of oral ALKS 5461 or placebo for a treatment period of four weeks. The study utilized a sequential parallel comparison design, a design developed ten years ago by Drs. Fava and Schoenfeld at Massachusetts General Hospital and now widely utilized in clinical trials. The primary endpoint of the study was the change from baseline in depressive symptoms over a four-week treatment period, as measured by the HAM-D17. Secondary endpoints included additional analyses of patient responses based on HAM-D17, MADRS and CGI-S scores. - This phase 1/2 multicenter, randomized, double-blind, placebo-controlled, parallel-group study was designed to evaluate the safety and tolerability and explore the efficacy of ALKS 5461 compared to placebo in 32 patients with MDD who had an inadequate response to a stable dose of either a selective serotonin reuptake inhibitor (SSRI) or a serotonin-norepinephrine reuptake inhibitor (SNRI). Patients received one of two sublingual dosing regimens of ALKS 5461 or placebo for seven days. In both dosing cohorts, patients administered ALKS 5461 demonstrated greater reductions from baseline in depressive symptoms, as measured by the HAM-D17, compared to those administered placebo. In one dosing cohort, these differences in depressive severity were statistically significant as measured by the HAM-D17. ALKS 5461 was generally well tolerated in both dosing cohorts.
The study utilized a sequential parallel comparison design (SPCD), a design developed ten years ago by Drs. Fava and Schoenfeld at Massachusetts General Hospital and now widely utilized in clinical trials. A SPCD trial involves two randomized, double-blind stages run in sequence. In the Initial Study Stage (stage 1), patients are randomized to either drug treatment or placebo. In the ALKS 5461 phase 2 study, the Initial Study Stage was a four-week treatment period. At the end of the Initial Study Stage, patients were reassigned treatment groups for the Successive Study Stage (stage 2), which in the ALKS 5461 phase 2 study was a second four-week treatment period. In the Successive Study Stage, patients who had been on drug in the Initial Study Stage were put on placebo. Patients who had been administered placebo in the Initial Study Stage were determined to be either responders, i.e., they responded positively to placebo treatment, or non-responders. Placebo responders were assigned to remain on placebo in the Successive Study Stage. Placebo non-responders were re-randomized to either placebo or drug treatment in the Successive Study Stage. SPCD studies are particularly useful in studies of depression, anxiety and other difficult psychiatric diseases to reduce the impact of placebo effect on the assessment of treatment response.
Latest
news: * On January 8, 2014, Alkermes has announced new developments related to its late-stage product candidates in its proprietary central nervous system (CNS) pipeline. Alkermes provided details regarding its pivotal phase 3 program for ALKS 5461. The phase 3 trials for ALKS 5461 will incorporate state-of-the-art study designs, and the pivotal program is expected to begin in the first quarter of 2014. The pivotal clinical program will include three core phase 3 efficacy studies and is expected to enroll a total of approximately 1,500 patients with MDD who have had an inadequate response to standard therapies. The three core efficacy studies will utilize sequential parallel comparison design (SPCD) to reduce the impact of clinically meaningful placebo response. The primary efficacy endpoint for all phase 3 studies will be the change in Montgomery-Åsberg Depression Rating Scale (MADRS) scores from baseline. The pivotal program will also evaluate remission as a secondary endpoint, following the recently reported remission data from the phase 2 study of ALKS 5461, in which 35-50% of patients in the study achieved remission, as evaluated by MADRS scores, across the two stages of the study. In addition to the three core efficacy studies, the pivotal program will also include studies to evaluate the long-term safety, pharmacokinetic profile, titration schedule and human abuse liability of ALKS 5461. The first study to commence in the ALKS 5461 pivotal program will be a study to evaluate onset of clinical effect, safety and tolerability.* On October 9, 2013, Alkermes has announced that it has successfully completed its End-of-Phase 2 interactions with the FDA, and the company plans to advance ALKS 5461 into phase 3 development in early 2014. The company and the FDA agreed on key elements of the development program, including preclinical and clinical requirements for the New Drug Application, the confirmatory study plans, the incorporation of innovative study designs that include the use of sequential parallel comparison design (SPCD), the primary endpoint and the statistical methodology.
* On May. 31, 2013, Alkermes has announced the presentation of positive phase 2 data for ALKS 5461, a novel opioid modulator, in patients with major depressive disorder (MDD) and inadequate response to standard therapies. In the phase 2 study, ALKS 5461 met its primary endpoint, met key secondary endpoints and demonstrated significant reduction in depressive symptoms versus placebo. The combined analysis of both doses at both stages showed statistically significant efficacy on multiple endpoints compared to placebo. Overall, the lower dose showed greater efficacy than the higher dose and, as a result, will be the top end of the dose range employed in future studies. Results for the lower dose from the Successive Study Stage of the study included:ALKS 5461 significantly reduced Hamilton Depression Rating Scale (HAM-D17) scores from baseline (p=0.013), with a reduction of 5.3 points, compared to a reduction of 1.2 points in the placebo group at the end of the four-week treatment period. ALKS 5461 also significantly reduced Montgomery-Åsberg Depression Rating Scale (MADRS) scores from baseline (p=0.004), with a reduction of 8.7 points, compared to a reduction of 1.8 points in the placebo group at the end of the four-week treatment period.ALKS 5461 had an onset of effect, as measured by MADRS, evident after one week of treatment.In the phase 2 results for the overall study population, including both the Initial Study Stage and the Successive Study Stage, patients who received either dose of ALKS 5461 for a treatment period of four weeks showed a significant reduction in depressive symptoms from baseline in HAM-D17 (p=0.026) and MADRS (p=0.004) scores, compared to placebo. The primary endpoint of the phase 2 study was the change from baseline in depressive symptoms over a four-week treatment period in the overall study population, as measured by HAM-D17, compared to placebo. Data from the study showed that ALKS 5461 was generally well tolerated. The most common adverse events observed in the study were nausea, headache and dizziness.* On April 17, 2013, Alkermes has announced positive preliminary topline results from a phase 2 study of ALKS 5461, its novel drug compound for major depressive disorder (MDD) in patients who have an inadequate response to standard therapies for clinical depression. Data from the study showed that ALKS 5461 significantly reduced depressive symptoms across a range of standard measures including the study's primary outcome measure, the Hamilton Depression Rating Scale (HAM-D17) (p=0.026), the Montgomery-Åsberg Depression Rating Scale (MADRS) (p=0.004) and the Clinical Global Impression - Severity Scale (CGI-S) (p=0.035). ALKS 5461 was generally well tolerated. Based on these results, as well as the positive phase 1/2 results previously reported, Alkermes plans to request a meeting with the FDA and advance ALKS 5461 into a pivotal development program. Data from this phase 2 study will be presented at the 53rd Annual New Clinical Drug Evaluation Unit (NCDEU) Meeting in Hollywood, Fla. , May 28-31, 2013 .* On May 29, 2012, Alkermes has presented positive results from the phase 1/2 study of ALKS 5461, a novel drug compound for major depressive disorder (MDD) in patients who have an inadequate response to standard therapies for clinical depression, in an oral session at the 52nd Annual New Clinical Drug Evaluation Unit (NCDEU) Meeting in Phoenix. In the phase 1/2 clinical study, ALKS 5461 was shown to significantly reduce depressive symptoms, as measured by the Hamilton Depression Rating Scale (HAM-D17; a standard, clinician-assessed measure of depression severity), in patients with MDD who received ALKS 5461 for the seven-day treatment period. Two dose ratios of the ALKS 5461 components, buprenorphine and ALKS 33, were evaluated (8:1 and 1:1). Patients received one of these two sublingual dosing regimens of ALKS 5461 or placebo for seven days. In both dosing cohorts, patients administered ALKS 5461 demonstrated greater reductions from baseline in depressive symptoms, as measured by the HAM-D17, compared to those administered placebo. In the 1:1 dosing cohort, where full blockade of the mu agonist effects of buprenorphine were achieved, these differences in depressive severity were statistically significant as measured by the HAM-D17 (p=0.032). ALKS 5461 was generally well tolerated in both dosing cohorts. Based on the positive results of the phase 1/2 study, a phase 2 study of ALKS 5461 was initiated in January 2012 to further evaluate the utility of ALKS 5461 in treating MDD. The phase 2 trial is a randomized, double-blind, multicenter, placebo-controlled study that will evaluate the efficacy and safety of ALKS 5461 when administered once daily for four weeks in approximately 130 patients with MDD who have inadequate response to antidepressant therapy. Data from the study are expected in the first half of calendar 2013.* On January 4, 2012, Alkermes has announced positive topline results from a phase 1/2 study of ALKS 5461, a novel drug compound for major depressive disorder (MDD) in patients who have an inadequate response to standard therapies for clinical depression. In the phase 1/2 clinical study, ALKS 5461 was shown to significantly reduce depressive symptoms, as measured by the Hamilton Depression Rating Scale (HAM-D17; a standard, clinician-assessed measure of depression severity), in patients with MDD who received ALKS 5461 for the seven-day treatment period. Data from the study showed that ALKS 5461 was generally well tolerated. Based on these results, Alkermes has accelerated the start of the phase 2 study of ALKS 5461 for MDD, which has initiated.
