Date: 2016-09-15
Type of information: Presentation of results at a congress
phase: 3
Announcement: presentation of results at at ECTRIMS
Company: BiogenIdec (USA - MA) AbbVie (USA - IL)
Product: Zinbryta™ (Daclizumab High-Yield Process - DAC HYP)
Action
mechanism: monoclonal antibody. Zinbryta™(DAC HYP) is a new form of humanized monoclonal antibody that selectively binds to the high-affinity interleukin-2 (IL-2) receptor subunit (CD25) that is expressed at high levels on T-cells that become abnormally activated in multiple sclerosis. DAC HYP modulates IL-2 signaling without causing general immune cell depletion. DAC HYP is believed to work by decreasing abnormally-activated T-cells and pro-inflammatory lymphoid tissue inducer cells, and increasing CD56bright natural killer (NK) cells, important cells that help regulate the immune system.
Disease: relapsing-remitting multiple sclerosis
Therapeutic area: Neurodegenerative diseases
Country: USA, Argentina, Australia,Brazil, Canada, Czech Republic, Denmark, Finland, France, Georgia, Germany, Greece, Hungary, India, Ireland, Israel, Italy, Mexico, Moldova, Republic of, Poland, Romania, Russian Federation, Serbia, Spain, Sweden, Switzerland, Ukraine, UK
Trial
details: DECIDE was a two to three year, Phase 3, global, randomized, double-blind, multicenter study designed to determine if DAC HYP would provide superior outcomes for certain clinical endpoints compared to treatment with IFN beta-1a. The study enrolled more than 1,800 people with RRMS in 28 countries. DECIDE was an active comparator study with two groups: 150 mg of subcutaneous DAC HYP every four weeks was compared to IFN ?-1a 30 mcg intramuscular injection once weekly. The primary endpoint in DECIDE was the reduction in ARR. Secondary endpoints included the number of new or newly enlarging T2-hyperintense lesions, the proportion of patients with sustained disability progression (EDSS), the proportion of relapse-free patients and the proportion of patients who experienced a worsening physical impact score on the Multiple Sclerosis Impact Scale (MSIS-29). (NCT01064401) After completing the DECIDE study, patients have the option to participate in an open-label extension study called EXTEND. The DAC HYP development program also includes the previously completed pivotal, placebo controlled, double-blind SELECT study. EXTEND is an ongoing, multicenter, open-label, Phase 3 extension study that is evaluating the long-term safety and efficacy of Zinbryta™ in patients with relapsing forms of multiple sclerosis (RMS) who completed the DECIDE, SELECTED or OBSERVE studies. The study has enrolled more than 1,500 RMS patients, who will receive 150 mg of subcutaneous Zinbryta™ every four weeks for up to five years.
Latest
news: * On September 15, 2016, a new post-hoc analysis from the pivotal DECIDE study shows that a significantly greater number of people treated with Zinbryta™ (daclizumab) achieved no evidence of disease activity (NEDA) compared to those taking Avonex® (interferon beta-1a) intramuscular injection. The findings continue to support the positive impact of Zinbryta™ on NEDA status. Additional new interim data from the long-term extension study, EXTEND, further affirm Zinbryta™ ’s efficacy on clinically meaningful measures of multiple sclerosis (MS) disease activity and provide additional information supporting Zinbryta™’s safety profile. These results were presented by Biogen and AbbVie at the 32nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) in London. Zinbryta™ is now available in the United States and Germany, and will soon be introduced in additional European countries. New NEDA Analysis Shows Significantly Greater Efficacy Versus Interferon Beta-1a: Previously reported findings from a post-hoc analysis of the Phase 3 DECIDE study demonstrated that a significantly greater percentage of patients taking Zinbryta™ achieved NEDA status at 96 weeks compared to those taking an active comparator, Avonex®. A new post-hoc analysis presented at ECTRIMS examined the percentage of patients achieving NEDA status by time interval (including 24–96 weeks) to further evaluate the impact of Zinbryta™ on this measure. NEDA was defined as the composite of no clinical relapses, no 12-week confirmed disability progression, no new/newly enlarging T2 hyperintense lesions and no gadolinium-enhancing (Gd+) lesions. Results of this new analysis show that significantly more Zinbryta™-treated patients achieved overall NEDA status compared to Avonex®-treated patients during the first six months of treatment, and that the difference between the treatments was more evident in the 24–96 week time period: Baseline to week 24: 41.5 percent of Zinbryta™ patients achieved NEDA status compared to 32.6 percent of Avonex® patients (p<0.0001). Interim EXTEND Data Reinforce Long-Term Efficacy and Further Define Safety Profile: The first interim results from EXTEND were also presented at ECTRIMS, including up to five years of data from patients previously enrolled in DECIDE. The data show that treatment with Zinbryta™ was associated with long-term benefits in the proportion of patients who remained relapse-free, as well as those who did not experience 24-week confirmed disability progression. EXTEND is an ongoing, Phase 3, open-label extension study assessing the safety and efficacy of Zinbryta™. Patients who were treated with Avonex® for two to three years (median of 26 months) in the DECIDE study switched to Zinbryta™ when they enrolled in EXTEND, and were compared to Zinbryta™ patients continuously treated in both DECIDE and EXTEND. The safety profile of Zinbryta™ was similar to that observed in the controlled clinical trial, DECIDE. The overall incidence of serious adverse events (AEs), excluding MS relapses, remained stable over time. Most AEs of special interest, including hepatic (liver) AEs, cutaneous (skin) AEs, infections and lymphadenopathy (abnormal enlargement of lymph nodes), were mild to moderate in severity. The interim EXTEND results provide additional data supporting the long-term safety profile of Zinbryta™. The interim efficacy data show: The annualized relapse rate (ARR) for patients who took Zinbryta™ continuously in the DECIDE and EXTEND studies remained stable (0.195 vs. 0.156, respectively). * On October 8, 2015, Biogen announced that full results from the Phase 3 DECIDE study have been published in the New England Journal of Medicine , as well as new post-hoc analyses of Phase 3 clinical data presented at an international congress, show once-monthly, investigational Zinbryta™ (daclizumab high-yield process [HYP]) improved results on key measures of multiple sclerosis disease activity in patients with relapsing-remitting MS (RRMS) compared to interferon beta-1a 30 mcg intramuscular (IM) injection. In the new post-hoc analyses, Zinbryta™ was shown to increase the percentage of patients achieving no evidence of clinical and MRI disease activity, improve cognitive processing speed and reduce 24-week confirmed disability progression across a broad range of subgroups at two years compared to interferon beta-1a IM. Lead investigators on behalf of Biogen (NASDAQ: BIIB) and AbbVie (NYSE: ABBV) presented these new findings at the 31st Congress of the European Committee for Treatment and Research in MS (ECTRIMS) in Barcelona, Spain (7-10 October). Efficacy Compared to Interferon Beta-1a IM: New post-hoc analyses of data from DECIDE presented at ECTRIMS assessed multiple measures of MS disease activity and showed that compared to interferon beta-1a IM over two years (p values are nominal). More Zinbryta™-treated patients exhibited no evidence of disease activity (NEDA) (24.6% versus 14.2%; p<0.0001; n=1,841). These results were based on a greater number of Zinbryta™ patients achieving both clinical NEDA (no relapses and no disability progression) and MRI NEDA (no new/newly enlarging T2-hyperintense lesions and no gadolinium-enhanced lesions). Thefull results from the pivotal Phase 3 DECIDE study were published in the 8 October 2015 issue of the NEJM. The DECIDE trial enrolled more than 1,800 patients with RRMS in 28 countries. Analysis of Safety Results: An integrated analysis of the safety and tolerability data from six clinical studies involving 2,236 RRMS patients treated with Zinbryta™, including some patients treated for more than five years, was presented at ECTRIMS (888 patients were treated for ?3 years, 211 patients were treated for ?5 years). These results support the known benefit-risk profile of Zinbryta™ and indicate that adverse events (AEs) did not appear to increase over time. Over a median of 30 months of exposure, the incidence of infections (59%), cutaneous events (33%), and hepatic events (16%) did not increase over time. The most common AEs (incidence ?10%) associated with Zinbryta™ were MS relapse (31%), nasopharyngitis (20%), upper respiratory infection (15%), headache (13%) and urinary tract infection (10%). A separate post-hoc analysis of cutaneous AEs occurring in the DECIDE study showed that cutaneous events were more common with Zinbryta™ treatment (37%) than with interferon beta-1a (19%). Most patients treated with Zinbryta™ who reported mild (81%) or moderate (73%) cutaneous events were not treated with a corticosteroid or were treated with topical corticosteroids. Serious cutaneous AEs (2%) were commonly managed in patients with systemic corticosteroids. * On September 12, 2014, Biogen Idec and AbbVie announced the full results from the Phase 3 DECIDE clinical trial, which show Zinbryta™ (daclizumab high-yield process), dosed subcutaneously once a month, demonstrated a statistically significant improvement in reducing disease activity in people with relapsing-remitting multiple sclerosis (RRMS) compared to Avonex® (interferon beta-1a). These results are being presented at the Sixth Triennial Joint Meeting of the Americas Committee for Treatment and Research in Multiple Sclerosis and the European Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS-ECTRIMS) in Boston. Primary Endpoint: Patients on Zinbryta™ demonstrated a statistically significant 45 percent reduction in annualized relapse rate (ARR) compared to patients treated with Avonex® (p<0.0001). * On June 16, 2014, Biogen Idec and AbbVie announced positive top-line results from the Phase 3 DECIDE clinical trial, designed to evaluate the superiority of once-monthly, subcutaneous daclizumab high-yield process (DAC HYP) when compared to intramuscular interferon beta-1a (IFN ?-1a), as a potential treatment for relapsing-remitting multiple sclerosis (RRMS). Results showed that DAC HYP was superior on the study’s primary endpoint, demonstrating a statistically significant 45 percent reduction in annualized relapse rate (ARR) compared to IFN ?-1a (p<0.0001). DAC HYP showed superiority on the first secondary endpoint, number of new or newly enlarging T2-hyperintense lesions at week 96, with a 54 percent reduction relative to IFN ?-1a (p<0.0001). On the second secondary endpoint, DAC HYP reduced the risk of three month confirmed disability progression as measured by the Expanded Disability Status Scale (EDSS) by 16 percent over IFN ?-1a, which was not statistically significant (p=0.16). Using a pre-specified sensitivity analysis that accounted for 67 patients who did not have a confirmatory disability assessment, DAC HYP showed a 21 percent reduction in the risk of sustained disability progression (p=0.047). The safety profile of DAC HYP in the study was consistent with what has been observed in prior studies. The overall incidence of adverse events was comparable across the DAC HYP and IFN ?-1a treatment groups. In patients treated with DAC HYP compared to IFN ?-1a, there was an increased incidence of serious infections (4 percent vs. 2 percent), serious cutaneous reactions (2 percent vs. < 1 percent), and elevations of liver transaminases greater than 5 times the upper limit of normal (6 percent vs. 3 percent). There were 4 deaths in the IFN ?-1a group and 1 death in the DAC HYP group, none of which was considered treatment related.
Weeks 24–96: 44.7 percent of Zinbryta™ patients achieved NEDA status compared to 22.4 percent of Avonex® patients (p<0.0001).
Patients who switched to Zinbryta™ in the EXTEND study experienced a decrease in ARR from 0.317 during the earlier treatment period with Avonex®, to 0.152 after receiving Zinbryta™.
From baseline to week 48 in EXTEND, improvements in MRI data were observed across EXTEND study participants (based on new T2 hyperintense lesions, new T1 hypointense lesions and the number of Gd+ lesions).
Patients treated continuously with Zinbryta™ from DECIDE baseline up to week 192 experienced a 21 percent relative risk reduction in 24-week confirmed disability progression, compared with patients who were treated with Avonex®, in DECIDE and then switched to Zinbryta™ in EXTEND (hazard ratio: 0.79; 95% confidence interval: 0.62–1.00; p=0.047).
Zinbryta™-treated patients showed improvement in cognitive processing speed and prevention of clinically meaningful cognitive decline, as measured by greater mean improvements from baseline on the Symbol Digit Modalities Test (SDMT; +4.08 [12.4] versus +2.89 [12.7]; p=0.0274). Higher percentages of Zinbryta™ patients had a ?3-point (60.0% versus 54.1%; p=0.0153) or ?4-point (55.4% versus 50.1%; p=0.0366) improvement in SDMT scores at week 96 (n=1,402).
Zinbryta™ treatment resulted in reductions in the risk of 24-week confirmed disability progression across a wide range of pre-specified patient subgroups based on baseline characteristics.
Secondary Endpoints: Zinbryta™ demonstrated superiority in reducing the number of new or newly enlarging T2-hyperintense lesions at week 96, with a 54 percent reduction relative to Avonex® (p<0.0001).
The risk of three-month confirmed disability progression, as measured by the Expanded Disability Status Scale (EDSS), was reduced by 16 percent in patients treated with Zinbryta™ compared to those on Avonex® (p=0.16). This was not statistically significant.
Seventy-three percent of Zinbryta™ patients were relapse-free compared to 59 percent of Avonex® patients (nominal p<0.0001) at week 96.
The risk of meaningful worsening in the physical impact of multiple sclerosis (MS) (> 7.5 point worsening in the Multiple Sclerosis Impact Scale [MSIS-29] physical score) was reduced by 24 percent in the Zinbryta™ group compared to the Avonex® group (nominal p=0.018).
DECIDE Safety Results: The safety profile of Zinbryta™ in the DECIDE study was generally consistent with the Phase 2 studies. The overall incidence of adverse events was comparable across the Zinbryta™ and Avonex® treatment groups.
In patients treated with Zinbryta™ compared to Avonex® , there was an increased incidence of serious infections (4 percent vs. 2 percent). The pattern and types of infections seen in the Zinbryta™ group were consistent with what has been previously observed in the MS population.
Also consistent with previous studies, patients in the Zinbryta™ group had a greater incidence of cutaneous adverse events (37 percent vs. 19 percent) and serious cutaneous reactions (2 percent vs. < 1 percent); and elevations of liver transaminases greater than five times the upper limit of normal (6 percent vs. 3 percent). There were four deaths in the Avonex® group and one death in the Zinbryta™ group, none of which was considered treatment related.
Based on the efficacy and safety data from the Zinbryta™ clinical development program, Biogen Idec and AbbVie plan to file marketing applications for Zinbryta™ with regulatory authorities during the first half of 2015.
Biogen Idec and AbbVie plan to work with regulatory agencies to determine appropriate timelines for filing. The companies intend to present detailed results from DECIDE at a future medical conference.
