Clinical Trials

Date: 2017-05-05

Type of information: Results

phase: 3

Announcement: results

Company: Teva Pharmaceuticals (Israel) Active Biotech (Sweden)

Product: laquinimod

Action mechanism: immunomodulating agent. This oral, once-daily, immunomodulator with a novel mechanism of action has been developed by Active Biotech. The positive ALLEGRO results are supported by new pre-clinical data, also presented at the AAN meeting, that further establish the mechanism of action of laquinimod, which led to a reduction in axonal damage, the main determinant of permanent clinical disability in MS. Data from the cuprizone model, designed to investigate the effect on neurodegeneration, independent of inflammation, demonstrated that laquinimod reduced demyelination and axonal damage while preserving more myelin-producing cells. This unique effect suggests a direct decrease in nerve damage in the central nervous system (CNS). Additionally, laquinimod was shown to modulate the brain-derived neurotrophic factor (BDNF) pathway, a key factor in maintaining axonal integrity.

Disease: relapsing-remitting multiple sclerosis (RRMS)

Therapeutic area: Autoimmune diseases - Neurodegenerative diseases

Country: Belarus, Bosnia and Herzegovina, Estonia, USA

Trial details: The third Phase III laquinimod trial CONCERTO will evaluate two doses of the investigational product (0.6mg and 1.2mg) in approximately 1,800 patients for up to 24 months, after which patients will continue to an active treatment period with laquinimod for an additional 24 months. The primary outcome measure will be time to confirmed disability progression as measured by the Expanded Disability Status Scale (EDSS). The study will also examine the impact of laquinimod on endpoints such as percent change in brain volume, as well as other clinical and MRI markers of disease activity. (NCT01707992)

Latest news:

• • On May 5, 2017, Teva Pharmaceutical Industries and Active Biotech announced results from the CONCERTO trial in patients with relapsing-remitting multiple sclerosis (RRMS). The primary endpoint in CONCERTO -- the evaluation of laquinimod (0.6 mg/daily capsules) versus placebo to evaluate the time to Confirmed Disability Progression (CDP) after at least 3 months - was not met. (Hazard Ratio of 0.937, p = 0.7057). Other data details show that on the secondary endpoint which measured change in brain volume-- an indicator of disability progression over time-- compared to baseline was positive (40% improvement over placebo at month 15, p < 0.0001). Other encouraging results were seen on the secondary endpoint of time to first relapse (risk reduced by 28%; p = 0.0001) and the exploratory endpoint of annualized relapse rate (risk reduced by 25%; p=0.0001).
• As with the primary endpoint, secondary endpoints measuring time to CDP at 6 and 9 months did not reach significance. On the exploratory endpoint of reduction of the number of gadolinium-enhancing T1 lesions at month 15, laquinimod demonstrated a 30% reduction (p=0.004). Teva announced that the company has no current plans to further pursue laquinimod in RRMS, and is continuing to study it in two other trials. Teva continues to evaluate the potential of laquinimod in primary progressive MS (PPMS) and Huntington disease (HD) with two other clinical trials unaffected by the results of the CONCERTO trial. Complete data from the CONCERTO trial will be published in a scientific journal and presented at a future medical meeting.
• • On September 19, 2016, Active Biotech provided an update on laquinimod which is being developed in multiple sclerosis and Huntington's disease by Teva Pharmaceutical. The FDA has informed Teva that the Special Protocol Assessment (SPA) for the Phase III CONCERTO clinical trial evaluating laquinimod in relapsing remitting multiple sclerosis (RRMS) was rescinded. Both companies confirmed in January 2016 that the highest dose arms in two MS trials and one trial in HD were discontinued at the recommendation of the Data Monitoring Committees (DMC). In February, 2016, Teva submitted to the FDA an amendment to the SPA to account for this change. However, per FDA regulatory process, the SPA was rescinded as all changes must be agreed to prior to implementation of the change. This requirement could not be fulfilled in the current case, since the DMC recommendation triggered an immediate action to withdraw the 1.2 mg dose for the treatment of RRMS in the interest of patient safety. The CONCERTO trial continues with one dose (0.6mg/day) vs. placebo on the original schedule, and Teva plans to use this pivotal trial to support filing for marketing approval for laquinimod in the US and EU, as previously communicated. No change is anticipated in the trial's completion date.
• • On January 4, 2016, Teva Pharmaceutical Industries and Active Biotech announced the discontinuation of higher doses of laquinimod in two ongoing studies in multiple sclerosis after the occurrence of cardiovascular events, none of which was fatal, in eight patients. The change comes at the recommendation of the data monitoring committee (DMC) overseeing two active clinical studies in MS. The DMC identified an imbalance in the number of cardiovascular events in the studies. Seven events were observed in patients receiving laquinimod daily at 1.2mg for treatment of relapsing-remitting MS (RRMS) in the CONCERTO trial. No events occurred in the 0.6mg or placebo groups. CONCERTO has 2,199 patients with 3,070 years of patient experience. One event was observed in the 1.5mg daily-dose arm of the ARPEGGIO trial in primary-progressive MS (PPMS). ARPEGGIO has enrolled 191 patients and has 35 years of patient experience. Teva is notifying trial sites to discontinue the higher doses immediately in both trials and will encourage participants to continue follow ups.
• Both trials, CONCERTO and ARPEGGIO, are continuing the lower-dose arms (0.6mg daily), and participants in the trials will be provided with an update to confirm re-consent for participation. The DMC did not identify a cardiovascular signal with the lower dose but recommended long-term monitoring. Teva has completed large trials and is conducting long-term extension studies at the 0.6mg dose currently without cardiovascular concerns.
• • On June 25, 2015, Teva Pharmaceutical and Active Biotech announced that the patient enrollment for the pivotal Phase III CONCERTO trial has been finalized, as well as a planned sample size re-assessment analysis of the study. CONCERTO, the third Phase III trial of laquinimod in patients with relapsing-remitting multiple sclerosis (RRMS), is designed to evaluate the safety and efficacy of laquinimod (0.6mg or 1.2mg/day) with a primary endpoint of time to Confirmed Disability Progression (CDP), as measured by the Expanded Disability Status Scale (EDSS). The sample size re-assessment was included as part of the protocol to confirm that the original assumptions are in line with the study and that the sample size is adequate. Based on recent agreement with FDA, under a Special Protocol Assessment (SPA) agreement, study completion will occur when either 260 events are reached or all patients complete 24 months of study treatment (whichever occurs first). CONCERTO study results are expected to be available toward mid-2017. Regulatory submission will follow study completion. • On March 06, 2013, Teva Pharmaceutical Industries and Active Biotech have announced enrollment of the first patient in the CONCERTO study - the third Phase III placebo-controlled study designed to evaluate the efficacy, safety and tolerability of once-daily oral laquinimod in patients with relapsing-remitting multiple sclerosis (RRMS). The primary outcome measure of CONCERTO will be confirmed disability progression as measured by the Expanded Disability Status Scale (EDSS). The global Phase III clinical development program evaluating oral laquinimod in MS includes two pivotal studies, ALLEGRO and BRAVO.
• • On August 8, 2012, Teva Pharmaceutical and Active Biotech have provided an update on the clinical development program of once-daily oral laquinimod for the treatment of relapsing-remitting multiple sclerosis. The companies are to initiate a third Phase III study of laquinimod, following the written agreement reached with the FDA on the Special Protocol Assessment (SPA).

Is general: Yes