Clinical Trials

Date: 2013-10-01

Type of information: Publication of results in a medical journal

phase: 3

Announcement:

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

Product: laquinimod

Action mechanism: 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: multiple sclerosis

Therapeutic area: Autoimmune diseases - Neurodegenerative diseases

Country:

Trial details: The global Phase III clinical development program evaluating oral laquinimod in MS consists of two pivotal studies, ALLEGRO and BRAVO. ALLEGRO was a two-year multi-national, multi-center randomized, double blind, placebo-controlled study designed to evaluate the efficacy, safety and tolerability of laquinimod in MS patients. The study was conducted at 139 sites in 24 countries and enrolled 1,106 MS patients. Patients were randomized to receive a once-daily oral dose of 0.6 mg laquinimod or matching placebo. The primary outcome measure was the number of confirmed relapses; secondary measures included confirmed disability progression and changes in MRI active lesions. Eighty percent of laquinimod and 77 percent of placebo patients completed the two-year study. Patients who completed the ALLEGRO study were offered to join an open-label extension phase, in which they are being treated with laquinimod 0.6 mg daily. BRAVO was a two-year, multi-national, multi-center, randomized, double-blind, parallel-group, placebo-controlled study designed to compare the safety, efficacy and tolerability of a once-daily oral dose of 0.6 mg laquinimod over placebo and to provide a descriptive comparison of the risk-benefit profiles of laquinimod and interferon beta-1a. The primary outcome measure was to assess the efficacy of 0.6 mg daily dose of laquinimod as measured by the relapse rate. Secondary outcome measures included impact on the accumulation of disability and brain atrophy. The BRAVO study completed enrollment in June 2009, recruiting more 1,331 patients at 153 sites worldwide.

Latest news:

• • On October 1, 2013, Teva Pharmaceutical Industries and Active Biotech have announced the publication of a pre-planned analysis of the Phase III ALLEGRO study demonstrating that once-daily oral laquinimod provides a beneficial impact on brain tissue damage, one of the most destructive aspects of multiple sclerosis. The results showed that when compared with placebo, patients treated with laquinimod experienced decreased rates in brain tissue damage shown by various MRI markers. Specifically, patients receiving laquinimod showed decreased rates of white matter (WM), grey matter (GM) and thalamic atrophy. These patientsaccumulated less damage in normal appearing brain tissue (NABT), WM and GM, when compared to patients receiving placebo. Laquinimod also reduced the number of permanent black holes (PBH) at 12 and 24 months evolving from active lesions (all p<0.05). By month 24, MTR decreased significantly in NABT (p=0.015), WM (p=0.011) and GM (p=0.034) in placebo-treated patients, but not in laquinimod-treated patients.  Teva is now planning clinical trial in primary progressive multiple sclerosis (PPMS) based on novel mechanism of action demonstrated in Phase III trial program.
• • On March 21, 2013, Teva Pharmaceutical and Active Biotech have announced results from the open-label extension of the Phase III ALLEGRO study that assessed the progression of disability and safety of oral laquinimod in early versus delayed-start relapsing-remitting multiple sclerosis (RRMS) patients. The study compared the effectiveness of laquinimod in patients who received 36 months (early-start) versus those who received 24 months of laquinimod treatment (delayed-start).
• Of the 864 RRMS patients who participated in the original double-blind ALLEGRO trial, 97% participated in the open-label extension and 87% completed one year of the open-label phase. Overall, during the entire conduct of the study (double blind and open label phase), early start patients were less likely to experience disease progression than those with a delayed start of Laquinimod (11.8% risk of confirmed disability progression vs. 16.7%, HR = 0.62, p < 0.0038). The study also supports a favorable safety and tolerability profile of laquinimod in RRMS patients. No new safety concerns arose during the open-label phase. Additionally, a preclinical study in animal models demonstrated the ability of laquinimod to increase the myelinated axons and mature oligodendrocytes in the brain. This data suggests laquinimod has potential restorative and anti-inflammatory properties. Results of both studies will be shared with the scientific community following a full analysis of the data.
• • On March 15, 2012, Teva Pharmaceutical Industries and Active Biotech have announced the publication of results from the laquinimod Phase III ALLEGRO study in the March 15 issue of The New England Journal of Medicine. Data from the two-year study showed that oral once-daily laquinimod reduced inflammatory disease activity as measured by clinical relapses and Magnetic Resonance Imaging (MRI), slowed disability progression and decreased brain tissue loss, while maintaining a favorable safety and tolerability profile in patients with relapsing-remitting multiple sclerosis (RRMS). The ALLEGRO results, along with results from the second global Phase III study of laquinimod, BRAVO, will be included in the application for regulatory approval planned for submission to the European Medicines Agency (EMA) in the second half of 2012. In the study, laquinimod showed a statistically significant 23 percent reduction in annualized relapse rate (P=0.002), the primary endpoint, along with a significant 36 percent reduction in the risk of confirmed disability progression, as measured by Expanded Disability Status Scale (EDSS). Additional analyses showed that the actual proportion of patients with confirmed disability progression at the last assessment was lower in the laquinimod group than in the placebo group (9.8 percent vs. 14.0 percent; P=0.04). Treatment with laquinimod was also associated with a significant reduction in brain tissue loss, as measured by a 33 percent reduction in progression of brain atrophy (P<0.001).
• The overall frequencies of adverse events, including incidence of infections, were comparable to those observed in the placebo group. The most commonly reported adverse events were headaches, nasopharyngitis and back pain. The incidence of liver enzyme elevation was higher in laquinimod treated patients; however, these elevations were transient, asymptomatic and reversible. No deaths were reported in laquinimod-treated patients. Eighty percent of laquinimod and 77 percent of placebo patients completed the two-year study. Patients who completed the ALLEGRO study were offered to join an open-label extension phase, in which they are being treated with laquinimod 0.6 mg daily.
• • On November 2, 2011, Teva Pharmaceutical Industries and Active Biotech have announced the presentation of Phase III clinical and pre-clinical data, which collectively demonstrate that once-daily oral laquinimod modulates the pathological processes of multiple sclerosis to impact disease activity, disability progression and brain volume loss. The data will be featured in more than 20 scientific posters and presentations this week at the 5th Joint Triennial Congress of the European and Americas Committees for Treatment and Research in Multiple Sclerosis (ECTRIMS and ACTRIMS). Findings from the second Phase III study, BRAVO, showed that at 24-months, the primary endpoint of reduction in annualized relapse rates (ARR) did not reach statistical significance (0 = 0.075); however, after applying a pre specified sensitivity analysis to correct for meaningful imbalances in baseline characteristics (MRI) between treatment groups, laquinimod significantly reduced ARR (21.3%, p = 0.026). Laquinimod also demonstrated a significant reduction in the risk of disability progression as measured by the Expanded Disability Status Scale (EDSS) (33.5%, p = 0.044) and in MRI-measured brain volume loss (27.5%, p =< 0.0001). The safety and tolerability profile of laquinimod was favorable.
• New exploratory analyses from ALLEGRO, the first Phase III study in the laquinimod clinical development program, demonstrated that laquinimod had an effect on the rate of severe relapses, showing a 38 percent reduction in the annualized rate of relapses requiring hospitalization and a 27 percent reduction in those requiring intravenous steroids. Treatment with laquinimod was also associated with a 36 percent reduction in the risk for three month confirmed EDSS progression (p=0.0122) and a 48 percent reduction in the risk for six month confirmed EDSS progression (p= 0.0023). Additionally, laquinimod had a positive impact on patient-reported fatigue and cognitive functioning, as assessed by the Modified Fatigue Impact Scale (MFIS) and the short-form (SF)-36 general health survey.
• Several pre-clinical studies being presented further elucidate the potential novel mechanisms of action of laquinimod. The product targets both neurodegeneration occurring directly in the CNS and peripheral inflammation."The cuprizone and EAE mouse model studies showed that laquinimod reduced demyelination, axonal damage and resulted in dose-dependent decreases in pro-inflammatory cytokines, further demonstrating that the compound acts directly on resident CNS cells to decrease neurodegeneration and brain volume loss," said Wolfgang Brück, M.D., Director of Neuropathology at Georg-August-University in Goettingen, Germany.
• • On August 2, 2011, Teva Pharmaceutical Industries Ltd. and Active Biotech have announced initial results from the Phase III BRAVO study, which was designed to evaluate the efficacy, safety and tolerability of oral laquinimod compared to placebo and to provide a benefit-risk assessment comparing oral laquinimod and a reference arm of injectable Interferon beta-1a (Avonex®). Results showed that the BRAVO study did not achieve its primary endpoint of reducing the annualized relapse rate (p=0.075). The randomization process for BRAVO was adequately performed; however, placebo and treatment study groups showed dissimilarity in two baseline magnetic resonance imaging (MRI) characteristics. According to a standard and pre-specified sensitivity analysis included within the original statistical analysis plan, when this imbalance was corrected laquinimod demonstrated a significant reduction in the annualized relapse rate (21.3%, p=0.026), in the risk of disability progression as measured by Expanded Disability Status Scale (EDSS) (33.5%, p=0.044) and in brain volume loss (27.5%, p<0.0001).
• The BRAVO findings support the direct effect of laquinimod in the central nervous system (CNS) and are in line with the results of the first laquinimod Phase III trial, ALLEGRO. Additionally, as in ALLEGRO, the BRAVO study found that laquinimod demonstrated a favorable safety and tolerability profile compared to placebo. Compared to placebo, treatment with Interferon beta-1a reduced annualized relapse rates; however, a reduction in brain tissue loss was not demonstrated and a reduction in the progression of disability was not significant. The BRAVO study was not designed to provide direct statistical comparisons of efficacy endpoints between the two active arms. Additional analyses of the BRAVO study data are ongoing, and results will be submitted for presentation at a scientific congress later in the year.
• • On April 11, 2011, Teva Pharmaceutical Industries and Active Biotech have announced results from the two-year Phase III ALLEGRO study of laquinimod, an oral, once-daily, investigational immunomodulator for the treatment of relapsing forms of multiple sclerosis (MS). These data will be presented as late-breaking research at the Annual Meeting of the American Academy of Neurology (AAN). In the ALLEGRO study, laquinimod showed a statistically significant 23 percent reduction in annualized relapse rate (p=0.0024), the primary endpoint, along with a significant 36 percent reduction in the risk of confirmed disability progression, as measured by Expanded Disability Status Scale (EDSS) (p=0.0122). Treatment with laquinimod was also associated with a significant reduction in brain tissue loss, as measured by a 33 percent reduction in progression of brain atrophy (p<0.0001). Laquinimod was safe and well-tolerated without immunosuppressive effects. The overall frequencies of adverse events, including incidence of infections, were comparable to those observed in the placebo group. The most commonly reported adverse events were headaches, nasopharyngitis and back pain. The incidence of liver enzyme elevation was higher in laquinimod treated patients; however, these elevations were transient, asymptomatic and reversible. No deaths were reported in laquinimod-treated patients. The second laquinimod Phase III study, BRAVO, is currently ongoing with results anticipated in the third quarter of 2011. This two-year, multi-national, multi-center, randomized, double-blind, parallel-group, placebo-controlled study has been designed to compare the safety, efficacy and tolerability of a once-daily oral dose of 0.6 mg laquinimod over placebo and to perform a comparative risk-benefit assessment between laquinimod and interferon beta-1a. Regulatory submissions are planned in the U.S. and the EU following the availability of the BRAVO results.

Is general: Yes