BOSTON — The latest data from long-term follow-up of patients receiving laquinimod (Nerventra, Teva Pharmaceutical Industries Ltd/Active Biotech) in clinical trials have shown "reassuring" results in terms of adverse effects, it has been reported.

Presenting the latest results from a pooled analysis of laquinimod clinical trials with patients receiving the drug for up to 4 years, Giancarlo Comi, MD, from San Raffaele University, Milan, Italy, noted that there have been no new adverse effects seen and no signal of any type of cancer, and the adverse event rate in general appears to be less in the extension phase than in the core studies.

Dr. Comi presented the update here at MSBoston 2014, the 2014 Joint Americas and European Committees for Treatment and Research in Multiple Sclerosis (ACTRIMS/ECTRIMS) meeting.

Cancer Concerns in Animal Studies

The drug is not yet available, having been turned down a second time by the European Medicines Agency's Committee for Medicinal Products for Human Use earlier this year because of concerns about cancer and possible teratogenic effects in animal studies of long-term exposure to laquinimod, as well as uncertain efficacy data from 2 phase 3 clinical trials.

Final results of the Assessment of Oral Laquinimod in Preventing Progression in Multiple Sclerosis (ALLEGRO) trial, published in the March 15 issue of the New England Journal of Medicine, showed that treatment with laquinimod reduced annualized relapse rates and delayed disability progression compared with placebo. However, results from a second pivotal phase 3 trial, BRAVO (Laquinimod Double Blind Placebo Controlled Study in RRMS Patients With a Rater Blinded Reference Arm of Interferon β-1a [Avonex®]), comparing laquinimod with interferon-beta-1a (Avonex, Biogen Idec), missed the primary endpoint of reducing annualized relapse rates, although the reduction seen with laquinimod was significant after researchers adjusted for an imbalance between groups in the volume of T2 disease and the number of gadolinium-enhancing lesions on magnetic resonance imaging.

Both trials, however, showed a reduction in disability that was unexpected, given the effect seen on relapse rates, raising the possibility that the agent might be affecting disability through some novel mechanism. There was also a reduction in brain atrophy in line with the effect on disability, which was another novel finding with this agent.

This larger-than-expected effect on disability has stimulated continued interest in this agent. A third phase 3 trial, CONCERTO (The Efficacy and Safety and Tolerability of Laquinimod in Subjects With Relapsing Remitting Multiple Sclerosis [RRMS]), is now underway.

Meanwhile, the current presentation focused on a pooled analysis of the 2 phase 3 trials (ALLEGRO and BRAVO), with additional safety data from a phase 2 study.

Cochair of the session at which the new data were presented, Tanuja Chitnis, MD, from Brigham and Women's Hospital, Boston, commented to Medscape Medical News: "In general, the regulatory authorities have been looking for more data on longer-term tolerability with laquinimod. I thought these data from the extension arms of the major studies were reassuring on that."

Good Option for Combination Therapy?

Dr. Chitnis noted that laquinimod had shown a different profile than most other multiple sclerosis (MS) drugs, in that it has a modest effect on relapse rate, but apparently a more robust effect on disability progression and brain atrophy measures than one may expect. "This raises the question of using it in combination with other therapies," she added.

Dr. Comi reported that the phase 3 core studies had identified only manageable or benign adverse effects with laquinimod, with the most common being back and neck pain. There was a slight increase in appendicitis (0.6% laquinimod vs 0.1% placebo). In addition, there were some mild changes in laboratory parameters, including an increase in liver enzymes, fibrinogen, C-reactive protein, and white blood cells and a decrease in hemoglobin and platelets.

Current data show that 1543 patients are involved in the extension phases of these studies. Of these, 1009 patients have been receiving laquinimod 0.6 mg for more than 2 years, 750 have received the drug for more than 3 years, and 194 for more than 4 years.

Efficacy data showed a continued decline in annual relapse rate that remained low during the extension studies, Dr. Comi reported.

Table 1. Annual Relapse Rate in Pooled Phase 3 Trials

Data Pool Control/Delayed Start Laquinimod
Core studies 0.374 0.301
Extension studies 0.232 0.202

Patients who received early treatment with laquinimod compared with delayed treatment maintain a significantly lower level of disability throughout the extension phase, with a 21% reduced risk for 6-month disability progression.

Table 2. Risk for 6-Month Disability Progression on Laquinimod

Endpoint Hazard Ratio (95% Confidence Interval) P
6-month disability progression 0.79 (0.64 - 0.97) .029

Safety data showed that less than 3% of patients discontinued treatment because of adverse events, the total adverse event and serious adverse event rates were lower in the long-term cohort than in the core study, and no new adverse events were identified, Dr. Comi reported.

Table 3. Adverse Event Rate Per 100 Patient Years

Endpoint Placebo Core Laquinimod Core Extension
Adverse event rate per 100 patient-years 8.3 9.5 8.6

The most frequent serious adverse event was appendicitis, which occurred in 0.3% of laquinimod patients vs 0.05% of patients receiving placebo.

There was no increase in the incidence of malignancies, pericarditis, pleuritis, myocardial infarction, peritonitis, pancreatitis, or infections compared with the core phase cohort, Dr. Comi said.

In terms of laboratory values, patients receiving laquinimod for more than 2 years showed fewer shifts to abnormal values of alanine transaminase (ALT) and aspartate transaminase (AST) than they had during the first 2 years, and fewer even than among patients on placebo. In addition, there was no increase in abnormal values of hematological and acute phase (C-reactive protein, fibrinogen) laboratory parameters over time.

Dr. Comi reports receiving compensation for consulting and/or speaking activities from Novartis, Teva Pharmaceutical Industries, Sanofi, Genzyme, Merck Serono, Biogen Idec, Bayer, Serono Symposia International Foundation, Almirall, Chugai, and Receptos.

MSBoston 2014: 2014 Joint Americas and European Committees for Treatment and Research in Multiple Sclerosis (ACTRIMS/ECTRIMS): Abstract FC1.3. Presented September 12, 2014.


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