COPENHAGEN, Denmark — More evidence is supporting the view that laquinimod (Teva Pharmaceuticals Inc/Active Biotech) may have a greater effect on disability in patients with multiple sclerosis (MS) than suggested by its effect on relapse rate and inflammation.

The new evidence comes from 3 new analyses of data from the 2 phase 3 studies of laquinimod — Assessment of Oral Laquinimod in Preventing Progression in Multiple Sclerosis (ALLEGRO) and BRAVO — presented at the recent 29th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

In his summary talk at the end of the meeting looking at meeting highlights, Bernd Kieseier, MD, Heinrich Heine University, Düsseldorf, Germany, pointed out these new analyses.

"We are seeing a relative reduction of 30% in 3-month disability progression. That is 6 times greater than predicted by the inflammatory data. We were all surprised by the great effect on disability seen with this drug while the effects on inflammation were not that pronounced," he said. "This suggests an underlying disconnect between neuroinflammation and neurodegeneration. And we may have a drug here that targets the neurodegeneration more."

Direct Effect on Disability?

Discussing this issue with Medscape Medical News, Jeffrey Cohen, MD, Cleveland Clinic, Ohio, who was not involved in these studies, said, "The benefit of this drug on disability seems to outweigh the benefit shown on relapse rate or inflammatory lesions. This suggests it might have a direct effect protective effect on disability."

Dr. Cohen explained that most of the drugs so far developed for MS have shown more potent activity on clinical relapses and MRI lesions in parallel with effects on disability.

"Other drugs appear to have some neuroprotective properties but as they show anti-inflammatory effects as well, the neuroprotection might be related to the anti-inflammatory action," he said. "But with laquinimod the neuroprotection does not seem to be related to inflammation. This could mean that it may have some independent neuroprotective properties. But the magnitude of the effect seen was relatively small so we must be careful not to make too much of it. Nevertheless, it is a very interesting observation that needs to be studied further."

Giancarlo Comi, MD, Università Vita-Salute San Raffaele, Italy, who was involved in these latest laquinimod analyses, said these new data are "fully in line with previous studies showing a much greater effect on brain atrophy than MRI lesions. It all points to the same conclusions: that laquinimod is doing something in the CNS [central nervous system] independent of its anti-inflammatory effect."

He added that it is now planned to explore the effect of the drug in secondary progressive MS because of the large effect on disability seen in these studies in relapsing/remitting MS. "The rationale is that if this drug can reduce disability independent of relapse/inflammation, it may work in the secondary progression phase of the disease where disability is independent of attacks," he commented.

In one of the studies, led by Maria Sormani, PhD, Università degli Studi di Genova, Italy, analyzed whether the effect of laquinimod on reducing the risk for confirmed disability progression in the pooled ALLEGRO and BRAVO studies was within the range of what would be predicted on the basis of its effect on relapse rate reduction. They found this not be the case.

Results showed that the risk ratio of laquinimod vs placebo on relapse rate was 0.79 (95% CI, 0.69 - 0.89). The researchers worked out that this would be expected to show a risk reduction for disability progression with laquinimod of about 5%, with a predicted risk ratio of 0.95. However, the observed reduction in risk of 3-month disability progression was 29% (relative risk, 0.71 [95% confidence interval (CI), 0.55 - 0.91]). This was approximately 6 times greater than that predicted.

"The effect of laquinimod treatment on the more robust measure, risk of disability progression at 6 months, is even greater," the researchers stated.

Disability Progression With and Without Relapses

In the study led by Professor Comi, he and colleagues analyzed data on relapse rate and disability progression from the ALLEGRO and BRAVO studies together and compared disability progression in patients with and without relapses.

He explained, "If disability progression was due to only the effects of attacks we should see progression only in those who are having attacks, but this was not the case."

Approximately one quarter of patients in ALLEGRO and BRAVO who had disability progression during the studies were relapse-free. This suggests that the pathogeneses of disability progression and relapses are not restricted to a common pathway, the researchers reported.

Table 1. Disability Progression in Patients With and Without Relapses

Variable Placebo, n (%) Laquinimod, n (%)
Relapse-free patients    
Disability progression 44 (7.6) 31 (4.8)
No disability progression 536 (92.4) 609 (95.2)
Relapsed patients    
Disability progression 94 (22.1) 65 (18.9)
No disability progression 332 (77.9) 279 (81.1)


In addition, laquinimod appeared to have a larger effect on disability in patients not having attacks.

Table 2. Treatment Effect of Laquinimod on Disability Progression in Relapsing and Relapse-Free Patients

Group Hazard Ratio (95% CI) for Reduced Disability Progression With Laquinimod vs Placebo
Relapse-free patients 0.61 (0.38 -0.97)
Relapsed patients 0.73 (0.53 - 1.01)


"The results of the pooled analysis support an effect of laquinimod on disability in patients who relapsed and in those who were relapse-free. This suggests laquinimod has an effect on both inflammation and on broader underlying disease pathology not associated with inflammation," the researchers concluded.

In a third study, a group led by Gary Cutter, PhD, University of Alabama, Birmingham, conducted a Bayesian analysis of laquinimod's effect on relapses and disability.

They found the results to be in line with classic statistics, suggesting a 60% probability for laquinimod to reduce relapses by at least 30%, with a greater effect on reducing disability progression.

Dr. Sormani and Professor Comi have received consulting fees for advisory boards and consultancy and speaker activities from Teva. Dr. Cutter participated in the last 12 months in Data Safety Monitoring Committees for Teva and has received consulting or speaking fees from the company. Dr. Kieseier has received honoraria for lecturing, travel expenses for attending meetings, and financial support for research from Teva, and Dr. Cohen reports personal compensation for serving as a consultant or speaker for Teva.

29th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). Abstracts #606, #1036, and #1080. Presented October 3 and 4, 2013.


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