Laquinimod Halted MS Disability But Not Relapses
The multiple sclerosis drug laquinimod did not reduce the risk of relapse in the BRAVO phase III trial, yet the investigational agent delayed the progression of disability to a greater extent than did placebo.
The BRAVO trial also included an open comparator arm against interferon beta-1a (IFNB-1a, Avonex), which proved to reduce brain lesions on MRI to a significantly greater extent relative to placebo than did laquinimod. But even though laquinimod’s effect against active brain inflammation did not appear to be as strong as that of IFNB-1a, it appeared to be potentially neuroprotective because it significantly halted loss of brain volume relative to placebo, whereas IFNB-1a did not.
Dr. Ralf Gold
The 1,331-patient BRAVO (Benefit-Risk Assessment of Avonex and Laquinimod) study is the second of two global phase III trials with laquinimod in patients with relapsing-remitting multiple sclerosis. The first was the 1,106-patient ALLEGRO study, completed earlier this year, in which laquinimod significantly reduced the annualized relapse rate (ARR), the risk of disability progression, and the percentage of total brain volume lost compared with placebo.
Patients in BRAVO had a mean age of about 37 years and were randomized to oral laquinimod 0.6 mg/day (n = 434), daily oral placebo (n = 450), or intramuscular IFNB-1a 30 mcg once per week (n = 447). Only the comparison between oral treatments was conducted in a double-blind fashion, said Dr. Timothy L. Vollmer, professor and director of clinical research in the neurology department at the University of Colorado, Aurora. He presented the study at the joint congress of the European and Americas Committees for Treatment and Research in Multiple Sclerosis (ECTRIMS/ACTRIMS).
Although patients in the BRAVO study were generally well matched in terms of baseline characteristics, a higher percentage of patients in the laquinimod arm had gadolinium-enhancing (GdE) T1 lesions than did patients in the placebo or IFNB-1a arms (39.6% vs. 33.4% and 38.1%, respectively). Laquinimod-treated patients also had a greater mean volume of T2 lesions at baseline (9.6 cm3), compared with the placebo (7.9 cm3) and IFNB-1a arms (8.6 cm3).
The 2-year ARR in patients treated with laquinimod was not significantly different from placebo (0.28 vs. 0.34, respectively). But after adjustment for multiple baseline factors, including the prestudy relapse rate, T2 lesion volume on MRI, and GdE T1 lesion status, the difference became significant (0.29 vs. 0.37, P = .03).
Disability progression at 3 months on the Expanded Disability Status Scale was significantly improved with laquinimod on the basis of a 33.5% reduction compared with placebo. In comparison, IFNB-1a reduced disability by 28.7% versus placebo. Laquinimod also significantly reduced the risk for 6-month confirmed disease progression (40.6% reduction vs. placebo), but IFNB-1a did not (28.3% reduction vs. placebo, P = .14).
Exploratory analyses showed that both GdE T1 and new T2 lesions significantly declined following laquinimod treatment versus placebo, although the reduction was less than what was observed in the IFNB-1a arm relative to placebo.
Nevertheless, laquinimod, but not IFNB-1a, appeared to be associated with a reduction in MRI-measured brain volume loss. Brain volume dropped significantly by a mean of –0.83% during treatment with laquinimod, compared with –1.14% for placebo and –1.25% for IFNB-1a. This translated into 27.4% less loss with laquinimod than with placebo, but a 9% increase in brain volume loss with IFNB-1a.
Consistent with the ALLEGRO trial, there were good safety and tolerability, especially when considered alongside existing therapies, Dr. Vollmer said.
There was, however, a higher rate of back pain (10.2%), arthralgia (5.5%), and depression (5.1%) in the laquinimod-treated patients than in the placebo group (7.1%, 4.0%, and 2.7%, respectively) or in the IFNB-1a arm (3.4%, 4.1%, and 4.8%).
During the discussion after his presentation, Dr. Vollmer suggested that laquinimod’s good safety profile and positive effect on disability might make it most useful in combination with other treatments for MS.
“I think the future of MS therapy probably will be combination … and [laquinimod] is actually quite attractive in that sense – that it’s not a primary immunosuppressant – and so therefore it could be combined with primary immunological therapies, and possibly get an additive, possibly a synergistic effect on the central nervous system as it has its direct effects there.”
While the exact mechanism of action of laquinimod is still under investigation, it is thought to target cells resident in the central nervous system such as the oligodendrocytes, astrocytes, and microglia, and have more modest effects on peripheral immune cells.
Dr. Ralf Gold of St. Josef and St. Elizabeth Hospital in Bochum, Germany, noted during a scientific highlights session at the congress that BRAVO was a “carefully executed study,” and that the dose of laquinimod used in the study was purposefully quite low.
Laquinimod is a derivative of the failed experimental drug linomide, Dr. Gold explained, and on the basis of experience with that drug, a 0.6-mg dose of laquinimod was used in the BRAVO trial. “Laquinimod seems to be absolutely safe, although there are higher doses currently being tested” he said.
In regard to the possible beneficial effects of laquinimod on brain atrophy, Dr. Gold noted that there appeared to be “dissociation” between the effect of the 0.6-mg dosage on acute inflammation in brain lesions and its effect on neuroprotection, based on its relative preservation of brain volume.
The study was funded by Teva Neuroscience. Dr. Vollmer and Dr. Gold disclosed financial relationships with the company. In addition, Dr. Vollmer disclosed acting as a scientific adviser or receiving institutional research grants now or in the past from Biogen Idec, which manufactures Avonex, and other companies that develop therapies for MS. Dr. Gold disclosed receiving honoraria and research support from Bayer HealthCare, Biogen Idec, Merck Serono, and Novartis.