Susan Jeffrey

October 24, 2011

October 24, 2011 (Amsterdam, the Netherlands) — A phase 3 comparison of oral laquinimod (Teva Pharmaceutical Industries Ltd/Active Biotech) with interferon-beta-1a (Avonex, Biogen Idec) missed the primary endpoint of reducing annualized relapse rate over the approved therapy in patients with relapsing-remitting multiple sclerosis (MS).

However, the reduction in relapses was significant after adjustment for an imbalance between groups on baseline disease activity on magnetic resonance imaging, investigators report. In addition, the fact that laquinimod reduced disability, potentially by a novel mechanism, probably means the drug may still move forward toward approval, particularly as the results are largely congruent with a second phase 3 trial already reported.

The full BRAVO results were presented here at the 5th Joint Triennial Congress of the European and Americas Committees for Treatment and Research in Multiple Sclerosis (ECTRIMS/ACTRIMS). Top-line results were released by the company August 1 and were reported by Medscape Medical News at that time.

BRAVO is the second of 2 pivotal phase 3 trials of the still-investigational agent. Positive results for the Assessment of Oral Laquinimod in Preventing Progression of MS trial, also called ALLEGRO, which was the first phase 3 trial using the same dose of laquinimod, were reported in April 2011 at the American Academy of Neurology annual meeting.

"The BRAVO data are quite consistent with the ALLEGRO findings," Timothy Vollmer, MD, professor and director of clinical research at the University of Colorado, Denver, told attendees. "In particular, we see a robust effect on markers of neurodegeneration, particularly cerebral atrophy and progression of disability. These seem to be consistent with the evolving story related to the mechanism of action of this drug."

Safety of the drug was good, "particularly considered in context of the other available agents," he concluded. "So as a result, we do think the data suggest that this drug may have an important role to play in the future treatment of [MS] patients."

Correction of Imbalance

"The study was confounded a bit at baseline, like many of these studies are, with some imbalances on a couple of key parameters," specifically the volume of T2 disease and the number of gadolinium-enhancing lesions, Dr. Vollmer told Medscape Medical News. "Those are very powerful predictors of on-study relapse rates." Once adjusted for that imbalance, the results were similar to those in ALLEGRO (an approximately 21% reduction vs 23%).

Dr. Timothy Vollmer

Also as was seen in ALLEGRO, there was a disproportionate "and impressive, in my view," effect of the drug on disability and brain volume relative to this modest effect on relapse rates, Dr. Vollmer noted. "The effects there were about a 33% reduction in probability of sustained disability progression and 27% to 30% reduction in brain atrophy rates, which is very close to what the ALLEGRO study showed," he said.

"So we now have this molecule that presents a bit of a challenge to us," Dr. Vollmer said. There appears to be dissociation between the acute inflammatory phase of the disease and the central nervous system inflammatory disease.

"This drug seems to work more in that central nervous system compartment, [and] less in the peripheral compartment, and as a result, it's dissociating the initial inflammatory process from the ultimate injury that occurs to neurons and oligodendrocytes," and acting to preserve them, Dr. Vollmer added. "That's a unique profile and has significant implications for long-term management, in terms of how we begin to use the drug in the clinical setting."

The baseline imbalance seen in this trial is a recurring problem in many modern trials, he said, where baseline volumetrics on T2 and gadolinium-enhancing lesions are available, but not yet used in the formal stratification process. "They can be corrected by statistical methods to a degree, but it would be far cleaner just not to have to deal with them," Dr. Vollmer added.

Dr. Giancarlo Comi

Giancarlo Comi, MD, director of the Department of Neurology and Institute of Experimental Neurology at the Scientific Institute and University Vita-Salute San Raffaele in Milan, Italy, who was the principal investigator of ALLEGRO, also pointed to the consistency of the data between the 2 trials, particularly the disproportionate effect on relapses in the face of its larger effect on disability and brain atrophy.

It is becoming clear that laquinimod has a moderate effect on inflammation but acts to preserve glial cells, a cell type that has been thought historically just to be a supporting structure for neurons, Dr. Comi told Medscape Medical News. "Now we know that these astrocytes and microglia play a major role in the condition of the brain...and laquinimod has an effect on both microglia and astrocytes."

"All together, I think these data determine a very important new role for laquinimod in MS treatment," Dr. Comi said. "I think this is for very many reasons a very good candidate, because the efficacy of the drug is extremely important, but is only half of the problem. The drug has to be safe, and from this point of view, laquinimod is very safe: no risk of cancer, no risk of infection, which are the 2 problems we have when we manipulate the immune system."

Dr. Comi pointed out that regulatory agencies have always said that what really matters in MS trials is disability as an outcome, but drug companies have pushed for relapses as an endpoint because it was easier to show an effect on relapses. These 2 trials show a clear effect on disability, with imaging to support an effect on disease burden, even if the primary endpoint of effect on relapses on 1 of the trials was missed.

"I would be surprised if this will not be appropriately addressed by the agencies," he said.

BRAVO

Laquinimod is a novel, once-daily, oral immunomodulatory compound being developed as a disease-modifying treatment for MS; it received fast track designation from the US Food and Drug Administration in February 2009.

BRAVO was a 2-year, multicenter, randomized, double-blind, parallel-group, placebo-controlled study comparing the safety, efficacy, and tolerability of a once-daily, oral, 0.6-mg dose of laquinimod with those of placebo. A third single-blinded group of patients receiving interferon beta-1a was added at the request of European regulatory authorities, for reference only, but did not have a matching placebo, Dr. Vollmer noted. The main comparison for laquinimod was with oral placebo.

Patients were required to have 1 relapse in the prior year or 2 relapses in the prior 2 years, or 1 relapse within 2 years and a gadolinium-enhancing lesion in the prior 2 years. Those who had received previous interferon treatment were excluded because of the chance that they might be randomly assigned to receive interferon in this study, Dr. Vollmer noted. Eligible patients were randomly assigned in a 1:1:1 manner to receive laquinimod (n = 434), placebo (n = 450), or 30 μg once weekly of interferon-beta-1a, given intramuscularly (n = 447).

The primary endpoint was the efficacy of 0.6 mg laquinimod daily, measured by annualized relapse rate vs placebo. Secondary outcome measures included effect on the accumulation of disability and brain atrophy. Enrolment was completed in June 2009; 1331 patients were recruited at 153 sites in 18 countries, including in the United States, Europe, Russia, Israel, and South Africa.

At 24 months in the unadjusted primary analysis, the annualized relapse rate for laquinimod vs placebo did not reach statistical significance, but showed a trend with an 18% reduction compared with a 29% reduction with interferon beta-1a; the reduction for interferon vs placebo was significant.

After the adjustment for baseline disease activity, the laquinimod comparison with placebo reached statistical significance: a 21% reduction in annualized relapse rate, and again a 29% reduction in the adjusted interferon beta-1a analysis.

Table 1. BRAVO: Primary Endpoint in Unadjusted and Adjusted Analyses

Endpoint Placebo Laquinimod P Inteferon beta-1a P
Annualized relapse rate (unadjusted analysis) 0.34 0.28 .075 0.26 .007
Annualized relapse rate (unadjusted analysis) 0.37 0.29 .03 0.27 .002

Exploratory analyses looking at acute inflammation showed there was a 22% reduction with laquinimod vs placebo (P = .062) in gadolinium-enhancing T2 lesions, and a 19% reduction in new T2 lesions (P = .037). "As would be expected based on prior experience, the interferon had an even larger effect on these parameters, with a 60% reduction in gadolinium-enhancing lesions and a 52% reduction in T2 lesions," Dr. Vollmer noted.

"Like the ALLEGRO study, the effect on markers of degenerative disease was actually somewhat more robust," Dr. Vollmer pointed out. For sustained 3-month confirmed progression of disability, there was a 33.5% reduction for laquinimod vs placebo (P = .04), and a 28.7% reduction (P = .09) with interferon. An additional ad hoc analysis to examine how robust this finding was showed a similar effect on 6-month confirmed progression of disability, with a 40.6% reduction with laquinimod (P = .04) vs placebo and a 28.3% reduction with interferon vs placebo (P = .14).

There was also a "robust" effect on brain volume with laquinimod over placebo, with a 27.4% improvement (P < .0001), Dr. Vollmer said, which was again similar to the ALLEGRO findings, but no effect with interferon on this endpoint, with a 9% increase in volume loss compared with placebo.

Safety Data

The adverse event profile was "generally quite good," Dr. Vollmer said. There was 1 death in the laquinimod group, a 44-year-old man exposed to radiation during the Chernobyl nuclear accident who developed sepsis that was judged not related to treatment. The other was a cardiac death in a patient with a cardiac history.

Herpes infections were "relatively balanced" across groups, and there were 2 malignant neoplasms in each of the laquinimod and interferon groups, with 1 case of thyroid cancer in each group, 1 case of skin squamous cell carcinoma in the laquinimod group, and 1 case of colon cancer in the interferon group.

Table 2. BRAVO: Serious Adverse Events

Serious Adverse Events Laquinimod Placebo Interferon beta-1a
Death, n (%) 1 (0.2) 0 1 (0.2)
Serious adverse events, n (%) 31 (7.2) 36 (8) 25 (5.7)
Pericarditis and pleural effusion, n (%) 0 3 (0.7) 0
Herpes viral infections, n (%) 12 (2.8) 11 (2.4) 11 (2.5)
Ischemic coronary artery disease, n (%) 0 0 3 (0.7)
Embolism and thrombosis, n (%) 1 (0.2) 4 (0.9) 5 (1.1)
Malignant neoplasms, n (%) 2 (0.5) 0 2 (0.5)

Back pain was also more common with laquinimod, as also seen in ALLEGRO, although patients tended still to stay on treatment, and it generally resolved on treatment. "We did see a slight increase in arthralgia and depression in this study, but we did not see the appendicitis that we saw in the ALLEGRO study," Dr. Vollmer added.

A signal related to increased liver enzymes has previously been reported for this drug, he noted. In BRAVO, the elevations tended to be mild — less than 5 times the upper limit of normal. Of patients receiving laquinimod, 28.9% had elevations between 1 and 3 times the upper limit of normal, and 4.2% had elevations greater than 3 times the upper limit of normal. A similar proportion of patients receiving interferon showed liver enzyme elevations in this range.

Elevations greater than 5 times and greater than 8 times normal were infrequent and evenly distributed between groups. "So the liver enzyme elevations we see in this study related to laquinimod tend to be mild and tend to resolve, even if patients stay on therapy," Dr. Vollmer noted.

Additional exploratory analyses from ALLEGRO presented here showed that laquinimod reduced severe relapses, with a 38% reduction in the annualized rate of relapses requiring hospitalization, and a 27% reduction in the requirement for use of intravenous steroids. There was a 36% reduction in the risk for 3-month confirmed Expanded Disability Status Scale progression (P = .0122), and a 48% reduction in the risk for 6-month confirmed progression (P = .0023).

Treatment with laquinimod also had a positive effect on patient-reported fatigue and cognitive functioning, measured using the Modified Fatigue Impact Scale and the short form–36 general health survey.

Dissociation of Effects

Ralf Gold, MD, professor and chair, Department of Neurology, St. Josef-Hospital, Ruhr-University, Bochum, Germany, gave a talk on the last day of the conference on the clinical highlights presented here, and listed these results from the BRAVO trial among them. He also was principal investigator of the DEFINE trial, presented October 21, of BG-12 or oral fumarate, which is also an investigational oral drug for MS.

Although he said it is clear that laquinimod is "absolutely safe," what came as a surprise was that the efficacy only achieved significance "when they were corrected for many parameters," Dr. Gold said. In addition, the interferon performed better than expected on relapses.

Of interest, however, were the effects of laquinimod on long-term disability and brain atrophy, he noted.

"I think what's exciting for us as a community, and therefore our patients, is we have [this agent] laquinimod, with dissociation, at least at this dosage, of the effects on acute inflammation in the lesion; there is not much, only weak effect on inflammation at this dosage, but we clearly have neuroprotection."

"I'm quite confident we'll see further studies of laquinimod, in the future and at higher dosages."

Lily Jung-Henson, MD, medical director of the Swedish Neuroscience Institute Eastside Neurology, chief of staff at Swedish Issaquah Hospital, Seattle, Washington, and a member of the American Academy of Neurology, was asked to comment on these findings.

"BRAVO was consistent in suggesting more of an effect on disability than on reducing relapses similar to ALLEGRO," Dr. Jung-Henson noted. "Certainly, given its comparison with an injectable and equal efficacy with a low side effect profile, [it is] a very attractive alternative."

Dr. Vollmer has served on scientific advisory boards for Teva Neuroscience, Acorda, Biogen Idec, Hoffman LaRoche, and Novartis and has been a consultant for Xenoport, Guidepoint Global, PRIME Education, Global Prairie, Daiichi Sankyo, Projects in Knowledge, Teva Neuroscience, Lilly USA, Medical Logix, MSDx, Esai Pharma, and Schering-Plough Biopharma. He has grant or pending grants payable to his institution from Teva Neuroscience, Biogen Idec, Lilly Research Laboratories, Genzyme, Ono Pharmaceuticals, Elan Pharmaceuticals, Acorda Therapeutics, Novartis, Sanofi Aventis, Pfizer, the National Institutes of Health, PDL Biopharma, Biosite, EMD Serono, Genentech, and Daiichi Sankyo. Disclosures for the coauthors appear in the abstract. Dr. Comi has received consulting fees for advisory boards, consultancy, and speaker activities from Novartis, Teva, Sanofi-Aventis, Merck Serono, and Bayer Schering, as well as lecture fees from Novartis, Teva, Sanofi-Aventis, Merck Serono, Biogen Dompé, and Bayer Schering Dr. Jung-Henson reports no ties with this study; she is a speaker for Biogen Idec, Serono, Teva, Novartis, and Sanofi-Aventis.

5th Joint Triennial Congress of the European and Americas Committees for Treatment and Research in Multiple Sclerosis (ECTRIMS/ACTRIMS): Abstracts 148, P708, P363. Presented October 22, 2011.

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