Laquinimod Slows Progression in MS: ALLEGRO Published

Susan Jeffrey

March 14, 2012

March 14, 2012 — Results of a phase 3 randomized trial show treatment with laquinimod, a still-investigational oral agent, reduced annualized relapse rates and delayed disability progression compared with placebo in patients with relapsing-remitting multiple sclerosis (MS).

Final results of the Assessment of Oral Laquinimod in Preventing Progression in Multiple Sclerosis (ALLEGRO) trial are published in the March 15 issue of the New England Journal of Medicine. Findings were first presented last year at the American Academy of Neurology's 63rd Annual Meeting and reported by Medscape Medical News at that time.

However, the situation with laquinimod, hoped to be the second oral agent for treatment of relapsing-remitting MS after fingolimod (Gilenya, Novartis), became more complex in the interim with presentation of results from a second pivotal phase 3 trial, BRAVO, comparing laquinimod with interferon-beta-1a (Avonex, Biogen Idec). That trial 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 (MRI).

Both trials, though, 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, another novel finding with this agent. BRAVO results were presented last fall at the 5th Joint Triennial Congress of the European and American Committees for Treatment and Research in Multiple Sclerosis (ECTRIMS/ACTRIMS) meeting in Amsterdam, the Netherlands.

"I think this is very important because for the first time it is evidence that in the treatment of MS, we should not only turn down inflammation but also — and even more important — we should try to protect the tissue that is affected by the disease from irreversible degeneration," said lead investigator 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.

Dr. Giancarlo Comi

Dr. Comi said the company is now planning a third phase 3 trial and is considering use of a higher dose of 1.2 mg daily, twice the dose of laquinimod investigated in the previous trials.

"We are completely convinced about the possibility of good results with this drug, so it is very important not to stop the development plan of laquinimod," Dr. Comi told Medscape Medical News.

Both ALLEGRO and BRAVO trials were funded by Teva Pharmaceutical Industries. In a statement, Teva confirmed that results from these trials will be included in their submission to the European Medicines Agency in the European Union (EU) slated for the latter half of 2012.

"The publication of the ALLEGRO results in a prestigious peer-reviewed journal is an important landmark as we continue to research and develop laquinimod," Lesley Russell, senior vice-president of Research & Development at Teva Global Branded Products said in the company statement. "We look forward to continue to work with regulatory authorities in both the EU and the US to bring this novel therapy to the MS community."

Novel Oral Compound

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 (FDA) in February 2009. The drug is also in phase 2 development for the treatment of Crohn’s disease and lupus.

In ALLEGRO, the researchers compared laquinimod against placebo in 1106 patients with relapsing-remitting MS from 139 sites in 24 countries. Patients were randomly assigned to receive a once-daily dose of 0.6 mg of laquinimod or placebo for 24 months.

The primary endpoint was annualized relapse rate at 24 months. Secondary endpoints included the cumulative number of gadolinium-enhancing and new or newly enlarging T2 lesions on MRI, as well as confirmed disability progression, defined as an increase in the Expanded Disability Status Scale (EDSS) score that was sustained for at least 3 months.

Positive top-line results of ALLEGRO were released in December 2010 and reported by Medscape Medical News at that time. The study authors note that 79.5% of treated and 76.8% of placebo patients completed follow-up. Mean time to discontinuation was about 1 year. The main reason for discontinuation was the patient's decision not to sign the additional informed consent form that was required by study protocol after a relapse or confirmed disability progression; this was the case for 8.0% of treated and 10.8% of placebo patients.

The study authors report that patients treated with laquinimod had a "modest" but statistically significant 23% reduction in annualized relapse rate compared with those taking placebo.

Table 1. ALLEGRO Primary Endpoint

Endpoint Placebo Laquinimod Relative Risk (95% Confidence Interval) P Value
Mean annualized relapse rate ± SD 0.39 ± 0.03 0.30 ± 0.02 0.77 (0.65 - 0.91) .002

SD = standard deviation

Treatment was also associated with a 36% reduction in EDSS disability progression vs placebo.

Table 2. Disability Progression on EDSS by Treatment in ALLEGRO

Endpoint Placebo (%) Laquinimod (%) Hazard Ratio (95% Confidence Interval) P Value
Confirmed disability progression on EDSS 15.7 11.1 0.64 (0.45 - 0.91) .01

 

Mean cumulative numbers of gadolinium-enhancing lesions and new or enlarging lesions on T2-weighted MRI were also significantly lower for patients treated with laquinimod vs placebo.

Table 3. New Gadolinium-Enhancing Lesions and New or Enlarging T2 Lesions by Treatment

Endpoint Placebo Laquinimod P Value
Mean cumulative gadolinium-enhancing lesions ± SD 2.12 ± 0.22 1.33 ± 0.14 <.001
New or enlarging T2 lesions ± SD 7.14 ± 0.07 5.03 ± 0.08 <.001

SD = standard deviation

In a prespecified exploratory analysis, the researchers also found that treatment with laquinimod was associated with a lower percentage of brain volume loss between baseline and 24-months: an adjusted mean loss of 0.87% with laquinimod vs a loss of 1.3% with placebo. The researchers call this an "interesting corollary to the effect on disability progression."

In terms of safety, no laquinimod recipients in ALLEGRO died vs 3 in the placebo group (1 died of suicide, 1 of injury, and 1 of pneumonia complications). Transient elevations in alanine aminotransferase levels greater than 3 times the upper limit of normal were seen more often with laquinimod (5%) than placebo (2%). Elevations greater than 5 times the upper limit of normal occurred in 6 patients in each group and resolved either without discontinuation or within 2 months of discontinuation of treatment.

Appendicitis was also more common with laquinimod (5 cases vs 1). There were 14 neoplasms (8 with laquinimod vs 6 with placebo), "with a large variation in the type of cancer," the researchers note.

"So I think this unique combination of a very good safety profile and this very unique activity on the brain and spinal cord, will promote this drug as an interesting treatment for MS," Dr. Comi said.

An open-label extension study of 844 of the 864 patients in this trial is ongoing, the authors conclude. "The data and safety monitoring committee has not reported any new safety signals so far in the extension study,"

they write.

What Next?

Asked for comment on these findings, Daniel Kantor, MD, medical director of Neurologique, president of the Florida MS Society, and a spokesman for the American Academy of Neurology, said the new publication is very much in line with what was seen previously of the ALLEGRO data.

"What has changed is people's perception of laquinimod," he said. The BRAVO results stopped what was expected to be a swift move toward submission of a New Drug Application to the FDA for laquinimod. "The question is now how much more they have to do," Dr. Kantor told Medscape Medical News.

"Some of us feel that the problem with laquinimod was the dose, that the dose was too low," he said. Others speculate that the place for the drug is in combination with other agents "because it had a robust effect on disability, yet only a modest effect according to ALLEGRO on relapses and certainly according to BRAVO as well."

Still, ALLEGRO was a positive trial, and the effect on disability and brain atrophy in both trials was "very hopeful," Dr. Kantor added. "So we don't want laquinimod to disappear. We want Teva to continue to invest in the laquinimod trials."

Timothy Coetzee, MD, chief research officer for the National Multiple Sclerosis Society (NMSS), said these published results are consistent with what has previously been reported in terms of relapse rates and progression to disability in the relapsing forms of MS.

"I think it's also interesting, some of the exploratory measures that they noted in the paper and also some of the public commentary, where they found a potential neuroprotective effect of the agent," Dr. Coetzee told Medscape Medical News. "It remains to be seen I think what the next steps will be for the agent in terms of its regulatory pathway."

The effect size was modest, though, he noted, and "that raises some questions probably for a longer term strategy."

The "take-away" he said, is that this illustrates some of the challenges in doing clinical trials in MS in terms of the variability of patients and issues with enrollment. But, "for me and certainly for us [at NMSS], the development of oral treatments for managing relapsing forms of MS is clearly an important priority area. However, that being said, an oral agent would be great, but an effective agent is what's really important. The modest results associated with this are giving some in the community pause about what is the next step related to this."

Although several options are now available and on the horizon for relapsing MS, he would like to see more investigation turn to primary progressive MS, Dr. Coetzee added. "It's great to see progress on the relapsing front, but we need to do more on the progressive front."

The ALLEGRO study was funded by Teva Pharmaceutical Industries. Full disclosure information for coauthors can be found at www.nejm.org .

N Engl J Med. 2012;366:1000-1009.

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