The European Medicines Agency's (EMA's) Committee for Medicinal Products for Human Use (CHMP) has recommended against approval of 2 new drugs for multiple sclerosis (MS) and for a small population of patients with Duchenne muscular dystrophy (DMD).
During their monthly meeting on January 23, the CHMP panel adopted a negative opinion on granting marketing authorization for laquinimod (Nerventra, Teva Pharma) in patients with relapsing-remitting MS.
The panel noted concerns about results from animal studies showing a higher occurrence of cancers after long-term exposure to laquinimod, noting that a similar long-term risk could not be ruled out in humans, "especially when considering that the way the medicine works in the body is unclear," the EMA noted in a press release.
There was also a possible risk from animal data on teratogenic effects in offspring of women taking the drug, the panel said. "The CHMP noted that the risk could not be excluded with current data and that animal studies suggest that any harmful effects may be delayed and only seen later on in the child's life. In addition, the Committee was not convinced about the effectiveness of the company's proposed measures to prevent pregnancies in women who would take the medicine."
The CHMP panel also pointed out that although the drug had been shown to slow the worsening of disability, its effect on relapses was "modest."
The 2 phase 3 trials of laquinimod completed to date were called ALLEGRO (Assessment of Oral Laquinimod in Preventing Progression in Multiple Sclerosis) and BRAVO. Hope was high for this agent after results of ALLEGRO were published in the New England Journal of Medicine, showing laquinimod reduced the annualized relapse rate as well as delayed progression of disability vs placebo.
In BRAVO, however, which compared oral laquinimod with an active comparator, interferon β-1a (Avonex, Biogen Idec), the trial missed the primary endpoint of a reduction of annualized relapse rates. However, the reduction seen with laquinimod was significant after researchers adjusted for an imbalance in the volume of T2 disease between groups and the number of gadolinium-enhancing lesions on MRI.
Both trials 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. A reduction in brain atrophy was also noted, which was in line with the effect on disability, another novel finding with this agent.
The upshot is that laquinimod is now being evaluated in a third phase 3 trial, CONCERTO, after a Special Protocol Assessment agreement was reached with the US Food and Drug Administration (FDA). The trial will assess 2 doses of laquinimod — 0.6 and 1.2 mg daily for up to 24 months — in about 1800 patients with relapsing-remitting MS. The primary outcome will be confirmed disability progression on the Expanded Disability Status Scale.
For its part, "the CHMP was of the view that the benefits of Nerventra in patients with relapsing-remitting MS do not outweigh the potential risks and recommended that it be refused marketing authorisation," the EMA release notes.
The CHMP opinion has is no consequences "for the time being" on any ongoing trials of laquinimod, it concludes.
Ataluren for DMD
In a second decision concerning treatment of a neurologic disease, CHMP also adopted a negative opinion on approval of ataluren (Translarna, PTC Therapeutics) for the treatment of DMD.
The application for authorization was for a subpopulation of patients 5 years of age and older with DMD whose disease is caused by a genetic defect called a "nonsense" mutation. It was designated an "orphan" drug on May 27, 2007, for this indication, an EMA release on the decision notes.
To support the application, the company had submitted results of 1 main placebo-controlled study in 174 patients with DMD. The primary endpoint of that study was the change in distance walked on the 6-minute walk test after 48 weeks of treatment.
"The CHMP noted that the main study failed to show that patients taking Translarna could walk in 6 minutes a greater distance than patients taking placebo," the EMA release notes. "Although the company performed additional analyses of the data, the CHMP considered that these were insufficient to provide enough evidence of effectiveness. When other measures of effectiveness were considered, including those directly linked to patients' daily activities, these provided only limited supportive evidence of the beneficial effects" of the drug.
Further, the opinion notes there are insufficient data on the drug's mechanism of action and how dose influences the effects.
"Therefore, at that point in time, the CHMP was of the opinion that the benefits of Translarna did not outweigh its risks and recommended that it be refused marketing authorisation," the EMA release concluded.
As with laquinimod, though, patients will continue to enroll in and receive treatment in an ongoing confirmatory trial with ataluren.
Both companies have 15 days from the receipt of notification to appeal the CHMP recommendation.
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Cite this: CHMP Recommends Against EU Approval of Drugs for MS, DMD - Medscape - Jan 28, 2014.
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