PARIS -- Moving the goal posts didn't work out so well for laquinimod, which failed to meet a primary endpoint of reduction in 3-month confirmed disability progression compared with placebo in a third phase III study in relapsing multiple sclerosis, researchers reported here.
Two previous phase III trials -- and BRAVO -- showed better effects on a secondary endpoint of disability than on the primary endpoint of relapse rate. But in the CONCERTO trial, which used disability as its main outcome, the drug had no effect over placebo at 3, 6, or 9 months, Giancarlo Comi, MD, of Ospedale San Raffaele in Milan, and colleagues reported at the joint .
Action Points
- Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.
Ironically, laquinimod did end up significantly reducing relapse risk in CONCERTO, Comi reported. But the results overall were sufficiently disappointing that drugmaker Teva Pharmaceutical Industries decided to pull the plug on laquinimod for the relapsing MS indication.
Laquinimod is a quinoline-carboxamide derivative that selectively activates the aryl hydrocarbon receptor, which has been shown to modulate the immune system, Comi said.
Following its limited effects on relapses in the two earlier trials, the drug's impact on MRI outcomes was also modest -- but its effects on disability progression and brain atrophy were "large and significant," Comi said, calling this sort of contradictory finding "unusual."
In the wake of ALLEGRO and BRAVO, Teva decided to conduct yet another phase III trial, enrolling more than 700 patients in each of three arms of CONCERTO: placebo versus one of two doses of laquinimod (0.6 mg and 1.2 mg).
The 1.2-mg dose group was stopped when it was 85% complete because of safety concerns -- predominantly cardiovascular issues, which Comi did not elaborate on.
Overall, laquinimod missed the primary endpoint of reduction in 3-month confirmed disability progression (CDP) over 24 months compared with placebo; nor did it have any significant effects on secondary endpoints of time to 6-month and 9-month CDP, Comi reported.
However, it did have a beneficial effect on clinical relapses, in terms of both first confirmed relapse (a secondary endpoint) and annualized relapse rate (an exploratory endpoint).
Both the 0.6-mg and 1.2-mg dose bested placebo on first confirmed relapse (HR 0.72, 95% CI 0.62-0.84, P<0.0001 and HR 0.58, 95% CI 0.49-0.69, P<0.0001, respectively, versus placebo). The same held true for adjusted mean annualized relapse rate (RR 0.75, 95% CI 0.65-0.87, P=0.0002 and RR 0.62, 95% CI 0.53-0.73, P<0.0001, both versus placebo).
In CONCERTO, laquinimod also had an impact on MRI outcomes, with significantly fewer gadolinium-enhancing lesions at 15 months for both the 0.6-mg (RR 0.70, 95% CI 0.54-0.91, P=0.0064) and the 1.2 mg-dose (RR 0.59, 95% CI 0.46-0.77, P=0.0001) -- although these were no longer significant at 24 months.
The 1.2-mg dose also had beat placebo on preservation of brain volume, with relative reductions of 40% at 15 months and 28% at 24 months, Comi reported.
He said the drug was well tolerated, with the most common adverse effects being headache, nasopharyngitis, and back pain.
John Corboy, MD, of the University of Colorado Denver, who wasn't involved in the study, said the reversal was unfortunate because laquinimod is "so well tolerated that you could use it as an add-on."
Teva had earlier announced that CONCERTO failed to meet its primary endpoint, and therefore the in relapsing MS. But it still has ongoing trials and development interest in laquinimod for primary progressive MS and for Huntington's disease.
Disclosures
Comi disclosed financial relationships with the majority of MS drugmakers.
Primary Source
ECTRIMS-ACTRIMS Meeting
Comi G, et al "CONCERTO: a placebo-controlled trial of oral laquinimod in patients with relapsing-remitting multiple sclerosis" ECTRIMS-ACTRIMS 2017; Abstract 231.