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COPENHAGEN -- The amyloid plaque-busting drug crenezumab for Alzheimer's disease failed to meet its primary endpoints in a phase II trial, but -- as was the case with another similar drug -- the drug did show promise in a subgroup with mild symptoms.

Among all patients with mild to moderate Alzheimer's disease enrolled in the so-called ABBY trial, those assigned to the study drug, a monoclonal antibody called crenezumab, showed a 16.8% reduction in the rate of cognitive decline over 68 weeks compared with a placebo group (P=0.19), reported , director of the Cleveland Clinic's Lou Ruvo Center for Brain Health in Las Vegas.

But although this overall difference between crenezumab and placebo did not achieve statistical significance and therefore missed its primary endpoint, Cummings reported at the Alzheimer's Association International Conference here that the subset of patients with the mildest disease (baseline Mini-Mental State Examination [MMSE] score 22 to 26) did show a significant improvement when receiving high-dose crenezumab relative to placebo.

In this post hoc analysis, the drug was associated with a 35.4% slower decline in MMSE score compared with placebo (P=0.036), Cummings reported.

In a second study called BLAZE, for which primary biomarker-based endpoints weren't yet available, a similar but nonsignificant trend was found toward clinical improvement in patients with mild disease (MMSE score 20 to 26) who were treated with crenezumab.

These findings are consistent with those previously seen with solanezumab, another anti-amyloid antibody drug, which is now being tested in patients with "preclinical" Alzheimer's disease -- those with little to no cognitive impairment but heavy beta-amyloid plaque burdens, putting them at high risk for Alzheimer's disease in the near future.

The ABBY and BLAZE results also support the emerging hypothesis that the best time to introduce anti-amyloid drugs is before cognition is substantially impaired.

ABBY had enrolled 431 patients who were assigned to one of four treatment arms: placebo or 300 mg of crenezumab (low dose) by subcutaneous injection every other week, or placebo or crenezumab at 15 mg/kg (high dose) by intravenous infusion every 4 weeks.

Change in MMSE score from baseline to the end of treatment at 68 weeks was the primary outcome. Secondary outcomes included scores on the Alzheimer's Disease Cooperative Study Activities of Daily Living scale (ADCS-ADL) and MRI-measured total brain volume.

Patients in the low-dose crenezumab group showed no difference from placebo either in the primary analysis or in the severity-stratified subgroups.

Also, a prespecified analysis for a subgroup defined by baseline MMSE score of 20 to 26 failed to show a significant improvement with high-dose IV crenezumab (relative reduction in decline rate 16.8%, P=0.13). Only the post hoc analysis in patients with the mildest degree of baseline impairment showed a significant advantage for the drug. Even in this analysis, the change in ADCS-ADL scores did not differ between high-dose crenezumab and placebo.

The BLAZE study involved 91 patients and the same four-arm treatment design. Its primary endpoint was beta-amyloid plaque burden in the brain, as measured with tracer-enabled PET scans. Those results were not yet available, but Cummings reported findings on secondary clinical outcomes including ADCS-ADL and the cognitive domain of the Alzheimer's Disease Assessment Scale (ADAS-Cog).

In the preliminary analysis reported here, cognitive decline with these measures was somewhat slower in a high-dose crenezumab subgroup with milder baseline impairment than in the placebo group. There was no benefit, however, for the low-dose regimen nor with the high dosage when analyzed across all patients enrolled.

Adverse events overall did not appear to differ between groups. Five patients died during the trial, with no obvious imbalance between treatment groups. The rate was about what would be expected in an elderly population over 15 months.

On the other hand, some potential safety signals were observed. One patient in the high-dose group developed sulcal effusions in the ABBY study, and overall numbers of pneumonia cases (serious and nonserious) were greater in the crenezumab groups.

Roche, which is developing the drug through its Genentech unit, said it would decide whether and how to continue pursuing the drug after fuller analysis of the two trials' results.

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