Phase I results move Alzheimer’s candidate drug aducanumab into phase III trials

SAN DIEGO – The antiamyloid antibody aducanumab significantly reduced amyloid brain plaques in Alzheimer’s disease patients who entered a second year of therapy in an open-label extension trial.

Plaque volume declined in a time- and dose-dependent manner, with a bit of movement even among patients who crossed over to the lowest 1-mg/kg dose after a year of taking placebo in the phase Ib PRIME study, Samantha Haeberlein, PhD, reported at the Clinical Trials on Alzheimer’s Disease conference.

The linear declines in plaque burden were dramatic enough to draw a collective gasp of appreciation from the packed auditorium. But the cognitive and functional data of aducanumab (Biogen), while deemed encouraging, were not as striking. The Clinical Dementia Rating Scale-sum of boxes (CDR-SB) and the Mini-Mental State Examination (MMSE) showed dose-dependent slowing of decline, but the drug’s effect approached statistical significance only among those who finished 2 years on 10 mg/kg aducanumab infused every 4 weeks. This group experienced relative stability of MMSE scores, which dropped only about 1 point from baseline, and also showed the greatest decline in amyloid plaque volume.

Biogen deemed this result on the MMSE, which represented a 3.27-point separation from the 1-mg/kg dose group, as “nominally significant,” with a P value noted as “less than .05.”

However, the finding must be viewed with extreme caution, said Dr. Haeberlein, Biogen’s vice president of clinical development. There were only 15 subjects in this group, and the study was not primarily intended to examine cognition.

“I must emphasize once again that these are exploratory data and these sample sizes are very small for these types of assessments,” she said. “Nonetheless, we find them informative.”

MMSE changes in the other dosing groups of 1, 3, and 6 mg/kg were not statistically significant at the end of the study. There were not any significant findings on the CDR-SB measure.

Alzheimer’s Association reaction

Maria C. Carrillo, PhD, chief science officer of the Alzheimer’s Association, was cautiously optimistic.

“For MMSE, the original placebo group continued to decline even when they switched to the 1-mg/kg treatment, and by a significant number of points. The 1- to 3-mg/kg switching group is interesting, as they do get a little bit of a bump. But we also had the 6-mg/kg arm continuing to decline in MMSE and not improve as much as the others, which is strange. It’s aberrant, but the same thing we saw in the first study report. The 10-mg/kg group, though, stays almost at baseline. That’s pretty amazing. Impressive. Again, small numbers but very encouraging.”

Full 12-month results

Biogen presented two aducanumab abstracts at the meeting, both describing its 12-month phase Ib PRIME study and its 12-month, open-label extension study. The drug is a monoclonal human antibody derived from B cells collected from a cohort of cognitively normal elderly subjects and cognitively impaired elderly subjects who exhibited unusually slow decline, according to the company. It binds to fibrillar and oligomeric amyloid aggregates, thus directly reducing amyloid plaque in the brain.

PRIME enrolled 165 patients with prodromal or mild Alzheimer’s disease. Importantly, all of the subjects had brain amyloid proven by PET imaging. PRIME is the first randomized trial of an antiamyloid compound to enroll a pure amyloid-positive cohort. These subjects were randomized to placebo or aducanumab at 1, 3, 6, or 10 mg/kg for 1 year. PRIME’s primary outcomes were safety and tolerability. The cognitive and functional outcomes, not usually assessed in a phase Ib study, were exploratory.

They must also be interpreted in light of the very small numbers, about 30 patients in each dosing group at baseline. In addition, just 69 patients finished the entire 24-month dosing period, leaving only 15-23 patients in each group by the end of the study.

Vissia Viglietta, MD, Biogen’s senior medical director of clinical development, presented the 12-month data. At 52 weeks, all dosing groups, even the 1 mg/kg, saw statistically significant reductions in amyloid plaque, compared with placebo. These changes were dose-dependent; the 10-mg/kg group had the largest reduction, with a P value of less than .001.

There also were dose-dependent changes in the CDR-SB and MMSE, and some of these reached statistical significance.

On the CDR-SB, patients taking placebo declined by an average of 1.89 points. Declines in the 1-, 3-, and 6-mg/kg groups were not significant relative to placebo. However, the 10-mg/kg arm experienced a significant separation from placebo, declining an average of 0.63 points (P less than .05).

The story was similar for the MMSE. Patients taking placebo declined by 2.45 points. The decline was 2.2 points in the 1-mg/kg group; 0.75 in the 3-mg/kg group; and 0.55 in the 10-mg/kg group. The only statistically significant results relative to placebo occurred with the 10-mg/kg group (P less than .05).

The 6-mg/kg group didn’t fit this pattern though, losing an average of 2 points. Biogen has been unable to explain this, but some researchers suggest such an outlying result isn’t surprising, given the small numbers in each group and the exploratory nature of the cognitive analysis.

Amyloid-related imaging abnormalities (ARIA), an inflammatory reaction thought to be related to the removal of amyloid plaque, were the most common adverse event (n = 27). Most of these (22) were in apolipoprotein E4 allele carriers.

Two patients in the placebo arm died, as well as one in the 10-mg/kg arm, but it was not considered related to the study drug. There were no significant changes in hematology, chemistry, urinalysis, electrocardiogram, or vital signs.