CHICAGO — Slower cognitive decline was seen in patients with early Alzheimer‘s disease following treatment with the investigational anti-Aβ protofibril monoclonal antibody BAN2401, according to a phase IIb trial reported here.
On average, the 161 patients who received 10 mg/kg of BAN2401 in biweekly infusions showed 30% less decline measured by an Alzheimer‘s Disease Composite Score (ADCOMS) after 18 months of treatment compared with placebo in patients with mild-to-moderate Alzheimer‘s disease (P=0.034), according to Lynn Kramer, MD, chief medical and clinical officer of manufacturer Eisai, speaking at the Alzheimer‘s Association International Conference.
This dose also showed significant slowing of cognitive decline measured by ADCOMS after 6 and 12 months, as well. On the other hand, other dosing regimens failed to show any statistically significant slowing of cognitive decline compared with placebo (n=247). These doses included 2.5 mg/kg biweekly (n=52), 5 mg/kg monthly (n=51), 5 mg/kg biweekly (n=92), and 10 mg/kg monthly (n=253).
The ADCOMS measure of benefit was a composite secondary endpoint in the trial, which took into account several factors such as memory, personal care, orientation, and drawing.
“This is the first large trial to support the amyloid hypothesis,” Kramer stated during a press briefing.
That was not exactly true — a 188-patient phase Ib trial with aducanumab, another anti-amyloid biologic that flopped in follow-on studies, also showed a slower rate of cognitive decline. Several other amyloid-targeted drugs similarly demonstrated positive clinical results in phase I and II studies, only to fail in truly large phase III studies.
“After a number of failures of similar drugs and other anti-amyloid therapies over the last several years, to see the movement in the biomarker and a clinical outcome — however in a very modest number of subjects — is encouraging,” said David Knopman, MD, Alzheimer‘s Association Medical & Scientific Advisory Council and clinical neurologist at the Mayo Clinic in Rochester, who wasn’t involved with the trial.
But, he added, “It’s got to be followed-up with a larger, longer phase III study.”
The trial, which utilized Bayesian statistics, identified 10 mg/kg biweekly as the “best dose,” and therefore adapted to randomize more individuals to that dose via computer model. All participants in the trial had early Alzheimer‘s disease, with either mild cognitive impairment due to Alzheimer‘s disease or mild Alzheimer‘s dementia. Patients also had to have positive findings on brain scans for amyloid plaques. Scores on the Mini-Mental State Examination at baseline were in the 22-30 range.
After 18 months, visual read also revealed a dose dependent conversion from amyloid positive to amyloid negative in 81% of individuals on 10 mg/kg of BAN2401 biweekly (P<0.0001). This was seen in 65% of patients at this dose after 12 months (P<0.0001).
Another secondary outcome, measured by ADAS-cog, also showed a benefit with treatment. After 18 months of 10 mg/kg of biweekly infusions, there was a 47% less of a cognitive decline compared with treatment (P=0.017). This benefit was also seen after 6 months of treatment (P<0.05), yet wasn’t statistically significantly better after 12 months of treatment (P=0.073).
The experimental treatment was generally safe, with a similar number of adverse events across the treatment groups and placebo. Additionally, there were no notable changing in labs, ECGs, nor vital signs with use of BAN2401. The most common treatment-emergent adverse event were infusion reactions, as well as amyloid-related imaging abnormalities. Edema related to the latter was perhaps most concerning: it occurred in 10% of patients receiving 10 mg/kg biweekly, compared with 1% of the placebo group. Two of these events were rated as severe, which could be a problem for a drug aimed at patients with only mild Alzheimer-type symptoms.
“I don’t think this trial was powered to see that effect in cognition, so more work as far as we’re concerned,” commented Maria C. Carrillo, PhD, Chief Science Officer of the Alzheimer‘s Association, adding how she’d like to see a larger, more confirmatory trial. “But it is encouraging to see that it is the second trial that has some hints that may be hope for amyloid treatments in the future, and I think they’re are … a lot of questions about this particular approach — the Bayesian design for the ADCOMS.”
She continued, adding that “the scientific community is in agreement that combination therapy is the future and that there won’t be a silver bullet. So being able to delay the disease, even for a year, can have a huge impact on lives, but it also in combination with perhaps something like changes in vascular dementia — like we saw earlier today in the SPRINT trial” — a secondary analysis of data from the controversial study of tight blood pressure control and cardiovascular events — “and other types of therapeutic approaches, including other amyloid approaches, including tau… can give us hope for a higher magnitude of effect that can lead us to treating this disease chronically instead of how we’re just waiting and symptomatic treatments, and continually people continue to die of this disease.”
The study was funded by Eisai and Biogen.