Susan Jeffrey

May 11, 2015

WASHINGTON, DC — Further analyses of early-phase data on a promising monoclonal antibody, aducanumab (formerly BIIB037, Biogen Inc), in Alzheimer's disease (AD) show it appears to be effective regardless of apolipoprotein E (APOE) status and disease stage.

The main results of a prespecified interim analysis of the phase 1b PRIME trial were presented in March at AD/PD 2015: International Conference on Alzheimer's and Parkinson's Diseases, and reported by Medscape Medical News at that time.

In the previous analysis, the researchers showed the monoclonal antibody was safe and well tolerated, that it reduced amyloid plaques on positron emission tomography (PET), and improved measures of cognition.

Further new results looking at subgroup treatment response were presented at the recent American Academy of Neurology (AAN) 67th Annual Meeting, as part of the featured Emerging Science session.

"Treatment with aducanumab results in a dose-dependent and time-dependent effect that is consistent across APOE ε4 carriers and noncarriers, and among subjects with both mild and prodromal disease," lead author Jeffrey Sevigny, MD, Biogen Inc, concluded.

"That's very important for us because it tells us that the drug works the same whether one is an APOE ε4 carrier or noncarrier — and keep in mind that 50% to 75% of people with AD are APOE ε4 carriers — and it tells us that independent of disease state, the drug works the same," Dr Sevigny told Medscape Medical News.

"Later in the year, we'll present results showing the clinical effect based on those two parameters, so this was the first step in showing this data," he added.

Monoclonal Antibody

Several monoclonal antibodies, including bapineuzumab (Pfizer Inc), solanezumab (Eli Lilly Inc), and gantenerumab (Hoffman LaRoche), were also promising in early studies but were not successful in late-stage trials. Investigation with two of the agents, solanezumab and gantenerumab, continues in other late-stage trials in various AD populations.

Aducanumab is a human recombinant monoclonal antibody that selectively binds aggregated forms of β-amyloid, including soluble oligomers and insoluble fibrils, but does not bind β-amyloid monomers such as others of these antibodies, Dr Sevigny explained. Solanezumab, for example, binds only the monomeric form of β-amyloid, so these two antibodies "are at the two ends of the spectrum."

The mechanism of action of aducanumab is thought to be microglial-mediated phagocytosis and clearance of β-amyloid through the IgG1 backbone, he said, "so it really heavily relies on the effector function. That's our hypothesis and that's been demonstrated in animal models. There may be other mechanisms but that's the key one for aducanumab."

In the double-blind, phase 1b PRIME trial, patients with prodromal or mild AD were randomly assigned to 1, 3, 6, or 10 mg/kg of drug or placebo in a 3:1 fashion, with approximately 30 patients per active treatment group. Patients were 50 to 90 years of age (mean age, 70.5 to 73.7 years across the groups), had confirmed β-amyloid deposition as assessed by florbetapir (18F-AV-45) PET, and met clinical criteria for prodromal or mild AD by Mini-Mental State Examination (MMSE) and Clinical Dementia Rating Scale-sum of boxes (CDR-sb) scores.

Patients received the drug or placebo intravenously once every 4 weeks for 54 weeks. Most patients were also taking concomitant AD medications.

The primary endpoints were safety and tolerability. Secondary endpoints were serum PK, the development of antibodies, and amyloid change on PET from baseline to week 26. The exploratory endpoints included change in MMSE and CDR-sob scores and change in PET amyloid from baseline to week 54.

A composite standard uptake value ratio (SUVR) of florbetapir was calculated from a volume of six brain regions of interest, specifically the frontal, parietal, lateral temporal, sensorimotor, anterior cingulate, and posterior cingulate regions, and was compared with whole cerebellum as a reference region.

"Approximately 1 month ago, we reported the results from this interim analysis," Dr Sevigny said. "Treatment with aducanumab results in a time- and dose-dependent reduction of amyloid plaques as measured by PET amyloid imaging."

The placebo group had "virtually no change" in plaques over the course of the study, which was an expected result, he noted. There was a dose-dependent, statistically significant reduction in amyloid plaque at week 26 for the groups receiving 3, 6, and 10 mg/kg, and a dose-dependent, statistically significant reduction in the groups receiving 3 and 10 mg/kg at week 54, Dr Sevigny said. The 6 mg/kg group is still ongoing.

Plaques decreased in the frontal, parietal, lateral temporal, sensorimotor, anterior cingulate, posterior cingulate, medial temporal, and occipital cortex, as well as in the striatum, he reported at the AD/PD 2015 meeting. In each area, plaque reduction was greater with the 10 mg/kg than with the 3 mg/kg dose.  

The mean SUVR starting values were 1.40 to 1.50. In healthy persons, the cut-point for florbetapir is less than 1.13. By week 54, the mean composite SUVR for the 10 mg/kg dose was about 1.15.

The main safety and tolerability finding was amyloid-related imaging abnormalities with edema and effusion (ARIA-E) on MRI, the primary analysis.

Three percent of aducanumab-treated patients developed antibodies against the drug, but titers were minimal and had no effect on pharmacokinetics or safety, the researchers reported.

Almost all patients had some adverse event. Serious adverse events occurred in 10% to 13% of patients at lower doses, in 38% of those in the highest dose group, and, curiously, in 38% in the placebo group. Six percent to 10% discontinued the study in the placebo and lower-dose groups, but 31% stopped in the 10 mg/kg group. Three patients died — two in placebo group and one in the 10 mg/kg group — but no deaths were considered treatment related.

ARIA-E occurred in a dose-dependent manner, affecting 33% and 41% of patients at the 6 mg/kg and 10 mg/kg doses, respectively. It was more prevalent in APOE ε4 carriers, they reported previously. Most cases occurred within the first five doses; 65% of cases were asymptomatic, and the rest were generally mild. Signs of ARIA-E resolved within 4 to 12 weeks after the drug was stopped. Patients could resume dosing at the next lower dose once ARIA resolved.

Headache occurred in 22% of patients receiving aducanumab compared with 5% in the placebo groups and appeared to be dose dependent, a company statement noted.

"We also reported that treatment with aducanumab had a statistically significant clinical effect measured by two commonly used outcome measures," the MMSE and the CDR-sob, Dr Sevigny reported at the AAN meeting here.

Aducanumab slowed the rate of decline in MMSE scores at the 3 mg/kg and 10 mg/kg doses by week 54. Whereas the placebo group had an adjusted mean decline in MMSE score compared with a baseline of 3.1, the difference from placebo was 2.39 points higher for the 3 mg/kg dose and 2.55 higher for the 10 mg/kg dose (both P < .05 vs placebo).

The CDR-sb adjusted mean score at 10 mg/kg was significantly lower (ie, better) than that with placebo (0.50 vs 2.00; P < .05).

New Data

"One important question we needed to ask ourselves was whether the pharmacodynamic effects observed with aducanumab were consistent across APOE ε4 status and disease stage," Dr Sevigny said.

First they looked at the results related to APOE ε4 status and found "a nice dose-dependent effect that is consistent among carriers and noncarriers" at weeks 26 and 54, Dr Sevigny said.

When the results were stratified by prodromal AD vs mild AD, again, at week 26, "you see a nice dose-dependent effect that's roughly equivalent at week 26 in both prodromal and mild subjects," he said. "Likewise, at week 54 we see the same consistent effects among prodromal and mild AD."

Additional key data will be coming out later this year, specifically the 1-year results on the 6 mg/kg cohort. "We hope to have those data presented at AAIC [Alzheimer's Association International Conference]," Dr Sevigny added. "We have also added a titration arm that recently completed enrollment and so that data will be available about a year from now."

On the basis of the encouraging phase 1b results, Dr Sevigny said they plan to go directly into a phase 3 trial.

"We've gathered enough information now to make a decision internally about next steps from the PRIME study," Dr Sevigny told Medscape Medical News. "We've developed a protocol, we've met with regulators, and we anticipate starting phase 3 in the second half of this year."

Asked whether going directly to phase 3 might represent a risk, he said they feel they have sufficient information to select the population and dosing for phase 3, although the dose they have chosen has not yet been disclosed. "If new information emerges, then we could modify the protocol if necessary, but we feel comfortable with what information we have at this point."

Live and Learn

Asked for comment on these findings, Dean Hartley, PhD, director of scientific initiatives in the Medical and Scientific Relations Division of the Alzheimer's Association, was positive about the findings with this antibody to date.

"I do think this is of interest because the fact that we saw the normal things [we see] in phase 1 trials — the safety was fine and that's not so surprising — but…to see a positive improvement in the cognitive score at such an early phase and small number of individuals, really made you think that there is probably a signal here," Dr Hartley told Medscape Medical News.

It also supports some of the findings that have come out of the EXPEDITION trials of solanezumab, he said. The earlier EXPEDITION 1 and 2 trials didn't meet primary outcomes but when the data were pooled, they found something on the order of a 34% slowing of the cognitive decline, Dr Hartley pointed out. "So that's why they decided to take it to phase 3, which they're enrolling for now," he said. The new result with aducanumab, "adds to more data in the field to suggest that indeed these therapies may be working."

New trials also build on findings of the previous studies, he added. EXPEDITION 1 and 2, for example, did not use amyloid scans, so it was not clear that those participants even had amyloid present in the brain, he said. In EXPEDITION 3, amyloid PET scans are being used to screen individuals and participants are being enrolled at an earlier stage of AD.

"I'm enthusiastic about this data and I think others are, and I think the question will be what happens when it goes into phase 3," Dr Hartley said. "We do know a lot of things fail at that point but we're very much interested in seeing, are we going to achieve some sense that these antibodies may be able to help, at least some subset of people who are affected by this disease?"

He was also unconcerned about going directly to phase 3 from phase 1b with this agent. "I don't know if it was a business decision or about the enthusiasm about the improvement that they saw at this level that really propelled them to go all the way to the phase 3, but you have to get there eventually and…they've got some pretty good data on any of the side effects."

As with any research, it's not clear what you are missing until you actually perform the larger trials, he added. "I think it's important to think about that pipeline of maybe 15 million people by mid-century that are going to have the disease, so the earlier we can get to these answers," the better, he said. "It may not be the answer that you want, but it means you need to go on and do something else, or you have to rethink what you were proposing."

As always, the Alzheimer's Association stresses the ongoing need for more federal funding for this disease, Dr Hartley added. "We know when you look at cancer, HIV, heart disease, the billions of dollars put into that research have given them effective treatments. We need to bring the dollars up to that same level. We need those $2 billion a year for the next 10 years, to hopefully find those effective treatments."

Amyloid Hypothesis

Also commenting on these findings, Sam Gandy, MD, PhD, Mount Sinai Endowed Chair in Alzheimer's Disease, research professor of neurology and of psychiatry, director of the Mount Sinai Center for Cognitive Health, and director of the NFL Neurological Center at Icahn School of Medicine at Mount Sinai, New York, called the aducanumab trials "the most convincing evidence that one can derive clinical benefit from an amyloid-lowering, disease-modifying intervention."

 
To be fair, the real potential of this drug is not yet clear; the euphoric reaction to the results is largely the result of 30 years of failure to prove the importance of the 'amyloid hypothesis' in humans. Aducanumab changes that. Dr Sam Gandy
 

"This is still a small trial and there were some dose-dependent side effects," Dr Gandy told Medscape Medical News. "Two large concurrent trials will begin this summer, and those should tell us, by 2017, if aducanumab has a sufficient effect on activities of daily living such that the FDA [Food and Drug Administration] would approve the drug for the treatment of Alzheimer's disease."

The data are "more impressive" than those derived from similar drugs from other companies, he added. "One cannot yet say whether aducanumab is truly a better drug than, say, bapineuzumab, or whether the Biogen trial design was superior to those used in the past. Most notably, the brain amyloid scan, approved by the FDA but so far not reimbursed by Medicare, was used to determine which patients with memory problems would be permitted into the Biogen aducanumab trial.

"To be fair, the real potential of this drug is not yet clear; the euphoric reaction to the results is largely the result of 30 years of failure to prove the importance of the 'amyloid hypothesis' in humans," Dr Gandy concluded. "Aducanumab changes that."

The study is funded by Biogen Idec. Dr Sevigny is an employee of Biogen Idec. Dr Hartley have disclosed no relevant financial relationships.

American Academy of Neurology (AAN) 67th Annual Meeting. Emerging Science Abstract 001. Presented April 22, 2015.

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