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Posted by on Sep 12, 2012 in Neurology, Neuropsychiatry, Pharma

For Alzheimer’s, Amyloid Hypothesis Remains Viable; But Bapineuzumab Is Probably Dead

For Alzheimer’s, Amyloid Hypothesis Remains Viable; But Bapineuzumab Is Probably Dead

The unequivocally negative clinical results of the phase 3 studies of bapineuzumab do little to promote or detract from the idea that accumulating amyloid in the brain is the instigator of Alzheimer disease. For continued supporters of the amyloid hypothesis, including Dr. Reisa Sperling, who presented the phase 3 results for APOE ε4 carriers at the recent EFNS meeting in Stockholm, the positive biomarker results (stabilization of brain amyloid* and reduction of CSF p-tau levels) suggest that we’re either intervening too late in the condition or that we need to reduce the amyloid burden more significantly to see clinically meaningful benefits with anti-amyloid compounds.

The unequivocally negative primary outcome with bapineuzumab in APOE ε4 carriers (change in mean ADAS-cog score from baseline).



Of course she may be right, and for those who cleave to the amyloid hypothesis of AD, higher doses of amyloid-reducing agents in established AD or earlier-intervention studies (which are underway with other anti-amyloid MAbs) will further support or undermine the amyloid hypothesis. But these avenues of continued research will probably not include bapineuzumab, because of dose-related safety concerns with the MAb.

In the phase 3 study of APOE ε4 carriers (who generally have a higher amyloid burden than noncarriers), ARIA-E was significantly more likely with bapineuzumab (0.5 mg/kg) than with placebo (15% [n = 103] vs 0.2% [n = 1]); although only a small minority of affected patients (n = 16) were symptomatic (eg, headache, confusion). Among serious adverse events, the imbalance between bapineuzumab- and placebo-treated patients was driven by the incidence of ARIA-E (2.1% vs 0).

In the phase 3 study the APOE ε4 noncarriers, the results of which were presented by Dr. Stephen Salloway, the biomarker effects were less robust than those in the carrier study; although there appeared to be a possible dose-related effect of bapineuzumab (1.0 vs 0.5 mg/kg) on these outcomes (ie, brain amyloid and p-tau). The incidence of ARIA-E was not as high in this study (9.4% with the 1.0-mg/kg dose vs 0.2% with placebo), probably because the amyloid burden was not as high in the enrollees (my conjecture, not Salloway’s). Notably 36% of enrollees did not meet the cutoff value for amyloid positivity in the brain, suggesting that PET imaging in noncarriers is much less sensitive for supporting the diagnosis of AD (also my conjecture). Other concerning safety data indicate that intracranial hemorrhage and seizure are more likely with higher doses of bapineuzumab.

The webcasts of both presentations at the EFNS can be found here and here. However, the all-important follow-up Q&A session was not recorded (or made available for online presentation).

ADAS-cog = Alzheimer’s Disease Assessment Scale, cognitive subscale; ARIA-E = amyloid-related imaging abnormalities, edema; CSF = cerebrospinal fluid; MAb = monoclonal antibody; p-tau = phosphorylated tau.
* Via PiB PET [Pittsburgh compound B with positron emission tomography].

N.B.–According to MarketWatch (and other sources), “Pfizer and J&J continue to study a subcutaneous formulation of bapineuzumab, and it’s possible that formulation could be tested in patients with early stages of Alzheimer’s.” Given the phase 3 results, it’s unlikely that a SQ formulation is going to be more efficacious (while possibly being safer) than an IV version of bapineuzumab. However, the primary intent here may be to prove safety, while reserving the possibility of efficacy for early-intervention studies. But the future remains dim for bapineuzumab in whatever form, IMHO.

bmartin (80 Posts)

A native East Tennessean, Barbara Martin is a formerly practicing, board-certified neurologist who received her BS (psychology, summa cum laude) and MD from Duke University before completing her postgraduate training (internship, residency, fellowship) at the Hospital of the University of Pennsylvania in Philadelphia. She has worked in academia, private practice, medical publishing, drug market research, and continuing medical education (CME). For the last 3 years, she has worked in a freelance capacity as a medical writer, analyst, and consultant. Follow Dr. Barbara Martin on and Twitter.