Background: Bapineuzumab, a humanized anti-amyloid-beta (A) monoclonal antibody for the potential treatment of Alzheimer disease (AD), was evaluated in a multiple ascending dose, safety, and efficacy study in mild to moderate AD.
Methods: The study enrolled 234 patients, randomly assigned to IV bapineuzumab or placebo in 4 dose cohorts (0.15, 0.5, 1.0, or 2.0 mg/kg). Patients received 6 infusions, 13 weeks apart, with final assessments at week 78. The prespecified primary efficacy analysis in the modified intent-to-treat population assumed linear decline and compared treatment differences within dose cohorts on the Alzheimer’s Disease Assessment Scale–Cognitive and Disability assessment for Dementia. Exploratory analyses combined dose cohorts and did not assume a specific pattern of decline.
Results: No significant differences were found in the primary efficacy analysis. Exploratory analyses showed potential treatment differences (p < 0.05, unadjusted for multiple comparisons) on cognitive and functional endpoints in study “completers” and APOE epsilon4 noncarriers. Reversible vasogenic edema, detected on brain MRI in 12/124 (9.7%) bapineuzumab-treated patients, was more frequent in higher dose groups and APOE epsilon4 carriers. Six vasogenic edema patients were asymptomatic; 6 experienced transient symptoms.
Conclusions: Primary efficacy outcomes in this phase 2 trial were not significant. Potential treatment differences in the exploratory analyses support further investigation of bapineuzumab in phase 3 with special attention to APOE epsilon4 carrier status.
Classification of evidence: Due to varying doses and a lack of statistical precision, this Class II ascending dose trial provides insufficient evidence to support or refute a benefit of bapineuzumab.
Salloway S, Sperling R, Gilman S, Fox NC, Blennow K, Raskind M, Sabbagh M, Honig LS, Doody R, van Dyck CH, Mulnard R, Barakos J, Gregg KM, Liu D, Lieberburg I, Schenk D, Black R, Grundman M, For the Bapineuzumab 201 Clinical Trial Investigators: Neurology, 73 (24): 2061–2070, December 2009.
Comment by Philip Scheltens
Currently available treatments for Alzheimer disease (AD) provide only symptomatic effects and are based either on inhibiting an enzyme degrading acetylcholine (acetylcholinesterase inhibitors) or a blockade of NMDA receptors to prevent the influx of calcium into the neurons (memantine). Since the reduction of cholinesterase activity is downstream pathology in the course of the disease, these approaches can only delay functional and cognitive decline in patients with AD. The loss of cognitive function at the stage of dementia is irrevocable because many neurons in critical brain regions are already dead, numerous connections have been lost and brain atrophy is present. The profitability of these symptomatic therapies is limited and the search for a cure for AD is ongoing and increasingly important.
The intense debate about AD pathogenesis in the past three decades lead to the consensus that a triggering factor which appears to be necessary, but not sufficient, for AD is the accumulation of amyloid beta in the brain (Hardy and Selkoe, 2002). There is evidence that these changes can precede the first clinical symptoms by at least a decade (Morris et al., 2009). The formation of intraneuronal neurofibrillary tangles consisting of hyperfosforylated tau protein is the next downstream step in the disease evolution. Sole tau pathology in the absence of beta amyloid can lead to other neurodegenerative diseases and reversing amyloid pathology in mice models can diminish the progression of tau pathology. Therefore attention has been paid mainly to amyloidogenesis which has been considered a major upstream process in the disease evolution.
However, attempts to pharmacologically reverse this cascade resulted in failed trials of drugs such as AlzheMed (tramiprosate), Flurizan (tarenflurbil), Eli Lilly phase III gamasecretase inhibitor (semagacestat). These failures may be explained by having bad targets, insensitive outcome measures, too severe population included, bad compounds or bad clinical trial design, or combinations of these.
One of the most advanced programs to date, addressing the same pathway, is the monoclonal antibody bapineuzumab, originally developed by Elan, and now being put forward by a Pfizer and Janssen alliance.
The article referenced here deals with the phase II clinical trial, that included 234 patients who were challenged to four doses of the drug delivered by six infusions 13 weeks apart within 78 weeks. Approximately 9.7% of the patients developed vasogenic oedema on MRI, which was more frequent in higher dose groups and ApoE4 carriers, but was symptomless in all. On average no significant cognitive benefit of bapineuzumab was found across all dose groups, but exploratory analysis showed significant benefits in patients, who completed 6 infusions and were ApoE4 non-carriers. The lower response to treatment in ApoE4 carriers has previously been reported also in rosiglitazone and tacrine clinical trials.
Encouraged by the, albeit quite weak, results of this phase 2 trial, a large scale phase 3 programme has started and inclusion is still ongoing. The results of this phase III are expected with high anticipation as a failure might elicit criticism to the amyloid hypothesis or might further prompt ongoing discussions about the design of clinical trials in AD.
Future clinical trials with potentially disease modifying agents should include patients with less advanced disease stages. The field of AD research and clinical practice is more open to these trends and new research criteria have been proposed (Dubois et al., 2007, McKhann et al., 2011, Albert et al., 2011).
Hardy J, Selkoe DJ.The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science. 2002 Jul 19;297(5580):353-6. Review. Erratum in: Science 2002 Sep 27;297(5590):2209.
Morris JC, Roe CM, Grant EA, Head D, Storandt M, Goate AM, Fagan AM, Holtzman DM, Mintun MA.Pittsburgh compound B imaging and prediction of progression from cognitive normality to symptomatic Alzheimer disease. Arch Neurol. 2009 Dec;66(12):1469-75.
Dubois B, Feldman HH, Jacova C, Dekosky ST, Barberger-Gateau P, Cummings J, Delacourte A, Galasko D, Gauthier S, Jicha G, Meguro K, O’brien J, Pasquier F, Robert P, Rossor M, Salloway S, Stern Y, Visser PJ, Scheltens P. Research criteria for the diagnosis of Alzheimer’s disease: revising the NINCDS-ADRDA criteria. Lancet Neurol. 2007 Aug;6(8):734-46. Review.
McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR Jr, Kawas CH, Klunk WE, Koroshetz WJ, Manly JJ, Mayeux R, Mohs RC, Morris JC, Rossor MN, Scheltens P, Carrillo MC, Thies B, Weintraub S, Phelps CH. The diagnosis of dementia due to Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011 May;7(3):263-9. Epub 2011 Apr 21.
Albert MS, Dekosky ST, Dickson D, Dubois B, Feldman HH, Fox NC, Gamst A, Holtzman DM, Jagust WJ, Petersen RC, Snyder PJ, Carrillo MC, Thies B, Phelps CH. The diagnosis of mild cognitive impairment due to Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011 May;7(3):270-9. Epub 2011 Apr 21.
Philip Scheltens is Professor of Neurology at the Free University in Amsterdam, The Netherlands and Chairman of the EFNS Scientist Panel on Dementia and Cognitive Neurology