A phase 2 multiple ascending dose trial of bapineuzumab in mild to moderate Alzheimer disease
Daniel T.Laskowitz, Duke University Medical Center, Box 2900 Duke University Medical Center, Durham NC 27710danl@neuro.duke.edu
Brad J. Kolls
Submitted February 22, 2010
We read with interest the recent manuscript by Salloway et al. who describe a phase 2 ascending dose trial where bapineuzumab, a monoclonal antibody directed at the N-terminus of A beta, was tested in patients with Alzheimer disease (AD). [1]
Although bapineuzumab did not affect the primary endpoint of cognitive outcome, APOE4 was associated with increased incidence of vasogenic edema. These results—along with other studies demonstrating an interaction between APOE polymorphism and treatment effect—highlight the importance of understanding pharmacogenomic interactions between APOE genotype and therapeutic strategies when designing future clinical trials. [2]
Since the original association was made between APOE genotype and risk of developing AD [3], there has been a strong focus on examining the isoform-specific effects of apoE on amyloid metabolism. Salloway et al. speculate that an increase in vascular amyloid burden may have resulted in vasogenic edema in APOE4 carriers. However, there is data suggesting that apoE modifies CNS inflammatory responses in an isoform-specific fashion; a potential common denominator for its role in acute and chronic neurological diseases.
In particular, the APOE4 polymorphism is associated with enhanced glial activation and neuroinflammatory responses. [4] Thus, although the effect of APOE4 on the development of vasogenic edema was unanticipated, it is consistent with the possibility that APOE4 carrier status is associated with increased and potentially dangerous neuroinflammatory responses in trials of immunotherapies designed to promote A beta clearance.
Conversely, therapies that suppress inflammatory responses, such as treatment with nonsteroidal anti- inflammatory agents, may benefit patients with the APOE4 allele. The Cardiovascular Health Study also demonstrated a protective effect of NSAIDs in APOE4 carriers, although there was no selective advantage in NSAIDs that lowered AB42. [5]
Although the amyloid cascade hypothesis supports the pathophysiology of AD, a more complete understanding of the adaptive and maladaptive role of glial activation and neuroinflammation is essential in targeting immunomodulatory therapies. It may be beneficial to focus on the isoform-specific role that apoE plays in modifying neuroinflammatory responses. Clarifying this role may target novel therapies and potential adverse effects.
References
1. Salloway S, Sperling R, Gilman S, et al. A phase 2 multiple ascending dose trial of bapineuzumab in mild to moderate Alzhemier’s disease. Neurology 2009;73:2061-2070.
2. Laskowitz DT, Vitek MP. Apolipoprotein E and neurological disease: therapeutic potential and pharmacogenomic interactions. Pharmacogenomics 2007;8:959-969.
3. Strittmatter WJ, Weisgraber KH, Huang DY, et al. Binding of human apolipoprotein E to synthetic amyloid beta peptide: Isoform-specific effects and implications for late-onset Alzheimer disease. Proc Natl Acad Sci (USA) 1993;90:8098-8102.
4. Laskowitz DT, Thekdi AD, Thekdi SD, et al. Downregulation of microglial activation by apolipoprotein E and apoE-mimetic peptides. Exper Neurol 2001;167:74-85.
5. Szekely CA, Breitner JC, Fitzpatrick AL, et al. NSAID use and dementia risk in the Cardiovascular Health Study: role of APOE and NSAID type. Neurology 2002;70:17-24.
Disclosures: Dr. Laskowitz receives research funding from NIH[R34NS06465, 1R41NS056856]; received research support from the Institute for the Study of Aging, Alzheimer’s Association, Transition Therapeutics, Astute Medical, Astra-Zeneca, and Roche; and serves as a consultant for NeurOp, Inc, Astute Medical, Inc, and Cognosci, Inc. Dr. Kolls receives research support from Jordan Neuroscience.
We read with interest the recent manuscript by Salloway et al. who describe a phase 2 ascending dose trial where bapineuzumab, a monoclonal antibody directed at the N-terminus of A beta, was tested in patients with Alzheimer disease (AD). [1]
Although bapineuzumab did not affect the primary endpoint of cognitive outcome, APOE4 was associated with increased incidence of vasogenic edema. These results—along with other studies demonstrating an interaction between APOE polymorphism and treatment effect—highlight the importance of understanding pharmacogenomic interactions between APOE genotype and therapeutic strategies when designing future clinical trials. [2]
Since the original association was made between APOE genotype and risk of developing AD [3], there has been a strong focus on examining the isoform-specific effects of apoE on amyloid metabolism. Salloway et al. speculate that an increase in vascular amyloid burden may have resulted in vasogenic edema in APOE4 carriers. However, there is data suggesting that apoE modifies CNS inflammatory responses in an isoform-specific fashion; a potential common denominator for its role in acute and chronic neurological diseases.
In particular, the APOE4 polymorphism is associated with enhanced glial activation and neuroinflammatory responses. [4] Thus, although the effect of APOE4 on the development of vasogenic edema was unanticipated, it is consistent with the possibility that APOE4 carrier status is associated with increased and potentially dangerous neuroinflammatory responses in trials of immunotherapies designed to promote A beta clearance.
Conversely, therapies that suppress inflammatory responses, such as treatment with nonsteroidal anti- inflammatory agents, may benefit patients with the APOE4 allele. The Cardiovascular Health Study also demonstrated a protective effect of NSAIDs in APOE4 carriers, although there was no selective advantage in NSAIDs that lowered AB42. [5]
Although the amyloid cascade hypothesis supports the pathophysiology of AD, a more complete understanding of the adaptive and maladaptive role of glial activation and neuroinflammation is essential in targeting immunomodulatory therapies. It may be beneficial to focus on the isoform-specific role that apoE plays in modifying neuroinflammatory responses. Clarifying this role may target novel therapies and potential adverse effects.
References
1. Salloway S, Sperling R, Gilman S, et al. A phase 2 multiple ascending dose trial of bapineuzumab in mild to moderate Alzhemier’s disease. Neurology 2009;73:2061-2070.
2. Laskowitz DT, Vitek MP. Apolipoprotein E and neurological disease: therapeutic potential and pharmacogenomic interactions. Pharmacogenomics 2007;8:959-969.
3. Strittmatter WJ, Weisgraber KH, Huang DY, et al. Binding of human apolipoprotein E to synthetic amyloid beta peptide: Isoform-specific effects and implications for late-onset Alzheimer disease. Proc Natl Acad Sci (USA) 1993;90:8098-8102.
4. Laskowitz DT, Thekdi AD, Thekdi SD, et al. Downregulation of microglial activation by apolipoprotein E and apoE-mimetic peptides. Exper Neurol 2001;167:74-85.
5. Szekely CA, Breitner JC, Fitzpatrick AL, et al. NSAID use and dementia risk in the Cardiovascular Health Study: role of APOE and NSAID type. Neurology 2002;70:17-24.
Disclosures: Dr. Laskowitz receives research funding from NIH[R34NS06465, 1R41NS056856]; received research support from the Institute for the Study of Aging, Alzheimer’s Association, Transition Therapeutics, Astute Medical, Astra-Zeneca, and Roche; and serves as a consultant for NeurOp, Inc, Astute Medical, Inc, and Cognosci, Inc. Dr. Kolls receives research support from Jordan Neuroscience.