TTP488 in Patients With Mild to Moderate Alzheimer's Disease
TTP488 in Patients With Mild to Moderate Alzheimer's Disease
Alzheimer's Disease (AD) is a neurodegenerative disorder with aspects of inflammatory, metabolic and vascular pathology. An overproduction of amyloid beta (Aβ) has been implicated as the leading mechanistic factor in AD pathology. Aβ is known to bind to The Receptor for Advanced Glycation Endproducts (RAGE) an immunoglobulin supergene family member expressed on multiple cell types in the brain and the periphery. RAGE is found on the cells of the neurovascular compartment: endothelial cells and microglia prominently express RAGE whose expression is upregulated in AD. RAGE ligands include Aβ, S100b, HMGB1 and Advanced Glycation Endproducts. RAGE-ligand interactions lead to sustained inflammatory states that play a role in chronic diseases such as diabetes, inflammation, and AD. In AD, RAGE has been proposed to contribute to AD pathology by: promoting vascular leakage, promoting influx of peripheral Aβ into brain; mediating Aβ-induced oxidative stress and Aβ mediated neuronal death.
The pleiotropic role of RAGE has been demonstrated in AD pathology has been described using rodent models. Mice expressing the human APP transgene in neurons develop significant biochemical and behavioral changes reminiscent of human AD. Double transgenic mouse overexpressing WT RAGE in the APP transgene background exhibit accelerated behavioral changes whereas double transgenic animals expressing a dominant negative mutant of RAGE are protected. This data suggests that RAGE plays a role in augmenting the chronic inflammatory state caused by overproduction of Aβ.
RAGE is thought to be involved in the transport of Aβ from peripheral to CNS compartments. In vivo, Aβ uptake into brain is dependent on RAGE as shown in RAGE null mice. Similarly, Aβ uptake in brain can be inhibited using either the secreted, soluble form of RAGE (called sRAGE) or an anti-RAGE antibody. In addition, plaque formation in a mouse model of cerebral amyloidosis was inhibited using sRAGE. These data suggest that RAGE is intimately involved in the pathogenesis of AD, and that sustained Aβ interaction with RAGE on blood brain barrier (BBB) and/or neuronal cells is an important element of amyloid plaque formation and chronic neuronal dysfunction.
TransTech Pharma, Inc. discovered TTP488, an orally active, centrally acting antagonist of RAGE-RAGE ligand interaction. Chronic oral dosing of TTP488 in AD transgenic mice led to a reduction of amyloid load in the brain, improved performance on behavioral testing and normalization of electrophysiological recordings from hippocampal slices.
The results of a phase 2 study examining the safety, tolerability and efficacy of TTP488 in mild to moderate AD have been reported elsewhere. Briefly, 399 patients were randomly assigned to one of two dose levels of TTP488 (60 mg loading dose for 6 days followed by 20 mg/day; 15 mg loading dose for 6 days followed by 5 mg/day) or placebo administered orally for 18 months. The pre-specified primary analysis, using a modified intent-to-treat population, was on the Alzheimer's Disease Assessment Scale-Cognitive (ADAS-cog11). Based on a pre-specified interim analysis when 50% of subjects had completed the 6 month visit, the 20 mg/day dose was discontinued due to an increased incidence of confusion, falls and greater ADAS-cog decline than placebo. No safety concerns were noted for the 5 mg/day group. Approximately 12 months after all subjects were randomized a second pre-specified interim analysis on 18-month completers compared the 5 mg/day dose and placebo groups for futility and safety. While safety data raised no concerns, the criterion for futility (less than 10% conditional power to observe a significant difference between low dose and placebo at 18 months) was met and treatment was discontinued. Final analysis showed a decreased decline on the ADAS-cog in the 5 mg/day group at month 18 (treatment-placebo difference = 3.1, p = 0.008, ANCOVA with multiple imputation) (Figure 1, panel A). The difference remained significant using other planned statistical models that cope with missing data differently (ANCOVA on observed cases (p = 0.02), ANCOVA with LOCF (p = 0.03), mixed-models repeated measures (p = 0.04), and GEE (p = 0.03)). The authors concluded that this post-futility analysis suggested benefit for 5 mg/day; however, definitive conclusions about the effects could not be made due to operational issues (dropouts and discontinuations from treatment) subsequent to the interim analysis.
(Enlarge Image)
Figure 1.
Estimated mean change from baseline over time on Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-cog 11). Increasing values represent worsening. Error bars represent one standard error. (A) ADAS-cog Observed cases all data. Treatment-placebo difference at 18 months = 3.1, p < 0.008; (B) ADAS-cog, on treatment observed cases. Treatment-placebo difference at 18 months = 2.7, p = 0.03.
This manuscript describes analyses of the effect of TTP488 5 mg/day, versus placebo, on the Alzheimer's Disease Assessment Scale-Cognitive (ADAS-cog) after 18 months of treatment, in patients on stable background therapy with acetylcholinesterase inhibitors and/or memantine, based on an "on-treatment" definition of the study population. Additionally, analysis of the ADAS-cog, Clinical Dementia Rating Sum of Boxes (CDR-sb) and the Alzheimer's Disease Cooperative Study – Activities of Daily Living scale (ADCS-ADL) for mild sub-population and characterization of the pharmacokinetic/pharmacodynamic relationship of TTP488 to ADAS-cog are described.
Background
Alzheimer's Disease (AD) is a neurodegenerative disorder with aspects of inflammatory, metabolic and vascular pathology. An overproduction of amyloid beta (Aβ) has been implicated as the leading mechanistic factor in AD pathology. Aβ is known to bind to The Receptor for Advanced Glycation Endproducts (RAGE) an immunoglobulin supergene family member expressed on multiple cell types in the brain and the periphery. RAGE is found on the cells of the neurovascular compartment: endothelial cells and microglia prominently express RAGE whose expression is upregulated in AD. RAGE ligands include Aβ, S100b, HMGB1 and Advanced Glycation Endproducts. RAGE-ligand interactions lead to sustained inflammatory states that play a role in chronic diseases such as diabetes, inflammation, and AD. In AD, RAGE has been proposed to contribute to AD pathology by: promoting vascular leakage, promoting influx of peripheral Aβ into brain; mediating Aβ-induced oxidative stress and Aβ mediated neuronal death.
The pleiotropic role of RAGE has been demonstrated in AD pathology has been described using rodent models. Mice expressing the human APP transgene in neurons develop significant biochemical and behavioral changes reminiscent of human AD. Double transgenic mouse overexpressing WT RAGE in the APP transgene background exhibit accelerated behavioral changes whereas double transgenic animals expressing a dominant negative mutant of RAGE are protected. This data suggests that RAGE plays a role in augmenting the chronic inflammatory state caused by overproduction of Aβ.
RAGE is thought to be involved in the transport of Aβ from peripheral to CNS compartments. In vivo, Aβ uptake into brain is dependent on RAGE as shown in RAGE null mice. Similarly, Aβ uptake in brain can be inhibited using either the secreted, soluble form of RAGE (called sRAGE) or an anti-RAGE antibody. In addition, plaque formation in a mouse model of cerebral amyloidosis was inhibited using sRAGE. These data suggest that RAGE is intimately involved in the pathogenesis of AD, and that sustained Aβ interaction with RAGE on blood brain barrier (BBB) and/or neuronal cells is an important element of amyloid plaque formation and chronic neuronal dysfunction.
TransTech Pharma, Inc. discovered TTP488, an orally active, centrally acting antagonist of RAGE-RAGE ligand interaction. Chronic oral dosing of TTP488 in AD transgenic mice led to a reduction of amyloid load in the brain, improved performance on behavioral testing and normalization of electrophysiological recordings from hippocampal slices.
The results of a phase 2 study examining the safety, tolerability and efficacy of TTP488 in mild to moderate AD have been reported elsewhere. Briefly, 399 patients were randomly assigned to one of two dose levels of TTP488 (60 mg loading dose for 6 days followed by 20 mg/day; 15 mg loading dose for 6 days followed by 5 mg/day) or placebo administered orally for 18 months. The pre-specified primary analysis, using a modified intent-to-treat population, was on the Alzheimer's Disease Assessment Scale-Cognitive (ADAS-cog11). Based on a pre-specified interim analysis when 50% of subjects had completed the 6 month visit, the 20 mg/day dose was discontinued due to an increased incidence of confusion, falls and greater ADAS-cog decline than placebo. No safety concerns were noted for the 5 mg/day group. Approximately 12 months after all subjects were randomized a second pre-specified interim analysis on 18-month completers compared the 5 mg/day dose and placebo groups for futility and safety. While safety data raised no concerns, the criterion for futility (less than 10% conditional power to observe a significant difference between low dose and placebo at 18 months) was met and treatment was discontinued. Final analysis showed a decreased decline on the ADAS-cog in the 5 mg/day group at month 18 (treatment-placebo difference = 3.1, p = 0.008, ANCOVA with multiple imputation) (Figure 1, panel A). The difference remained significant using other planned statistical models that cope with missing data differently (ANCOVA on observed cases (p = 0.02), ANCOVA with LOCF (p = 0.03), mixed-models repeated measures (p = 0.04), and GEE (p = 0.03)). The authors concluded that this post-futility analysis suggested benefit for 5 mg/day; however, definitive conclusions about the effects could not be made due to operational issues (dropouts and discontinuations from treatment) subsequent to the interim analysis.
(Enlarge Image)
Figure 1.
Estimated mean change from baseline over time on Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-cog 11). Increasing values represent worsening. Error bars represent one standard error. (A) ADAS-cog Observed cases all data. Treatment-placebo difference at 18 months = 3.1, p < 0.008; (B) ADAS-cog, on treatment observed cases. Treatment-placebo difference at 18 months = 2.7, p = 0.03.
This manuscript describes analyses of the effect of TTP488 5 mg/day, versus placebo, on the Alzheimer's Disease Assessment Scale-Cognitive (ADAS-cog) after 18 months of treatment, in patients on stable background therapy with acetylcholinesterase inhibitors and/or memantine, based on an "on-treatment" definition of the study population. Additionally, analysis of the ADAS-cog, Clinical Dementia Rating Sum of Boxes (CDR-sb) and the Alzheimer's Disease Cooperative Study – Activities of Daily Living scale (ADCS-ADL) for mild sub-population and characterization of the pharmacokinetic/pharmacodynamic relationship of TTP488 to ADAS-cog are described.
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