- Email: [email protected]
Development of a disease-modifying treatment for Alzheimer’s disease: Alzhemed
Alzheimer’s & Dementia 2 (2006) 153–154
Perspectives
Development of a disease-modifying treatment for Alzheimer’s disease: Alzhemed Paul S. Aisen* Departments of Neurology and Memory Disorders Program, Georgetown University Medical Center, Washington, DC, USA
Alzheimer’s disease (AD) treatments currently available in the United States are neurotransmitter-based interventions, targeting cholinergic or glutamatergic synaptic activity. They are generally assumed to provide symptomatic benefits without altering the underlying pathophysiology of the disease. Recently, there have been growing efforts to develop treatments directed not at neurotransmitter systems, but rather at the amyloid and tau cascades that are believed to represent the key pathophysiology of AD. Several such interventions are now in Phase II and III clinical testing [1]. Because, in general, such interventions do not provide short-term symptomatic benefits, trial design must be based on demonstration of a slowed rate of cognitive and clinical decline; this has significant implications for the number of subjects, duration of treatment, and selection of outcome measures. For example, a trial duration of 12 to 26 weeks, generally sufficient to demonstrate the impact of a cholinesterase inhibitor or N-methyl-D-aspartate (NMDA) antagonist that improves cognition, is not likely to be sufficient to demonstrate a reduced rate of cognitive decline as a result of an anti-amyloid intervention. Thus, most trials of anti-amyloid and anti-tau agents last at least 12 months and often 18 to 24 months. Demonstration of clinical efficacy in a Phase II study of limited duration may not be feasible; use of surrogate markers of efficacy in Phase II studies may be necessary. If treatment with a putative disease-modifying agent shows a beneficial effect on cognition and function or global clinical status in a long term trial, can the sponsor claim that the treatment modifies the course of AD? Prior guidance from the US Food and Drug Administration (FDA) has indicated that trials should be designed to show an impact on the disease process; that is, a second randomization should be used to show that placebo-treated subjects later given active treatment do not “catch up” to those *Corresponding author. Tel.: 202-784-6671; Fax: 202-784-4332. E-mail address: [email protected]
initially selected randomly to receive active drug (“randomized start”), or that subjects for whom active treatment is withdrawn retain an advantage over those initially selected randomly to receive placebo (“randomized withdrawal”) [2]. It is unclear how long subjects would need to undergo follow-up after the second randomization. But the duration of such double randomization trials would be necessarily very long, increasing the impact of informative drop-outs. Indeed, a traditional single randomization parallel group study of long duration may provide a clearer indication of disease modification if the results indicate no short-term efficacy (that is, no symptomatic benefit) but favorable impact on cognitive and clinical measures that increases with time (change of slope of decline, presumably indicating disease modification). Biomarkers of pharmacodynamic activity may provide evidence of potentially disease-modifying activity. Thus, anti-amyloid agents that alter diffusible amyloid peptide levels in cerebrospinal fluid (or perhaps plasma), or influence brain amyloid load as indicated by neuroimaging, are plausible disease-modifying agents. A neuroprotective or anti-tau phosphorylation agent may influence cerebrospinal fluid (CSF) tau or brain atrophy rate. Coupling such biomarker evidence with statistical evidence consistent with slowed rate of decline may provide a compelling case for a disease-modifying effect. Alzhemed is an anti-amyloid agent under development as a potentially disease-modifying treatment for AD. The compound was identified as a glycosaminoglycan-mimetic, to interfere with the fibrillization of amyloid peptide that is stimulated by exposure to proteoglycans. Its anti-aggregation activity has been documented in vitro, and in vivo using transgenic mice [3]. The Alzhemed development program is instructive. As expected (based on its mechanism of action), Alzhemed has no short-term effect on cognition [4]. Thus, relatively short, Phase II studies cannot show clinical efficacy. Rather, a
1552-5260/06/$ – see front matter © 2006 The Alzheimer’s Association. All rights reserved. doi:10.1016/j.jalz.2006.03.009
154
P.S. Aisen / Alzheimer’s & Dementia 2 (2006) 153–154
large, long-term treatment trial is necessary to show that the anti-amyloid effect of the drug slows cognitive and clinical progression of AD. What then, beyond safety experience, can be accomplished in a Phase II study? A relatively small Phase II study can provide evidence of the desired pharmacodynamic effect evaluating the impact of treatment on a biomarker of amyloid accumulation. Candidate biomarkers of brain amyloid accumulation include imaging modalities such as positron emission tomography with the Pittsburgh Compound-B [5], as well as biochemical measures of amyloid in the blood or cerebrospinal fluid [6]. Each candidate has drawbacks; none has been adequately validated in therapeutic clinical trials. For the Alzhemed Phase II trial, CSF measurement of A peptide was selected as the biomarker. A number of studies in various animal species have found that CSF A levels reflect diffusible A in brain [7–9]. Short-term treatment with an agent that promotes amyloid clearance might be expected to reduce diffusible brain A and thus CSF A. There is concern that the load of amyloid plaques in brain represents a confounding factor (CSF A42 is lower in AD than in age-matched normal controls, presumably because the peptide adheres to the plaques in the AD brain), but over a 12-week period, a significant change in plaque load would not be expected, so change in CSF A should reflect change in diffusible brain A. The Phase II Alzhemed study was a small 4-group randomized controlled clinical trial, comparing treatment with placebo with 3 doses of the drug (given orally twice daily) for 12 weeks [4]. Standard cognitive, behavioral, clinical, and safety data were collected, and subjects had lumbar punctures for CSF collection before and after the treatment period. As expected, treatment had no effect on cognitive or clinical measures; because there was no decline in the placebo group over this brief period, no slowing of decline could be detected. The safety and tolerability profile was favorable. Most interestingly, the CSF studies found a doserelated reduction in A42 [4]. This evidence of the desired pharmacodynamic effect was considered sufficient to justify launch of pivotal Phase III studies, which are now in progress. The Phase III studies were designed to show efficacy on standard measures, and safety and to provide evidence for disease modification. Two types of biomarkers were included for subsets of study participants. Some subjects have magnetic resonance imaging scans to determine rate of hippocampal and brain atrophy. Another subset undergoes 2 lumbar punctures to determine change in CSF A42 and tau with treatment. If the active treatment shows efficacy on standard measures (cognition, by the ADAScog, and clinical status, by the CDR-SB), reduced atrophy rate or favor-
able impact on CSF markers will provide evidence that the benefit is indicative of disease modification. It can also be argued that the absence of cognitive and clinical benefit in 12 weeks (as shown in the Phase II study) and perhaps 6 months, in conjunction with increasing evidence of efficacy at 12 and 18 months, would be strong evidence of a diseasemodifying effect. It is difficult to envision a symptomatic (eg, neurotransmitter-based) effect that would produce this result. The most important measures in the Phase III Alzhemed trials (and indeed in all disease modification AD trials) are the standard outcome measures. Without demonstration of benefit on the coprimary cognitive and clinical measures, the biomarker data are not useful. But, as shown in the Alzhemed development program, biomarker data in Phase II can provide an early indication of the anticipated pharmacodynamic activity and in Phase III can provide supportive evidence of disease modification. References [1] Aisen PS. The development of anti-amyloid therapy for Alzheimer’s disease: from secretase modulators to polymerisation inhibitors. CNS Drugs 2005;19:989 –96. [2] Leber P. Slowing the progression of Alzheimer disease: Methodologic issues. Alzheimer Dis Assoc Disord 1997;11(Suppl 5):S10 – S20. [3] Gervais F, Chalifour R, Garceau D, Kong X, Laurin J, et al. 2001. Glycosaminoglycan mimetics: A therapeutic approach to cerebral amyloid angiopathy. Amyloid 2001; (8 Suppl 1): 28 –35. [4] Aisen PS, Mehran M, Poole R, Lavoie I, Gervais F, et al. Clinical data on Alzhemed after 12 months of treatment in patients with mild to moderate Alzheimer’s disease. Neurobiol Aging 2004;25:20. [5] Klunk WE, Lopresti BJ, Ikonomovic MD, Lefterov IM, Koldamova RP, et al. Binding of the positron emission tomography tracer Pittsburgh compound-B reflects the amount of amyloid-beta in Alzheimer’s disease brain but not in transgenic mouse brain. J Neurosci 2005;25:10598 – 606 [6] Thal LJ, Kantarci K, Reiman EM, Klunk WE, Weiner MW, et al. The role of biomarkers in clinical trials for Alzheimer disease. Alzheimer Dis Assoc Disord 2006;20:6 –15. [7] Barten DM, Guss VL, Corsa JA, Loo AT, Hansel SB, et al. Dynamics of {beta}-amyloid reductions in brain, cerebrospinal fluid and plasma of {beta}-amyloid precursor protein transgenic mice treated with a {gamma}-secretase inhibitor. J Pharmacol Exp Ther 2004;312:635– 43. [8] Best JD, Jay MT, Otu F, Churcher I, Reilly M, et al. In vivo characterisation of A{beta}(40) changes in brain and CSF using the novel {gamma}-secretase inhibitor MRK-560 (N-[cis-4-[(4-chlorophenyl)sulfonyl]-4- (2,5-difluorophenyl)cyclohexyl]-1,1,1- trifluoromethanesulfonamide) in the rat. J Pharmacol Exp Ther 2006;317: 786 –90. [9] Lemere CA, Beierschmitt A, Iglesias M, Spooner ET, Bloom JK, et al. 2004. Alzheimer’s disease abeta vaccine reduces central nervous system abeta levels in a non-human primate, the Caribbean vervet. Am J Pathol 2004;165:283–97.
Perspectives
Development of a disease-modifying treatment for Alzheimer’s disease: Alzhemed Paul S. Aisen* Departments of Neurology and Memory Disorders Program, Georgetown University Medical Center, Washington, DC, USA
Alzheimer’s disease (AD) treatments currently available in the United States are neurotransmitter-based interventions, targeting cholinergic or glutamatergic synaptic activity. They are generally assumed to provide symptomatic benefits without altering the underlying pathophysiology of the disease. Recently, there have been growing efforts to develop treatments directed not at neurotransmitter systems, but rather at the amyloid and tau cascades that are believed to represent the key pathophysiology of AD. Several such interventions are now in Phase II and III clinical testing [1]. Because, in general, such interventions do not provide short-term symptomatic benefits, trial design must be based on demonstration of a slowed rate of cognitive and clinical decline; this has significant implications for the number of subjects, duration of treatment, and selection of outcome measures. For example, a trial duration of 12 to 26 weeks, generally sufficient to demonstrate the impact of a cholinesterase inhibitor or N-methyl-D-aspartate (NMDA) antagonist that improves cognition, is not likely to be sufficient to demonstrate a reduced rate of cognitive decline as a result of an anti-amyloid intervention. Thus, most trials of anti-amyloid and anti-tau agents last at least 12 months and often 18 to 24 months. Demonstration of clinical efficacy in a Phase II study of limited duration may not be feasible; use of surrogate markers of efficacy in Phase II studies may be necessary. If treatment with a putative disease-modifying agent shows a beneficial effect on cognition and function or global clinical status in a long term trial, can the sponsor claim that the treatment modifies the course of AD? Prior guidance from the US Food and Drug Administration (FDA) has indicated that trials should be designed to show an impact on the disease process; that is, a second randomization should be used to show that placebo-treated subjects later given active treatment do not “catch up” to those *Corresponding author. Tel.: 202-784-6671; Fax: 202-784-4332. E-mail address: [email protected]
initially selected randomly to receive active drug (“randomized start”), or that subjects for whom active treatment is withdrawn retain an advantage over those initially selected randomly to receive placebo (“randomized withdrawal”) [2]. It is unclear how long subjects would need to undergo follow-up after the second randomization. But the duration of such double randomization trials would be necessarily very long, increasing the impact of informative drop-outs. Indeed, a traditional single randomization parallel group study of long duration may provide a clearer indication of disease modification if the results indicate no short-term efficacy (that is, no symptomatic benefit) but favorable impact on cognitive and clinical measures that increases with time (change of slope of decline, presumably indicating disease modification). Biomarkers of pharmacodynamic activity may provide evidence of potentially disease-modifying activity. Thus, anti-amyloid agents that alter diffusible amyloid peptide levels in cerebrospinal fluid (or perhaps plasma), or influence brain amyloid load as indicated by neuroimaging, are plausible disease-modifying agents. A neuroprotective or anti-tau phosphorylation agent may influence cerebrospinal fluid (CSF) tau or brain atrophy rate. Coupling such biomarker evidence with statistical evidence consistent with slowed rate of decline may provide a compelling case for a disease-modifying effect. Alzhemed is an anti-amyloid agent under development as a potentially disease-modifying treatment for AD. The compound was identified as a glycosaminoglycan-mimetic, to interfere with the fibrillization of amyloid peptide that is stimulated by exposure to proteoglycans. Its anti-aggregation activity has been documented in vitro, and in vivo using transgenic mice [3]. The Alzhemed development program is instructive. As expected (based on its mechanism of action), Alzhemed has no short-term effect on cognition [4]. Thus, relatively short, Phase II studies cannot show clinical efficacy. Rather, a
1552-5260/06/$ – see front matter © 2006 The Alzheimer’s Association. All rights reserved. doi:10.1016/j.jalz.2006.03.009
154
P.S. Aisen / Alzheimer’s & Dementia 2 (2006) 153–154
large, long-term treatment trial is necessary to show that the anti-amyloid effect of the drug slows cognitive and clinical progression of AD. What then, beyond safety experience, can be accomplished in a Phase II study? A relatively small Phase II study can provide evidence of the desired pharmacodynamic effect evaluating the impact of treatment on a biomarker of amyloid accumulation. Candidate biomarkers of brain amyloid accumulation include imaging modalities such as positron emission tomography with the Pittsburgh Compound-B [5], as well as biochemical measures of amyloid in the blood or cerebrospinal fluid [6]. Each candidate has drawbacks; none has been adequately validated in therapeutic clinical trials. For the Alzhemed Phase II trial, CSF measurement of A peptide was selected as the biomarker. A number of studies in various animal species have found that CSF A levels reflect diffusible A in brain [7–9]. Short-term treatment with an agent that promotes amyloid clearance might be expected to reduce diffusible brain A and thus CSF A. There is concern that the load of amyloid plaques in brain represents a confounding factor (CSF A42 is lower in AD than in age-matched normal controls, presumably because the peptide adheres to the plaques in the AD brain), but over a 12-week period, a significant change in plaque load would not be expected, so change in CSF A should reflect change in diffusible brain A. The Phase II Alzhemed study was a small 4-group randomized controlled clinical trial, comparing treatment with placebo with 3 doses of the drug (given orally twice daily) for 12 weeks [4]. Standard cognitive, behavioral, clinical, and safety data were collected, and subjects had lumbar punctures for CSF collection before and after the treatment period. As expected, treatment had no effect on cognitive or clinical measures; because there was no decline in the placebo group over this brief period, no slowing of decline could be detected. The safety and tolerability profile was favorable. Most interestingly, the CSF studies found a doserelated reduction in A42 [4]. This evidence of the desired pharmacodynamic effect was considered sufficient to justify launch of pivotal Phase III studies, which are now in progress. The Phase III studies were designed to show efficacy on standard measures, and safety and to provide evidence for disease modification. Two types of biomarkers were included for subsets of study participants. Some subjects have magnetic resonance imaging scans to determine rate of hippocampal and brain atrophy. Another subset undergoes 2 lumbar punctures to determine change in CSF A42 and tau with treatment. If the active treatment shows efficacy on standard measures (cognition, by the ADAScog, and clinical status, by the CDR-SB), reduced atrophy rate or favor-
able impact on CSF markers will provide evidence that the benefit is indicative of disease modification. It can also be argued that the absence of cognitive and clinical benefit in 12 weeks (as shown in the Phase II study) and perhaps 6 months, in conjunction with increasing evidence of efficacy at 12 and 18 months, would be strong evidence of a diseasemodifying effect. It is difficult to envision a symptomatic (eg, neurotransmitter-based) effect that would produce this result. The most important measures in the Phase III Alzhemed trials (and indeed in all disease modification AD trials) are the standard outcome measures. Without demonstration of benefit on the coprimary cognitive and clinical measures, the biomarker data are not useful. But, as shown in the Alzhemed development program, biomarker data in Phase II can provide an early indication of the anticipated pharmacodynamic activity and in Phase III can provide supportive evidence of disease modification. References [1] Aisen PS. The development of anti-amyloid therapy for Alzheimer’s disease: from secretase modulators to polymerisation inhibitors. CNS Drugs 2005;19:989 –96. [2] Leber P. Slowing the progression of Alzheimer disease: Methodologic issues. Alzheimer Dis Assoc Disord 1997;11(Suppl 5):S10 – S20. [3] Gervais F, Chalifour R, Garceau D, Kong X, Laurin J, et al. 2001. Glycosaminoglycan mimetics: A therapeutic approach to cerebral amyloid angiopathy. Amyloid 2001; (8 Suppl 1): 28 –35. [4] Aisen PS, Mehran M, Poole R, Lavoie I, Gervais F, et al. Clinical data on Alzhemed after 12 months of treatment in patients with mild to moderate Alzheimer’s disease. Neurobiol Aging 2004;25:20. [5] Klunk WE, Lopresti BJ, Ikonomovic MD, Lefterov IM, Koldamova RP, et al. Binding of the positron emission tomography tracer Pittsburgh compound-B reflects the amount of amyloid-beta in Alzheimer’s disease brain but not in transgenic mouse brain. J Neurosci 2005;25:10598 – 606 [6] Thal LJ, Kantarci K, Reiman EM, Klunk WE, Weiner MW, et al. The role of biomarkers in clinical trials for Alzheimer disease. Alzheimer Dis Assoc Disord 2006;20:6 –15. [7] Barten DM, Guss VL, Corsa JA, Loo AT, Hansel SB, et al. Dynamics of {beta}-amyloid reductions in brain, cerebrospinal fluid and plasma of {beta}-amyloid precursor protein transgenic mice treated with a {gamma}-secretase inhibitor. J Pharmacol Exp Ther 2004;312:635– 43. [8] Best JD, Jay MT, Otu F, Churcher I, Reilly M, et al. In vivo characterisation of A{beta}(40) changes in brain and CSF using the novel {gamma}-secretase inhibitor MRK-560 (N-[cis-4-[(4-chlorophenyl)sulfonyl]-4- (2,5-difluorophenyl)cyclohexyl]-1,1,1- trifluoromethanesulfonamide) in the rat. J Pharmacol Exp Ther 2006;317: 786 –90. [9] Lemere CA, Beierschmitt A, Iglesias M, Spooner ET, Bloom JK, et al. 2004. Alzheimer’s disease abeta vaccine reduces central nervous system abeta levels in a non-human primate, the Caribbean vervet. Am J Pathol 2004;165:283–97.