Comment
When should neuroprotective drugs move from mice to men? About one in 100 000 people older than 60 years have progressive supranuclear palsy (PSP), a degenerative disease of the brain affecting nuclei that control eye movements and parts of the basal ganglia, brainstem, cortex cerebellum, and spinal cord.1 Individuals with PSP develop problems with eye movements, gait, and balance, and eventually develop a dementia syndrome, usually complicated by psychological symptoms. The cause is unknown. A pathological characteristic is the accumulation of abnormally phosphorylated tau protein in the form of intraneuronal neurofibrillary tangles. A variant in the gene for the tau protein, the H1 haplotype, has been linked to PSP2 and seems to be necessary but not sufficient to cause the illness. There is no effective treatment: current efforts have focused on symptom mitigation with antiparkinsonian medications, botulinum injections, walking aids, adaptive eye lenses, and assistance with swallowing disturbances. PSP and other dementias have a devastating effect on patients and their families. Over the past 20 years, several clinical trials have been done to try to prevent the underlying pathobiology of various diseases that cause dementia, particularly Alzheimer’s disease. Because a clinical diagnosis of PSP is likely to be associated with pathological PSP or related tau pathologies, there is much interest in testing experimental treatments directed toward aberrant tau biology. However, there is a dearth of adequately powered multicentre trials. Adam Boxer and colleagues3 have done a double-blind clinical trial of davunetide in 313 patients with PSP. Davunetide is an experimental agent that has shown neuroprotective effects in various cell models and has attenuated hyperphosphorylated tau deposition, resulting in improvement in behavioural measures in transgenic mice with one or more H1 tau gene mutations associated with the rarer forms of human autosomal dominant disease. The results of Boxer and colleagues’ trial3 showed no effects on the yearly rate of cognitive or functional decline, volumetric MRI measurements, or CSF biomarkers of neurodegeneration. This clinical trial is one of the largest done in patients with PSP, an uncommon and previously understudied group, and sets a precedent for future studies with the operational lessons learned, infrastructure development, outreach to patients, and accrual of substantial longitudinal clinical
and biomarker data that should be helpful for designing future trials. According to the investigators, the trial was designed in such a way that it could have contributed to approval for use, so one infers that regulatory agencies were supportive of the design and willing to review the data, another crucial and unprecedented advance in drug development for this disorder. Cautionary notes can be sounded for those of us planning and executing novel types of clinical trials for patients and for cognitively healthy people at high or even certain imminent risk of symptoms, such as the several trials that are underway in patients with preclinical Alzheimer’s disease.4–7 Trial participants, especially with uncommon diseases, are a precious resource. Under what circumstances should we take a potential therapy from the laboratory and test it in the clinic? Certainly, one compelling rationale would be the existence of basic and animal data for the disease pathways of relevance, which was the case in the study by Boxer and colleagues.3 However, as the investigators suggested, the absence of pharmacokinetic, pharmacodynamic, and target engagement data in this study, and in CNS disorders in general, raises the risk of trials with negative or null results. Partly because of the dearth of pharmacokinetic and pharmacodynamic data, clinical trials in patients with neurodegenerative diseases, including the study by Boxer and colleagues,3 increasingly embed fluid and imaging biomarkers in the hope that they will be informative—for instance, showing altered trajectory of brain atrophy or CSF measures of neurodegeneration. The true usefulness of such measures remains to be established, however. The findings with biomarkers will be of more value if they can be replicated in animal models and serve as a translatable signal, but caution is warranted in clinical trials at this juncture. There are ample precedents of expected or unexpected biomarker findings in clinical trials that bear no relation to clinical outcome. Systematic investigation will be necessary to establish the prognostic, predictive, or theragnostic usefulness of these biomarkers: clinical outcome remains the gold standard for now.8 As the dementia research community contemplates novel trials, we will hopefully share hitherto private ideas and information about how to improve decision making and design, to find ways to treat or even prevent dementias such as PSP as quickly as possible.
www.thelancet.com/neurology Published online May 27, 2014 http://dx.doi.org/10.1016/S1474-4422(14)70112-7
Lancet Neurol 2014 Published Online May 27, 2014 http://dx.doi.org/10.1016/ S1474-4422(14)70112-7 See Online/Articles http://dx.doi.org/10.1016/ S1474-4422(14)70088-2
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Comment
Precedents for precompetitive collaboration exist— eg, the Alzheimer’s Association Research Roundtable meetings9 and the newly formed Collaboration for Alzheimer’s Prevention.10 These communication mechanisms have, for instance, allowed experts to share ideas about when to move agents from the laboratory to the clinic, and which ones, as well as which clinical and biomarker outcomes to use, in the unprecedented dementia prevention research space: are all relevant to the challenges faced by the PSP research community.10
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Pierre N Tariot Banner Alzheimer’s Institute, 901 E Willetta Street, Phoenix, AZ 85006, USA [email protected] I report personal fees from Abbott Laboratories, AbbVie, AC Immune, Adamas, Boehringer-Ingelheim, California Pacific Medical Center, Chase Pharmaceuticals, Chiesi, Continuing Medical Education, Elan, Medavante, Merz, Otsuka, and Sanofi-Aventis; personal fees and site compensation for research activities from Avanir, Avid, Bristol Myers Squibb, Cognoptix, GlaxoSmithKline, Janssen, Eli Lilly, Medivation, Merck and Company, and Roche; and site compensation for research activities from AstraZeneca, Baxter Healthcare, Functional Neuromodulation, General Electric, Genentech, Pfizer, Targacept, Toyama, National Institute on Aging, and Arizona Department of Health Services, and stock options from Adamas unrelated to the submitted work. I also have a patent pending for Biomarkers of Alzheimer’s Disease.
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NINDS. Progressive supranuclear palsy fact sheet. http://www.ninds.nih. gov/disorders/psp/detail_psp.htm (accessed May 17, 2014). Hoglinger GU, Melhem NM, Dickson DW, et al. Identification of common variants influencing risk of the tauopathy progressive supranuclear palsy. Nat Genet 2011; 43: 699–705. Boxer AL, Lang AE, Grossman M, et al, on behalf of the AL-108-231 Investigators. Davunetide in patients with progressive supranuclear palsy: a randomised, double-blind, placebo-controlled trial. Lancet Neurol 2014; published online May 27. http://dx.doi.org/10.1016/S14744422(14)70088-2. Reiman EM, Langbaum JB, Fleisher AS. Alzheimer’s Prevention Initiative: a plan to accelerate the evaluation of presymptomatic treatments. J Alzheimers Dis 2011; 26 (suppl 3): 321–29. Sperling RA, Rentz DM, Johnson KA, et al. The A4 Study: stopping AD before symptoms begin? Sci Transl Med 2014; 6: 228fs13. Morris JC, Aisen PS, Bateman RJ, et al. Developing an international network for Alzheimer research: the Dominantly Inherited Alzheimer Network. Clin Investig (Lond) 2012; 2: 975–84. Crenshaw DG, Gottschalk WK, Lutz MW, et al. Using genetics to enable studies on the prevention of Alzheimer’s disease. Clin Pharmacol Ther 2013; 93: 177–85. Food and Drug Administration. Guidance for industry Alzheimer’s disease: developing drugs for the treatment of early stage disease. Draft guidance. Silver Spring, MD: US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), 2013. Alzforum. Research Roundtable. http://www.alz.org/research/funding/ alzheimers_research_roundtable.asp (accessed May 18, 2014). Alzforum. Collaborative Umbrella CAPs Three Prevention Trial Initiatives http://www.alzforum.org/news/conference-coverage/collaborativeumbrella-caps-three-prevention-trial-initiatives (accessed May 18, 2014).
www.thelancet.com/neurology Published online May 27, 2014 http://dx.doi.org/10.1016/S1474-4422(14)70112-7
When should neuroprotective drugs move from mice to men? About one in 100 000 people older than 60 years have progressive supranuclear palsy (PSP), a degenerative disease of the brain affecting nuclei that control eye movements and parts of the basal ganglia, brainstem, cortex cerebellum, and spinal cord.1 Individuals with PSP develop problems with eye movements, gait, and balance, and eventually develop a dementia syndrome, usually complicated by psychological symptoms. The cause is unknown. A pathological characteristic is the accumulation of abnormally phosphorylated tau protein in the form of intraneuronal neurofibrillary tangles. A variant in the gene for the tau protein, the H1 haplotype, has been linked to PSP2 and seems to be necessary but not sufficient to cause the illness. There is no effective treatment: current efforts have focused on symptom mitigation with antiparkinsonian medications, botulinum injections, walking aids, adaptive eye lenses, and assistance with swallowing disturbances. PSP and other dementias have a devastating effect on patients and their families. Over the past 20 years, several clinical trials have been done to try to prevent the underlying pathobiology of various diseases that cause dementia, particularly Alzheimer’s disease. Because a clinical diagnosis of PSP is likely to be associated with pathological PSP or related tau pathologies, there is much interest in testing experimental treatments directed toward aberrant tau biology. However, there is a dearth of adequately powered multicentre trials. Adam Boxer and colleagues3 have done a double-blind clinical trial of davunetide in 313 patients with PSP. Davunetide is an experimental agent that has shown neuroprotective effects in various cell models and has attenuated hyperphosphorylated tau deposition, resulting in improvement in behavioural measures in transgenic mice with one or more H1 tau gene mutations associated with the rarer forms of human autosomal dominant disease. The results of Boxer and colleagues’ trial3 showed no effects on the yearly rate of cognitive or functional decline, volumetric MRI measurements, or CSF biomarkers of neurodegeneration. This clinical trial is one of the largest done in patients with PSP, an uncommon and previously understudied group, and sets a precedent for future studies with the operational lessons learned, infrastructure development, outreach to patients, and accrual of substantial longitudinal clinical
and biomarker data that should be helpful for designing future trials. According to the investigators, the trial was designed in such a way that it could have contributed to approval for use, so one infers that regulatory agencies were supportive of the design and willing to review the data, another crucial and unprecedented advance in drug development for this disorder. Cautionary notes can be sounded for those of us planning and executing novel types of clinical trials for patients and for cognitively healthy people at high or even certain imminent risk of symptoms, such as the several trials that are underway in patients with preclinical Alzheimer’s disease.4–7 Trial participants, especially with uncommon diseases, are a precious resource. Under what circumstances should we take a potential therapy from the laboratory and test it in the clinic? Certainly, one compelling rationale would be the existence of basic and animal data for the disease pathways of relevance, which was the case in the study by Boxer and colleagues.3 However, as the investigators suggested, the absence of pharmacokinetic, pharmacodynamic, and target engagement data in this study, and in CNS disorders in general, raises the risk of trials with negative or null results. Partly because of the dearth of pharmacokinetic and pharmacodynamic data, clinical trials in patients with neurodegenerative diseases, including the study by Boxer and colleagues,3 increasingly embed fluid and imaging biomarkers in the hope that they will be informative—for instance, showing altered trajectory of brain atrophy or CSF measures of neurodegeneration. The true usefulness of such measures remains to be established, however. The findings with biomarkers will be of more value if they can be replicated in animal models and serve as a translatable signal, but caution is warranted in clinical trials at this juncture. There are ample precedents of expected or unexpected biomarker findings in clinical trials that bear no relation to clinical outcome. Systematic investigation will be necessary to establish the prognostic, predictive, or theragnostic usefulness of these biomarkers: clinical outcome remains the gold standard for now.8 As the dementia research community contemplates novel trials, we will hopefully share hitherto private ideas and information about how to improve decision making and design, to find ways to treat or even prevent dementias such as PSP as quickly as possible.
www.thelancet.com/neurology Published online May 27, 2014 http://dx.doi.org/10.1016/S1474-4422(14)70112-7
Lancet Neurol 2014 Published Online May 27, 2014 http://dx.doi.org/10.1016/ S1474-4422(14)70112-7 See Online/Articles http://dx.doi.org/10.1016/ S1474-4422(14)70088-2
1
Comment
Precedents for precompetitive collaboration exist— eg, the Alzheimer’s Association Research Roundtable meetings9 and the newly formed Collaboration for Alzheimer’s Prevention.10 These communication mechanisms have, for instance, allowed experts to share ideas about when to move agents from the laboratory to the clinic, and which ones, as well as which clinical and biomarker outcomes to use, in the unprecedented dementia prevention research space: are all relevant to the challenges faced by the PSP research community.10
1 2
3
4
5 6
Pierre N Tariot Banner Alzheimer’s Institute, 901 E Willetta Street, Phoenix, AZ 85006, USA [email protected] I report personal fees from Abbott Laboratories, AbbVie, AC Immune, Adamas, Boehringer-Ingelheim, California Pacific Medical Center, Chase Pharmaceuticals, Chiesi, Continuing Medical Education, Elan, Medavante, Merz, Otsuka, and Sanofi-Aventis; personal fees and site compensation for research activities from Avanir, Avid, Bristol Myers Squibb, Cognoptix, GlaxoSmithKline, Janssen, Eli Lilly, Medivation, Merck and Company, and Roche; and site compensation for research activities from AstraZeneca, Baxter Healthcare, Functional Neuromodulation, General Electric, Genentech, Pfizer, Targacept, Toyama, National Institute on Aging, and Arizona Department of Health Services, and stock options from Adamas unrelated to the submitted work. I also have a patent pending for Biomarkers of Alzheimer’s Disease.
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7
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9 10
NINDS. Progressive supranuclear palsy fact sheet. http://www.ninds.nih. gov/disorders/psp/detail_psp.htm (accessed May 17, 2014). Hoglinger GU, Melhem NM, Dickson DW, et al. Identification of common variants influencing risk of the tauopathy progressive supranuclear palsy. Nat Genet 2011; 43: 699–705. Boxer AL, Lang AE, Grossman M, et al, on behalf of the AL-108-231 Investigators. Davunetide in patients with progressive supranuclear palsy: a randomised, double-blind, placebo-controlled trial. Lancet Neurol 2014; published online May 27. http://dx.doi.org/10.1016/S14744422(14)70088-2. Reiman EM, Langbaum JB, Fleisher AS. Alzheimer’s Prevention Initiative: a plan to accelerate the evaluation of presymptomatic treatments. J Alzheimers Dis 2011; 26 (suppl 3): 321–29. Sperling RA, Rentz DM, Johnson KA, et al. The A4 Study: stopping AD before symptoms begin? Sci Transl Med 2014; 6: 228fs13. Morris JC, Aisen PS, Bateman RJ, et al. Developing an international network for Alzheimer research: the Dominantly Inherited Alzheimer Network. Clin Investig (Lond) 2012; 2: 975–84. Crenshaw DG, Gottschalk WK, Lutz MW, et al. Using genetics to enable studies on the prevention of Alzheimer’s disease. Clin Pharmacol Ther 2013; 93: 177–85. Food and Drug Administration. Guidance for industry Alzheimer’s disease: developing drugs for the treatment of early stage disease. Draft guidance. Silver Spring, MD: US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), 2013. Alzforum. Research Roundtable. http://www.alz.org/research/funding/ alzheimers_research_roundtable.asp (accessed May 18, 2014). Alzforum. Collaborative Umbrella CAPs Three Prevention Trial Initiatives http://www.alzforum.org/news/conference-coverage/collaborativeumbrella-caps-three-prevention-trial-initiatives (accessed May 18, 2014).
www.thelancet.com/neurology Published online May 27, 2014 http://dx.doi.org/10.1016/S1474-4422(14)70112-7
