- Email: [email protected]
Anti-tau vaccine in Alzheimer's disease: a tentative step
Comment
No disease-modifying treatment is available for Alzheimer’s disease, which is the most common form of dementia. In the past 20 years, most therapeutic approaches for Alzheimer’s disease were directed against the production and accumulation of amyloid β but, up to now, these approaches have not shown clinical efficacy.1 Amyloid pathology is not always present in the brain of people with clinically diagnosed Alzheimer’s disease, suggesting that dementia can arise as a consequence of tau pathology in the absence of amyloid β.2 Tau pathology in Alzheimer’s disease is principally characterised by abnormal phosphorylation of tau proteins,3 but also proteolytic cleavage (truncation), glycation, nitration, acetylation, O-GlcNAcylation, ubiquitination, and other abnormal post-translational modifications.4 Both hyperphosphorylated tau by itself and oligomeric tau are involved in synaptic loss. Proteolytically stable tau oligomers are able to propagate between neurons and initiate the cascade of self-propagating misfolded proteins from neuron to neuron.5 The pharmacological targeting of tau in Alzheimer’s disease includes several approaches: microtubule-stabilising drugs, tau protein kinase inhibitors, tau aggregation inhibitors, active and passive immunotherapies, and inhibitors of tau acetylation.4 Animal studies have shown that both active and passive approaches can remove tau pathology and, in some cases, improve cognitive function.4 Two active vaccines targeting either non-phosphorylated (AADVac1) or phosphorylated (ACI-35) tau are being assessed in phase 1 studies.4 AADvac1 is a synthetic 12-aminoacid peptide corresponding to the 294-305 sequence of tau (KDNIKHVPGGGS). AADvac1 has been designed to target N-terminally truncated tau151-391/4R, which is believed to dysregulate nuclear localisation of tau.6 The peptide is coupled to keyhole limpet haemocyanin, a carrier protein, at an N-terminal cysteine, and administered with an alum-immune adjuvant. In transgenic rats expressing human truncated tau, AADvac1 was shown to reduce tau pathology and associated behavioural deficits.7 In a randomised controlled trial reported in The Lancet Neurology, Novak and colleagues8 describe the results of the first-in-man study of AADvac1 in patients with Alzheimer’s disease. The primary goal in this phase 1, 12 week, double-blind, placebo-controlled
study was to assess the safety of the vaccine. The study involved 30 patients, 24 of whom were given monthly subcutaneous injections of AADvac1 (40 μg plus aluminium hydroxide) and the other six patients received placebo (aluminium hydroxide). Two patients from the AADvac1 group withdrew from the study because of the occurrence of serious adverse events, one of which (a viral infection followed by epileptic seizure) was possibly related to the treatment. The remaining 28 patients entered a 12 week, open-label, extension phase and received three subcutaneous injections of AADvac1 at 4 week intervals. 25 patients completing this 24 week study entered a further 18 month open-label extension (NCT02031198). Serum samples from 25 of the 28 patients given AADvac1 recognised recombinant truncated tau 151-391/4R and other forms of tau proteins, from monomeric to oligomeric forms, including the A68 tau triplet, a marker for the neurofibrillary tangles seen in Alzheimer’s disease. The serum antibodies recognised tau 151-391/4R with about six times higher affinity than the naturally occurring 2N4R tau isoform. However, because only one dose of the vaccine (40 μg) was used in the trial, they also did not assess if the immune response against pathological tau is dose-dependent. More importantly, because only a few individuals provided CSF samples, the study does not clarify if CSF concentrations of tau or other Alzheimer’s disease-related biomarkers were modified by the vaccine. These limitations might partly undermine the interpretation of the results in terms of safety and, particularly, that of a possible biological effect of the vaccine on tau pathology in the brain. Furthermore, MRI brain volumetric data at 12 weeks suggested atrophy, with different rates of progression in the total cortex and ventricle volumes possibly suggesting a higher total brain atrophy rate in the AADvac1-treated patients than in patients receiving placebo. Although this observation could be attributed to the small number of patients in this phase 1, it should be carefully considered in further studies in view of the short duration of the treatment. Cognitive results are unremarkable because of the short duration of the placebo-controlled part of the study (12 weeks) and because of the few patients (six patients started on placebo vs 24 started on AADvac1). A phase 2, 24 month, double-blind, placebo-controlled study of AADvac1 is
www.thelancet.com/neurology Published online December 9, 2016 http://dx.doi.org/10.1016/S1474-4422(16)30340-4
Burger/Phanie/Science Photo Library
Anti-tau vaccine in Alzheimer’s disease: a tentative step
Lancet Neurol 2016 Published Online Month date, 2015 http://dx.doi.org/10.1016/ S1474-4422(16)30340-4 See Online/Articles http://dx.doi.org/10.1016/ S1474-4422(16)30331-3
1
Comment
recruiting patients with mild Alzheimer’s disease, with a target number of 185 patients and February, 2019, as an estimated study completion date (NCT02579252, ADAMANT). The primary outcome will be safety; secondary outcomes will include cognitive and clinical batteries and a measure of immunogenicity. ¹⁸F-fluorodeoxyglucose PET, MRI volumetry, and CSF biochemistry will be exploratory outcomes. This study will hopefully clarify the safety of this anti-tau vaccine after a treatment longer than 24 weeks and possibly show the vaccine’s ability to engage the biological target in the CNS.
We declare no competing interests. 1
2
3
4
5 6
7
*Francesco Panza, Giancarlo Logroscino Neurodegenerative Disease Unit, Department of Basic Medicine, Neuroscience, and Sense Organs, University of Bari Aldo Moro, Bari 70100, Italy (FP, GL); Department of Clinical Research in Neurology, University of Bari Aldo Moro, Pia Fondazione Cardinale G Panico, Tricase, Lecce, Italy (FP, GL); and Geriatric Unit & Laboratory of Gerontology and Geriatrics, Department of Medical Sciences, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia, Italy (FP) [email protected]
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8
Panza F, Seripa D, Solfrizzi V, et al. Emerging drugs to reduce abnormal β-amyloid protein in Alzheimer’s disease patients. Expert Opin Emerg Drugs 2016; published online Oct 6. DOI:10.1080/14728214.2016.1241232. Ahmed RM, Paterson RW, Warren JD, et al. Biomarkers in dementia: clinical utility and new directions. J Neurol Neurosurg Psychiatry 2014; 85: 1426–34. Grundke-Iqbal I, Iqbal K, Tung YC, et al. Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology. Proc Natl Acad Sci USA 1986; 83: 4913–17. Panza F, Solfrizzi V, Seripa D, et al. Tau-based therapeutics for Alzheimer’s disease: active and passive immunotherapy. Immunotherapy 2016; 8: 1119–34. Clavaguera F, Bolmont T, Crowther RA, et al. Transmission and spreading of tauopathy in transgenic mouse brain. Nat Cell Biol 2009; 11: 909–13. Paholikova K, Salingova B, Opattova A, et al. N-terminal truncation of microtubule associated protein tau dysregulates its cellular localization. J Alzheimers Dis 2015; 43: 915–26. Kontsekova E, Zilka N, Kovacech B, et al. First-in-man tau vaccine targeting structural determinants essential for pathological tau-tau interaction reduces tau oligomerisation and neurofibrillary degeneration in an Alzheimer’s disease model. Alzheimers Res Ther 2014; 6: 44. Novak P, Schmidt R, Kontsekova E, et al. The first-in-man tau vaccine for the treatment of Alzheimer’s disease “AADvac1” displays a favourable safety and tolerability profile and high immunogenicity: a randomised double-blind placebo-controlled Phase I study. Lancet Neurol 2016; published online Dec 9. http://dx.doi.org/10.1016/S14744422(16)30331-3.
www.thelancet.com/neurology Published online December 9, 2016 http://dx.doi.org/10.1016/S1474-4422(16)30340-4
No disease-modifying treatment is available for Alzheimer’s disease, which is the most common form of dementia. In the past 20 years, most therapeutic approaches for Alzheimer’s disease were directed against the production and accumulation of amyloid β but, up to now, these approaches have not shown clinical efficacy.1 Amyloid pathology is not always present in the brain of people with clinically diagnosed Alzheimer’s disease, suggesting that dementia can arise as a consequence of tau pathology in the absence of amyloid β.2 Tau pathology in Alzheimer’s disease is principally characterised by abnormal phosphorylation of tau proteins,3 but also proteolytic cleavage (truncation), glycation, nitration, acetylation, O-GlcNAcylation, ubiquitination, and other abnormal post-translational modifications.4 Both hyperphosphorylated tau by itself and oligomeric tau are involved in synaptic loss. Proteolytically stable tau oligomers are able to propagate between neurons and initiate the cascade of self-propagating misfolded proteins from neuron to neuron.5 The pharmacological targeting of tau in Alzheimer’s disease includes several approaches: microtubule-stabilising drugs, tau protein kinase inhibitors, tau aggregation inhibitors, active and passive immunotherapies, and inhibitors of tau acetylation.4 Animal studies have shown that both active and passive approaches can remove tau pathology and, in some cases, improve cognitive function.4 Two active vaccines targeting either non-phosphorylated (AADVac1) or phosphorylated (ACI-35) tau are being assessed in phase 1 studies.4 AADvac1 is a synthetic 12-aminoacid peptide corresponding to the 294-305 sequence of tau (KDNIKHVPGGGS). AADvac1 has been designed to target N-terminally truncated tau151-391/4R, which is believed to dysregulate nuclear localisation of tau.6 The peptide is coupled to keyhole limpet haemocyanin, a carrier protein, at an N-terminal cysteine, and administered with an alum-immune adjuvant. In transgenic rats expressing human truncated tau, AADvac1 was shown to reduce tau pathology and associated behavioural deficits.7 In a randomised controlled trial reported in The Lancet Neurology, Novak and colleagues8 describe the results of the first-in-man study of AADvac1 in patients with Alzheimer’s disease. The primary goal in this phase 1, 12 week, double-blind, placebo-controlled
study was to assess the safety of the vaccine. The study involved 30 patients, 24 of whom were given monthly subcutaneous injections of AADvac1 (40 μg plus aluminium hydroxide) and the other six patients received placebo (aluminium hydroxide). Two patients from the AADvac1 group withdrew from the study because of the occurrence of serious adverse events, one of which (a viral infection followed by epileptic seizure) was possibly related to the treatment. The remaining 28 patients entered a 12 week, open-label, extension phase and received three subcutaneous injections of AADvac1 at 4 week intervals. 25 patients completing this 24 week study entered a further 18 month open-label extension (NCT02031198). Serum samples from 25 of the 28 patients given AADvac1 recognised recombinant truncated tau 151-391/4R and other forms of tau proteins, from monomeric to oligomeric forms, including the A68 tau triplet, a marker for the neurofibrillary tangles seen in Alzheimer’s disease. The serum antibodies recognised tau 151-391/4R with about six times higher affinity than the naturally occurring 2N4R tau isoform. However, because only one dose of the vaccine (40 μg) was used in the trial, they also did not assess if the immune response against pathological tau is dose-dependent. More importantly, because only a few individuals provided CSF samples, the study does not clarify if CSF concentrations of tau or other Alzheimer’s disease-related biomarkers were modified by the vaccine. These limitations might partly undermine the interpretation of the results in terms of safety and, particularly, that of a possible biological effect of the vaccine on tau pathology in the brain. Furthermore, MRI brain volumetric data at 12 weeks suggested atrophy, with different rates of progression in the total cortex and ventricle volumes possibly suggesting a higher total brain atrophy rate in the AADvac1-treated patients than in patients receiving placebo. Although this observation could be attributed to the small number of patients in this phase 1, it should be carefully considered in further studies in view of the short duration of the treatment. Cognitive results are unremarkable because of the short duration of the placebo-controlled part of the study (12 weeks) and because of the few patients (six patients started on placebo vs 24 started on AADvac1). A phase 2, 24 month, double-blind, placebo-controlled study of AADvac1 is
www.thelancet.com/neurology Published online December 9, 2016 http://dx.doi.org/10.1016/S1474-4422(16)30340-4
Burger/Phanie/Science Photo Library
Anti-tau vaccine in Alzheimer’s disease: a tentative step
Lancet Neurol 2016 Published Online Month date, 2015 http://dx.doi.org/10.1016/ S1474-4422(16)30340-4 See Online/Articles http://dx.doi.org/10.1016/ S1474-4422(16)30331-3
1
Comment
recruiting patients with mild Alzheimer’s disease, with a target number of 185 patients and February, 2019, as an estimated study completion date (NCT02579252, ADAMANT). The primary outcome will be safety; secondary outcomes will include cognitive and clinical batteries and a measure of immunogenicity. ¹⁸F-fluorodeoxyglucose PET, MRI volumetry, and CSF biochemistry will be exploratory outcomes. This study will hopefully clarify the safety of this anti-tau vaccine after a treatment longer than 24 weeks and possibly show the vaccine’s ability to engage the biological target in the CNS.
We declare no competing interests. 1
2
3
4
5 6
7
*Francesco Panza, Giancarlo Logroscino Neurodegenerative Disease Unit, Department of Basic Medicine, Neuroscience, and Sense Organs, University of Bari Aldo Moro, Bari 70100, Italy (FP, GL); Department of Clinical Research in Neurology, University of Bari Aldo Moro, Pia Fondazione Cardinale G Panico, Tricase, Lecce, Italy (FP, GL); and Geriatric Unit & Laboratory of Gerontology and Geriatrics, Department of Medical Sciences, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia, Italy (FP) [email protected]
2
8
Panza F, Seripa D, Solfrizzi V, et al. Emerging drugs to reduce abnormal β-amyloid protein in Alzheimer’s disease patients. Expert Opin Emerg Drugs 2016; published online Oct 6. DOI:10.1080/14728214.2016.1241232. Ahmed RM, Paterson RW, Warren JD, et al. Biomarkers in dementia: clinical utility and new directions. J Neurol Neurosurg Psychiatry 2014; 85: 1426–34. Grundke-Iqbal I, Iqbal K, Tung YC, et al. Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology. Proc Natl Acad Sci USA 1986; 83: 4913–17. Panza F, Solfrizzi V, Seripa D, et al. Tau-based therapeutics for Alzheimer’s disease: active and passive immunotherapy. Immunotherapy 2016; 8: 1119–34. Clavaguera F, Bolmont T, Crowther RA, et al. Transmission and spreading of tauopathy in transgenic mouse brain. Nat Cell Biol 2009; 11: 909–13. Paholikova K, Salingova B, Opattova A, et al. N-terminal truncation of microtubule associated protein tau dysregulates its cellular localization. J Alzheimers Dis 2015; 43: 915–26. Kontsekova E, Zilka N, Kovacech B, et al. First-in-man tau vaccine targeting structural determinants essential for pathological tau-tau interaction reduces tau oligomerisation and neurofibrillary degeneration in an Alzheimer’s disease model. Alzheimers Res Ther 2014; 6: 44. Novak P, Schmidt R, Kontsekova E, et al. The first-in-man tau vaccine for the treatment of Alzheimer’s disease “AADvac1” displays a favourable safety and tolerability profile and high immunogenicity: a randomised double-blind placebo-controlled Phase I study. Lancet Neurol 2016; published online Dec 9. http://dx.doi.org/10.1016/S14744422(16)30331-3.
www.thelancet.com/neurology Published online December 9, 2016 http://dx.doi.org/10.1016/S1474-4422(16)30340-4