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Has inhibition of Aβ production adequately been tested as therapeutic approach in mild AD? A model-based meta-analysis of γ-secretase inhibitor data

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Abstract

Purpose

To date, γ-secretase inhibition is the most frequently studied mechanism of reducing Aβ in clinical trials with as yet no therapeutic success for AD patients, as measured by the slowing down of cognitive decline or an improvement in cognitive function. The aims of this investigation were to evaluate whether the amyloid hypothesis has been tested clinically, and to explore whether preclinical data are predictive of clinical Aβ effects.

Methods

A model-based-meta analysis on Aβ levels and drug exposure over time was performed on published and in-house (pre-)clinical data with γ-secretase inhibitors (GSIs; semagacestat, avagacestat, begacestat, PF-3074014, and MK0752).

Results

The clinical data available did not show any significant or robust reduction of CNS Aβ over time at dose levels intended for AD patients. In contrast, these doses resulted in an average increase in plasma Aβ levels over a 24-h interval. A general agreement between preclinical and clinical data was found and allowed for interspecies extrapolations.

Conclusions

More substantially, CNS Aβ-lowering drugs are needed to test whether inhibition of Aβ production is efficacious in mild AD. Predictions based on preclinical data could assist in the selection of drug candidates and trial design.

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References

  1. Alzheimer's Association (2012) 2012 Alzheimer's disease facts and figures. Alzheimer Dement 8:131–168

    Article  Google Scholar 

  2. D'Onofrio G, Panza F, Frisardi V, Solfrizzi V, Imbimbo BP, Paroni G, Cascavilla L, Seripa D, Pilotto A (2012) Advances in the identification of gamma-secretase inhibitors for the treatment of Alzheimer's disease. Expert Opin Drug Discov 7:19–37

    Article  PubMed  Google Scholar 

  3. Golde TE, Schneider LS, Koo EH (2011) Anti-abeta therapeutics in Alzheimer's disease: the need for a paradigm shift. Neuron 69:203–213

    Article  PubMed  CAS  Google Scholar 

  4. Panza F, Frisardi V, Imbimbo BP, Capurso C, Logroscino G, Sancarlo D, Seripa D, Vendemiale G, Pilotto A, Solfrizzi V (2010) Review: gamma-Secretase inhibitors for the treatment of Alzheimer's disease: the current state. CNS Neurosci Ther 16:272–284

    Article  PubMed  CAS  Google Scholar 

  5. Hardy J (2009) The amyloid hypothesis for Alzheimer's disease: a critical reappraisal. J Neurochem 110:1129–1134

    Article  PubMed  CAS  Google Scholar 

  6. Karran E, Mercken M, De Strooper B (2011) The amyloid cascade hypothesis for Alzheimer's disease: an appraisal for the development of therapeutics. Nat Rev Drug Discov 10:698–712

    Article  PubMed  CAS  Google Scholar 

  7. Wolfe MS (2012) gamma-Secretase inhibitors and modulators for Alzheimer's disease. J Neurochem 120 [Suppl 1]:89–98

    Article  PubMed  CAS  Google Scholar 

  8. Walsh DM, Teplow DB (2012) Alzheimer's disease and the amyloid beta-protein. Prog Mol Biol Transl Sci 107:101–124

    Article  PubMed  CAS  Google Scholar 

  9. Lichtenthaler SF, Haass C, Steiner H (2011) Regulated intramembrane proteolysis—lessons from amyloid precursor protein processing. J Neurochem 117:779–796

    Article  PubMed  CAS  Google Scholar 

  10. Citron M (2010) Alzheimer's disease: strategies for disease modification. Nat Rev Drug Discov 9:387–398

    Article  PubMed  CAS  Google Scholar 

  11. Kreft AF, Martone R, Porte A (2009) Recent advances in the identification of gamma-secretase inhibitors to clinically test the Abeta oligomer hypothesis of Alzheimer's disease. J Med Chem 52:6169–6188

    Article  PubMed  CAS  Google Scholar 

  12. Burton CR, Meredith JE, Barten DM, Goldstein ME, Krause CM, Kieras CJ, Sisk L, Iben LG, Polson C, Thompson MW, Lin XA, Corsa J, Fiedler T, Pierdomenico M, Cao Y, Roach AH, Cantone JL, Ford MJ, Drexler DM, Olson RE, Yang MG, Bergstrom CP, McElhone KE, Bronson JJ, Macor JE, Blat Y, Grafstrom RH, Stern AM, Seiffert DA, Zaczek R, Albright CF, Toyn JH (2008) The amyloid-beta rise and gamma-secretase inhibitor potency depend on the level of substrate expression. J Biol Chem 283:22992–23003

    Article  PubMed  CAS  Google Scholar 

  13. Jamsa A, Belda O, Edlund M, Lindstrom E (2011) BACE-1 inhibition prevents the gamma-secretase inhibitor evoked Abeta rise in human neuroblastoma SH-SY5Y cells. J Biomed Sci 18:76

    Article  PubMed  Google Scholar 

  14. Lanz TA, Karmilowicz MJ, Wood KM, Pozdnyakov N, Du P, Piotrowski MA, Brown TM, Nolan CE, Richter KE, Finley JE, Fei Q, Ebbinghaus CF, Chen YL, Spracklin DK, Tate B, Geoghegan KF, Lau LF, Auperin DD, Schachter JB (2006) Concentration-dependent modulation of amyloid-beta in vivo and in vitro using the gamma-secretase inhibitor, LY-450139. J Pharmacol Exp Ther 319:924–933

    Article  PubMed  CAS  Google Scholar 

  15. Kumamoto M, Nakano M, Uenaka K, Lowe S, Nishiuma S, Nakamichi N, Dean R, Siemers E, Mohs R (2008) P4-379: safety, tolerability, pharmacokinetics and pharmacodynamics of multiple-dose administration of a gamma-secretase inhibitor in Japanese subjects. Alzheimer Dement 4:T785

    Article  Google Scholar 

  16. Siemers ER, Dean RA, Friedrich S, Ferguson-Sells L, Gonzales C, Farlow MR, May PC (2007) Safety, tolerability, and effects on plasma and cerebrospinal fluid amyloid-beta after inhibition of gamma-secretase. Clin Neuropharmacol 30:317–325

    Article  PubMed  CAS  Google Scholar 

  17. Tong G, Wang JS, Sverdlov O, Huang SP, Slemmon R, Croop R, Castaneda L, Gu H, Wong O, Li H, Berman RM, Smith C, Albright CF, Dockens RC (2012) Multicenter, randomized, double-blind, placebo-controlled, single-ascending dose study of the oral gamma-secretase inhibitor BMS-708163 (avagacestat): tolerability profile, pharmacokinetic parameters, and pharmacodynamic markers. Clin Ther 34:654–667

    Article  PubMed  CAS  Google Scholar 

  18. Martone RL, Zhou H, Atchison K, Comery T, Xu JZ, Huang X, Gong X, Jin M, Kreft A, Harrison B, Mayer SC, Aschmies S, Gonzales C, Zaleska MM, Riddell DR, Wagner E, Lu P, Sun SC, Sonnenberg-Reines J, Oganesian A, Adkins K, Leach MW, Clarke DW, Huryn D, Abou-Gharbia M, Magolda R, Bard J, Frick G, Raje S, Forlow SB, Balliet C, Burczynski ME, Reinhart PH, Wan HI, Pangalos MN, Jacobsen JS (2009) Begacestat (GSI-953): a novel, selective thiophene sulfonamide inhibitor of amyloid precursor protein gamma-secretase for the treatment of Alzheimer's disease. J Pharmacol Exp Ther 331:598–608

    Article  PubMed  CAS  Google Scholar 

  19. Frick G, Raje S, Wan H, Forlow SB, Balliet C, Pastore A, Burczynski ME, Jhee S, Ereshefsky L, Paul J (2008) P4-366: GSI-953, a potent and selective gamma-secretase inhibitor: modulation of beta-amyloid peptides and plasma and cerebrospinal fluid pharmacokinetic/pharmacodynamic relationships in humans. Alzheimer Dement 4:T781

    Article  Google Scholar 

  20. Tai LM, Jacobsen H, Ozmen L, Flohr A, Jakob-Roetne R, Caruso A, Grimm HP (2012) The dynamics of Abeta distribution after gamma-secretase inhibitor treatment, as determined by experimental and modelling approaches in a wild type rat. J Pharmacokinet Pharmacodyn 39:227–237

    Article  PubMed  CAS  Google Scholar 

  21. Lu Y, Riddell D, Hajos-Korcsok E, Bales K, Wood KM, Nolan CE, Robshaw AE, Zhang L, Leung L, Becker SL, Tseng E, Barricklow J, Miller EH, Osgood S, O’Neill BT, Brodney MA, Johnson DS, Pettersson M (2012) CSF Abeta as an effect biomarker for brain Abeta lowering verified by quantitative preclinical analyses. J Pharmacol Exp Ther 342:366–375

    Article  PubMed  CAS  Google Scholar 

  22. Lu Y, Zhang L, Nolan CE, Becker SL, Atchison K, Robshaw AE, Pustilnik LR, Osgood SM, Miller EH, Stepan AF, Subramanyam C, Efremov I, Hallgren AJ, Riddell D (2011) Quantitative pharmacokinetic/pharmacodynamic analyses suggest that the 129/SVE mouse is a suitable preclinical pharmacology model for identifying small-molecule gamma-secretase inhibitors. J Pharmacol Exp Ther 339:922–934

    Article  PubMed  CAS  Google Scholar 

  23. Fleisher AS, Raman R, Siemers ER, Becerra L, Clark CM, Dean RA, Farlow MR, Galvin JE, Peskind ER, Quinn JF, Sherzai A, Sowell BB, Aisen PS, Thal LJ (2008) Phase 2 safety trial targeting amyloid beta production with a gamma-secretase inhibitor in Alzheimer disease. Arch Neurol 65:1031–1038

    Article  PubMed  Google Scholar 

  24. Bateman RJ, Siemers ER, Mawuenyega KG, Wen G, Browning KR, Sigurdson WC, Yarasheski KE, Friedrich SW, Demattos RB, May PC, Paul SM, Holtzman DM (2009) A gamma-secretase inhibitor decreases amyloid-beta production in the central nervous system. Ann Neurol 66:48–54

    Article  PubMed  CAS  Google Scholar 

  25. Wang J, Castaneda L, Sverdlov A, Huang S, Slemmon R, Gu H, Wong O, Li H, Berman RM, Smith C, Albright CF, Dockens R, Tong G, Arroyo S (2010) A placebo-controlled, ascending, multiple-dose study to evaluate the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of BMS-708163 in healthy young and elderly subjects. Alzheimer Dement 6:S540

    Article  Google Scholar 

  26. Meredith J, Albright CF, Dockens RC, Olson RE, Lentz KA, Wang JS, Denton RR, Pilcher G, Zaczek R, Macor JE, Houston J, Wong O, Gu H, Berman RM, Tong G (2011) BMS-708163, a Notch-sparing GSI, decreases central Aβ in rats, dogs, and humans with a therapeutic margin relative to Notch toxicity

  27. Tong G, Wang JS, Sverdlov O, Huang SP, Slemmon R, Croop R, Castaneda L, Wu H, Wong O, Li H, Berman RM, Smith C, Albright CF, Dockens R (2012) A contrast in safety, pharmacokinetics, and pharmacodynamics across age groups after a single 50-mg oral dose of the gamma-secretase inhibitor avagacestat. Br J Clin Pharmacol doi:10.1111/j.1365-2125.2012.04339.x

    Google Scholar 

  28. Wan H, Bard J, Martone R, Rage S, Forlow S, Kreft A, Jacobsen S, Silver P, Paul J, Frick G (2008) P3-101: GSI-953, a potent and selective gamma-secretase inhibitor, modulates Abeta peptides in mice and humans: translating the PK/PD biomarker relationships in different biological compartments between rodent and human. Alzheimer Dement 4:T548

    Article  Google Scholar 

  29. Qiu R, Willavize S, Fullerton T, Gastonguay MR (2009) Modeling and simulation of plasma AÎ2 in humans after multiple oral doses of PF-3084014, a potent gamma-secretase inhibitor. Alzheimer Dement 5:P253

    Article  Google Scholar 

  30. Soares H, Raha N, Sikpi M, Liston D, Brodney M, Coffman K, Tate B, Qiu R, Wang EQ, Li X, Hidi R, Banerjee S, Jhee S, Ereshefsky L, Fullerton T (2009) Aβ variability and effect of gamma secretase inhibition on cerebrospinal fluid levels of Aβ in healthy volunteers. Alzheimer Dement 5:P252–P253

    Article  Google Scholar 

  31. Lanz TA, Wood KM, Richter KE, Nolan CE, Becker SL, Pozdnyakov N, Martin BA, Du P, Oborski CE, Wood DE, Brown TM, Finley JE, Sokolowski SA, Hicks CD, Coffman KJ, Geoghegan KF, Brodney MA, Liston D, Tate B (2010) Pharmacodynamics and pharmacokinetics of the gamma-secretase inhibitor PF-3084014. J Pharmacol Exp Ther 334:269–277

    Article  PubMed  CAS  Google Scholar 

  32. Das R, Nachbar RB, Edelstein-Keshet L, Saltzman JS, Wiener MC, Bagchi A, Bailey J, Coombs D, Simon AJ, Hargreaves RJ, Cook JJ (2010) Modeling effect of a gamma-secretase inhibitor on amyloid-beta dynamics reveals significant role of an amyloid clearance mechanism. Bull Math Biol 73:230–247

    Article  PubMed  Google Scholar 

  33. Cook JJ, Wildsmith KR, Gilberto DB, Holahan MA, Kinney GG, Mathers PD, Michener MS, Price EA, Shearman MS, Simon AJ, Wang JX, Wu G, Yarasheski KE, Bateman RJ (2010) Acute gamma-secretase inhibition of nonhuman primate CNS shifts amyloid precursor protein (APP) metabolism from amyloid-beta production to alternative APP fragments without amyloid-beta rebound. J Neurosci 30:6743–6750

    Article  PubMed  CAS  Google Scholar 

  34. Ereshefsky L et al (2008) Demonstrating proof of principle in Alzheimers disease: the role of CSF ‘dynabridging’ studies. Society for CNS Clinical trials and Methodology

  35. Stone J (2009) Modeling of Ab dynamics in animals and humans. American Society for Clinical Pharmacology and Therapeutics (ASCPT) Annual Meeting

  36. Rosen LB, Stone JA, Plump A, Yuan J, Harrison T, Flynn M, Dallob A, Matthews C, Stevenson D, Schmidt D, Palmieri T, Leibowitz M, Jhee S, Ereshefsky L, Salomon R, Winchell G, Shearman MS, Murphy MG, Gottesdiener KM (2006) O4-03-02: the gamma secretase inhibitor MK-0752 acutely and significantly reduces CSF Abeta40 concentrations in humans. Alzheimer Dement 2:S79

    Article  Google Scholar 

  37. Jusko WJ, Ko HC (1994) Physiologic indirect response models characterize diverse types of pharmacodynamic effects. Clin Pharmacol Ther 56:406–419

    Article  PubMed  CAS  Google Scholar 

  38. Beal SL, Sheiner LB, Boeckmann AJ, Bauer RJ (1989–2009) NONMEM Users Guides

  39. Siemers E, Skinner M, Dean RA, Gonzales C, Satterwhite J, Farlow M, Ness D, May PC (2005) Safety, tolerability, and changes in amyloid beta concentrations after administration of a gamma-secretase inhibitor in volunteers. Clin Neuropharmacol 28:126–132

    Article  PubMed  CAS  Google Scholar 

  40. Li J, Llano DA, Ellis T, Leblond D, Bhathena A, Jhee SS, Ereshefsky L, Lenz R, Waring JF (2011) Effect of human cerebrospinal fluid sampling frequency on amyloid-beta levels. Alzheimers Dement 8:295–303

    Article  PubMed  Google Scholar 

  41. Gillman KW, Starrett JE, Parker MF, Xie K, Bronson JJ, Marcin LR, McElhone KE, Bergstrom CP, Mate RA, Williams R, Meredith JE, Burton CR, Barten DM, Toyn JH, Roberts SB, Lentz KA, Houston JG, Zaczek R, Albright CF, Decicco CP, Macor JE, Olson RE (2010) Discovery and evaluation of BMS-708163, a potent, selective and orally bioavailable γ-secretase inhibitor. ACS Med Chem Lett 1:120–124

    Article  CAS  Google Scholar 

  42. Portelius E, Van Broeck B, Andreasson U, Gustavsson MK, Mercken M, Zetterberg H, Borghys H, Blennow K (2010) Acute effect on the Abeta isoform pattern in CSF in response to gamma-secretase modulator and inhibitor treatment in dogs. J Alzheimer Dis 21:1005–1012

    CAS  Google Scholar 

  43. Janson J, Eketjäll S, Yan H, Tunblad K, Jeppsson F, Briem S, Dahlqvist C, Radesäter AC, Fälting J, Visser SAG (2012) Population PKPD modeling of BACE1 inhibitors induced reduction in brain Aβ levels in vivo

  44. Morgan P, Van Der Graaf PH, Arrowsmith J, Feltner DE, Drummond KS, Wegner CD, Street SD (2012) Can the flow of medicines be improved? Fundamental pharmacokinetic and pharmacological principles toward improving Phase II survival. Drug Discov Today 17:419–424

    Article  PubMed  CAS  Google Scholar 

  45. Doody RS, Cole PE, Miller DS, Siemers E, Black R, Feldman H, Schindler R, Graham S, Heath T, Khachaturian AS, Evans R, Carrillo MC (2011) Global issues in drug development for Alzheimer's disease. Alzheimer Dement 7:197–207

    Article  Google Scholar 

  46. Abramowski D, Wiederhold KH, Furrer U, Jaton AL, Neuenschwander A, Runser MJ, Danner S, Reichwald J, Ammaturo D, Staab D, Stoeckli M, Rueeger H, Neumann U, Staufenbiel M (2008) Dynamics of Abeta turnover and deposition in different beta-amyloid precursor protein transgenic mouse models following gamma-secretase inhibition. J Pharmacol Exp Ther 327:411–424

    Article  PubMed  CAS  Google Scholar 

  47. Dutta S, Ebling WF (1997) Parameter estimability of biphasic response models. J Pharm Sci 86:44–51

    Article  PubMed  CAS  Google Scholar 

  48. Li T, Huang Y, Jin S, Ye L, Rong N, Yang X, Ding Y, Cheng Z, Zhang J, Wan Z, Harrison DC, Hussain I, Hall A, Lee DHS, Lau L, Matsuoka Y (2012) γ-Secretase modulators do not induce Aβ-rebound and accumulation of β-C-terminal fragment. J Neurochem 121:277–286

    Article  PubMed  CAS  Google Scholar 

  49. Ortega F, Stott J, Visser SAG, Bendtsen C (2012) Interplay between α, β and γ-secretases determines biphasic Aβ levels in the presence of a γ-secretases inhibitor. J Biol Chem doi: 10.1074/jbc.M112.419135

    Google Scholar 

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Acknowledgements

The authors would like to thank Karin Agerman, Rebecka Klintenberg, Kristina Eliason, and Hongmei Yan for their contributions to the in vivo experiments.

Author contributions

C.N., J.L, S.V, designed experiments; F.O. carried out in vitro experiments; S.V. performed data extraction; J.P, E.v.S, S.V performed PKPD modeling; S.V and J.L supervised the project, and C.N., J.P, F.O, and S.V wrote the paper.

Competing financial interests

The authors declare no competing financial interests. All authors, except for E.v.S. were AstraZeneca employees at the time of conducting the research.

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Authors and Affiliations

  1. Neuroscience, CNSP Innovative Medicines, AstraZeneca, Södertälje, Sweden

    Camilla Niva, Fredrik Olsson & Johan Lundkvist

  2. Modeling & Simulation, CNSP Innovative Medicines, AstraZeneca, Södertälje, Sweden

    Joanna Parkinson

  3. Exprimo NV, Mechelen, Belgium

    Erno van Schaick

  4. Global DMPK Centre of Excellence, Innovative Medicines AstraZeneca, 15185, Södertälje, Sweden

    Sandra A. G. Visser

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  1. Camilla Niva
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  2. Joanna Parkinson
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  3. Fredrik Olsson
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  6. Sandra A. G. Visser
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Correspondence to Sandra A. G. Visser.

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Niva, C., Parkinson, J., Olsson, F. et al. Has inhibition of Aβ production adequately been tested as therapeutic approach in mild AD? A model-based meta-analysis of γ-secretase inhibitor data. Eur J Clin Pharmacol 69, 1247–1260 (2013). https://doi.org/10.1007/s00228-012-1459-3

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  • DOI: https://doi.org/10.1007/s00228-012-1459-3

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