Abstract
Since the approval of riluzole for the treatment of amyotrophic lateral sclerosis (ALS) 17 years ago, more than 30 large clinical trials have been conducted, but none has proved successful. The failure to translate positive preclinical results into the clinical setting raises questions about the validity of the rodent model that is used to study ALS, and about the quality of both preclinical and clinical studies. However, the greatest challenge is the disease itself as, with rare exceptions, the causes are unknown. In this Perspectives article, we highlight key issues related to the pathophysiology, preclinical studies and clinical trials that should be addressed in the future. These areas include the relationships between different disease mechanisms, the challenges presented by the heterogeneity of the disease, and the need for early intervention, optimal dose selection and effective biomarkers.
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References
Swash, M. We have a problem: why have ALS trials been negative? Amyotroph. Lateral Scler. 8, 259 (2007).
Swash, M. Lithium time-to-event trial in amyotrophic lateral sclerosis stops early for futility. Lancet Neurol. 9, 449–451 (2010).
Aggarwal, S. & Cudkowicz, M. ALS drug development: reflections from the past and a way forward. Neurotherapeutics 5, 516–527 (2008).
Ludolph, A. C. et al. Guidelines for preclinical animal research in ALS/MND: a consensus meeting. Amyotroph. Lateral Scler. 11, 38–45 (2010).
Mitsumoto, H. et al. Randomized control trials in ALS: lessons learned. Amyotroph. Lateral Scler. Other Motor Neuron Disord. 5 (Suppl. 1), 8–13 (2004).
Rothstein, J. D. Current hypotheses for the underlying biology of amyotrophic lateral sclerosis. Ann Neurol. 65 (Suppl. 1), S3–S9 (2009).
Boillée, S., Vande Velde, C. & Cleveland, D. W. ALS: a disease of motor neurons and their nonneuronal neighbors. Neuron 52, 39–59 (2006).
Ravits, J., Paul, P. & Jorg, C. Focality of upper and lower motor neuron degeneration at the clinical onset of ALS. Neurology 68, 1571–1575 (2007).
Johnson, K. A. & Brown, P. H. Drug development for cancer chemoprevention: focus on molecular targets. Semin. Oncol. 37, 345–358 (2010).
Sreeramoju, P. & Libutti, S. K. Strategies for targeting tumors and tumor vasculature for cancer therapy. Adv. Genet. 69, 135–152 (2010).
Glass, C. K., Saijo, K., Winner, B., Marchetto, M. C. & Gage, F. H. Mechanisms underlying inflammation in neurodegeneration. Cell 140, 918–934 (2010).
Schwartz, M. & Shechter, R. Systemic inflammatory cells fight off neurodegenerative disease. Nat. Rev. Neurol. 6, 405–410 (2010).
Gao, H. M. & Hong, J. S. Gene–environment interactions: key to unraveling the mystery of Parkinson's disease. Prog. Neurobiol. 94, 1–19 (2011).
Postuma, R. B. & Montplaisir, J. Predicting Parkinson's disease—why, when, and how? Parkinsonism Relat. Disord. 15 (Suppl. 3), S105–S109 (2009).
Aluise, C. D. et al. Preclinical Alzheimer disease: brain oxidative stress, Aβ peptide and proteomics. Neurobiol. Dis. 39, 221–228 (2010).
Elias, M. F. et al. The preclinical phase of Alzheimer disease: a 22-year prospective study of the Framingham Cohort. Arch. Neurol. 57, 808–813 (2000).
Berg, D. Biomarkers for the early detection of Parkinson's and Alzheimer's disease. Neurodegener. Dis. 5, 133–136 (2008).
Swash, M. & Ingram, D. Preclinical and subclinical events in motor neuron disease. J. Neurol. Neurosurg. Psychiatry 51, 165–168 (1988).
Aggarwal, A. & Nicholson, G. Detection of preclinical motor neurone loss in SOD1 mutation carriers using motor unit number estimation. J. Neurol. Neurosurg. Psychiatry 73, 199–201 (2002).
Guégan, C. & Przedborski, S. Programmed cell death in amyotrophic lateral sclerosis. J. Clin. Invest. 111, 153–161 (2003).
Banerjee, R., Beal, M. F. & Thomas, B. Autophagy in neurodegenerative disorders: pathogenic roles and therapeutic implications. Trends Neurosci. 33, 541–549 (2010).
Gurney, M. E. The use of transgenic mouse models of amyotrophic lateral sclerosis in preclinical drug studies. J. Neurol. Sci. 152 (Suppl. 1), S67–S73 (1997).
Scott, S. et al. Design, power, and interpretation of studies in the standard murine model of ALS. Amyotroph. Lateral Scler. 9, 4–15 (2008).
Milane, A. et al. Brain and plasma riluzole pharmacokinetics: effect of minocycline combination. J. Pharm. Pharm. Sci. 12, 209–217 (2009).
Leigh, P. N., Meininger, V., Bensimon, G., Cudkowicz, M. & Robberecht W. Minocycline for patients with ALS. Lancet Neurol. 7, 119–120 (2008).
Swarup, V. & Julien, J. P. ALS pathogenesis: recent insights from genetics and mouse models. Prog. Neuropsychopharmacol. Biol. Psychiatry 35, 363–369 (2011).
Kabashi, E. et al. Gain and loss of function of ALS-related mutations of TARDBP (TDP-43) cause motor deficits in vivo. Hum. Mol. Genet. 19, 671–683 (2010).
Meininger, V. et al. Efficacy and safety of xaliproden in amyotrophic lateral sclerosis: results of two phase III trials. Amyotroph. Lateral Scler. Other Motor Neuron Disord. 5, 107–117 (2004).
Miller, R. et al. Phase II/III randomized trial of TCH346 in patients with ALS. Neurology 69, 776–784 (2007).
Meininger, V. et al. Pentoxifylline European Group. Pentoxifylline in ALS: a double-blind, randomized, multicenter, placebo-controlled trial. Neurology 66, 88–92 (2006).
Miller, R. G. et al. A placebo-controlled trial of recombinant human ciliary neurotrophic (rhCNTF) factor in amyotrophic lateral sclerosis. rhCNTF ALS Study Group. Ann. Neurol. 39, 256–260 (1996).
[No authors listed] A controlled trial of recombinant methionyl human BDNF in ALS: the BDNF Study Group (Phase III). Neurology 52, 1427–1433 (1999).
Sorenson, E. J. et al. Subcutaneous IGF-1 is not beneficial in 2-year ALS trial. Neurology 71, 1770–1775 (2008).
Cudkowicz, M. E. et al. A randomized, placebo-controlled trial of topiramate in amyotrophic lateral sclerosis. Neurology 6, 456–464 (2003).
Miller, R. G. et al. Phase III randomized trial of gabapentin in patients with amyotrophic lateral sclerosis. Neurology 56, 843–848 (2001).
Gordon, P. H. et al. Efficacy of minocycline in patients with amyotrophic lateral sclerosis: a phase III randomised trial. Lancet Neurol. 6, 1045–1053 (2007).
Meininger, V. et al. Glatiramer acetate has no impact on disease progression in ALS at 40 mg/day: a double-blind, randomized, multicentre, placebo-controlled trial. Amyotroph. Lateral Scler. 10, 378–383 (2009).
Bellingham, M. C. A review of the neural mechanisms of action and clinical efficiency of riluzole in treating amyotrophic lateral sclerosis: what have we learned in the last decade? CNS Neurosci. Ther. 17, 4–31 (2011).
Lacomblez, L., Bensimon, G., Leigh, P. N., Guillet, P. & Meininger, V. Dose-ranging study of riluzole in amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis/Riluzole Study Group II. Lancet 347, 1425–1431 (1996).
Lacomblez, L. et al. Xaliproden in amyotrophic lateral sclerosis: early clinical trials. Amyotroph. Lateral Scler. Other Motor Neuron Disord. 5, 99–106 (2004).
Pascuzzi, R. M. et al. A phase II trial of talampanel in subjects with amyotrophic lateral sclerosis. Amyotroph. Lateral Scler. 11, 266–271 (2010).
Gordon, P. H. et al. A novel, efficient, randomized selection trial comparing combinations of drug therapy for ALS. Amyotroph. Lateral Scler. 9, 212–222 (2008).
Schoenfeld, D. A. & Cudkowicz, M. Design of phase II ALS clinical trials. Amyotroph. Lateral Scler. 9, 16–23 (2008).
Finkelstein, D. M., Wang, R., Ficociello, L. H. & Schoenfeld, D. A. A score test for association of a longitudinal marker and an event with missing data. Biometrics 66, 726–732 (2010).
Chiò, A., Calvo, A., Moglia, C., Mazzini, L. & Mora, G. ; PARALS study group. Phenotypic heterogeneity of amyotrophic lateral sclerosis: a population based study. J. Neurol. Neurosurg. Psychiatry. 82, 740–746 (2011).
Paillisse, C. et al. Prognostic factors for survival in amyotrophic lateral sclerosis patients treated with riluzole. Amyotroph. Lateral Scler. Other Motor Neuron Disord. 6, 37–44 (2005).
Eisen, A. Amyotrophic lateral sclerosis—evolutionary and other perspectives. Muscle Nerve 40, 297–304 (2009).
Valdmanis, P. N., Daoud, H., Dion, P. A. & Rouleau, G. A. Recent advances in the genetics of amyotrophic lateral sclerosis. Curr. Neurol. Neurosci. Rep. 9, 198–205 (2009).
Turner, M. R., Kiernan, M. C., Leigh, P. N. & Talbot, K. Biomarkers in amyotrophic lateral sclerosis. Lancet Neurol. 8, 94–109 (2009).
Ganesalingam, J. & Bowser, R. The application of biomarkers in clinical trials for motor neuron disease. Biomark. Med. 4, 281–297 (2010).
Shefner, J. M. Statistical motor unit number estimation and ALS trials: the effect of motor unit instability. Suppl. Clin. Neurophysiol. 60, 135–141 (2009).
de Carvalho, M. & Swash, M. Sensitivity of electrophysiological tests for upper and lower motor neuron dysfunction in ALS: a six-month longitudinal study. Muscle Nerve 41, 208–211 (2009).
Shefner, J. M, Cudkowicz, M. E., Zhang, H., Schoenfeld, D. & Jillapalli, D. The use of statistical MUNE in a multicenter clinical trial. Muscle Nerve 30, 463–469 (2004).
Rovaris, M., Agosta, F., Pagani, E. & Filippi, M. Diffusion tensor MR imaging. Neuroimaging Clin. N. Am. 19, 37–43 (2009).
Zhang, Y. et al. Progression of white matter degeneration in amyotrophic lateral sclerosis: a diffusion tensor imaging study. Amyotroph. Lateral Scler. http://dx.doi.org/10.3109/17482968.2011.593036.
Turner, M. R. et al. Distinct cerebral lesions in sporadic and 'D90A' SOD1 ALS: studies with [11C] flumazenil PET. Brain 128, 1323–1329 (2005).
Habert, M. O. et al. Brain perfusion imaging in amyotrophic lateral sclerosis: extent of cortical changes according to the severity and topography of motor impairment. Amyotroph. Lateral Scler. 8, 9–15 (2007).
Ryberg, H. et al. Discovery and verification of amyotrophic lateral sclerosis biomarkers by proteomics. Muscle Nerve 42, 104–111 (2010).
Levine, T. D., Bowser, R., Hank, N. & Saperstein, D. A pilot trial of memantine and riluzole in ALS: correlation to CSF biomarkers. Amyotroph. Lateral Scler. 11, 514–519 (2010).
Yoshino, H. & Kimura, A. Investigation of the therapeutic effects of edaravone, a free radical scavenger, on amyotrophic lateral sclerosis (phase II study). Amyotroph. Lateral Scler. 7, 241–224 (2006).
Cudkowicz, M. E. et al. Trial of celecoxib in amyotrophic lateral sclerosis. Ann. Neurol. 60, 22–31 (2006).
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Gordon, P., Meininger, V. How can we improve clinical trials in amyotrophic lateral sclerosis?. Nat Rev Neurol 7, 650–654 (2011). https://doi.org/10.1038/nrneurol.2011.147
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DOI: https://doi.org/10.1038/nrneurol.2011.147
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