The Advantages of FTD Drug Development ( Part 2 of FTD : The Next Therapeutic Frontier )

Frontotemporal Degeneration (FTD) encompasses a spectrum of related neurodegenerative disorders with behavioral, language and motor phenotypes for which there are currently no effective therapies. This manuscript is the second of two articles that summarize the presentations and discussions that occurred at two symposia in 2011 sponsored by the Frontotemporal Dementia Treatment Study Group (FTSG), a collaborative group of academic and industry researchers that is devoted to developing treatments for FTD. This manuscript discusses the current status of FTD clinical research that is relevant to the conduct of clinical trials and why FTD research may be an attractive pathway for developing therapies for neurodegenerative disorders. The clinical and molecular features of FTD, including rapid disease progression and relatively pure molecular pathology, suggest that there are advantages to developing drugs for FTD as compared to other dementias. FTD qualifies as orphan indication, providing additional advantages for drug development. Two recent sets of consensus diagnostic criteria will facilitate the identification of patients with FTD, and a variety of neuropsychological, functional and behavioral scales have been shown to be sensitive to disease progression. Moreover, quantitative neuroimaging measurements demonstrate progressive brain atrophy in FTD at rates that may surpass Alzheimer's disease (AD). Finally, the similarities between FTD and other neurodegenerative diseases with drug development efforts already underway suggest that FTD researchers will be able to draw upon this experience to create a roadmap for FTD drug development. We conclude that FTD research has reached sufficient maturity to pursue clinical development of specific FTD therapies. Boxer et al. Page 2 Alzheimers Dement. Author manuscript; available in PMC 2014 March 01. N IH PA Athor M anscript N IH PA Athor M anscript N IH PA Athor M anscript

[1]  B. Miller,et al.  Multicenter validation of a bedside antisaccade task as a measure of executive function , 2012, Neurology.

[2]  C. Jack,et al.  Rates of brain atrophy and clinical decline over 6 and 12-month intervals in PSP: determining sample size for treatment trials. , 2012, Parkinsonism & related disorders.

[3]  Janet Woodcock,et al.  Accelerating identification and regulatory approval of investigational cancer drugs. , 2011, JAMA.

[4]  J. Kornak,et al.  Amyloid Vs Fdg-pet in the Differential Diagnosis of Ad And , 2022 .

[5]  Bruce L. Miller,et al.  Expanded GGGGCC Hexanucleotide Repeat in Noncoding Region of C9ORF72 Causes Chromosome 9p-Linked FTD and ALS , 2011, Neuron.

[6]  Nick C Fox,et al.  Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia. , 2011, Brain : a journal of neurology.

[7]  A. Kertesz,et al.  The effects of oxytocin on social cognition and behaviour in frontotemporal dementia. , 2011, Brain : a journal of neurology.

[8]  Albert C. Ludolph,et al.  Disease Severity and Progression in Progressive Supranuclear Palsy and Multiple System Atrophy: Validation of the NNIPPS – PARKINSON PLUS SCALE , 2011, PloS one.

[9]  J. Gunter,et al.  Trajectories of brain and hippocampal atrophy in FTD with mutations in MAPT or GRN , 2011, Neurology.

[10]  M. Cudkowicz,et al.  Emerging targets and treatments in amyotrophic lateral sclerosis , 2011, The Lancet Neurology.

[11]  Zhinan Yin,et al.  The Growth Factor Progranulin Binds to TNF Receptors and Is Therapeutic Against Inflammatory Arthritis in Mice , 2011, Science.

[12]  J. Hodges,et al.  Screening for Cognitive Dysfunction in Corticobasal Syndrome: Utility of Addenbrooke’s Cognitive Examination , 2011, Dementia and Geriatric Cognitive Disorders.

[13]  Robert V Farese,et al.  Suberoylanilide Hydroxamic Acid (Vorinostat) Up-regulates Progranulin Transcription , 2011, The Journal of Biological Chemistry.

[14]  B. Miller,et al.  Classification of primary progressive aphasia and its variants , 2011, Neurology.

[15]  K. Sleegers,et al.  Rescue of Progranulin Deficiency Associated with Frontotemporal Lobar Degeneration by Alkalizing Reagents and Inhibition of Vacuolar ATPase , 2011, The Journal of Neuroscience.

[16]  Philip S. Insel,et al.  Treatment with cholinesterase inhibitors and memantine of patients in the Alzheimer's Disease Neuroimaging Initiative. , 2011, Archives of neurology.

[17]  Chengjie Xiong,et al.  Autosomal-dominant Alzheimer's disease: a review and proposal for the prevention of Alzheimer's disease , 2011, Alzheimer's Research & Therapy.

[18]  J. Garre-Olmo,et al.  Incidence and subtypes of early-onset dementia in a geographically defined general population , 2010, Neurology.

[19]  T. Coté,et al.  The Impact of the Orphan Drug Act on the Development and Advancement of Neurological Products for Rare Diseases: A Descriptive Review , 2010, Clinical pharmacology and therapy.

[20]  J. Trojanowski,et al.  Novel CSF biomarkers for frontotemporal lobar degenerations , 2010, Alzheimer's & Dementia.

[21]  W. Oertel,et al.  Rational therapeutic approaches to progressive supranuclear palsy. , 2010, Brain : a journal of neurology.

[22]  M. Hornberger,et al.  Clinical Staging and Disease Progression in Frontotemporal Dementia Supplemental Data at Www.neurology.org , 2022 .

[23]  Nick C Fox,et al.  Measuring disease progression in frontotemporal lobar degeneration , 2010, Neurology.

[24]  J. Neuhaus,et al.  Off-Label Medication Use in Frontotemporal Dementia , 2010, American journal of Alzheimer's disease and other dementias.

[25]  Eric B Larson,et al.  Late-life dementias: does this unyielding global challenge require a broader view? , 2009, JAMA.

[26]  K. Romero,et al.  The Coalition Against Major Diseases: Developing Tools for an Integrated Drug Development Process for Alzheimer's and Parkinson's Diseases , 2009, Clinical pharmacology and therapeutics.

[27]  J. Trojanowski,et al.  Advances in tau-focused drug discovery for Alzheimer's disease and related tauopathies , 2009, Nature Reviews Drug Discovery.

[28]  M. Freedman,et al.  Apathy symptom profile and behavioral associations in frontotemporal dementia vs dementia of Alzheimer type. , 2009, Archives of neurology.

[29]  B. L. Miller,et al.  Brain and ventricular volumetric changes in frontotemporal lobar degeneration over 1 year , 2009, Neurology.

[30]  R. Petersen,et al.  Plasma progranulin levels predict progranulin mutation status in frontotemporal dementia patients and asymptomatic family members , 2009, Brain : a journal of neurology.

[31]  H. Akiyama,et al.  Phosphorylated TDP-43 in Alzheimer’s disease and dementia with Lewy bodies , 2009, Acta Neuropathologica.

[32]  John R Hodges,et al.  Activities of Daily Living in Behavioral Variant Frontotemporal Dementia: Differences in Caregiver and Performance-based Assessments , 2009, Alzheimer disease and associated disorders.

[33]  Y. Agid,et al.  Riluzole treatment, survival and diagnostic criteria in Parkinson plus disorders: The NNIPPS Study , 2008, Brain : a journal of neurology.

[34]  J R Hodges,et al.  Incidence of early-onset dementias in Cambridgeshire, United Kingdom , 2008, Neurology.

[35]  Nathaniel Mercaldo,et al.  Development of methodology for conducting clinical trials in frontotemporal lobar degeneration. , 2008, Brain : a journal of neurology.

[36]  Peter Heutink,et al.  Mutations in progranulin (GRN) within the spectrum of clinical and pathological phenotypes of frontotemporal dementia , 2008, The Lancet Neurology.

[37]  C. Schade-Brittinger,et al.  Short‐term effects of coenzyme Q10 in progressive supranuclear palsy: A randomized, placebo‐controlled trial , 2008, Movement disorders : official journal of the Movement Disorder Society.

[38]  P. Uhlir,et al.  Pathways across the valley of death: novel intellectual property strategies for accelerated drug discovery. , 2008, Yale journal of health policy, law, and ethics.

[39]  A. Kertesz,et al.  Galantamine in Frontotemporal Dementia and Primary Progressive Aphasia , 2008, Dementia and Geriatric Cognitive Disorders.

[40]  David A. Bennett,et al.  Mixed brain pathologies account for most dementia cases in community-dwelling older persons , 2007, Neurology.

[41]  R. Barker,et al.  The utility of the Cambridge Behavioural Inventory in neurodegenerative disease , 2007, Journal of Neurology Neurosurgery & Psychiatry.

[42]  J. Grace,et al.  The Frontal Systems Behavior Scale discriminates frontotemporal dementia from Alzheimer’s disease , 2007, Alzheimer's & Dementia.

[43]  J R Hodges,et al.  Activities of daily living in frontotemporal dementia and Alzheimer disease , 2007, Neurology.

[44]  L. Golbe,et al.  A clinical rating scale for progressive supranuclear palsy. , 2007, Brain : a journal of neurology.

[45]  Clifford R Jack,et al.  Rates of cerebral atrophy differ in different degenerative pathologies. , 2006, Brain : a journal of neurology.

[46]  John R Hodges,et al.  The Addenbrooke's Cognitive Examination Revised (ACE‐R): a brief cognitive test battery for dementia screening , 2006, International journal of geriatric psychiatry.

[47]  Jordan Grafman,et al.  A systematic review of neurotransmitter deficits and treatments in frontotemporal dementia , 2006, Neurology.

[48]  K Yaffe,et al.  Frontotemporal dementia progresses to death faster than Alzheimer disease , 2005, Neurology.

[49]  C. DeCarli,et al.  Rate of progression differs in frontotemporal dementia and Alzheimer disease , 2005, Neurology.

[50]  Jennifer Farmer,et al.  Cerebrospinal fluid profile in frontotemporal dementia and Alzheimer's disease , 2005, Annals of neurology.

[51]  F. Pasquier,et al.  Frontotemporal Dementia: A Randomised, Controlled Trial with Trazodone , 2004, Dementia and Geriatric Cognitive Disorders.

[52]  B. Sahakian,et al.  Paroxetine does not improve symptoms and impairs cognition in frontotemporal dementia: a double-blind randomized controlled trial , 2004, Psychopharmacology.

[53]  R. Petersen,et al.  The incidence of frontotemporal lobar degeneration in Rochester, Minnesota, 1990 through 1994 , 2004, Neurology.

[54]  A. Bava,et al.  Frontotemporal Dementia: Paroxetine as a Possible Treatment of Behavior Symptoms , 2002, European Neurology.

[55]  J R Hodges,et al.  The prevalence of frontotemporal dementia , 2002, Neurology.

[56]  M. Hallett,et al.  Randomized placebo-controlled trial of donepezil in patients with progressive supranuclear palsy , 2001, Neurology.

[57]  D. Burn,et al.  The prevalence of progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome) in the UK. , 2001, Brain : a journal of neurology.

[58]  P. S. Mathuranath,et al.  A brief cognitive test battery to differentiate Alzheimer's disease and frontotemporal dementia , 2000, Neurology.

[59]  A. Kertesz,et al.  Frontal Behavioral Inventory: Diagnostic Criteria for Frontal Lobe Dementi , 1997, Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques.

[60]  M. Hallett,et al.  Clinical research criteria for the diagnosis of progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome) , 1996, Neurology.

[61]  L. Golbe,et al.  Prevalence and natural history of progressive supranuclear palsy , 1988, Neurology.

[62]  S. Folstein,et al.  "Mini-mental state". A practical method for grading the cognitive state of patients for the clinician. , 1975, Journal of psychiatric research.

[63]  C. Volteau,et al.  Memantine in behavioral variant frontotemporal dementia: negative results. , 2011, Journal of Alzheimer's disease : JAD.

[64]  J. Trojanowski,et al.  Nomenclature for neuropathologic subtypes of frontotemporal lobar degeneration: consensus recommendations , 2008, Acta Neuropathologica.