Currently available treatments for AD (donepezil, rivastigmine, galantamine and memantine) are symptomatic and do not decelerate or prevent the progression of the disease. However, these therapies demonstrate modest, but particularly consistent, benefit for cognition, global status and functional ability [Herrmann et al. 2011
The search for disease-modifying interventions has focused largely on compounds targeting the Aβ pathway. To date, many treatments targeting this pathway, such as tarenflurbil, tramiprosate and semagacestat, have been unsuccessful in demonstrating efficacy in the final clinical stages of testing [Gauthier et al. 2009
; Imbimbo and Giardina, 2011
However, colostrinin, scyllo-inositol, PBT2, avagacestat, etazolate and active and passive immunization methods, treatments also targeting the Aβ pathway, are being tested in advanced clinical trials.
At the same time, other possible neuronal mechanisms that seem to play important roles in the pathophysiology of this multifactorial disorder, such as tau deposition and hyperphosphorylation, neuroinflammation and oxidative stress, are being researched as promising therapeutic targets. Clinical trials with drugs interfering with tau deposition or phosphorylation (lithium)
are ongoing [Martinez and Perez, 2008
]. Clinical trials of potential antioxidants such as vitamin E and ω3 fatty acids did not show beneficial effects in patients with AD [Barten and Albright, 2008
Etanercept, a TNF inhibitor that is now widely used for the treatment of systemic diseases associated with inflammation, provided sustained improvement in cognitive function in patients with mild to severe AD after perispinal administration in a 6-month, open-label pilot study. However, etanercept merits further study in RCTs [Griffin, 2008
Modulation of cholesterol and vascular-related risk factors is an additional possible disease-modifying approach. CLASP is an ongoing phase III trial investigating the effectiveness of simvastatin in slowing down the progression of AD [McGuinness et al. 2010
The development of disease-modifying drugs for AD is recognized as a worldwide necessity. These must presumably be drugs that will modify, either by stabilizing or slowing, the molecular pathological steps leading to neurodegeneration and finally dementia.
The required design of clinical trials to test this concept raises many questions regarding the study populations, the duration of trials, the necessary primary and secondary endpoints, including biomarkers [Vellas et al. 2007
]. It has been recognized that, to modify AD, which has recently been redefined to have presymptomatic and symptomatic phases, one must attempt to treat patients when neuronal dysfunction is far from full blown and largely irreversible [Dubois et al. 2010
; Sperling et al. 2011
The following considerations have emerged that should be taken into account when planning future clinical trials:
- The mechanisms underlying the pathogenesis of AD need to be thoroughly investigated before focusing on the development of novel disease-modifying compounds. Despite promising premises related to different pathogenic mechanisms, large phase III trials with potentially disease-modifying properties have failed to demonstrate any effect on cognition. It is of crucial importance to better understand the relationship between tau, Aβ and other factors to develop successful disease-modifying drugs [Galimberti and Scarpini, 2011].
- Treatments of AD appear effective only in certain phases of the disease. A few disease-modifying compounds have shown some benefits in mild but not moderate AD or even in MCI. Therapeutic trials should therefore be carried out as early as possible during the course of the disease, which requires the identification of more accurate tools for early diagnosis. New criteria for the diagnosis of AD have enlarged the window for the detection of the early stages of the disease and include biomarkers mechanistically related to AD pathology. Adoption of these early biomarkers in implementing design of future studies is highly desirable [Galimberti and Scarpini, 2011; Salomone et al. 2011].
- AD is heterogeneous in clinical presentation, underlying neuropathology and mixed causes (especially in late-onset AD). This fact is one more reason to improve our tools for detecting patients with amnestic MCI at high risk of converting to AD before the different full-blown clinical features of the disease appear. A major challenge will also be to identify subgroups with homogeneous biomarkers. At present, the focus in AD drug development is shifting from treatment to prevention [Salomone et al. 2011; Vellas et al. 2011].
- Indicators useful as surrogate outcome measures (surrogate biomarkers like magnetic resonance imaging, CSF tau and Aβ, and amyloid positron emission tomography) should be identified to have substitutes for clinical endpoints (i.e. neuropsychological testing), tools able to predict clinical benefit or the opposite, and to demonstrate whether the drug has disease-modifying properties [Galimberti and Scarpini, 2011].
- Prolonged development times delay effective therapies from reaching patients in need. Several strategies are promising for answering the crucial question of, ‘How much information is sufficient to proceed to phase III without excessive risk for failure?’ Phase II proof of concept (POC) (IIa) and dose-finding (IIb) studies represent major challenges in drug development. Biomarkers, population enrichment with risk factors, clinical measures with greater sensitivity than standard trial instruments and adaptive dose–response designs might represent other strategies applicable to POC studies. All of these strategies are being considered as means of shortening phase IIb studies and creating a seamless interface with phase III. None of these strategies have been validated in a successful drug development program [Cummings, 2008b].
In conclusion, the new strategies seem to focus on examining the potential neuroprotective activity of disease-modifying drugs in the presymptomatic stages of AD, with the help of biomarkers that predict disease progression before development of overt dementia.