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Introduction: Tauopathies are heterogeneous clinicopathological entities characterized by abnormal neuronal and/or glial inclusions of the microtubule-binding protein tau. Primary tauopathies considered to be diseases correspond to a major class of frontotemporal lobar degeneration (FTLD) neuropathology (FTLD-Tau), including several forms of frontotemporal dementia (FTD) clinical syndromes. Little progress has been made in the past 20 years in developing effective disease-modifying drugs for primary tauopathies and available symptomatic treatments have limited efficacy. Areas covered: Potential disease-modifying drugs in clinical development to slow neuropathological progression of primary tauopathies. Expert opinion: Since the underlying pathology of primary tauopathies consists of abnormal tau protein aggregates, treatments are being developed to interfere with the aggregation process or to promote the clearance of this protein. Unfortunately, disease-modifying treatments remain years away as demonstrated by the recent negative Phase III findings of a tau aggregation inhibitor (LMTM) for treating the behavioral variant of FTD. Further evidence will come from ongoing Phase I/II trials on novel drugs and immunotherapeutics with various targets – prevention of deposition or removal of tau aggregates, inhibition of tau phosphorylation/acetylation, modulation of O-GlcNAcylation, activation of autophagy or ubiquitin-proteasome system pathways, and rescue of selected tau loss of function or suppression of tau gene expression. [ABSTRACT FROM AUTHOR]

Introduction: The amyloid hypothesis of Alzheimer’s disease (AD) affirms that brain accumulation of amyloid-β (Aβ) oligomers and soluble aggregates represent the major pathological event of the disease. Several anti-Aβ small organic molecules, monoclonal antibodies and antigens were developed to interfere with Aβ production and clearance, including β-site amyloid precursor protein cleaving enzyme (BACE) inhibitors, blocking the first enzymatic step of Aβ formation. All these approaches, including BACE inhibitors, have failed in large randomized clinical trials (RCTs) in mild-to-moderate AD, but further studies are now being carried out in patients at early AD stages and in asymptomatic subjects at risk of developing AD. Areas covered: The paper provides a comprehensive review of BACE inhibitors for AD treatment, focusing on the most advanced compounds in Phase III RCTs. Expert commentary: BACE inhibitors inhibited robustly, and dose-dependently, Aβ formation in cerebrospinal fluid of AD patients, but without cognitive, clinical, or functional benefit in large RCTs. BACE inhibition may be not sufficient to decrease brain Aβ plaques and aggregates. Indeed, several BACE inhibitors were found to be poorly tolerated and some of them failed also in patients with prodromal AD. This may indicate that blocking the formation of nascent Aβ is not useful in AD. [ABSTRACT FROM AUTHOR]

Hereditary amyloid polyneuropathy is a type of protein misfolding disease. Transthyretin (TTR) is a homotetrameric serum protein and TTR tetramer dissociation is the limiting step in amyloid fibril formation. Thus, prevention of TTR dissociation is a promising therapeutic approach and some TTR stabilizers have been approved for the treatment of TTR amyloidosis. CSP-1103 (CHF5074) is a non-steroidal anti-inflammatory derivative that lacks cyclooxygenase inhibitory activity.In vitro, CSP-1103 stabilizes the TTR tetramer by binding to the thyroxine (T4) binding site. We have previously shown that serum TTR levels were increased by oral CSP-1103 administration through stabilization of TTR tetramers in humanized mice at both theTtrlocus and theRbp4locus. To determine whether CSP-1103 stabilizes TTR tetramers in humans, multiple CSP-1103 oral doses were administered for two weeks to 48 healthy human volunteers in a double-blind, placebo-controlled, parallel-group study. CSP-1103 treatment stabilized TTR tetramers in a dose-dependent manner under normal or denaturing stress conditions, thereby increasing serum TTR levels. Preincubation of serum with CSP-1103 or diflunisalin vitroincreased the TTR tetramer stability. Computer simulation analysis revealed that the binding affinities of CSP-1103 with TTR at pH 7.0 were similar to those of tafamidis, thus confirming that CSP-1103 has potent TTR-stabilizing activity. [ABSTRACT FROM AUTHOR]

Small molecular weight compounds able to inhibit formation of tau oligomers and fibrils have already been tested for Alzheimer’s disease (AD) treatment. The most advanced tau aggregation inhibitor (TAI) is methylthioninium (MT), a drug existing in equilibrium between a reduced (leuco-methylthioninium) and oxidized form (MT+). MT chloride (also known as methylene blue) was investigated in a 24-week Phase II study in 321 mild-to-moderate AD patients at the doses of 69, 138, and 228 mg/day. This trial failed to show significant positive effects of MT in the overall patient population. The dose of 138 mg/day showed potential benefits on cognitive performance of moderately affected patients and cerebral blood flow in mildly affected patients. A follow-up compound (TRx0237) claimed to be more bioavailable and less toxic than MT, is now being developed. Phase III clinical trials on this novel TAI in AD and in the behavioral variant of frontotemporal dementia are underway. [ABSTRACT FROM PUBLISHER]

Among active and passive anti-β-amyloid (Aβ) immunotherapies for Alzheimer's disease (AD), bapineuzumab and solanezumab, two humanized monoclonal antibodies, failed to show significant clinical benefits in mild-to-moderate AD patients in large Phase III clinical trials. Another ongoing Phase III trial of solanezumab aims to confirm positive findings in mild AD patients. Gantenerumab is the first fully human anti-Aβ monoclonal antibody directed to both N-terminal and central regions of Aβ. A 6-month PET study in 16 AD patients showed that gantenerumab treatment dose-dependently reduced brain Aβ deposition, possibly stimulating microglial-mediated phagocytosis. Two ongoing Phase III trials of gantenerumab in patients with prodromal or mild dementia due to AD will determine if any reduction in brain Aβ levels will translate into clinical benefits. An ongoing secondary prevention trial of gantenerumab in presymptomatic subjects with genetic mutations for autosomal-dominant AD will verify the utility of anti-Aβ monoclonal antibodies as prevention therapy. [ABSTRACT FROM AUTHOR]

Both active and passive anti-β-amyloid (Aβ) immunotherapies for the treatment of Alzheimer's disease (AD) have demonstrated clearance of brain Aβ deposits. Among passive immunotherapeutics, two Phase III clinical trials in mild-to-moderate AD patients with bapineuzumab, a humanized monoclonal antibody directed at the N-terminal sequence of Aβ, were disappointing. Also solanezumab, directed at the mid-region of Aβ, failed in two Phase III trials in mild-to-moderate AD. Another Phase III trial with solanezumab is ongoing in mildly affected AD patients based on encouraging results in this subgroup. Second-generation active Aβ vaccines (CAD106, ACC-001, and Affitope AD02) and new passive anti-Aβ immunotherapies (gantenerumab and crenezumab) have been developed and are under clinical testing. These new anti-Aβ immunotherapies are being tested in prodromal AD, in presymptomatic subjects with AD-related mutations, or in asymptomatic subjects at risk of developing AD. These primary and secondary prevention trials will definitely test the Aβ cascade hypothesis of AD. [ABSTRACT FROM AUTHOR]

Solanezumab (LY2062430) is a humanized monoclonal antibody that binds to the central region of &bgr;-amyloid, a peptide believed to play a key role in the pathogenesis of Alzheimer's disease (AD). Eli Lilly & Co is developing an intravenous formulation of solanezumab for the treatment of mild-to-moderate AD. Acute and subchronic treatment with solanezumab of transgenic mice attenuated or reversed memory deficits with no effects on incidence or severity of cerebral amyloid angiopathy-associated microhemorrhages, a severe side effect associated with bapineuzumab, another monoclonal antibody. Phase II studies in AD patients have shown a good safety profile with encouraging indications on cerebrospinal and plasma biomarkers. The drug is currently being investigated in Phase III trials. While there is a strong hope that solanezumab may represent the first effective passive vaccine for AD treatment, skepticism still exists on the ability of the drug to slow the rate of deterioration in patients with fully established disease. INSET: Key issues. [ABSTRACT FROM AUTHOR]