Alzheimer’s disease (AD) is the most common type of dementia and in Europe it accounts for 61 per cent of all dementia cases. The majority of AD cases occur in adults after the age of 65 years (late-onset AD) and there is no obvious inheritance pattern (sporadic AD). Age is the main risk factor for AD and the disease prevalence is set to rise as the ageing population increases.
Earlier research focused on symptomatic treatments but these are expected to be usurped by disease-modifying drugs that target AD much earlier in its course. The majority of drugs in development for AD target amyloid-beta (Aß) aggregation into neurotoxic amyloid plaques in the brain. Despite many products starting clinical development, there have been a number of failures over the last decade, with most being due to lack of efficacy rather than safety issues. This indicates deficiencies in our knowledge of AD pathogenesis. Nevertheless, more than 40 drugs targeting Aß and other disease pathways are in phase II development, and a few are in phase III.
Targeting amyloid-beta (Aß)
Earlier in 2012, two intravenous (IV) anti-Aß drugs, bapineuzumab (Pfizer, Johnson & Johnson, Elan) and solanezumab (Lilly), failed large phase III clinical trials. Clinical development of IV bapineuzumab was discontinued, but phase II development of a subcutaneous (SC) formulation is ongoing. Pooled analyses from two solanezumab phase III trials showed slowing of cognitive decline, suggesting the amyloid hypothesis need not be discarded entirely. Consequently, Lilly launched the phase III EXPEDITION3 trial to test whether solanezumab will slow the cognitive and functional decline of Alzheimer’s disease in patients with mild forms of the illness.
Monoclonal antibodies with high affinity for Aß in phase II development include: SC gantenerumab (Roche) that targets abnormal Aß build-up in the cerebrum (phase II/III in early-stage AD in the EU, USA and South America); crenezumab (Genentech) that is being investigated in a long-term safety extension of phase II trials and a landmark AD prevention trial (see later); and BAN 2401 (BioArctic Neuroscience, Eisai) that targets Aß-peptide protofibrils.
MK 8931 (Merck & Co.) is a potential first-in-class, potent Aß precursor protein cleaving enzyme (BACE1) inhibitor. Phase II/III development of this oral agent is underway in patients with mild-to-moderate AD. LY 2886721 (Lilly) is another BACE1 inhibitor that was in phase I/II development in the US, Japan and some EU countries, but the phase II part of the study was discontinued in June 2013 due to abnormal liver biochemistry findings.
Phase II agents that prevent peptides from aggregating to form Aß plaques include: the amyloid precursor protein secretase inhibitors ACI 91 (AC Immune) and NIC 515 (Humanetics Corporation); the selective – secretase modulator EVP 0962 (EnVivo Pharmaceuticals); the metal protein-attenuating compound called PBT 2 (Prana Biotechnology); and ELND 005 (Speranza Therapeutics).
In terms of vaccine development for AD, targeting the Aß pathway has resulted in the most promising AD therapies to date. Phase II agents include vanutide cridificar (Elan, Pfizer, Janssen Alzheimer Immunotherapy), intramuscular and SC formulations of CAD 106 (Novartis, Cytos Biotechnology), and SC affitope AD02 (GlaxoSmithKline Biologicals).
Targeting tau
Besides amyloid plaques, neurofibrillary tangles (i.e. aggregates of tau protein inside brain neurons) are a well-known pathological feature of AD. Several compounds targeting tau have reached phase II or III trials. Of these, TRx 0237 (leuco-methylthioninium, TauRx Pharmaceuticals), an oral agent shown to inhibit tau aggregation, is in phase III trials in the US and the UK in patients with mild-to-moderate AD receiving stable acetylcholinesterase (AChE) inhibitor and/or memantine.
An intranasal formulation of davunetide (Allon Therapeutics), which is derived from activity-dependent neuroprotective protein (ADNP), is also in phase II development for the treatment of AD and other neurological conditions.
Two agents targeting tau have been discontinued recently at phase II – methylthioninium chloride (Rember; TauRx Therapeutics) and tideglusib (Nypta; Noscira). Tideglusib is an inhibitor of glycogen synthase kinase 3 (GSK-3), which is an enzyme believed to play a role in tau formation.
Improving synaptic neurotransmission
Levels of neurotransmitters (especially acetylcholine) are significantly reduced in AD, contributing to memory impairment and cognitive deficits. Three agents currently marketed worldwide for treating AD symptoms (donepezil, rivastigmine and galantamine) increase levels of the neurotransmitter acetylcholine by inhibiting AChE.
Adamas Pharmaceuticals is conducting phase II trials of immediate-release donepezil and extended-release memantine, as a once-daily, fixed-dose combination therapy. Other AChE inhibitors in phase II development include methanesulfonyl fluoride (SeneXta Therapeutics), ladostigil (Avraham), rilapladib (GlaxoSmithKline) and R-phenserine (QR Pharma).
Another way to improve acetylcholine signalling between neurons is to stimulate acetylcholine release (eg ST 101 [Sonexa Therapeutics] in phase II development for AD) or by increasing the response to the ‘messenger’ acetylcholine by using nicotinic and muscarinic acetylcholine receptor agonists. Four nicotinic acetylcholine receptor agonists are in phase II development: ispronicline (AstraZenenca), AZD 1446 (AstraZeneca), ABT 126 (AbbVie) and EVP 6124 (EnVivo Pharmaceuticals; phase III AD trial expected to begin in 2013).
Orion Pharma is developing an oral 2c adrenergic receptor antagonist, ORM 12741, for the treatment of AD. A phase II trial in this indication has been completed in Finland and Spain.
Serotonin is also reduced in AD patients. Early trials have shown that the serotonin 6 receptor, primarily found in areas of the brain involved in cognition, could offer a potential target for cognitive disorders. Two serotonin 6 receptor antagonists have completed phase II clinical trials in AD – Lu AE 58054 (Lundbeck A/S) as adjunctive therapy to donepezil and SB 742457 (GlaxoSmithKline) as monotherapy/adjunctive therapy. Lundbeck’s pivotal phase III study for Lu AE 58054 as adjunctive therapy to donepezil in more than 2,500 patients with mild-to-moderate AD, will begin later this year. PF 5212377 (Pfizer) is in phase II development in patients with mild-to-moderate symptomatic AD on a stable dose of donepezil.
Another avenue for improving neurotransmission is via the histamine pathway. Histamine H3 receptors are predominantly found in the CNS and control the production and release of histamine and inhibit the release of other neurotransmitters. Blocking the H3 receptor may improve symptoms of AD by improving neurotransmission. Four histamine H3 receptor antagonists are in phase II development: ABT 288 (AbbVie), AZD 5213 (AstraZeneca), GSK 239512 (GlaxoSmithKline), S38093 (Servier) and SAR 110894 (Sanofi).
Hitting metabolic pathways, oxidative stress and inflammatory pathways
AD has been proposed to be an inflammatory disease. Although agents targeting these pathways have not had much success to date, masitinib (AB Science), an orally active protein tyrosine kinase inhibitor, is proving to be a promising compound and is now in phase III as adjunctive treatment for AD in the EU. It may have potential to treat inflammatory/CNS diseases via activity on mast cells and kinases implicated in activating inflammatory pathways. A pivotal 24-week phase III trial of oral masitinib as an add-on to standard therapy is currently enrolling patients with mild-to-moderate AD from Spain, Poland, Greece, UK and the US (additional trial sites are planned). Another agent HF 0220 (Newron Pharmaceuticals), an oral epiandrosterone derivative thought to protect against oxidative stress-induced neuronal cell death, is in phase II trials in AD.
AC 1204 (Accera) is an oral caprylic triglyceride in phase II/III development for the management of the metabolic processes (errors in glucose metabolism and utilisation) associated with mild-to-moderate AD. In March 2013, a US-based, phase II/III trial (NOURISH AD) began to assess AC 1204 in approximately 480 patients with mild-to-moderate AD with and without the epsilon 4 variant of the apolipoprotein E gene (APOE4).
Ground breaking prevention trials imminent
Researchers are also putting more effort into developing therapies that could ultimately prevent AD, signalling a critical turning point in the search for the elusive cure. Three complementary landmark prevention trials for patients at risk of developing AD are planned or underway.
The first trial (organised by the Banner Alzheimer’s Institute in the US) will assess crenezumab and a BACE inhibitor in asymptomatic patients with a presenilin 1 (PSEN1) E280A mutation that predisposes its carriers to early-onset AD (i.e. development of mild cognitive impairment by age 44 and development of AD dementia by age 49), over a five-year period. Enrolment of subjects of Colombian descent is expected to begin in 2013.
The second five-year trial planned by the Dominantly Inherited Alzheimer Network (DIAN; based at Washington University School of Medicine) will assess two anti-Aß agents (gantenerumab and solanezumab) and a BACE inhibitor (to be decided) in approximately 160 subjects (aged 18-80 years) with gene mutations that virtually guarantee they will develop AD at a young age.
Finally, the Anti-A treatment in Asymptomatic Alzheimer’s disease (A4) trial will enrol approximately 1,000 asymptomatic elderly individuals (70-85 years) who have abnormal A plaque levels or have an increased risk of developing sporadic AD (mutant APOE4 carriers). Subjects will receive solanezumab, a BACE inhibitor (to be decided), or placebo. Enrolment in this three-year, US NIH-funded trial is due to begin after September in the US.
Looking upstream
Research into AD therapies is at a critical point, with investigators turning away from diagnosed AD groups and starting to focus further upstream, anxious to see if new therapies can prevent AD itself, or if patients with very early-stage AD might respond. Scientists are now able to track Aß plaques using brain scans, which have shown that even in patients with mild AD dementia such plaques are already abundant in the areas of the brain responsible for thinking and memory.
Given that build-up of Aß plaques can be detectable as early as 20 years before patients with AD begin to experience dementia, it is possible that this approach could provide researchers with the stimulus to discover and develop the first-ever prophylactic therapy for this devastating disease. Despite recent setbacks, the hunt for the elusive cure for AD must continue to help combat one of the fastest growing health epidemics of our time.