The approved Abeta immunotherapies that decrease the brain load of the toxic amyloid (Ab) oligomers/aggregates provide only a delayed and modest improvement. Therefore, there is an urgent need for treatments to improve cognitive function in Alzheimer’s Disease (AD) in a fast way.An extremely early event in the pathogenesis of AD is the selective degeneration of basal forebrain cholinergic nuclei leading to a deficit in acetylcholine while post-synaptic M1 muscarinic receptors (M1 mAChR) are preserved. The M1 mAChR is a fundamental player in learning and memory and a primary drug target for the treatment of memory deficits, psychosis, and disease-modifying therapy. Activation of M1 mAChR can be achieved through direct-acting M1 muscarinic agonists that interact with the post-synaptic M1 mAChR, and unlike the SOC cholinesterase inhibitors, their activity is independent of the functional or anatomical integrity of the cholinergic terminals and would likely retain efficacy as the disease progresses. Such a potential drug is the orthosteric selective M1-agonist, AF267B, licensed to NSC. New patents were filed for specific polymorphic structures and have already been granted in several territories (USA, Japan, Europe). AF267B (NSC001) is selective for M1 mAChR, highly brain penetrable, and lacks typical dose-limiting side effects as shown in 4 phase 1 studies. Due to increased cholinergic stimulation, a fast pro-cognitive effect of NSC001 in AD patients is expected. In addition, preclinical studies showed that NSC001 has the potential to be a disease-modifier in AD based on its combined beneficial effects on cognition, decreased Ab, tau, and a-synuclein pathologies, and its control of TREM2 ectodomain shedding which influences neuroinflammatory reactions.  

NSC001 is ready for phase 2.  To find the optimal balance between efficacy and tolerability, a slow dose titration over 4 weeks to the highest well-tolerated dose will be done in patients suffering from mild to moderate AD. In parallel, a second treatment arm will be investigated with concomitant dosing of a peripheral muscarinic antagonist (Trospium) to explore if this will increase tolerability and potentially even allow an increase in daily dosing. After the decision about the maximum dose in both arms, a total of 90 patients will be treated for another 3 months. Then treatment effects on safety, tolerability, and cognitive function, as well as on changes in plasma AD biomarkers will be investigated. The study will provide important data for the later confirmatory trials in AD.