Overview


Pipeline


For Alzheimer's


For Schizophrenia



Overview


NeuroSolis has developed a pipeline of drugs treating serious neurological and psychiatric disorders. The most advanced of these is clinical candidate NSX-0527 (NeuroSolis EXperimental Compound #0527). Follow-on compound NSX-0559 has undergone similar preclinical testing. Also in development are two formulations, NSX-0527f and NSX-0559f, designed to allow higher dosing without accompanying side effects. NSX-0527 can be taken orally, enters the bloodstream, and penetrates the blood-brain barrier to stimulate various brain regions. It is ready for formal animal toxicology and safety pharmacology testing necessary as a precursor to human clinical trials.


Technical Description


NSX-0527 is a muscarinic agonist, a class of drugs that mimic the neurotransmitter acetylcholine, which activates five receptor subtypes (M1-M5) in the muscarinic class. In the brain, activation of the M1 receptor is known to improve memory and cognition, while activation of the M4 receptor is known to regulate dopamine release, the overabundance of which contributes heavily to the "positive symptoms" of schizophrenia. A wide variety of muscarinic agonists have demonstrated both memory enhancing and antipsychotic activity in a number of animal models as well as human clinical trials. One of these, the muscarinic agonist xanomeline, significantly improved memory and cognition and measurably reduced delusions and hallucinations. Ultimately, xamomeline was abandoned due to poor tolerability and low potency. NSX-0527 has been extensively tested in animals and demonstrates excellent potency with manageable side effects.




For Alzheimer's


The signaling molecule acetylcholine (a neurotransmitter) plays a critical role in numerous brain circuits, facilitating communication between nerve cells (neurons) essential for learning, memory, and cognition. Neurons responsible for the production of acetylcholine are some of the first to die during the earliest stages of Alzheimer's disease. The resulting deficits can be treated to some extent by a class of drugs called acetylcholinesterase inhibitors (AChEIs), which includes the most commonly prescribed drug for Alzheimer's called donepezil (Aricept). These drugs inhibit the natural breakdown of acetylcholine, and thus increase its concentration in the brain. However, their benefits are modest and short-lived. As the disease progresses and more neurons die, even less acetylcholine is produced. Ultimately, AChEIs cannot counteract dropping levels of acetylcholine and lose their effectiveness as the disease enters the moderate stage. NSX-0527, the clinical candidate under development by NeuroSolis, mimics acetylcholine directly, thereby replacing dwindling stores of the neurotransmitter in order to support and maintain memory and cognition.


NSX-0527 has three distinct advantages compared to Aricept and the other acetylcholinesterase inhibitors: (1) It will provide greater benefit as the disease progresses through the moderate and severe stages. (2) NSX-0527 preferentially activates acetylcholine signaling pathways utilizing the M1 and M4 receptors, which are thought to be the most important for memory and cognition. (3) Finally, muscarinic agonists like NSX-0527 may have the potential to modify Alzheimer's disease progression by reducing the production of beta amyloid, the main component of plaques seen in the brains of patients.


For Schizophrenia


Although several antipsychotics are approved for schizophrenia, treatment with drugs remains problematic. Antipsychotics are effective at easing the well known positive symptoms (delusions and hallucinations). But schizophrenia has equally disruptive negative symptoms (emotional blunting and lack of motivation), as well as cognitive symptoms (poor memory and difficulty with decision making). Common side effects of current treatments include drowsiness, weight gain, and metabolic disruption. Importantly, these side effects can contribute to the development of other diseases (e.g., diabetes, hypercholesterolemia), which make patients less likely to continue medication. New treatments with fewer side effects that address the negative or cognitive symptoms are in great need. NSX-0527 represents a novel treatment for schizophrenia with the potential to be the first drug to concurrently treat the wide array of symptoms seen in the disorder without the harsh side effects associated with current therapies.