Alzheimer’s Disease (AD) continues to be a pressing global health concern, affecting millions of people worldwide. Reduced cholinergic transmission has been identified as a crucial neurotransmitter dysfunction in AD. In light of this, researchers have been investigating potential treatments such as NXX-066, a physostigmine analog and acetylcholinesterase (AChE) inhibitor. This article delves deep into the findings of a bridging study conducted to determine the maximum tolerated dose (MTD) of NXX-066 in AD patients.
What is Alzheimer’s Disease?
Alzheimer’s Disease is a neurodegenerative disorder characterized by progressive cognitive decline, memory loss, and behavioral changes. It is the most common cause of dementia, accounting for approximately 60-80% of all dementia cases. AD typically affects older individuals, with the risk increasing significantly after the age of 65.
What is Cholinergic Transmission?
Cholinergic transmission refers to the transmission of signals between nerve cells that involves the neurotransmitter acetylcholine. This neurotransmitter plays a crucial role in various cognitive functions, including memory, attention, and learning. However, in Alzheimer’s Disease, cholinergic transmission is impaired, leading to the characteristic cognitive decline.
What is NXX-066 and how does it work?
NXX-066 is a physostigmine analog and acetylcholinesterase inhibitor. Acetylcholinesterase is an enzyme responsible for breaking down acetylcholine in the synaptic cleft, effectively terminating its signaling. By inhibiting acetylcholinesterase, NXX-066 helps increase the levels of acetylcholine, thereby enhancing cholinergic transmission.
NXX-066 has shown promise in animal models of memory function, suggesting its potential as a treatment for Alzheimer’s Disease. Prior studies have also demonstrated its tolerability in healthy subjects at various doses. However, the effects of AChE inhibitors can differ in AD patients compared to healthy volunteers, necessitating the need for further investigation in this target population.
What were the results of the bridging study?
The bridging study conducted was a randomized, placebo-controlled, double-blind, single-center, inpatient trial. AD patients were grouped into seven concurrent panels, with each panel receiving a fixed oral dose of NXX-066 for seven days. The dosage for each subsequent panel depended on the tolerability of lower doses.
Through this study, the researchers determined that the maximum tolerated dose (MTD) of NXX-066 for AD patients was found to be 70 mg BID (twice a day). It is important to note that when the dosage was increased to 80 mg BID, four out of six patients had to discontinue the study prematurely due to adverse events, including nausea, vomiting, dizziness, headache, asthenia, and gastric symptoms.
Moreover, the study revealed wide variability in the plasma levels of NXX-066 across all dose panels. While AChE inhibition in whole blood correlated with the maximum plasma concentration and dose, it did not predict the occurrence of adverse events.
What were the adverse events observed in the study?
The adverse events observed during the study primarily involved gastrointestinal symptoms such as nausea and vomiting, along with mild to moderate dizziness, headache, and asthenia in some patients. These findings highlight the importance of determining the maximum tolerated dose to minimize the occurrence of such side effects in future treatments.
It is worth noting that AD patients tolerated larger daily doses of NXX-066 on a BID regimen compared to healthy subjects who tolerated it with QD dosing. The study suggests the possibility that the differing tolerability between these two groups may be due to variations in their dosing intervals.
“AD patients tolerated larger daily doses of NXX-066 on a BID regimen than healthy normal subjects had tolerated with QD dosing.”
These intriguing results warrant further research to explore the unique tolerability patterns that AD patients exhibit compared to healthy individuals and to investigate whether the reduced dosing interval contributes to this difference. Such studies would contribute valuable insights towards developing more effective treatments for Alzheimer’s Disease.
Sources:
NXX-066 in patients with Alzheimer’s disease: a bridging study