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Solanezumab (proposed INN, LY2062430) is a monoclonal antibody being investigated by Eli Lilly as a neuroprotection International Nonproprietary Names for Pharmaceutical Substances (INN, prepublication copy), World Health Organization. for patients with Alzheimer's disease. The drug originally attracted extensive media coverage proclaiming it a breakthrough, but it has failed to show promise in Phase III trials.
Aside from Alzheimer's disease, there are other amyloid beta related diseases, in which solanezumab could be used, e.g., Down syndrome or cerebral amyloid angiopathy. However, this has not been studied so far.
Other anti-amyloid beta antibodies caused amyloid-related imaging abnormalities, which is not the case for solanezumab.
Solanezumab is thought to act as an "amyloid beta sink" that is "facilitating flux of amyloid beta from a central to peripheral compartment". This increases the peripheral elimination of both amyloid beta and the antibody. Amyloid beta plaques mostly consist of amyloid beta42. Solanezumab binds free amyloid beta which causes amyloid beta42 to solubilize to reestablish the equilibrium in the cerebrospinal fluid.
In 2011, TPG-Axon Capital funded part of the phase 3 trials. It will receive an estimated $70 million of based on sales milestones after the launch of the product.
Due to those results, it is postulated that m266 binds free amyloid beta in the plasma and, therefore, changes the amyloid beta equilibrium between plasma and brain.
Plasma amyloid beta levels increased dose dependently over the course of treatment. In the cerebrospinal fluid amyloid beta40 increased, whereas amyloid beta42 increased. This could be due to a change in equilibrium between plasma, cerebrospinal fluid and amyloid beta plaques. However, there were no significant changes in cognition and memory.
A total of 1012 patients participated in EXPEDITION 1, EXPEDITION 2 enrolled another 1040 patients. Both studies were not able to show a difference in cognition and memory between the treated and the placebo group. However, a subgroup analysis of only patients with mild Alzheimer's disease showed less worsening of cognition in patients receiving solanezumab compared to placebo, which means the progression of the disease was slowed down. There was no effect on disease progression in patients with moderate symptoms.
Since the first two EXPEDITION trials show a positive effect in patients with mild Alzheimer's disease, Lilly launched another phase 3 trial, EXPEDITION 3 (NCT01900665). Patients with mild Alzheimer's disease received 400 mg solanezumab every 4 weeks for 80 weeks. Afterwards they can continue treatment for a total of 208 weeks, if wanted. This trial failed to show positive results, despite the high expectations. The trial will be finalized in 2020.
The Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) study is a phase 3 clinical trial to evaluate whether solanezumab can slow cognitive decline in cognitively unimpaired older adults with elevated levels of amyloid β. In July 2023, the final data showed that it did not slow cognitive decline as compared with placebo over a period of 240 weeks in persons with preclinical Alzheimer's disease.
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