SAN DIEGO – Smaller companies looking to move their Alzheimer’s disease drugs into late-stage testing as quickly as possible are eschewing cognitive endpoints that can take years to readout for biomarkers and functional assays of brain activity.
"Biomarkers are very important because it’s difficult and messy to measure cognition and function; you need a lot of patients and large trials," Lindsay Burns, vice president of neuroscience at Cassava Sciences Inc. told BioWorld.
Cassava looked at biomarkers for a phase IIa study of PTI-125, which binds altered filamin A (FLNA), an intracellular scaffolding protein that interacts with more than 90 proteins in its normal function and ultimately influences many signaling pathways.
In Alzheimer’s disease patients, the conformation of FLNA can become altered, which allows amyloid beta 42 signaling through the alpha7-nicotinic acetylcholine receptor leading to the hyperphosphorylation of tau, which causes tau to lose function and aggregate in filaments. Amyloid beta 42 can also signal through toll-like receptor 4 to produce chronic neuroinflammation. PTI-125 binds to altered FLNA and restores the proper shape and function of the protein.
Data presented at the 12th Clinical Trials on Alzheimer’s Disease Meeting (CTAD) last week showed 13 patients treated with PTI-125 for 28 days had their phosphorylated tau in their cerebrospinal fluid reduced by 34% (p<0.0001 by paired t-test). Cytokines interleukin-6 and interleukin-1beta, markers of inflammation, were reduced by 14% and 11%, respectively (p<0.0001 by paired t-test for both). Cassava also saw an 8% increase in amyloid beta 42 levels, suggesting the protein was released from the acetylcholine receptors.
Cassava is in the process of running a phase IIb placebo-controlled study of PTI-125 with data expected next year. The study will measure the same biomarkers because "the main criticism of the first trial is that it wasn’t placebo controlled," Burns explained. The phase IIb study will also test a second lower dose to try and show a dose response and will also look at exploratory measures of cognition to use as a guide in late-stage studies.
In a phase Ia/b study of NDX-1017 in 88 healthy subjects and Alzheimer’s disease patients, Athira Pharma Inc., of Seattle, used quantitative electroencephalography (qEEG) as a biomarker of brain circuitry activity and an event-related potential (ERP) as a measure of working memory access and cognitive processes in the brain.
"You don’t have to wait 12 months to see changes in the brain," Leen Kawas CEO and president of Athira said of the objective measures of brain function.
NDX-1017 is an agonist of hepatocyte growth factor (HGF) met receptor, which was historically named for where it was first discovered but also has a role in regeneration and the promotion of synapses in the brain. By activating HGF in Alzheimer’s patients with neurodegeneration, Athira representatives think NDX-1017 can tip the balance towards regeneration.
At CTAD, Athira presented qEEG data showing NDX-1017 stimulated higher frequency gamma activity in the brain compared to baseline one and three hours after dosing on days four and eight in healthy subjects and Alzheimer’s disease patients.
The ERP test measures cognitive processing of a task, which occurs after about 300 milliseconds in a healthy person but is typically delayed to about 400 milliseconds in Alzheimer’s disease patients. Treatment with NDX-1017 for eight days reduced the latency by about 74 milliseconds compared to a reduction of 10.25 milliseconds for placebo (p<0.05).
Next year, Athira is planning to start a 26-week phase II/II study which will measure cognition, clinician’s impression, function and other measures.
Cortexyme Inc., of South San Francisco, is testing the hypothesis that infection with P. gingivalis results in neurodegeneration and inflammation in the brains of Alzheimer’s disease patients. P. gingivalis use amino acids, rather than sugars, as energy and carbon sources, secreting gingipains to break down the hosts’ proteins.
At CTAD, Cortexyme presented data showing that gingipains from the bacteria cleave apolipoprotein E (ApoE) and prefer cleaving the ApoE4 variant, which is linked to a higher risk of developing Alzheimer’s disease, compared to ApoE3. Cortexyme’s lead molecule, COR-388, was able to block the cleavage of ApoE in vitro.
In a phase Ib study, treatment of Alzheimer’s disease patients with COR-388 for 28 days reduced the level of ApoE fragments in the cerebrospinal fluid to about 70% of baseline, while those treated with placebo had no change. The company also looked at cognitive function and saw trends in the right direction with COR-388 performing better than placebo, although the study wasn’t powered to show an effect with just six patients treated with COR-388 and three patients treated with placebo.
"This is consistent with the idea that some neurons are left, but they’re dysfunctional because of the inflammation and because of the gingipains that are there," Casey Lynch, CEO, co-founder, and chairman of Cortexyme told BioWorld, noting that the company needed to confirm the result in a larger study.
Cortexyme is currently running a 570-patient phase II/III study of COR-388 with top line data expected in the fourth quarter of 2021.