EIP Pharma has secured proof-of-mechanism for neflamapimod (earlier named as VX-745), with the results of two recently completed Phase IIa clinical trials that indicated significant Alzheimer's disease-relevant pharmacological activity.
Neflamapimod is a brain-penetrant, oral small-molecule that inhibits the intra-cellular enzyme p38 mitogen activated protein kinase alpha (p38 MAPKα).
The findings are from Study 302 (12-week treatment) and Study 303 (six-week treatment).
Each study was conducted in patients with Mild Cognitive Impairment (MCI) due to Alzheimer's disease (AD), or mild Alzheimer's disease.
Major efficacy findings from the clinical phase IIa studies show a statistically significant improvement in tests of episodic memory and learning. As assessed by Wechsler Memory Scale (WMS), there were immediate and delayed recall composite measures in Study 302, and Hopkins Verbal Learning Test – Revised (HVLT-R) in Study 303.
There were reductions in brain amyloid plaque load as assessed in Study 302 by quantitative dynamic amyloid PET scan.
Definition of 40mg twice daily was found to be the optimal dose for neflamapimod in the treatment of Alzheimer's disease.
Additionally, neflamapimod at a dose level up to 125mg twice daily for 12 weeks was very well tolerated in patients with Alzheimer's disease, and neflamapimod was confirmed to be the blood-brain-barrier penetrant in humans.
Amsterdam-based VU Medical Center Alzheimers Centre director and principal investigator for Study 302 professor Philip Scheltens said: "Neflamapimod treatment showed improvement in memory tests that assess immediate and delayed recall in both Phase 2a studies; strongly suggestive of reversal of synaptic dysfunction.
“In addition, in our study, 12 weeks treatment at a 40mg dose level led to a reductions in brain amyloid plaque load as assessed by dynamic PET scanning.
"With the demonstration of proof-of-mechanism and the definition of an optimal dose, neflamapimod is well positioned to demonstrate proof-of-concept on clinical cognitive endpoints in a next study in patients with early Alzheimer's disease."
For the Study 302, 16 patients aged 60 to 85 with MCI due to AD or mild AD were randomised on a blinded basis to 40mg or 125mg neflamapimod twice daily with food for 12 weeks.
The main efficacy endpoint was a change in amyloid load as measured quantitatively using dynamic [11C]-PiB (Pittburgh-B) PET scans, performed at baseline and at end-of-treatment (day 84), analysed by reference parametric mapping (RPM2) using cerebellum as reference tissue.
Given that the quantitative dynamic approach to PET scanning reduces test-retest variability to 2-3%, the pre-specified responder definition was a greater than 7% reduction in PET signal.
Secondary outcome measures included change in WMS and Mini-Mental-Status-Examination (MMSE).
For Study 303, patients with MCI due to AD or mild AD and an MRI consistent with AD were included.
Originally, 16 patients were to be randomised to either 40mg or 125mg neflamapimod twice daily with food for six weeks.
After three subjects were enrolled, the higher dose group was, however, discontinued due to US-specific regulatory authority requirement to limit dosing to expected plasma drug exposure levels, offering ten-fold safety margin relative to long-term animal toxicology findings.
Cerebrospinal fluid (CSF) cytokines and Aβ peptides were assessed at baseline and at week six (end-of-treatment), and intensive plasma and CSF pharmacokinetics obtained on days one and 41. Verbal learning / episodic memory was assessed with the Hopkins Verbal Learning Test – Revised (HVLT-R). MMSE was evaluated at screening and day 40.
A total of 25 patients were enrolled in the two studies: 16 in Study 302 (nine at 40mg and seven at 125mg for 12 weeks), and nine in Study 303 (eight at 40mg and one at 125mg for up to six weeks).