Prior to licensing by EIP Pharma, neﬂamapimod was evaluated clinically in non-brain disorders and had preliminarily demonstrated activity in patients with rheumatoid arthritis. The combination of blood-brain-barrier penetration and demonstrated clinical activity positioned neﬂamapimod to target p38 alpha in the brain, affording us the opportunity to pursue the treatment of Alzheimer’s disease and other CNS diseases.
To date, neﬂamapimod’s activity in CNS disease has been evaluated in two phase 2a clinical studies, both focusing on early-stage Alzheimer’s disease.
- Study 302, a 12-week treatment study conducted at VU Medical Center in Amsterdam, Netherlands.
- Study 303, a 6-week treatment study conducted at the Early Clinical Phase Unit – Los Angeles, part of Parexel International.
Both studies were completed in early 2017, with 40 mg neflamapimod twice daily recommended as the dose for the treatment of Alzheimer’s. Results from these studies demonstrated that neflamapimod is well tolerated, crosses the blood brain barrier and is pharmacologically active in the brain. Furthermore, we obtained preliminary evidence that neflamapimod improves outcomes in tests of episodic memory function, consistent with it reversing synaptic dysfunction.
Study 302 (NCT02423122)
Sixteen patients with early Alzheimer’s were enrolled in this study and were randomized to receive either 40 mg or 120 mg neflamapimod twice daily for 12 weeks. Neflamapimod was well tolerated at both dose levels, with no severe or serious adverse events resulting in discontinuation of the study drug. The most common adverse event was diarrhea in three subjects of the sixteen subjects in the study; two of these events were mild in severity, with the third event, that was moderate in severity, considered as not related as the event did not recur during an additional 56 days of treatment after a brief treatment interruption.
At the end of treatment the major clinical finding was statistically significant improvement in episodic memory function with neflamapimod, as assessed by immediate recall (p=0.005) and delayed recall (p < 0.001) composites of the relevant components of the Wechsler Memory Scale (WMS). The improvement was progressive over the 3-months of treatment. The within-subject treatment effect size was in the medium to large range: 0.59 for immediate recall and 0.67 for delayed recall. In addition, individual subject plasma drug concentration profiles were highly significantly positively correlated with the change in combined WMS immediate and delayed recall (p < 0.0001, r2 = 0.70).
The primary biomarker endpoint in the study was change in brain amyloid plaque load by quantitative dynamic amyloid PET scanning, with 4 of the 16 patients meeting pre-defined responder criteria for a significant reduction in brain amyloid plaque load between baseline and month 3 PET scans. No correlation was evident between improvement in episodic memory function and reduction in brain amyloid plaque load.
Study 303 (NCT02423200)
Nine patients with early-stage Alzheimer’s were enrolled in this study, with eight patients receiving neflamapimod at 40 mg twice daily and one patient receiving neflamapimod at 125 mg twice daily. Both cohorts were treated for up to 6 weeks. Neflamapimod was well tolerated with no significant adverse events. Mild back pain and mild headache were reported in four patients each, possibly related to the cerebrospinal fluid (CSF) collection, as these events were not reported in Study 302.
CSF cytokines and amyloid beta peptides were assessed at baseline and at week 6 (end-of-treatment). Episodic memory was assessed by immediate and delayed recall composites of the Hopkins Verbal Learning Test (HVLT-R), a well validated word-learning test to measure memory function. Patients experienced a statistically significant improvement in episodic memory function with neflamapimod. Total immediate recall (range of 0 to 36) improved from 19.1 (+/-1.5) at baseline to 22.6 (+/-2.1) at week 6 (p=0.029 vs. baseline; p=0.015 for improvement). Delayed recall (range of 0 to 12) increased from 5.4 (+/-0.6) to 7.5 (+/-1.1) (p=0.055; p=0.028 for improvement).
Of nine cytokines assessed, only CSF IL-8 was quantifiable at the measured time points. CSF IL-8 at week 6 was significantly reduced compared to baseline (p < 0.001) in the three subjects who had the highest plasma drug levels. A concentration-dependent trend was seen for CSF amyloid beta: the three subjects with the highest plasma drug exposure had higher levels of amyloid beta peptides at week 6 compared to baseline, while the remaining subjects had similar or lower levels of amyloid beta peptides at week 6 compared to baseline.
"Neflamapimod treatment showed improvement in memory tests that assess immediate and delayed recall in two phase 2a studies, strongly suggestive of reversal of synaptic dysfunction. 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 subsequent study in patients with early Alzheimer's disease."