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.
Neﬂamapimod’s activity in CNS disease has been evaluated in two types of dementias: Dementia with Lewy bodies and Alzheimer’s disease.
Dementia with Lewy Bodies (DLB)
AscenD-LB was a Phase 2 double-blind, placebo-controlled, 16-week treatment proof-of-concept study (“AscenD-LB”) of neflamapimod in mild-to-moderate dementia with Lewy bodies (DLB) conducted at 22 centers in the United States and two centers in the Netherlands. 91 patients were enrolled between October 2019 and March 2020 and randomized to receive 40 mg neflamapimod capsules or matching placebo capsules (randomized 1:1) for 16 weeks. The dosing regimen was based on weight, with study participants weighing less than 80 kg receiving capsules twice daily (BID) and those weighing greater than or equal to 80 kg receiving capsules three times daily (TID). All patients had to have already been receiving oral cholinesterase inhibitor therapy for at least 3 months (stable dose for greater than 6 weeks) and continued such therapy without dose modification during the study.
The study met the primary endpoint, with significant, clinically-relevant effect size improvement in cognition in patients receiving neflamapimod 40mg three times daily (TID) compared to those receiving either placebo or neflamapimod 40mg twice daily (BID), as assessed by a Neuropsychological Test Battery (NTB) designed to evaluate attention and executive function. The positive effect on the NTB was evident at week 4 and was maintained throughout the 16-week study period. Multiple sensitivity analyses (with or without imputation of any missing data) support the primary analysis, demonstrating significantly improved outcomes on the NTB in the neflamapimod TID patients compared to those receiving placebo.
Analyses of secondary endpoints demonstrated statistically significant clinically relevant effects on the Timed Up and Go Test, indicating a positive effect on functional mobility, and Clinical Dementia Rating Sum-of-boxes (CDR-SB), a measure of dementia severity. In addition, encouraging positive trends on the 10-item Neuropsychiatric Inventory (NPI-10), particularly with respect to hallucinations.
Initial results were presented at the 13th Clinical Trials in Alzheimer’s Disease (CTAD) meeting in November 2020 and final results will be presented at 14th CTAD meeting in November 2021.
Alzheimer’s Disease (AD)
Reverse-SD was a phase 2b study in patients with early-stage Alzheimer’s disease (AD). 161 patients were enrolled at 38 sites in the Czech Republic (5 sites), Denmark (3 sites), Netherlands (3 sites), United Kingdom (11 sites) and USA (16 sites); and were randomized 1:1 to receive neflamapimod 40 mg capsules or matching placebo capsules twice daily with food for 24 weeks. Inclusion criteria were as follows: aged 55 to 85, with CDR-Global score of 0.5 or 1.0; CDR memory sub-score of at least 0.5; MMSE score of 20 to 28, inclusive; positive biomarker for AD, as defined by CSF Aβ1-42 <1000 pg/mL and phospho-tau/Aβ1-42 >0.024 in the Roche Eclesys® immunoassay; receiving either no AD-specific therapy or on a stable dose monotherapy (either cholinesterase inhibitor or memantine; dual therapy excluded).
In the full efficacy population there was no evident difference between the neflamapimod and placebo groups in the primary study clinical efficacy endpoint, the combined change from baseline to week 24 in the z-scores of Hopkins Verbal Learning Test (HVLT) Total Recall and Delayed Recall. In the analysis of CSF biomarkers, there were statistically significant effects of neflamapimod treatment, with a reduction relative to placebo, in the change from baseline to week 24 in CSF protein levels of p-tau181 (p=0.01) and total tau (p=0.03), and a trend on CSF neurogranin (p=0.07).
As a single dose of neflamapimod was utilized in the trial, pre-specified pharmacokinetic pharmacodynamic (PK-PD) analyses were conducted to evaluate the results for potential dose-dependency. These analyses showed improvement, relative to the placebo group, in tests of episodic memory in neflamapimod-treated patients with the highest (top quartile) trough plasma drug concentrations; with positive trends evident both for the primary endpoint (combined change in z-scores of HVLT total recall and delayed recall) and the major secondary endpoint of change in Wechsler Memory Scale Combined Immediate and Delayed Recall composites.
Phase 2a studies in early Alzheimer’s disease 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.
"The demonstrated positive effects on the AscenD-LB study’s primary endpoint, cognition, and as well as on a number of secondary endpoints, establishes proof-of-concept for neflamapimod as a possible treatment for patients with dementia with Lewy bodies. If these findings are confirmed in phase 3 clinical studies, neflamapimod could potentially become the first approved therapy for this devastating disease. DLB is not only the second most common neurodegenerative dementia but is also associated with substantial reduction of patient quality of life and high caregiver burden.”