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. As the primary objective when the study was initiated was to evaluate the effect on cognition, the primary outcome measure for the study was a cognitive test battery (Neuropsychological Test Battery, NTB) designed to evaluate attention and executive function. Secondary outcome measures included the gold-standard dementia rating scale, the Clinical Dementia Rating Sum of Boxes (CDR-SB), and a measure of functional mobility, the Timed Up and Go Test (TUG).
In the analyses of the full efficacy analysis that included both the low and high dose neflamapimod treated patients, neflamapimod treatment led to significant improvement relative to placebo in the CDR-SB and the TUG test, though not on the NTB. In secondary exploratory analyses to understand dose-response, the higher dose of 40mg TID demonstrated significant improvement relative to placebo on the NTB, cognitive tests that measured attention, as well as the CDR-SB and TUG. The most consistent treatment effects were seen on the CDR-SB and the TUG, which we believe is related to the ability of those tests to measure both cognitive and motor effects. In addition, encouraging positive trends were on the 10-item Neuropsychiatric Inventory (NPI-10), particularly with respect to the severity of hallucinations.
The results of the AscenD-LB clinical study have been published in the journal Nature Communications. Read – https://www.nature.com/articles/s41467-022-32944-3
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.
The results of the Reverse-SD clinical study have been published in the journal Alzheimer’s Research and Therapy.
"The positive effects in the AscenD-LB clinical study on cognitive and motor function demonstrate neflamapimod has potential as a treatment for patients with dementia with Lewy bodies. If these findings are confirmed in phase 2b and phase 3 clinical studies, neflamapimod could 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.”