December 5, 2019
EIP Pharma Announces Presentation of Phase 2b Clinical Trial Results of Neflamapimod in Early-stage Alzheimer’s Disease at Clinical Trials in Alzheimer’s Disease (CTAD) meeting
Results demonstrate target engagement and proof-of-mechanism
Boston, Mass., December 5, 2019 – EIP Pharma, Inc. (www.eippharma.com), a CNS-focused therapeutics company, today announced that the efficacy and safety data from the REVERSE-SD clinical study were presented at the Clinical Trials in Alzheimer’s Disease (CTAD) meeting in San Diego by the principal investigator of the study, Professor Philip Scheltens of the VU Medical Center in Amsterdam, Netherlands. As previously announced, the 24-week, double-blind placebo-controlled Phase 2b study evaluating the oral p38⍺ kinase inhibitor neflamapimod in early-stage Alzheimer’s disease did not meet its primary objective of improving episodic memory, but did meet its secondary objectives of target engagement and proof-of-mechanism through demonstrating statistically significant reductions relative to placebo in cerebrospinal fluid (CSF) levels of phospho-tau and tau. In addition, in pre-specified pharmacokinetic-pharmacodynamic (PK-PD) analyses, positive trends relative to placebo on both the Hopkins Verbal Learning Test (HVLT) and Wechsler Memory Scale (WMS) were evident in neflamapimod-treated patients whose plasma drug concentrations were in the highest quartile within the study. Neflamapimod at 40 mg twice daily, the dose evaluated in the study, was well tolerated. The full presentation is available on the Company’s website at www.eippharma.com/presentations.
“The CSF biomarker effects of neflamapimod demonstrate (1) target engagement and (2) p38⍺ kinase inhibition impacts the AD disease process, that is, provides proof-of-mechanism,” concluded Professor Philip Scheltens of the VU Medical Center in Amsterdam, and the principal investigator of the study. “The CSF biomarker effects, combined with the episodic memory effects in patients with the highest blood concentrations of neflamapimod, indicate that a study of longer duration and at a higher dose of neflamapimod in patients with early-stage AD is merited and has the potential to demonstrate proof-of-concept.”
“While in the overall study population, treatment with neflamapimod did not demonstrate improved episodic memory relative to placebo in this relatively short duration study, the PK-PD (pharmacokinetic-pharmacodynamic) analysis strongly suggests the dose of neflamapimod was too low for a significant clinical effect, with an optimal dose likely to be 50 to 100 percent higher than the dose evaluated in the REVERSE-SD study,” said Dr. John Alam, President and CEO of EIP Pharma. “Importantly, neflamapimod appeared to have the intended effects on the underlying disease process in early-stage Alzheimer’s disease, providing the first evidence that the therapeutic potential of p38⍺ kinase inhibition that has been extensively documented in scientific literature translates into an effect on the human disease process.”
About the REVERSE-SD Study
161 patients with early-stage Alzheimer’s disease (AD) 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 >0.24 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 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.
- 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=0.012 vs. placebo; mean difference= – 2.0 pg/mL, 95% confidence interval (CI): -3.6, -0.5] and total tau (p=0.03; mean difference=-18.9 pg/mL, 95% CI: -36.0, -1.8), and a trend on CSF neurogranin (p=0.071; mean difference=-20.9 pg/mL, 95% CI: -43.6, 1.9).
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.
Neflamapimod was well tolerated with only 2 discontinuations (vs. 2 in placebo) for adverse events, one for nausea and one for diagnosis of myeloma. There were two Serious Adverse Events (SAEs) reported in neflamapimod patients (vs. three in placebo), hypokalemia and myeloma; both considered unrelated. The most common adverse events were upper respiratory tract infection (5% neflamapimod, 8% placebo), headache (5%, 6%) falls (6%, 4%), diarrhea (5%, 2%), post lumbar puncture syndrome (4%, 4%), vomiting (3%, 4%), depressed mood (3%, 4%), and fatigue (1%, 5%). One subject in the neflamapimod arm (vs. none in the placebo arm) developed liver enzyme (ALT, AST) elevation to three times upper limit of normal; this patient’s liver enzyme elevation started resolving during one additional week of dosing, and then the subject withdrew from the study.
Neflamapimod is a brain-penetrant, oral small molecule that inhibits the intra-cellular enzyme p38 MAP kinase alpha (p38α). P38α, which is expressed in neurons under conditions of stress and disease, plays a major role in inflammation-induced synaptic toxicity, leading to impairment of synaptic function. Synaptic dysfunction is known to be a major drive of the deficits in cognitive function that are defining characteristics of many CNS diseases. In addition to the Reverse-SD trial neflamapimod is currently being studied in separate Phase 2 trials in patients with dementia with Lewy bodies and with Huntington’s disease who have evidence of cognitive dysfunction.
About EIP Pharma Inc
EIP Pharma, Inc. is a private, Boston, MA-based company advancing CNS-focused therapeutics to benefit patients with neurodegenerative diseases.
For more information, please visit www.eippharma.com.