New Alzheimer's Drug Candidate a
Head Scratcher

July 16, 2019

A trial of a new Alzheimer's drug candidate is proving to be a bit of a head scratcher for researchers.

Phase 2 results of edonerpic maleate (Fujifilm Toyama Chemical Co) reduced cerebrospinal fluid (CSF) tau levels but had no clinical benefit at 1 year.

"This drug has an interesting preclinical profile and a strong rationale for clinical testing in Alzheimer's. It is disappointing not to have shown any benefit on symptoms in a well-powered clinical study," study investigator Howard Feldman, MD, University of California San Diego School of Medicine, told Medscape Medical News

The study was published online July 9 in JAMA Neurology.

Preclinical Promise

Edonerpic maleate has shown promise in preclinical studies, with findings suggesting it may guard against amyloid-induced neurotoxicity and memory deficits. It has also been shown that it preserves hippocampal synapses and spatial memory in tau transgenic mice.

In an earlier phase 2 trial in Alzheimer's disease (AD), a dose of 224 mg/day of edonerpic maleate for 1 year did not demonstrate efficacy on primary and secondary outcomes, but there was post hoc evidence for a positive cognitive effect in patients with moderate impairment who had Mini-Mental State Examination (MMSE) scores of less than 20.

For the current study, 484 patients with mild to moderate AD and MMSE scores of 12 to 22, and who were taking stable doses of donepezil or rivastigmine, with or without memantine, were randomly assigned 1:1:1 to placebo, 224 mg of edonerpic maleate, or 448 mg of edonerpic maleate, once daily.

After 1 year, no effect was seen on the two co-primary outcomes: scores on the Alzheimer's Disease Assessment Scale–Cognitive Subscale (ADAS-Cog) and Alzheimer's Disease Cooperative Study–Clinical Impression of Change (ADCS-CGIC).

Discontinuation of treatment because of adverse events occurred in 4% of placebo patients vs 13.9% of the edonerpic maleate 224 mg group and 14.6% of the 448 mg group. The most frequent adverse events were diarrhea and vomiting.

CSF biomarker outcomes showed no difference in amyloid beta levels between the various groups, but did show a significant reduction in tau vs placebo in the high-dose edonerpic maleate group.

"We don't want to overstate it, but we saw an intriguing effect on CSF tau and phospho-tau — both were significantly reduced in the treatment group compared with the placebo group," said Feldman.

"But this was only in a small subgroup of about 60 people who agreed to undergo lumber punctures. This was not the primary hypothesis of the study and must be interpreted with caution. I would say this is an interesting finding that merits further study, but we can't say much more about this at present," he added.

Table. CSF Tau and Phospho-Tau Results 


Placebo baseline

Placebo change from baseline

Edonerpic maleate 448 mg


Edonerpic maleate 448 mg

change from baseline 

Difference versus placebo

P value

Tau  (pg/mL)







Phospho-Tau  (pg/mL)








The authors note that although there may be a suggestion that the 448 mg edonerpic maleate dose was associated with decreased p-tau and total tau, baseline values were not balanced and the effect sizes were implausibly large. Any inference that edonerpic maleate showed neuroprotection in this study would be speculative and would lack supporting clinical evidence, they note.

However, they add there is a possibility that the drug "eventually may be shown to have neuroprotective effects in other conditions, other tauopathy, earlier-stage Alzheimer disease, and potentially in cerebrovascular injury models."

"Tau has been identified as a potential biomarker of Alzheimer's, and it has been the view that lowering tau should be beneficial, but at present we don't have any validation that altering any biomarker in this disease makes any difference to clinical symptoms," Feldman added.

The investigators also found an increase in ventricular volume in the 448-mg edonerpic maleate group compared with placebo (29.16 procedure-defined units vs 23.17 procedure-defined units). This was unexpected, said Feldman, and again the meaning is uncertain.

The investigators also note that although increased ventricular volumes have generally suggested brain volume loss, where such findings have been described with amyloid-lowering treatment, the effect has been explained as related to amyloid removal, fluid shifts, or neuroinflammatory effects with fluid shifts.

Another analysis showed reduced hippocampal volume loss with the lower edonerpic maleate dose compared with placebo, which the researchers note is also of unclear significance in the absence of clinical effect.

Still Hopeful

Feldman said he does not know if any further studies of edonerpic maleate in AD are planned.

"The future of the development of this drug is not our decision. It is up to the company.  But these results do not provide any clinical evidence that it is effective."

He explained that the drug modifies microglial function.

"This is an interesting target. It is thought that the pathology of Alzheimer's seems to trigger the activation of microglia and the release of inflammatory cytokines. There has long been interest in pursuing anti-inflammatory approaches in Alzheimer's. This is one of those approaches by targeting microglial function."

However, said Feldman, the lack of clinical benefit in the study does not necessarily mean this approach is ineffective. 

"We may need to focus earlier in the disease process. We are starting to get better at identifying Alzheimer's pathology in waiting. We have PET ligands for amyloid and tau, and 25% of the population over age 55 test positive for amyloid on PET scan. Some may argue that we should be intervening at this stage even though these individuals do not have any dementia symptoms," he said.  

Feldman also emphasized that AD researchers need to diversify their approach.

"We are working on identifying additional biomarkers," he noted. "We need to explore many other new targets until we find one that correlates with symptomatic benefit."

The study was funded by Fujifilm Toyama Chemical Co Ltd. Feldman reports receiving grants and travel expenses from Toyama Chemical Co Ltd during the conduct of the study.

JAMA Neurol. Published online July 8, 2019. Full text

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