Background

T-817MA is an orally available neurotrophic agent being developed for the treatment of Alzheimer's disease by Toyama Chemical, a company of the Fujifilm Group. T-817MA reportedly activates sigma receptors. The compound has been reported in various cell-based and preclinical models to protect neurons against Aβ-induced neurotoxicity and memory deficits (e.g. Hirata et al., 2005; Nguyen et al., 2007; Kimura et al., 2009). T-817MA appears to act by promoting neurite outgrowth and preserving synaptic plasticity in the cortex and hippocampus (Takamura et al., 2013). 

A treatment benefit has also been reported in sensorimotor gating, which is a biomarker for cognitive deficits in schizophrenia, as well as in models of hearing loss; however, no clinical development is ongoing in these indications (Seo et al., 2008; Uehara et al., 2012; Yamashita et al., 2008).

Edonerpic was reported to enhance cortical synaptic plasticity and motor function recovery after stroke, both in mice (Abe et al., 2018; Pines et al., 2019). In Abe et al., edonerpic’s target was proposed to be collapsin response mediator protein 2 (CRMP2), a cytosolic phosphoprotein involved in neurite outgrowth, ion channel trafficking, and synaptic plasticity. However, other investigators dispute that edonerpic binds to CRMP2 (Moutal et al., 2019, reviewed in Takahashi 2019; Khanna et al., 2020). The compound was subsequently reported to act via CRMP2 and the Arc protein to improve long-term neurological recovery in a mouse model of traumatic brain injury (Chen et al., 2022).

Findings

Phase 1 development for T-817MA began in 2005. From 2008 to 2011, a multicenter Phase 2a trial in North America compared a once-daily dose of 224 mg of T-817MA to placebo in 373 patients with mild to moderate Alzheimer's disease who are stable on donepezil. The primary outcome was cognitive function as measured by the ADAS-cog; secondary outcomes were safety and overall impression using the ADCS Global Clinical Impression of Change (CGIC) and ADCS Activities of Daily Living (ADL). In this trial, only 72.1 percent of patients on placebo, versus 61.6 percent on T-817MA, completed the trial, limiting conclusions that can be drawn from its results. Within these limitations, T-817MA appeared to show potential to slow cognitive and functional decline. Numerical differences on cognitive, clinical, and functional readouts favored treatment but fell short of statistical significance. Results of a neuropsychiatric measure favored placebo, also without statistical significance. A small imaging sub-study indicated trends favoring T-817MA, again not statistically significantly. Side effects included diarrhea, nausea, dizziness, and headache; two serious adverse events were considered possibly related to the study drug (Schneider et al., 2013).

In March 2014, the North American consortium Alzheimer's Disease Cooperative Study (ADCS) started another one-year, Phase 2 study of T-817MA called Noble. It compared 224 mg to 448 mg of T-817MA once daily and to placebo. It enrolled 484 patients with mild to moderate Alzheimer's disease who were already taking donepezil or rivastigmine, with or without memantine. This study used the ADAS-cog and ADCS-CGIC as primary outcomes, and safety as well as ADCS-ADL, FAQ, NPI, and MMSE as secondary outcomes. Unlike most ADCS trials, this study received no federal funding but was fully sponsored by Toyama. This trial was completed in May 2017.

On July 19, 2017, Fujifilm Corporation announced that the Noble trial had failed to reach its primary endpoint, and that there were no differences between the groups on secondary endpoints. According to the press release, exploratory analyses spotted biomarker signals in CSF p-tau levels and hippocampal volume, and post-hoc analyses hinted at a possible subgroup effect on cognition. Fujifilm announced its intention to continue developing T-817MA (see company press release). In November 2017, results presented at CTAD confirmed that Edonerpic had failed to outperform placebo on the primary or any of the secondary outcomes. Some biomarkers showed changes, but the changes did not all trend in the same direction. Diarrhea, vomiting, and weight loss were more common in the treatment groups than placebo, and more people in the treatment arms discontinued the trial. Dropouts in the placebo, low and high dose were 11.4, 29.5, and 24.1 percent, respectively (see Dec 2017 conference news).

The complete trial data has been published (Jul 2019 news; Schneider et al., 2019). Among biomarkers, CSF phospho-tau181 and total tau decreased in the high-dose group compared with placebo, while Aβ40 and Aβ42 did not change. Treatment caused no change in hippocampal volume, but ventricular volume increased in the high-dose group.

In February 2016, another Phase 1 trial started. It compared pharmacokinetic parameters of a single dose of T-817MA between otherwise healthy volunteers with mildly, moderately, or severely impaired liver function and people with normal liver function. This trial enrolled 36 people in Florida, and was completed in August 2016.

In April 2019, the company began a Phase 2 trial, enrolling 45 people in Japan to evaluate whether edonerpic improves rehabilitation of partial arm paralysis due to stroke.

A Phase 2 trial began in December 2019 to assess edonerpic’s effect on disease-related biomarkers in 200 people with mild cognitive impairment due to AD, or mild AD, whose clinical diagnosis was confirmed by CSF Aβ and tau abnormality. Participants took 224 mg edonerpic daily for one month, then 448 mg or placebo for an additional 17 months. The primary outcome was change in CSF pTau181 from baseline. Secondary outcomes included CSF total tau, pTau217, Aβ, NfL, neurogranin, and YKL; plasma NfL and Aβ, clinical dementia rating, brain volume, EEG measures, safety, and pharmacokinetics. The trial enrolled 221 participants at 31 sites in Europe. It failed to meet its primary endpoint, according to results presented at the October 2023 CTAD conference. Edonerpic did not change CSF ptau181 compared to placebo. Treatment did not affect most of the secondary endpoints, including the CDR-SB and the Cognitive-Functional Composite, and EEG measures. Just more than 80 percent of the treated group completed the trial. Treatment was deemed safe, although those on edonerpic ended with lower total brain volume and higher ventricular volume, with no change in hippocampal volume.

For details on T-817MA trials, see clinicaltrials.gov.