NDX-1017 is a brain-penetrant small molecule that activates signaling via the hepatocyte growth factor (HGF)/MET receptor system. HGF promotes proliferation and survival of neurons, enhances hippocampal synaptic plasticity, and boosts learning and memory (Akimoto et al., 2004; Kato et al., 2012). NDX-1017 is being developed as a subcutaneous once daily injection.
Hippocampal expression of MET receptors is diminished in Alzheimer’s disease (Hamasaki et al., 2014). Conversely, expression of HGF by gene transfer improved Aβ-induced cognitive deficits induced in mice, and prevented motor symptoms and neuron loss in a rat model of parkinsonism (Takeuchi et al., 2008; Koike et al., 2006).
Direct, intrathecal administration of hepatocyte growth factor itself has been studied in a rat model of ALS and a marmoset model of traumatic brain injury, and is being investigated clinically for ALS in Japan (Aoki et al., 2019).
No preclinical studies of NDX-1017 have been published. The drug may be related to N-hexanoic-Tyr-Ile-(6) aminohexanoic amide, aka Dihexa, U.S. Patent 8598118B2. This small-molecule, brain-penetrant angiotensin IV analog was invented by researchers at Washington State University, Pullman. Dihexa activates HGF/MET signaling to stimulate dendritic arborization and synaptogenesis, and improves learning/memory in aged rats, and in rats with scopolamine-induced amnesia (ScienceDaily news story; McCoy et al., 2013; Benoist et al., 2014; reviewed in Wright and Harding, 2015).
Athira Pharma was founded to commercialize the technology, and further development led to NDX-1017.
In October 2017, the company began a first-in-human, Phase 1 safety study of single- and multiple-ascending doses in healthy people and AD patients. Funded by ADDF and others, the placebo-controlled trial tested doses from 2 to 90 mg, injected subcutaneously. Outcomes were drug-related adverse events and pharmacokinetics.
Results were presented at the 2019 CTAD conference (Dec 2019 conference news). In the single-ascending-dose portion, 48 healthy volunteers received up to 90 mg and no drug-related adverse events were seen. Likewise, multiple dosing of 29 healthy elderly and 11 AD patients with up to 80 mg/day for nine days raised no safety issues, with dose-proportional pharmacokinetics in all groups.
Quantitative electroencephalography (qEEG) and event related potential (ERP) measures were evaluated as noninvasive markers of brain penetration and target engagement by NDX-1017. EEG gamma power is associated with learning, memory and executive functions, while ERP P300 latency is a marker of cognitive processing speed. In people with AD, gamma power is reduced, and P300 latency is lengthened. In the trial, NDX-1017 was reported to cause a dose-related increase in gamma power in healthy people; in the AD group, multiple dosing led to improvements in gamma power and p300 latency. The trial included no cognitive assessments.
A Phase 2/3 trial is being planned for 2020. It will enroll 120-300 people with mild to moderate AD, and compare several doses of NDX-1017 to placebo, given once daily using prefilled syringes for 26 weeks. Primary outcomes will be safety and a global statistical test. Secondary endpoints will include ADAS-Cog11, ADCS CGIC, Disability assessment for dementia (DAD), NPI and COWAT. Quantitative EEG and ERP P300 latency will be exploratory endpoints.
For details on NDX-1017 trials, see clinicaltrials.gov.
Last Updated: 21 Feb 2020
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