Therapeutics

NDX-1017

Overview

Name: NDX-1017
Therapy Type: Small Molecule (timeline)
Target Type: Other (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 1)
Company: Athira Pharma

Background

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 DihexaU.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 storyMcCoy 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.

Findings

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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References

News Citations

  1. At CTAD, Early Failures and Hints of Success, from Small Trials

Paper Citations

  1. . Hepatocyte growth factor as an enhancer of nmda currents and synaptic plasticity in the hippocampus. Neuroscience. 2004;128(1):155-62. PubMed.
  2. . Hepatocyte growth factor overexpression in the nervous system enhances learning and memory performance in mice. J Neurosci Res. 2012 Sep;90(9):1743-55. PubMed.
  3. . Down-regulation of MET in hippocampal neurons of Alzheimer's disease brains. Neuropathology. 2014 Jun;34(3):284-90. Epub 2014 Jan 21 PubMed.
  4. . Alleviation of Abeta-induced cognitive impairment by ultrasound-mediated gene transfer of HGF in a mouse model. Gene Ther. 2008 Apr;15(8):561-71. PubMed.
  5. . Prevention of onset of Parkinson's disease by in vivo gene transfer of human hepatocyte growth factor in rodent model: a model of gene therapy for Parkinson's disease. Gene Ther. 2006 Dec;13(23):1639-44. Epub 2006 Jun 22 PubMed.
  6. . [Application of Hepatocyte Growth Factor for Amyotrophic Lateral Sclerosis]. Brain Nerve. 2019 Nov;71(11):1253-1260. PubMed.
  7. . Evaluation of Metabolically Stabilized Angiotensin IV Analogs as Procognitive/Antidementia Agents. J Pharmacol Exp Ther. 2013 Jan;344(1):141-54. PubMed.
  8. . The procognitive and synaptogenic effects of angiotensin IV-derived peptides are dependent on activation of the hepatocyte growth factor/c-met system. J Pharmacol Exp Ther. 2014 Nov;351(2):390-402. Epub 2014 Sep 3 PubMed.
  9. . The Brain Hepatocyte Growth Factor/c-Met Receptor System: A New Target for the Treatment of Alzheimer's Disease. J Alzheimers Dis. 2015;45(4):985-1000. PubMed.

External Citations

  1. clinicaltrials.gov
  2. Dihexa
  3. U.S. Patent 8598118B2
  4. ScienceDaily news story

Further Reading