Therapy Type: Small Molecule (timeline)
Target Type: Other (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 2)
Company: Athira Pharma
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).
M3 Biotechnology was founded to commercialize Dihexa (see WSU article). The company told Alzforum that further development led to NDX-1017. M3 Biotechnology in 2019 was renamed Athira Pharma, and NDX-107 in 2020 was renamed ATH-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.
In September 2020, the company began a Phase 2 trial under the new name ATH-1017. Called LIFT-AD, the study plans to enroll 300 participants with clinically diagnosed mild to moderate AD, and compare two doses of drug to placebo, given once daily using prefilled syringes, for six months. The primary outcome will be the Global Statistical Test, a combination of scores from the ADAS-Cog11 and the ADCS-Clinical Global Impression of Change. Secondary endpoints will include ADAS-Cog11, ADCS CGIC, and ADCS-ADL. As of October 2020, the trial is recruiting at three sites in the United States, one in Florida and two in Washington state. The study is expected to be completed in October 2022.
A second Phase 2 study, to begin in October 2020, will assess the relationship between event-related potential (ERP) changes and cognition in 75 people with mild to moderate AD. Participants will receive high- or low-dose ATH-1017 or placebo daily for six months. The primary outcome will be ERP P300 latency; secondary outcome is ADAS-Cog11. The trial is slated to run until March 2022.
For details on NDX-1017/ATH-1017 trials, see clinicaltrials.gov.
Last Updated: 07 Oct 2020
- Akimoto M, Baba A, Ikeda-Matsuo Y, Yamada MK, Itamura R, Nishiyama N, Ikegaya Y, Matsuki N. Hepatocyte growth factor as an enhancer of nmda currents and synaptic plasticity in the hippocampus. Neuroscience. 2004;128(1):155-62. PubMed.
- Kato T, Funakoshi H, Kadoyama K, Noma S, Kanai M, Ohya-Shimada W, Mizuno S, Doe N, Taniguchi T, Nakamura T. 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.
- Hamasaki H, Honda H, Suzuki SO, Hokama M, Kiyohara Y, Nakabeppu Y, Iwaki T. Down-regulation of MET in hippocampal neurons of Alzheimer's disease brains. Neuropathology. 2014 Jun;34(3):284-90. Epub 2014 Jan 21 PubMed.
- Takeuchi D, Sato N, Shimamura M, Kurinami H, Takeda S, Shinohara M, Suzuki S, Kojima M, Ogihara T, Morishita R. 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.
- Koike H, Ishida A, Shimamura M, Mizuno S, Nakamura T, Ogihara T, Kaneda Y, Morishita R. 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.
- Aoki M, Warita H, Kato M, Suzuki N. [Application of Hepatocyte Growth Factor for Amyotrophic Lateral Sclerosis]. Brain Nerve. 2019 Nov;71(11):1253-1260. PubMed.
- McCoy AT, Benoist CC, Wright JW, Kawas LH, Bule-Ghogare JM, Zhu M, Appleyard SM, Wayman GA, Harding JW. Evaluation of Metabolically Stabilized Angiotensin IV Analogs as Procognitive/Antidementia Agents. J Pharmacol Exp Ther. 2013 Jan;344(1):141-54. PubMed.
- Benoist CC, Kawas LH, Zhu M, Tyson KA, Stillmaker L, Appleyard SM, Wright JW, Wayman GA, Harding JW. 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.
- Wright JW, Harding JW. 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.
- Ho JK, Nation DA. Cognitive benefits of angiotensin IV and angiotensin-(1-7): A systematic review of experimental studies. Neurosci Biobehav Rev. 2018 Sep;92:209-225. Epub 2018 May 4 PubMed.
- Wright JW, Kawas LH, Harding JW. The development of small molecule angiotensin IV analogs to treat Alzheimer's and Parkinson's diseases. Prog Neurobiol. 2015 Feb;125:26-46. Epub 2014 Nov 29 PubMed.