Fosgonimeton (Athira Pharma), a small-molecule positive modulator of the hepatocyte growth factor (HGF) system, previously showed neuroprotective, neurotrophic, and anti-inflammatory effects in preclinical models of dementia.1 Presented at the 2023 Clinical Trials on Alzheimer’s Disease (CTAD) conference, held October 24-27, in Boston, Massachusetts, new preclinical findings on the agent demonstrated protective impacts from amyloid-β-induced toxicity on neurons in Alzheimer disease (AD).1 The presented data underscored the therapy’s potential to address key aspects of AD pathology, including amyloid-ß -mediated toxicity, and also supports its continued advancement including a phase 2/3 trial (NCT04488419) assessing the candidate in patients with mild-to-moderate AD.
In vivo models, fosgonimeton rescued amyloid-ß -driven cognitive dysfunction, suggesting the neuroprotective effects lead to functional improvement, further supporting previous in vitro data of the therapy’s ability to improve cognitive performance. Both in vivo and in vitro, fosgonimeton protected cortical neurons from amyloid-ß -induced toxicity through several mechanisms including decreased oxidative stress, increased expression of autophagic markers, reduced tau pathology, and stimulation of prosurvival signaling pathways.
Recently, senior author Kevin Church, PhD, the chief scientific officer at Athira Pharma, sat down in an interview with NeurologyLive® to discuss the data further. He talked about how fosgonimeton potentially blocks the toxic effects of amyloid-ß on neurons, and the implications it this has for treatment in patients with AD. Church also spoke about the results of fosgonimeton's in vivo testing in rat models of AD, and how it relates to cognitive improvements. In addition, he shared the why the effects of fosgonimeton on autophagy markers was surprising, and how this might impact its potential for patients with AD.
- Fosgonimeton shows promise as a novel treatment for Alzheimer disease by blocking the harmful effects of amyloid-ß on neurons, potentially slowing neurodegeneration.
- In rat models of AD, fosgonimeton not only protects neurons but also improves cognitive function, showing promise as a potential treatment for patients with AD.
- Fosgonimeton's unique approach to providing broad neuroprotection suggests it may have a significant impact on the complex pathology of AD, potentially offering multiple benefits to patients.
NeurologyLive: What were the main findings from this preclinical data on fosgonimeton for AD?
Kevin Church, PhD: There were several key findings from this research. The first is that fosgonimeton is able to block the toxic effects of amyloid-ß on neurons in vitro. Amyloid-ß accumulation is believed to be a key driver of neurodegeneration in AD, and we can model those effects in vitro by adding toxic levels of amyloid beta to cultured neurons. At those levels, amyloid-ß causes several types of dysfunction in the neurons, including increased oxidative stress, neurite degradation, and tau phosphorylation, which ultimately lead to cell death. When we added the active metabolite of fosgonimeton, it was able to decrease oxidative stress, preserve neurites, reduce levels of phosphorylated tau, and prevent neuron death. Fosgonimeton is a potentially first-in-class HGF modulator designed to enhance the activity of the HGF system, a critical neurotrophic and neuroprotective signaling system that promotes neuron health and normal function, and these results demonstrate its robust neuroprotective properties in counteracting many of the downstream toxic effects of amyloid-ß.
The second main finding is that fosgonimeton had procognitive effects in an in vivo model of AD. We tested fosgonimeton in an amyloid-ß model of AD in rats because we wanted to assess whether the neuroprotective effects we observed in vitro could translate to functional improvements in vivo. In the rat model of AD, amyloid-ß induced significant cognitive deficits, and this was rescued by treatment with fosgonimeton. This finding indicates that improvements in neuronal health and function that were observed following fosgonimeton treatment in amyloid-ß models in vitro, translates well to improvements in cognitive behavior in animal models of AD.
These neuroprotective effects were in line with our previous research with fosgonimeton and our understanding of the mechanism of action through HGF. However, we were surprised by the effects of fosgonimeton on markers of autophagy, which is a cellular process that can remove toxic protein aggregates and is compromised in AD. We did not expect fosgonimeton to impact these markers, since there is little known about how HGF could influence autophagy, but we found that fosgonimeton restores the expression of key proteins involved in the process. This suggests another mechanism by which fosgonimeton could help promote normal neuronal function and may, at least in part, be responsible for the reduction in phosphorylated tau levels we observed in vitro.
What are the implications of these preclinical results and how should they be translated?
These results further support the therapeutic potential of fosgonimeton in promoting neurotrophic signaling, reducing tau pathology, and helping to protect neurons from toxic amyloid-ß in AD models. If the activity translates from our preclinical models to people with AD, fosgonimeton could potentially slow or stop neurodegeneration and cognitive decline, hopefully allowing patients to retain their memory, function, and quality of life for substantially longer.
What are the next steps in terms of research of fosgonimeton in its development in AD?
We are currently investigating fosgonimeton in late-stage clinical trials in AD. We look forward to those results to understand the potential impact of fosgonimeton on cognition and function in patients with AD. We will also continue to seek to understand the manner in which fosgonimeton appears to protect neurons from various insults in AD and how this mechanism of promoting neurotrophic HGF signaling may extend to other neurodegenerative diseases with our platform of HGF positive modulators.
What are the most notable takeaways from this preclinical research and from the uniqueness of fosgonimeton?
Fosgonimeton represents a novel, pleiotropic approach to promote neuroprotection from the complex and multi-faceted pathology in AD. Fosgonimeton provided robust protection of neurons from toxic amyloid beta in these models, however, we know that other factors are involved in neurodegeneration in AD including neuroinflammation, synaptic loss, tau pathology, excitotoxicity, and metabolic dysfunction. Other work presented previously has shown fosgonimeton has the potential to protect against each of these factors, not just toxic amyloid-ß. Since fosgonimeton is not targeted to a singular aspect of the pathology, but instead seeks to provide broad neuroprotection, fosgonimeton may be uniquely suited to provide benefit in AD.
Transcript edited for clarity. Click here for more coverage of CTAD 2023.
1. Johnston JL, Reda SM, Setti SE, et al. Fosgonimeton, a Novel Positive Modulator of the HGF/MET System, Promotes Neurotrophic and Procognitive Effects in Models of Dementia. Neurotherapeutics. 2023;20(2):431-451. doi:10.1007/s13311-022-01325-52. Reda SM, Setti SE, Berthiaume AA, et al. Fosgonimeton, a Small-Molecule Positive Modulator of the HGF/MET System, Attenuates Amyloid-β–Mediated Toxicity in Preclinical Models of Alzheimer’s Disease. Presented at: Clinical Trials on Alzheimer’s Disease conferece; Oct 24-27, 2023; Boston, MA. Abstract 175.