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Restoring

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Drug Design Approach

Developing Small Molecule Therapeutics for a Broad Range of Neurodegenerative Diseases

Our small molecules are designed to restore neuronal health by enhancing the naturally occurring neurotrophic hepatocyte growth factor (HGF) system. We have shown preclinically that enhancing the HGF signaling system has the potential to reduce inflammation, slow neurodegeneration, and provide neuroprotection. Subject to ongoing clinical testing, we believe our small molecules have the potential to modify the course of disease for patients across a broad range of neurodegenerative diseases.

Explore our pipeline of small molecule candidates

Targeting the Neurotrophic HGF System

Our novel approach may offer the ability to both protect and repair neuronal networks from neurodegenerative diseases.

Proposed mechanism of action for ATH product candidates.

Select Scientific Publications on neurotrophic HGF and its Role in Neurodegenerative Diseases

Click below to see links. By clicking on the links below, you will leave Athira’s website. Athira does not endorse or update information on such third-party websites.

HGF Background

Select Athira Scientific Publications

By clicking on the links below, you will access PDF reprints of peer-reviewed publications made available by scientific journals via open-access.

Fosgonimeton, a Novel Positive Modulator of the HGF/MET System, Promotes Neurotrophic and Procognitive Effects in Models of Dementia

The Case for a Novel Therapeutic Approach to Dementia: Small Molecule Hepatocyte Growth Factor (HGF/MET) Positive Modulators

Predictive Power of Cognitive Biomarkers in Neurodegenerative Disease Drug Develpoment: Utility of the P300 Event-Related Potential

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Alzheimer’s

Fosgonimeton improves markers of inflammation

Preclinical

Data from THP-1 cells presented as mean ± SEM.

Statistics applied: 1-way ANOVA with Dunnett’s test. *p<0.05, **p<0.01, ***p<0.001 vs. LPS Control; n = 3.

Fosgo-AM, fosgonimeton active metabolite; IL-1β, interleukin-1β; IL-6, interleukin-6; LPS, lipopolysaccharide; TNF-α, tumor necrosis factor-α.

Data presented at Athira R&D Day 2022 and published in Johnston et al., 2022

Clinical Observations

N=5 for placebo treatment; N=11 or 12 for fosgonimeton treatment.

Data presented as least-squared means ± SEM.

CFB, change from baseline.

Data presented at Athira R&D Day 2022 and CTAD 2022

Fosgonimeton improves hallmarks of Alzheimer’s disease

Preclinical

Data from primary rat cortical neurons presented as mean ± SEM. Statistics applied: Aβ assay: One-way ANOVA with Dunnett’s posttest. ***p<0.001 versus Aβ Control; n = 5-6. Scale bar: 100 µm.

Aβ, amyloid beta; AT100, hyperphospho-tau antibody; fosgo-AM; fosgonimeton active metabolite; MAP-2, microtubule-associated protein-2.

Data presented at Athira R&D Day 2022

Clinical Observations

N=5 for placebo treatment; N=11 for fosgonimeton treatment.

Aβ, amyloid beta; p-Tau181, tau phosphorylated at threonine-181.

Data presented at Athira R&D Day 2022 and CTAD 2022

Fosgonimeton reduces markers of neurodegeneration

Preclinical

Data from primary rat cortical neurons presented as mean ± SEM. Statistics applied: Aβ assay: One-way ANOVA with Dunnett’s posttest. ***p<0.001 versus Aβ Control; n = 5-6. Scale bar: 100 µm.

Aβ, amyloid beta; AT100, hyperphospho-tau antibody; fosgo-AM; fosgonimeton active metabolite; MAP-2, microtubule-associated protein-2.

Data presented at Athira R&D Day 2022

Clinical Observations

N=5 for placebo treatment; N=12 for fosgonimeton treatment.

NfL, neurofilament light chain.

Data presented at Athira R&D Day 2022 and CTAD 2022

Fosgonimeton promotes neurotrophic effects

Preclinical

Data from primary rat hippocampal neurons presented as mean ± SEM. Scale bar = 20 µm.

Statistics applied – 1-way ANOVA with Dunnett posttest for synaptic count; Unpaired t-test for neurite outgrowth *p<0.05, ****p<0.0001 vs. Control; n = 10 images from 3 wells per treatment.

Fosgo-AM, fosgonimeton active metabolite; HGF, hepatocyte growth factor.

Data presented at Athira R&D Day 2022 and published in Johnston et al., 2022

Clinical Observations

*Primary endpoint, ERP P300 latency, was not met in the exploratory Phase 2 ACT-AD study; observed effect against placebo was not statistically significant.

mITT population without background therapy. Data presented as unadjusted mean ± SEM.

AD, Alzheimer’s disease; ERP, Event Related Potential; mITT, modified intent-to-treat; W, week.

Data presented at Athira R&D Day 2022 and AAIC 2022

Fosgonimeton demonstrates improved cognition and function

Preclinical

Data presented as means ± SEM. Statistics applied: One-way ANOVA with Dunnett’s multiple comparisons.

*** p < 0.001, **** p < 0.0001 vs. LPS Control; n = 10 mice per group.

LPS, lipopolysaccharide.

Data presented at Athira R&D Day 2022 and published in Johnston et al., 2022

Clinical Observations

Alzheimer’s disease assessment scale-Cognitive subscale 11 (ADAS-Cog11) measurements showed a directional improvement of -3.3 points (79%) over placebo over 6 months in patients without background therapy

Alzheimer’s disease cooperative study-Activities of daily living 23 (ADCS-ADL23) measurements showed a directional improvement of +2.1 points (51%) over placebo over 6 months in full study population

For ADAS-Cog11: mITT population; data presented as unadjusted mean ± SEM; not statistically significant.

AD, Alzheimer’s disease; ADAS-Cog11, Alzheimer’s Disease Assessment Scale–Cognitive Subscale; ADCS-ADL23, Alzheimer’s Disease Cooperative Study–Activities of Daily Living, 23-item version; mITT, modified intent-to-treat.

Data presented at Athira R&D Day 2022 and AAIC 2022

Parkinson’s

Fosgonimeton improves markers of inflammation in preclinical models

Data from THP-1 cells presented as mean ± SEM.

Statistics applied: 1-way ANOVA with Dunnett’s test. *p<0.05, **p<0.01, ***p<0.001 vs. LPS Control; n = 3.

Fosgo-AM, fosgonimeton active metabolite; IL-1β, interleukin-1β; IL-6, interleukin-6; LPS, lipopolysaccharide; TNF-α, tumor necrosis factor-α.

Data presented at Athira R&D Day 2022 and published in Johnston et al., 2022

Fosgonimeton reduces Parkinson’s protein pathology in dopaminergic neurons

Data presented as mean ± SEM. Scale bar: 100 µm.

Statistics applied: 1-way ANOVA with Fisher least significant difference test. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 versus disease control.

Fosgo-AM, fosgonimeton active metabolite; HGF, hepatocyte growth factor; TH, tyrosine hydroxylase.

Data presented at Athira R&D Day 2022 and Neuroscience 2022

Data presented as mean ± SEM. Scale bar: 100 µm.

Statistics applied: 1-way ANOVA with Fisher least significant difference test. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 versus disease control.

6-OHDA, 6-hydroxydopamine; Fosgo-AM, fosgonimeton active metabolite; HGF, hepatocyte growth factor; TH, tyrosine hydroxylase.

Data presented at Neuroscience 2022

In preclinical models, fosgonimeton protects against neurotoxic insults and promotes dopaminergic neuron health

Fosgonimeton promotes survival of cortical neurons challenged with neurotoxic insults

Data presented as mean ± SEM.

Statistics applied: 1-way ANOVA with Tukey test. *P < 0.05, **P < 0.01, ***P < 0.001 versus insult control.

Fosgo-AM, fosgonimeton active metabolite; H2O2, hydrogen peroxide; MPP+, 1-methyl-4-phenylpyridinium; LPS, lipopolysaccharide.

Data presented at Neuroscience 2022

Fosgonimeton promotes dopaminergic neuron health

Data presented as mean ± SEM. Scale bar: 100 µm.

Statistics applied: 1-way ANOVA with Fisher least significant difference test. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 versus disease control.

Fosgo-AM, fosgonimeton active metabolite; HGF, hepatocyte growth factor; TH, tyrosine hydroxylase.

6-OHDA, 6-hydroxydopamine; TH, tyrosine hydroxylase.

Scale bar: 100 µm.

Statistics applied: 1-way ANOVA with Fisher least significant difference test. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 versus disease control.

Data presented as mean ± SEM.

Data presented at Neuroscience 2022

Fosgonimeton promotes synaptogenesis and neurite outgrowth in hippocampal neuron cultures

Data from primary rat hippocampal neurons presented as mean ± SEM. Scale bar = 20 µm.

Statistics applied – 1-way ANOVA with Dunnett posttest for synaptic count; Unpaired t-test for neurite outgrowth *p<0.05, ****p<0.0001 vs. Control; n = 10 images from 3 wells per treatment.

Fosgo-AM, fosgonimeton active metabolite; HGF, hepatocyte growth factor.

Data presented at Athira R&D Day 2022 and published in Johnston et al., 2022

In an animal model of Parkinson’s disease, fosgonimeton improves several motor behavior deficits

Grip strength is improved after fosgonimeton treatment

Statistics applied: 2-way ANOVA with Dunnett test. Statistical significance indicated with * represent sham control versus disease control; # represent fosgo versus disease control. The following applies to all symbols: *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 versus disease control.

Data presented at Athira R&D Day 2022 and Neuroscience 2022

Fosgonimeton improves motor function and coordination

Data presented at Neuroscience 2022

ALS

ATH-1105 significantly improves markers of inflammation in preclinical models of ALS

Data from THP-1 cells presented as mean ± SEM.

Statistics applied: 1-way ANOVA with Dunnett’s test. *p<0.05, **p<0.01, ***p<0.001 vs. LPS Control; n = 3.

ALS, amyotrophic lateral sclerosis; IL-6, interleukin-6; TNF-α, tumor necrosis factor-α.

Data presented at Athira R&D Day 2022 and MNDA 2022

ATH-1105 significantly reduces protein hallmarks of ALS and enhances neuron survival in preclinical models

Data from primary rat spinal motor neurons presented as mean ± SEM. Scale bar: 100 µm.

Statistics applied: 1-way ANOVA with Fisher least significant difference test. *P<0.05, ** P < 0.01, ***P < 0.001 versus Glutamate Control; n = 6.

ALS, amyotrophic lateral sclerosis; MAP-2, microtubule-associated protein-2; TDP-43, TAR DNA-binding protein 43.

Data presented at Athira R&D Day 2022

ATH-1105 significantly protects against degeneration and demyelination in a preclinical model of ALS

Reduced marker of neurodegeneration

Data presented as mean ± SEM.

Statistical significance was determined by 2-way ANOVA with the Dunnett test versus ALS + vehicle. ****P < 0.0001.

ALS, amyotrophic lateral sclerosis; NfL, neurofilament light chain; TDP-43, TAR DNA-binding protein 43; WT, wild-type.

Data presented at Athira R&D Day 2022 and MNDA 2022

Protection against axon degeneration and demyelination

Histologic images of sciatic nerve semithin cross sections stained with toluidine blue; arrows point to degenerated axons; stars indicate regions with loss/thinning of myelin.

Graphical representation of the number of axons, the distribution of axonal diameters, the mean g-ratio.

Data for graphical panels are presented as mean ± SEM; statistical significance was determined by one-way ANOVA with Dunnett’s test, compared with ALS + vehicle. **p < 0.01, ***p < 0.001, ****p < 0.0001.

ALS, amyotrophic lateral sclerosis; WT, wild-type.

Data presented at Athira R&D Day 2022 and MNDA 2022

Neurotrophic effects with ATH-1105 coming soon

Decreases in biomarkers significantly correlate with improvements in cognitive and functional measures.

ATH-1105 improved nerve and motor function

Data presented as mean ± SEM.

Statistical significance was determined by 2-way ANOVA with the Dunnett test versus ALS + vehicle. *p < 0.05 ,**p < 0.01; ***p < 0.001; ****p < 0.0001. n = 10 mice per group.

ALS, amyotrophic lateral sclerosis; CMAP, compound muscle action potential; NCV, nerve conduction velocity; TDP-43, TAR DNA-binding protein 43; WT, wild-type.

Data presented at Athira R&D Day 2022 and MNDA 2022

Drug Design Approach

Developing Small Molecule Therapeutics for a Broad Range of Neurodegenerative Diseases

Targeting the Neurotrophic HGF System

Our novel approach may offer the ability to both protect and repair neuronal networks from neurodegenerative diseases.

Select Scientific Publications on neurotrophic HGF and its Role in Neurodegenerative Diseases

Select Athira Scientific Publications

Fosgonimeton improves markers of inflammation

Preclinical

Clinical Observations

Fosgonimeton improves hallmarks of Alzheimer’s disease

Preclinical

Clinical Observations

Fosgonimeton reduces markers of neurodegeneration

Preclinical

Clinical Observations

Fosgonimeton promotes neurotrophic effects

Preclinical

Clinical Observations

Fosgonimeton demonstrates improved cognition and function

Preclinical

Clinical Observations

Fosgonimeton improves markers of inflammation in preclinical models

Fosgonimeton reduces Parkinson’s protein pathology in dopaminergic neurons

In preclinical models, fosgonimeton protects against neurotoxic insults and promotes dopaminergic neuron health

Fosgonimeton promotes survival of cortical neurons challenged with neurotoxic insults

Fosgonimeton promotes dopaminergic neuron health

Fosgonimeton promotes synaptogenesis and neurite outgrowth in hippocampal neuron cultures

In an animal model of Parkinson’s disease, fosgonimeton improves several motor behavior deficits

Grip strength is improved after fosgonimeton treatment

Fosgonimeton improves motor function and coordination

ATH-1105 significantly improves markers of inflammation in preclinical models of ALS

ATH-1105 significantly reduces protein hallmarks of ALS and enhances neuron survival in preclinical models

ATH-1105 significantly protects against degeneration and demyelination in a preclinical model of ALS

Reduced marker of neurodegeneration

Protection against axon degeneration and demyelination

Neurotrophic effects with ATH-1105 coming soon

Decreases in biomarkers significantly correlate with improvements in cognitive and functional measures.

ATH-1105 improved nerve and motor function

ATH positive modulators significantly reduced pain behaviors that persisted even after extended washout periods

Significantly reduced pain behaviors over the treatment period

Reduction in pain persisted after extended drug washout periods