A SUPER-powered WP Engine Atlas Test Site

Joe&#039;s Atlas Experimentation Site

Treatment with the experimental oral therapy ATH-1105 significantly reduced nerve damage, improved motor function, and prolonged survival in preclinical models of <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS), a study reports.
The work was funded by ATH-1105&#8217;s developer <a href="https://www.athira.com/">Athira Pharma</a>, which plans to move the therapy into the first stages of clinical testing in the next few months.
The findings <a href="https://alsnewstoday.com/news/als-mouse-model-sees-prolonged-survival-with-ath-1105/">were first presented</a> at last year&#8217;s American Academy of Neurology (AAN) Annual Meeting and are published now in &#8220;<a href="https://www.frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2024.1348157/full#h4">ATH-1105, a small-molecule positive modulator of the neurotrophic HGF system, is neuroprotective, preserves neuromotor function, and extends survival in preclinical models of ALS,</a>&#8221; in <a href="https://www.frontiersin.org/journals/neuroscience">Frontiers in Neuroscience</a>.
&#8220;The results reported in this peer-reviewed publication suggest that ATH-1105 demonstrated consistent translation of neuroprotective and anti-inflammatory effects &#8230; which led to improved motor function and survival in an ALS animal model. These findings further support our plans to progress ATH-1105 into first-in-human studies in the first half of 2024,&#8221; Mark Litton, PhD, president and CEO of Athira, said in a <a href="https://www.globenewswire.com/news-release/2024/02/08/2826428/0/en/Athira-Pharma-Announces-Publication-in-Frontiers-in-Neuroscience-Highlighting-Therapeutic-Potential-of-ATH-1105-in-Amyotrophic-Lateral-Sclerosis-ALS.html">company press release</a>.
ATH-1105 is designed to activate a molecular signaling pathway called the hepatocyte growth factor (HGF) system, which is important for the maintenance and health of nerve cells. By activating it, the therapy should counteract several processes that contribute to ALS.
[recommended-reading id=85657]
<h3>ATH-1105 in cell, mouse models of ALS</h3>
Here, researchers at Athira assessed the impact of ATH-1105 in cell and animal models of the neurodegenerative condition.
In a battery of cell experiments, they demonstrated that ATH-1105 does activate the HGF system as designed. The experimental therapy was neuroprotective in nerve cell models, reducing cell damage from a range of cellular toxins and stressors. It also reduced the inflammatory activity of microglia, a type of immune cell in the brain.
After those proof-of-concept tests, ATH-1105 was tested in an ALS mouse model carrying mutations in TARDBP,  the gene responsible for producing TDP-43. In the first experiments, treatment was started at one month of age, which is before motor problems start developing in earnest in this model.
Mice given ATH-1105 maintained higher body weight, indicating better overall health, and better motor function, over untreated mice. ATH-1105 also lowered the severity of nerve dysfunction and reduced markers of inflammation and disease markers, including toxic TDP-43 levels in nerve fibers, a hallmark of ALS. ALS mice given ATH-1105 also lived longer than their untreated counterparts.
&#8220;Daily oral treatment with ATH-1105 in this model of ALS resulted in statistically significant and dose-dependent improvement across a battery of assessments for motor performance and nerve structure and function, ultimately resulting in prolonged survival,&#8221; the researchers wrote.
In separate experiments, mice were started on ATH-1105 at a later point after symptoms began developing to better mimic a clinical setting.
While the findings weren&#8217;t as dramatic, mice given the treatment maintained significantly better scores on several measures of motor function. ATH-1105 also reduced levels of neurofilament light chain (NfL), a marker of nerve damage.
&#8220;ATH-1105 protects spinal motor neurons from ALS-relevant insults in vitro and in animal models of ALS, prevents the progressive decline of motor and nerve function, reduces inflammation, preserves body weight and extends survival. Also, the significant reduction in plasma neurofilament light chain (NfL) levels, an established biomarker of neurodegeneration in ALS, is highly encouraging,” said Kevin Church, PhD, chief scientific officer of Athira.
&#8220;Given these data and the critical unmet medical need and devastating disease progression of ALS, we are encouraged to continue the development of ATH-1105 as a potential therapeutic agent for people living with ALS,&#8221; the scientists said.

Potential ALS treatment ATH-1105 due to enter clinical testing this year

<a href="https://www.athira.com">Athira Pharma</a>’s experimental therapy ATH-1105 shows anti-inflammatory and neuroprotective effects, promoting neuron growth and reducing damage associated with mechanisms of <a href="https://alsnewstoday.com">amyotrophic lateral sclerosis</a> (ALS) and frontotemporal dementia (FTD), a related condition.
The small molecule reduced inflammation and the buildup of a faulty version of TDP-43, a protein that’s thought to drive neuronal damage in both ALS and FTD.
That’s according to new data from preclinical studies in lab-grown cells and a mouse model of the two diseases that were shared in a poster at this year’s Alzheimer’s Association International Conference (AAIC), July 16-20, virtually and in person in Amsterdam, the Netherlands.
The poster was titled “<a href="https://www.athira.com/wp-content/uploads/2023/07/AAIC2023_FTD_L5_6July2023.pdf">ATH-1105, a small-molecule positive modulator of the HGF/MET system, is neuroprotective and attenuates TDP-43 protein pathology in ALS and frontotemporal dementia-relevant preclinical models</a>.”
The findings add to previous evidence that ATH-115 <a href="https://alsnewstoday.com/news/als-mouse-model-sees-prolonged-survival-with-ath-1105/">extended lifespan</a> and <a href="https://alsnewstoday.com/news/ath-1105-aid-nerve-health-motor-skills-als-mouse-model/">improved motor function</a> in ALS mouse models.
“We are encouraged by the growing body of preclinical research supporting ATH-1105, which shows the molecule is protective against several [disease-causing mechanisms] common to ALS and FTD,” Kevin Church, PhD, Athira’s chief scientific officer, said in a <a href="https://www.globenewswire.com/news-release/2023/07/17/2705476/0/en/Athira-Pharma-Presents-Phase-2-Clinical-Data-Correlating-Improvements-in-Biomarkers-of-Neurodegeneration-and-Neuroinflammation-with-Improvements-in-Measures-of-Cognition-and-Functi.html">company press release</a>.
[recommended-reading id=85595]
<h3>Effects of ATH-1105 on ALS, FTD</h3>
Mutations in the TARDBP gene, which codes for TDP-43, have been linked to the risk of <a href="https://alsnewstoday.com/causes-of-als/">developing ALS</a>. The mutations cause the protein to fold into the wrong shape and form toxic clumps.
Nearly everybody (97%) with ALS grow these TDP-43 aggregates in motor neurons, the nerve cells that control voluntary movement and are progressively lost with the disease. The damage results in <a href="https://alsnewstoday.com/symptoms-of-als/#Muscular_symptoms">muscle weakness</a> and an inability to control movement. The aggregates also form in roughly half of people with FTD.
ATH-115 works as a <a href="https://www.athira.com/science/">positive modulator</a> of the HGF/MET system, meaning it activates it. The HGF/MET system is a signaling pathway that helps safeguard neurons from damage by promoting their growth, repair, and survival.
“Positive modulation of the HGF/MET system has been shown to protect against several drivers of neurodegeneration in preclinical models, and this approach may represent a potential therapeutic strategy for ALS and FTD,” wrote the researchers, who tested ATH-115 in lab-grown neurons from the hippocampus of healthy rats. The hippocampus is a brain region linked to memory and learning, and TDP-43 clumps <a href="https://alsnewstoday.com/news/study-links-cognitive-impairment-with-toxic-protein-clumps-in-als/">also build up there</a>.
Neurons treated with ATH-115 grew about twice as many neurites, or projections that form connections with other neurons, and about three times more synapses, which are the points of contact between them.
The effect had about the same magnitude as treatment with HGF, the growth factor in the HGF/MET system.
<h3>ATH-1105 offers protection</h3>
The scientists then used four chemicals in amounts that were toxic to lab-grown rat cortical neurons, or neurons from the brain’s outermost layer. The chemicals were the neurotransmitter glutamate, bacteria-derived lipopolysaccharide (LPS), hydrogen peroxide, and 1-methyl-4-phenylpyridinium, a neurotoxin.
Each of them reduced the number of neurons that remained alive. However, when treated with ATH-1105 beforehand, the neurons were protected against their associated damage and didn&#8217;t die as much. In fact, almost all remained alive.
The researchers then analyzed the effects of ATH-1105 when added to LPS-exposed lab-grown human macrophages, a type of immune cell. LPS exposure increased the cells’ production of IL-6 and TNF-alpha, two pro-inflammatory signaling molecules, while ATH-1105 significantly reduced their levels.
Inflammation induced by LPS can cause cognitive impairment. In mice, this can be studied using a test called a T-maze. Compared with a placebo, ATH-1105 (given by mouth once daily for 14 days) eased cognitive impairment in LPS-exposed mice.
Finally, the researchers used a mouse model of ALS and FTD that produces a faulty version of human TDP-43. Some mice were given ATH-1105 by mouth once daily from 1-3 months of age. Others were given a placebo.
Similar to data from previous preclinical studies, ATH-1105 reduced blood IL-6 and TNF-alpha levels. It also reduced the levels of neurofilament light chain, a marker of neuronal damage.
Moreover, ATH-1105 reduced TPD-43 levels in the mice’s sciatic nerve by about three times, nearly reaching those seen in healthy mice. The sciatic nerve is a long nerve that runs from the lower back down the lower limbs.
“The consistency and breadth of these effects in reducing markers of inflammation, neurodegeneration, and TPD-43 protein pathology continue to support the broad therapeutic potential and continued advancement of ATH-1105,” Church said.

ATH-1105 protects against common ALS, FTD disease mechanisms

ATH-1105, a treatment candidate by <a href="https://www.athira.com/">Athira Pharma</a>, significantly prolonged survival in a mouse model of <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS), according to a <a href="https://www.globenewswire.com/news-release/2023/05/11/2667327/0/en/Athira-Pharma-Reports-First-Quarter-2023-Financial-Results-and-Recent-Pipeline-and-Business-Updates.html">company update</a>.
Consistent with previous analyses, the treatment also reduced neurodegeneration, inflammation, and the toxic buildup of the TDP-43 protein in nerve cells, which resulted in significant motor and nerve function improvements.
The findings were presented in a poster at the American Academy of Neurology (AAN) Annual Meeting last month.
Athira is completing preclinical studies so it can submit an investigational new drug application to conduct in-human studies of the therapeutic candidate. The company hopes to initiate clinical studies in 2024.
“We are encouraged by the compelling preclinical evidence with ATH-1105, which demonstrates statistically significant improvements on survival and nerve and motor function in an ALS animal model,&#8221; Kevin Church, PhD, Athira&#8217;s chief scientific officer, said in a <a href="https://investors.athira.com/news-releases/news-release-details/athira-pharma-presents-new-clinical-and-preclinical-data">press release</a> announcing the presentation last month. &#8220;We are advancing IND-enabling studies with ATH-1105 and plan to begin clinical evaluation next year.&#8221;
ALS is marked by progressive neurodegeneration and inflammation. Nearly all patients exhibit abnormal clumps of the TDP-43 protein in nerve cells, which is thought to be a key driver of nerve cell damage in the disease.
ATH-1105 is an oral small molecule that activates the HGF/MET system, a signaling pathway involved in maintaining nerve cell health via its ability to counteract neurotoxicity, inflammation, and oxidative stress, a type of cell damage implicated in ALS.
A growing body of evidence indicates boosting the pathway&#8217;s activity may help treat neurodegenerative diseases like ALS.
[recommended-reading id=84040]
<h3>Prolonged survival with ATH-1105</h3>
Last year, the company presented data indicating nerve cells treated with ATH-1105 in cell cultures showed <a href="https://alsnewstoday.com/news/ath-1105-aid-nerve-health-motor-skills-als-mouse-model/">significantly better survival</a> under toxic conditions than untreated cells.
ATH-1105 was also associated with higher body weight, lower levels of inflammatory markers, preserved nerve cell health, and better motor function in a mouse model of ALS. The model featured mutations in TARDBP,  the gene responsible for producing TDP-43, leading to ALS-like symptoms and TDP-43 buildup.
In the AAN poster &#8220;<a href="https://www.athira.com/wp-content/uploads/2023/04/AAN2023_ALS_04172023.pdf">ATH-1105, a Small-Molecule Positive Modulator of Hepatocyte Growth Factor (HGF)/MET, Is Neuroprotective in a TDP-43 Mouse Model of Amyotrophic Lateral Sclerosis</a>,&#8221; researchers provided additional findings from this TDP-43 mouse model.
TDP-43 mice were treated with 20 mg/kg ATH-1105 or a placebo daily for four months to assess its effects on survival.
ATH-1105 significantly prolonged survival in the ALS model, delaying the time to a first death from 59 days in the placebo group to 101 days, results showed.
Two months of treatment also led to measures of motor function stabilizing, while untreated mice saw significant declines over time, which was consistent with previous analyses.
&#8220;Together, these behavioral data demonstrate that ATH-1105 helps to preserve balance, coordination, and muscle strength, which progressively decline in ALS mice,&#8221; Jewel Johnston, PhD, the director of in vivo pharmacology at Athira, said in the poster presentation.
The therapy was also associated with preserved muscle and nerve function, and it protected mice from nerve cell degeneration and loss of <a href="https://multiplesclerosisnewstoday.com/myelin-sheath/">myelin</a>, the fatty substance that surrounds and protects nerve cells.
Treated mice treated also had significant reductions in key inflammatory markers, as well as neurofilament light chain (NfL), a biomarker of nerve cell degeneration. The accumulation of TDP-43 in nerve cells was significantly reduced in ATH-1105-treated mice over those given the placebo.
Finally, mice given ATH-1105 saw increases in body weight that resembled those seen in healthy animals, indicating good general health, while untreated mice had consistently lower body weight.
&#8220;This study highlights the therapeutic potential of ATH-1105 in a mouse model of ALS and supports further investigation of ATH-1105 in this disease indication,&#8221; the researchers wrote.

ATH-1105 prolongs survival in mouse model of ALS

Use of ATH-1105, a small molecule being developed by <a href="https://www.athira.com/" rel="nofollow">Athira Pharma</a> to treat <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS), protected against nerve damage and improved motor function in a mouse model of the disease, according to data shared in a recent <a href="https://investors.athira.com/static-files/40ed1eb5-fa61-4be4-98fe-1204be7a12a5" rel="nofollow">company presentation</a>.
Athira is planning to file an investigational new drug application with the U.S. Food and Drug Administration (FDA), essentially a request for permission to begin clinical testing of ATH-1105 in people.
&#8220;Our dedication to advancing new therapeutics to impact neurodegenerative diseases remains steadfast,&#8221; Mark Litton, PhD, the company&#8217;s president and CEO, said in a<a href="https://www.globenewswire.com/news-release/2023/01/05/2583521/0/en/Athira-Pharma-Provides-2023-Pipeline-Outlook.html"> press release</a>.
[recommended-reading id=81462]
<h3>Small molecule aiming to treat ALS by maintaining nerve cell health</h3>
ATH-1105 is designed to activate the HGF/MET system, a molecular signaling pathway that plays numerous roles in maintaining the health of nerve cells. Research over the past two decades has shown that increasing the activity of the HGF-MET pathway can reduce disease severity in laboratory models of ALS.
In the December presentation, motor neurons — the specialized nerve cells controlling movement that die in ALS — in lab dishes treated with ATH-1105 were reported to show significantly better survival under toxic conditions.
The experimental therapy also was tested in a mouse model of ALS caused by<a href="https://alsnewstoday.com/als-and-genetics/"> mutations in the TARDBP gene</a> that provides instructions for making the TDP-43 protein. Mutations in this gene account for about 4% of familial ALS cases and 1% of sporadic cases. Yet, atypical clumps of the TDP-43 protein are found in almost all cases of ALS, and thought to help drive the disease.
Compared with untreated mice in the model, those given ATH-1105 maintained significantly higher body weight, indicating generally better health. Treated mice also had significantly lower levels of inflammatory markers, namely TNF-alpha and IL-6, and lower levels of neurofilament light chain (NfL), a marker of nerve damage, researchers reported.
Analyses of the mice&#8217;s nerve cells showed that those treated with ATH-1105 had less degeneration and better electrical activity. These mice also performed better on tests of motor function, although their performance was significantly poorer than that of healthy animals.
&#8220;These results highlight the therapeutic potential of ATH-1105 in ALS and support further development,&#8221; the researchers concluded.
Athira is currently developing several other experimental therapies targeting the HGF/MET pathway, including one called fosgonimeton that is <a href="https://alzheimersnewstoday.com/news/continuation-alzheimers-lift-ad-trial-backed-safety-board/">currently in a clinical trial</a> in <a href="https://alzheimersnewstoday.com/what-is-alzheimers-disease/">Alzheimer&#8217;s</a> patients and a <a href="https://parkinsonsnewstoday.com/news/first-patient-dosed-shape-trial-ath-1017-parkinsons-dementia/">separate trial</a> that includes people with <a href="https://parkinsonsnewstoday.com/what-is-parkinsons-disease/">Parkinson&#8217;s disease</a> dementia.
&#8220;The consistency of data from preclinical models across various neurodegenerative diseases and in Alzheimer’s patients suggest that our small molecule product candidates may be neuroprotective, neurotrophic, procognitive and potentially disease-modifying,&#8221; Litton said.
&#8220;We expect to complete enrollment of the LIFT-AD study [testing fosgonimeton in] mild-to-moderate Alzheimer’s disease … [and] to filing an IND application for ATH-1105 as a potential treatment for ALS,&#8221; Litton added. &#8220;We also plan to publish and present additional data that further support that HGF/MET enhancement may play an important role in treating neurodegenerative disease.&#8221;

Tag: ATH-1105

Potential ALS treatment ATH-1105 due to enter clinical testing this year

ATH-1105 protects against common ALS, FTD disease mechanisms

ATH-1105 prolongs survival in mouse model of ALS

ATH-1105 Aids Nerve Health and Motor Skills in Mice, Trial Possible