BACKGROUND:Diagnostic criteria for apathy in neurocognitive disorders (DCA-NCD) have recently been updated. OBJECTIVES:We investigated whether validated scales measuring apathy severity capture the three dimensions of the DCA-NCD (diminished initiative, diminished interest, diminished emotional expression). MEASUREMENTS:Degree of mapping ("not at all", "weakly", or "strongly") between items on two commonly used apathy scales, the Neuropsychiatric Inventory-Clinician (NPI-C) apathy and Apathy Evaluation Scale (AES), with the DCA-NCD overall and its 3 dimensions was evaluated by survey. DESIGN:Survey participants, either experts (n = 12, DCA-NCD authors) or scientific community members (n = 19), rated mapping for each item and mean scores were calculated. Interrater reliability between expert and scientific community members was assessed using Cohen's kappa. RESULTS:According to experts, 9 of 11 (81.8%) NPI-C apathy items and 6 of 18 (33.3%) AES items mapped strongly onto the DCA-NCD overall. For the scientific community group, 10 of 11 (90.9%) NPI-C apathy items and 7 of 18 (38.8%) AES items mapped strongly onto the DCA-NCD overall. The overall mean mapping scores were higher for the NPI-C apathy compared to the AES for both expert (t (11) = 3.13, p = .01) and scientific community (t (17) = 3.77, p = .002) groups. There was moderate agreement between the two groups on overall mapping for the NPI-C apathy (kappa= 0.74 (0.57, 1.00)) and AES (kappa= 0.63 (0.35, 1.00)). CONCLUSIONS:More NPI-C apathy than AES items mapped strongly and uniquely onto the DCA-NCD and its dimensions. The NPI-C apathy may better capture the DCA-NCD and its dimensions compared with the AES.

Background:Fosgonimeton, a small-molecule positive modulator of the neurotrophic hepatocyte growth factor (HGF) system, was studied in participants with Alzheimer's disease (AD). Objective:To assess the efficacy and safety of fosgonimeton in AD. Methods:LIFT-AD was a randomized, placebo-controlled, Phase 2/3 trial (NCT04488419; 23Jun2020), the primary analysis (N = 287) included participants with mild-to-moderate AD not receiving concomitant acetylcholinesterase inhibitors (AChEIs) randomized 1:1 to daily subcutaneous fosgonimeton 40 mg or placebo. The primary endpoint, the Global Statistical Test (GST) score, combined ADAS-Cog11 and ADCS-ADL23. Secondary endpoints included ADAS-Cog11, ADCS-ADL23, and NfL. Exploratory endpoints included plasma biomarkers of AD. Safety included all dosed participants, including those receiving and not receiving AChEIs or randomized to fosgonimeton 70 mg (N = 549). Results:The trial did not achieve its primary or secondary endpoints; between-group difference in the least-square mean change (SE) from baseline to Week 26 in the GST score was -0.08 (0.10) (p = 0.70), -0.70 (0.77) (p = 0.35) in ADAS-Cog11, and +0.67 (0.92) (p = 0.61) in ADCS-ADL23. This showed small differences favoring fosgonimeton versus placebo. Nominally significant changes in plasma biomarkers were observed in p-τ217 only. Fosgonimeton had an acceptable safety profile. Serious AEs were balanced between groups (4.2% fosgonimeton, 6.9% placebo). More participants in the fosgonimeton group (14.2%) discontinued due to AEs versus placebo (4.6%), mostly from injection site reactions. Conclusions:Fosgonimeton did not significantly improve ADAS-Cog11 or ADCS-ADL23 versus placebo. However, the consistently observed non-significant improvements favoring fosgonimeton suggests potentially relevant biological activity with fosgonimeton and that positive modulation of HGF signaling may impact components of the pathophysiologic processes of neurodegenerative diseases.

The newly proposed revised criteria for diagnosis and staging of Alzheimer's disease (AD) by the Alzheimer's Association (AA) Workgroup represent a significant milestone in the field. These criteria offer objective measures for diagnosing and staging biological AD, bridging the gap between research and clinical care. Although implementation feasibility may vary across regions and settings, improving the availability and accuracy of biomarkers, especially plasma biomarkers, is expected to enhance the applicability of these criteria in clinical practice. The Fall 2023 Alzheimer's Association Research Roundtable (AARR) meeting served as a forum for gathering industry perspectives and feedback on these revised criteria, ensuring that the new criteria inform research, clinical trial design, and clinical care. In this article, we outline a summary of the newly proposed "Revised Criteria for Diagnosis and Staging of AD: AA Workgroup" and provide highlights from the AARR meeting in fall 2023. Highlights:The Alzheimer's Association Research Roundtable (AARR) convened leaders from industry, academia, and government, to review the Revised Criteria for Diagnosis and Staging of AD: AA Workgroup, and gather industry perspectives and feedback on these revised criteria before its publication.The newly proposed revised criteria for diagnosis and staging of Alzheimer's disease (AD) by the AA's Workgroup represent a significant milestone, offering objective measures for the biological and staging of AD and bridging the gap between research and clinical care.Improving the availability and accuracy of biomarkers, especially blood-based biomarkers (BBMs) is expected to improve clinical research and enhance the applicability of these criteria in clinical practice.

Positive modulation of hepatocyte growth factor (HGF) signaling may represent a promising therapeutic strategy for Alzheimer's disease (AD) based on its multimodal neurotrophic, neuroprotective, and anti-inflammatory effects addressing the complex pathophysiology of neurodegeneration. Fosgonimeton is a small-molecule positive modulator of the HGF system that has demonstrated neurotrophic and pro-cognitive effects in preclinical models of dementia. Herein, we evaluate the neuroprotective potential of fosgonimeton, or its active metabolite, fosgo-AM, in amyloid-beta (Aβ)-driven preclinical models of AD, providing mechanistic insight into its mode of action. In primary rat cortical neurons challenged with Aβ (Aβ1-42), fosgo-AM treatment significantly improved neuronal survival, protected neurite networks, and reduced tau hyperphosphorylation. Interrogation of intracellular events indicated that cortical neurons treated with fosgo-AM exhibited a significant decrease in mitochondrial oxidative stress and cytochrome c release. Following Aβ injury, fosgo-AM significantly enhanced activation of pro-survival effectors ERK and AKT, and reduced activity of GSK3β, one of the main kinases involved in tau hyperphosphorylation. Fosgo-AM also mitigated Aβ-induced deficits in Unc-like kinase 1 (ULK1) and Beclin-1, suggesting a potential effect on autophagy. Treatment with fosgo-AM protected cortical neurons from glutamate excitotoxicity, and such effects were abolished in the presence of an AKT or MEK/ERK inhibitor. In vivo, fosgonimeton administration led to functional improvement in an intracerebroventricular Aβ25-35 rat model of AD, as it significantly rescued cognitive function in the passive avoidance test. Together, our data demonstrate the ability of fosgonimeton to counteract mechanisms of Aβ-induced toxicity. Fosgonimeton is currently in clinical trials for mild-to-moderate AD (NCT04488419; NCT04886063).

IntroductionAmyotrophic lateral sclerosis (ALS), a progressive and fatal neurodegenerative disorder, primarily affects the motor neurons of the brain and spinal cord. Like other neurodegenerative conditions, ongoing pathological processes such as increased inflammation, excitotoxicity, and protein accumulation contribute to neuronal death. Hepatocyte growth factor (HGF) signaling through the MET receptor promotes pro-survival, anti-apoptotic, and anti-inflammatory effects in multiple cell types, including the neurons and support cells of the nervous system. This pleiotropic system is therefore a potential therapeutic target for treatment of neurodegenerative disorders such as ALS. Here, we test the effects of ATH-1105, a small-molecule positive modulator of the HGF signaling system, in preclinical models of ALS.MethodsIn vitro, the impact of ATH-1105 on HGF-mediated signaling was assessed via phosphorylation assays for MET, extracellular signal–regulated kinase (ERK), and protein kinase B (AKT). Neuroprotective effects of ATH-1105 were evaluated in rat primary neuron models including spinal motor neurons, motor neuron-astrocyte cocultures, and motor neuron-human muscle cocultures. The anti-inflammatory effects of ATH-1105 were evaluated in microglia- and macrophage-like cell systems exposed to lipopolysaccharide (LPS). In vivo, the impact of daily oral treatment with ATH-1105 was evaluated in Prp-TDP43A315T hemizygous transgenic ALS mice.ResultsIn vitro, ATH-1105 augmented phosphorylation of MET, ERK, and AKT. ATH-1105 attenuated glutamate-mediated excitotoxicity in primary motor neurons and motor neuron- astrocyte cocultures, and had protective effects on motor neurons and neuromuscular junctions in motor neuron-muscle cocultures. ATH-1105 mitigated LPS-induced inflammation in microglia- and macrophage-like cell systems. In vivo, ATH-1105 treatment resulted in improved motor and nerve function, sciatic nerve axon and myelin integrity, and survival in ALS mice. Treatment with ATH-1105 also led to reductions in levels of plasma biomarkers of inflammation and neurodegeneration, along with decreased pathological protein accumulation (phospho-TDP-43) in the sciatic nerve. Additionally, both early intervention (treatment initiation at 1 month of age) and delayed intervention (treatment initiation at 2 months of age) with ATH-1105 produced benefits in this preclinical model of ALS.DiscussionThe consistent neuroprotective and anti-inflammatory effects demonstrated by ATH-1105 preclinically provide a compelling rationale for therapeutic interventions that leverage the positive modulation of the HGF pathway as a treatment for ALS.

Objective:Evaluate the preclinical efficacy of the small molecule positive modulator of hepatocyte growth factor (HGF)/MET, ATH-1105, in a mouse model of amyotrophic lateral sclerosis (ALS).Background:Activation of the MET receptor by HGF promotes neuroprotective, neurotrophic, and anti-inflammatory mechanisms. Small molecule positive modulators of HGF/MET, including ATH-1105, have been developed to explore the therapeutic potential of this target. ALS is characterized by progressive motor neuron degeneration and demyelination, accompanied by systemic inflammation and pathological aggregation of TAR DNA-binding protein 43 (TDP-43) in 97% of patients. We hypothesized that treatment with ATH-1105 would be beneficial in a TDP-43 mouse model of ALS.Design/Methods:ATH-1105 at 10 or 20 mg/kg was orally administered daily to male Prp-TDP43A315T mice (n=10/group) for two months. At baseline and after one and two months of treatment, we conducted a battery of motor behavior tests, and assessed sciatic nerve health by compound muscle action potential (CMAP) and nerve conduction velocity (NCV) measurements. Plasma biomarkers of inflammation (IL-6, TNF-α) and neurodegeneration (neurofilament light chain [NfL]) were interrogated after one and two months of treatment. Sciatic nerves were stained for quantification of axonal and myelin parameters as well as phospho-TDP-43 aggregation at study termination.Results:The deterioration of motor function in TDP-43 animals was significantly mitigated in a dose-dependent manner after treatment with ATH-1105, and significant functional improvement of sciatic nerve conduction was observed. Additionally, plasma levels of all biomarkers assessed were significantly decreased, indicating reduced systemic inflammation and neurodegeneration in treated TDP-43 mice. Sciatic nerve histology revealed a protection of motor axon numbers and myelination, as well as a reduction in axonal phospho-TDP-43 aggregation by ATH-1105.Conclusions:ATH-1105 was found to be protective across a multitude of functional and structural measures of ALS disease progression. These findings support the continued development of this small molecule positive modulator of HGF/MET for ALS. Disclosure: Mrs. Kleist has received personal compensation for serving as an employee of Athira Pharma. Mrs. Kleist has received personal compensation for serving as an employee of Alpine Immune Sciences. Mrs. Kleist has stock in Athira Pharma. Mrs. Kleist has stock in Alpine Immune Sciences. Dr. Berthiaume has received personal compensation for serving as an employee of Athira Pharma. Dr. Berthiaume has stock in Athira Pharma. An immediate family member of Dr. Berthiaume has stock in Athira Pharma. Dr. Johnston has received personal compensation for serving as an employee of Athira Pharma, Inc. Dr. Johnston has stock in Athira Pharma, Inc. An immediate family member of Dr. Johnston has stock in Athira Pharma, Inc. Dr. Johnston has received intellectual property interests from a discovery or technology relating to health care. Dr. Reda has received personal compensation for serving as an employee of Athira Pharma, Inc. . Dr. Reda has stock in Athira Pharma, Inc. . Dr. Moebius has received personal compensation in the range of $100,000-$499,999 for serving as an officer or member of the Board of Directors for Athira Pharma, Inc.. Dr. Moebius has stock in Athira Pharma, Inc.. Dr. Church has received personal compensation for serving as an employee of Athira Pharma. Dr. Church has stock in Athira Pharma. Dr. Church has received intellectual property interests from a discovery or technology relating to health care.

An estimated 6.5 million Americans aged 65 years or older have Alzheimer's disease (AD), which will grow to 13.8 million Americans by 2060. Despite the growing burden of dementia, no fundamental change in drug development for AD has been seen in > 20 years. Currently approved drugs for AD produce only modest symptomatic improvements in cognition with small effect sizes. A growing mismatch exists between the urgent need to develop effective drugs for symptomatic AD and the largely failed search for disease modification. The failure rate of clinical trials in AD is high overall, and in particular for disease-modifying therapies. Research efforts in AD have focused predominantly on amyloid-β and tau pathologies, but limiting clinical research to these "classical hallmarks" of the disease does not address the most urgent patient, caregiver, or societal needs. Rather, clinical research should consider the complex pathophysiology of AD. Innovative approaches are needed that provide outside-the-box thinking, and re-imagine trial design, interventions, and outcomes as well as progress in proteomics and fluid biomarker analytics for both diagnostics and disease monitoring. A new approach offering a highly specific, yet multi-pronged intervention that exerts positive modulation on the HGF/MET neurotrophic system is currently being tested in mid-to-late-stage clinical trials in mild to moderate AD. Findings from such trials may provide data to support novel approaches for development of innovative drugs for treating AD at various disease stages, including among patients already symptomatic, and may offer benefits for other neurodegenerative diseases.

Despite the multifactorial nature of Alzheimer’s disease (AD), research has primarily targeted amyloid-beta and tau; other approaches are needed. Fosgonimeton, a small-molecule positive modulator of the hepatocyte growth factor (HGF)/MET system, was evaluated in a randomized, double-blind, placebo-controlled, 6-month, exploratory phase 2 trial (ACT-AD; NCT04491006) a and an open-label extension trial (NCT04886063) a . To evaluate fosgonimeton in participants with mild-to-moderate AD, changes from baseline (CFB) in plasma biomarkers were compared with placebo in post hoc analyses. Multifactorial correlations were assessed against the global statistical test (GST), a composite score of cognition (ADAS-Cog11) and activities of daily living (ADCS-ADL23) assessments. Blood samples from baseline (n = 59-61) and week 26 were assessed for biomarkers of neurodegeneration (NfL), neuroinflammation (GFAP; YKL-40), and proteinopathy (Aβ42/40 ratio; p-Tau181). Baseline biomarker levels were similar between treatments. An ANOVA, including baseline levels, yielded a statistically significant CFB in NfL (−6.49 pg/mL; SE, 2.79; p = 0.0241) and numerical improvements in GFAP (−35.17 pg/mL; SE, 30.0; p = 0.2469), YKL-40 (−47.37 ng/L; SE, 27.5; p = 0.0916), Aβ42/40 ratio (0.006; SE, 0.0035; p = 0.0938), and p-Tau181 (−0.67 pg/mL; SE 0.60; p = 0.2715) were observed in fosgonimeton-treated participants versus placebo, each without background therapy. APOE4 genotype, baseline Mini-Mental State Examination score, sex, or age did not affect results. Additional biomarker and correlation analyses are being conducted. The potential association of biomarkers with clinical outcomes is supported by the CFB relative to GST, which significantly correlated with changes in NfL (r = 0.40; p = 0.0023) and GFAP (r = 0.35; p = 0.0408). In this first randomized, placebo-controlled, 6-month trial of fosgonimeton, a statistically significant reduction in NfL and numerical improvements in GFAP, YKL-40, Aβ42/40, and p-Tau181 plasma concentrations were observed, suggesting a multimodal neuroprotective mechanism of action of fosgonimeton and potential to impact AD-specific proteinopathies. The significant correlation of NfL and GFAP reduction with the composite endpoint further supports potential clinical relevance. a The ACT-AD trial and open-label extension thereof are supported by a grant from the National Institute on Aging of the National Institutes of Health (award number R01AG06268). The information presented herein is solely the responsibility of Athira and does not necessarily represent the official views of the National Institutes of Health.

Objective: To evaluate changes from baseline in plasma biomarkers in subjects with mild-to-moderate Alzheimer's disease (AD) treated with fosgonimeton, a small-molecule positive modulator of the hepatocyte growth factor (HGF)/MET system, compared with placebo and to assess multifactorial correlations with the global statistical test (GST), a composite score informed by both ADAS-Cog11 and activities of daily living (ADCS-ADL23). Background: Despite the multifactorial nature of AD, research has primarily targeted proteotoxicity; approaches addressing other contributory factors are needed. Fosgonimeton was evaluated in the randomized, double-blind, placebo-controlled, phase 2 ACT-AD study (NCT04491006); biomarker results are reported here. Design/Methods: Blood samples were collected at baseline (N=77) and week 26 of treatment. Biomarkers assessed include neurofilament light chain (NfL; indicates ongoing neurodegeneration), GFAP (indicates microglial activation), YKL-40 (indicates neuroinflammation), and amyloid beta 40 and 42 (Aβ40, Aβ42). Results are represented for pooled active arms versus placebo, without background therapy. Results: Baseline biomarker levels were similar between treatments. A statistically significant change from baseline versus placebo in NfL (−7.9 pg/mL; SE, 2.7; P=0.0059) and directionally favorable improvements in GFAP (−29.3 pg/mL; SE, 28.6; P=0.312), YKL-40 (−34.9 ng/mL; SE, 26.5; P=0.195), and Aβ42/40 ratio (0.0066; SE, 0.0035; P=0.064) were observed in fosgonimeton-treated subjects. ApoE4 genotype, baseline Mini-Mental State Examination score, sex, or age did not affect these results. In an analysis to confirm correlation of biomarkers and clinical outcomes, the composite endpoint GST proved to be highly correlated with changes in NfL (r=0.46; P=0.0011) and GFAP (r=0.30; P=0.0394). Conclusions: In this first-ever, randomized, placebo-controlled trial of fosgonimeton, a statistically significant reduction in NfL and descriptive, congruent GFAP and YKL-40 plasma concentration improvements were observed, which would be consistent with a neuroprotective effect and multimodal mechanism of action of fosgonimeton. The significant correlation of NfL and GFAP reduction with the composite clinical endpoint further supports clinical relevance. Disclosure: Dr. Moebius has received personal compensation in the range of $100,000-$499,999 for serving as an officer or member of the Board of Directors for Athira Pharma, Inc.. Dr. Moebius has stock in Athira Pharma, Inc.. Ms. Ooi has received personal compensation for serving as an employee of Athira Pharma Inc. Ms. Ooi has stock in Athira Pharma Inc. Dr. Hale has received personal compensation for serving as an employee of Athira Pharma. Dr. Hale has received personal compensation in the range of $50,000-$99,999 for serving as a Consultant for Takeda. Dr. Hale has stock in Amgen. Dr. Setti has received personal compensation for serving as an employee of Athira Pharma. Dr. Setti has stock in Athira Pharma. Mrs. Kleist has received personal compensation for serving as an employee of Athira Pharma. Mrs. Kleist has received personal compensation for serving as an employee of Alpine Immune Sciences. Mrs. Kleist has stock in Athira Pharma. Mrs. Kleist has stock in Alpine Immune Sciences. Dr. Bernick has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Lilly. Dr. Bernick has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Optina. Dr. Bernick has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Eisai. Dr. Bernick has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Corium. Dr. Bernick has stock in Aurora. The institution of Dr. Bernick has received research support from UFC. The institution of Dr. Bernick has received research support from Top Rank Promotions. The institution of Dr. Bernick has received research support from Haymon Boxing.

Neurodegenerative diseases, such as Alzheimer's disease (AD), and their associated deterioration of cognitive function are common causes of disability. The slowly developing pathology of neurodegenerative diseases necessitates early diagnosis and monitored long-term treatment. Lack of effective therapies coupled with an improved rate of early diagnosis in our aging population have created an urgent need for the development of novel drugs, as well as the need for reliable biomarkers for treatment response. These issues are especially relevant for AD, in which the rate of clinical trial drug failures has been very high. Frequently used biomarker evaluation procedures, such as positron emission tomography or cerebrospinal fluid measurements of phospho-tau and amyloid beta, are invasive and costly, and not universally available or accessible. This review considers the functionality of the event-related potential (ERP) P300 methodology as a surrogate biomarker for predicting the procognitive potential of drugs in clinical development for neurocognitive disorders. Through the application of standardized electroencephalography (EEG) described here, ERP P300 can be reliably measured. The P300 waveform objectively measures large-scale neuronal network functioning and working memory processes. Increased ERP P300 latency has been reported throughout the literature in disorders of cognition, supporting the potential utility of ERP P300 as a biomarker in many neurological and neuropsychiatric disorders, including AD. Specifically, evidence presented here supports ERP P300 latency as a quantitative, unbiased measure for detecting changes in cognition in patients with AD dementia through the progression from mild to moderate cognitive impairment and after drug treatment.

Background: Fosgonimeton (ATH-1017) is being developed as a first-in-class regenerative therapy for people with Alzheimer’s disease (AD) and dementia; potentially improving dementia symptoms and altering disease progression by reversing synaptic disconnection and neuronal loss. Objective: This randomized, double-blind, placebo-controlled phase I trial (NCT03298672) evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of fosgonimeton. Methods: Fosgonimeton was administered once daily via subcutaneous injection to 88 subjects. The single ascending dose study enrolled healthy young male subjects (n = 48; age, 33.4±6.3 years; dose, 2, 6, 20, 40, 60, or 90 mg); the multiple ascending dose study enrolled healthy elderly subjects (n = 29; age, 63.8±4.0 years; dose, 20, 40, 60, or 80 mg; 9-day duration); and the fixed-dose study enrolled AD subjects (n = 11; age, 69.2±7.1 years; dose, 40 mg; 9-day duration). Quantitative electroencephalogram (qEEG) and event-related potential (ERP) P300 measured neurophysiological signals following fosgonimeton treatment, supporting brain penetration and target engagement. Results: Fosgonimeton and placebo were shown to be safe and well-tolerated across all doses. Pharmacokinetic results for fosgonimeton were dose-proportional, with no sex effect or accumulation over 9 days. The main effect of fosgonimeton on qEEG was acute and sustained gamma power induction. In AD subjects, there was a significant effect toward ERP P300 latency normalization compared with placebo (p = 0.027; n = 7 at 40 mg fosgonimeton versus n = 4 placebo). Conclusion: These results support the continued development of fosgonimeton as a novel therapeutic for people with AD and dementia. The fast-onset normalization of ERP P300 latency in AD subjects suggests enhancement of synaptic function and potential procognitive effects.

All types of dementia, including Alzheimer’s disease, are debilitating neurodegenerative conditions marked by compromised cognitive function for which there are few effective treatments. Positive modulation of hepatocyte growth factor (HGF)/MET, a critical neurotrophic signaling system, may promote neuronal health and function, thereby addressing neurodegeneration in dementia. Here, we evaluate a series of novel small molecules for their ability to (1) positively modulate HGF/MET activity, (2) induce neurotrophic changes and protect against neurotoxic insults in primary neuron culture, (3) promote anti-inflammatory effects in vitro and in vivo, and (4) reverse cognitive deficits in animal models of dementia. Through screening studies, the compound now known as fosgonimeton-active metabolite (fosgo-AM) was identified by use of immunocytochemistry to be the most potent positive modulator of HGF/MET and was selected for further testing. Primary hippocampal neurons treated with fosgo-AM showed enhanced synaptogenesis and neurite outgrowth, supporting the neurotrophic effects of positive modulators of HGF/MET. Additionally, fosgo-AM protected against neurotoxic insults in primary cortical neuron cultures. In vivo, treatment with fosgo-AM rescued cognitive deficits in the rat scopolamine amnesia model of dementia. Although fosgo-AM demonstrated several procognitive effects in vitro and in vivo, a prodrug strategy was used to enhance the pharmacological properties of fosgo-AM, resulting in the development of fosgonimeton (ATH-1017). The effect of fosgonimeton on cognition was confirmed in a lipopolysaccharide (LPS)–induced neuroinflammatory mouse model of dementia. Together, the results of these studies support the potential of positive modulators of HGF/MET to be used as novel therapeutics and suggest the drug candidate fosgonimeton might protect against neurodegeneration and be therapeutic in the management of Alzheimer’s disease and other types of dementia.

Fosgonimeton (ATH‐1017) is a positive modulator of HGF/MET, a key neurotrophic pathway impaired in Alzheimer’s disease (AD). Neuronal MET expression is decreased in the cortex and hippocampus, which may contribute to synaptic loss, neurodegeneration, and functional decline. ACT‐AD seeks to replicate and extend the previously shown improvement of event‐related potential (ERP) P300 latency in AD patients demonstrated in an 8‐day randomized, placebo‐controlled, double‐blind Phase 1 trial. ERP P300 latency is a noninvasive, objective, quantitative biomarker of cognitive performance without learning effects.

Key Points Question What is the safety, tolerability, pharmacodynamic, and pharmacokinetic profile of the histone deacetylase inhibitor FRM-0334 in participants with progranulin gene (GRN) haploinsufficiency? Findings In this randomized placebo-controlled clinical trial including 27 participants with GRN haploinsufficiency, FRM-0334 was safe and well tolerated; however, it failed to increase plasma progranulin and cerebrospinal fluid progranulin and failed to demonstrate dose-dependent oral bioavailability. Meaning The studied formulation of FRM-0334 should not be investigated in future clinical trials enrolling participants with GRN haploinsufficiency; this study did not fully address the potential of histone deacetylase inhibition to alter GRN expression.

INTRODUCTION:Apathy is common in neurocognitive disorders (NCD) but NCD-specific diagnostic criteria are needed.METHODS:The International Society for CNS Clinical Trials Methodology Apathy Work Group convened an expert group and sought input from academia, health-care, industry, and regulatory bodies. A modified Delphi methodology was followed, and included an extensive literature review, two surveys, and two meetings at international conferences, culminating in a consensus meeting in 2019.RESULTS:The final criteria reached consensus with more than 80% agreement on all parts and included: limited to people with NCD; symptoms persistent or frequently recurrent over at least 4 weeks, a change from the patient's usual behavior, and including one of the following: diminished initiative, diminished interest, or diminished emotional expression/responsiveness; causing significant functional impairment and not exclusively explained by other etiologies.DISCUSSION:These criteria provide a framework for defining apathy as a unique clinical construct in NCD for diagnosis and further research.

Athira Pharma, Inc. is developing a new class of blood‐brain barrier (BBB)‐penetrant small molecule drugs aimed at activating the neurotrophic system HGF/MET to promote multiple neurorestorative processes, with the potential to ultimately improve brain function. ATH‐1017 is the lead clinical candidate for the treatment of Alzheimer’s disease (AD). Electroencephalogram (EEG) plays a growing role in facilitating dose exploration of investigational agents like ATH‐1017 by demonstrating brain penetration and target engagement, helping to accelerate CNS drug development.

Dementia is characterized by a significant decline in one of several cognitive domains such as memory, language and executive function, affecting independence and representing a significant deterioration from a previous level of functioning (1). Alzheimer’s Disease (AD) represents the most common form of dementia and contributes up to 70% of the almost 50 million dementia cases worldwide, a number that is projected to double in 20 years (2).