Fosgonimeton in mild-to-moderate Alzheimer's disease

Abstract

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.

Keywords

acetylcholinesterase inhibitor activities of daily living Alzheimer's disease biomarkers clinical trials/studies cognitive assessment fosgonimeton global statistical test neuroprotective neurotrophic

Introduction

Alzheimer's disease (AD) is a progressive neurodegenerative disease that is the most common cause of dementia in older adults and is associated with substantial medical, financial, and humanistic burden on patients, families, and caregivers.^1–5 The underlying pathophysiology of AD is multifactorial, and the hallmarks of AD include amyloid-β (Aβ) plaques and tau tangles.^2,6 Aβ plaque accumulation is associated with a cascade of pathological events, including neuroinflammation, mitochondrial dysfunction, oxidative stress, and synaptic dysfunction.^2,6,7 These events can overwhelm normal cellular processes (e.g., autophagy and ubiquination) and may further propagate Aβ/tau accumulation.⁸ The downstream effect of this pathophysiological cycle culminates in loss of neuronal connectivity and ultimately neuronal death, leading to decline in cognition and function.⁹ Acetylcholinesterase inhibitors (AChEIs) are approved therapies for mild-to-moderate AD that inhibit the enzyme that degrades acetylcholine. Recently approved anti-Aβ antibodies can reduce brain amyloid burden and modestly slow cognitive and functional declines in individuals with pre-dementia or early stages of AD.^10–12 However, despite reduction of amyloid burden, the disease continues to progress.^11,12 New treatments that target multiple aspects of AD could potentially enhance neuronal health and brain function, leading to improved clinical outcomes.

Fosgonimeton (ATH-1017) is a small-molecule positive modulator of hepatocyte growth factor (HGF) signaling.^3,13 HGF and its receptor, MET, are expressed in various cell types in the central nervous system, including neurons and glia, and comprise an endogenous neurotrophic pathway.³ By promotion of HGF signaling, fosgonimeton through its active metabolite has exhibited neurotrophic and neuroprotective effects in preclinical models of AD.^3,13,14 In these models, fosgonimeton has shown neuroprotective activity by inducing pleiotropic effects, including promotion of prosurvival signaling, reduction in oxidative stress and levels of pathological proteins (e.g., tau), improved synaptic and mitochondrial function, and decreased inflammation.^3,13 In Aβ animal models, fosgonimeton significantly improved neuron survival, reduced markers of mitochondrial dysfunction, and improved cognitive performance.^13,14 These preclinical results indicate this mechanism may potentially attenuate the pathological processes underlying neurodegeneration in AD.

Phase 1 (NCT03298672) clinical trial results supported an effect of fosgonimeton in the brain; quantitative electroencephalogram (qEEG) and event-related potential (ERP) P300 measured neurophysiological signals following fosgonimeton treatment, suggesting brain penetration and target engagement.¹⁵ The Phase 1 trial showed an acceptable safety profile for fosgonimeton. The translational Phase 2 study, ACT-AD (NCT04491006), was designed to explore the time-course of changes in pharmacodynamic effects (ERP P300 latency; primary endpoint), clinical cognitive and functional performance, and to establish longer-term safety in mild-to-moderate AD.¹⁶ The results of ACT-AD informed adjustments to the Phase 2/3 LIFT-AD trial, the efficacy and safety results of which are presented herein.

Methods

Trial design and oversight

LIFT-AD (NCT04488419; 23Jun2020) was a multicenter, randomized, double-blind, placebo-controlled, 26-week, trial conducted in the United States that assessed the efficacy and safety of fosgonimeton in participants with mild-to-moderate AD. Eligible participants were randomly assigned to receive subcutaneous fosgonimeton 40 mg or placebo, via prefilled syringe, daily for 26 weeks (1:1 ratio) (Figure 1). Randomization was stratified by mild versus moderate dementia as assessed by the Mini-Mental Status Exam (MMSE; mild, 20–24; moderate, 14–19).¹⁷ A randomization sequence was developed by independent unblinded statisticians and deployed through an Interactive Response Technology (IRT) system to assign all randomized participants to treatment groups. Dispensation of fosgonimeton or placebo was determined by the IRT system and assured blinding for site staff, participants, and study sponsor personnel. Study drug was packaged in identical kits and pre-filled syringes. Unblinded personnel, such as Data Safety Monitoring Board statisticians and drug supply managers, had no interactions with blinded study personnel and/or participants.

Figure 1.

LIFT-AD study schema and endpoints. AChEI: acetylcholinesterase inhibitor; AD: Alzheimer’s disease; ADAS-Cog₁₁; Alzheimer's Disease Assessment Scale–Cognitive Subscale; ADCS-ADL23: Alzheimer's Disease Cooperative Study–Activities of Daily Living; Aβ: amyloid-β; CDR: Clinical Dementia Rating; GFAP: glial fibrillary acidic protein; GST: global statistical test; MMSE: Mini-Mental State Examination; mg: milligram; NfL: neurofilament light chain; p-tau: phosphorylated tau; SC: subcutaneous.

Training for safe and effective use of prefilled syringes was provided to participants and their caregivers. Participants were allowed to self-administer upon the judgment of site staff; participants deemed not capable were administered study drug by their caregiver (Supplemental Material 1). At clinic visits, study drug administration was assessed on-site under the supervision of site staff.

Early versions of the protocol included a group assigned to fosgonimeton 70 mg. While LIFT-AD was ongoing, the Phase 2 trial (ACT-AD) results suggested similar efficacy between the 40 mg and 70 mg dose, with lower tolerability and higher discontinuation rates in the 70 mg dose; therefore, further randomization to fosgonimeton 70 mg was discontinued in LIFT-AD. Participants assigned to fosgonimeton 70 mg remained eligible to complete the 26-week study duration. To account for the discontinuation of randomization to fosgonimeton 70 mg, all randomization codes for fosgonimeton 70 mg were omitted and randomization continued to fosgonimeton 40 mg or placebo (1:1 ratio). Herein, fosgonimeton 70 mg safety data are reported for the safety population, and fosgonimeton pooled 40 mg and 70 mg efficacy data are reported for the modified intent-to-treat (mITT) population.

The trial was conducted across 90 US sites and in accordance with the International Council for Harmonisation guidelines, ethical principles outlined in the Declaration of Helsinki, and applicable regulatory requirements. All participants and caregivers provided written informed consent. A legally authorized representative (LAR) could consent to the study on behalf of the participant, if the participant was sufficiently limited by their AD symptoms. The LAR could have been different from the caregiver; caregiver consent was also completed to ensure the caregiver understood their role in the trial. The protocol was approved by an Institutional Review Board at all sites. An independent data safety monitoring board regularly reviewed and assessed the unblinded safety data throughout the trial duration. The sponsor, Athira Pharma Inc., provided funding for the trial conduct and analysis of the data. All authors attest to the accuracy of the data reported and the fidelity of the trial to the protocol.

Eligibility criteria

Key eligibility criteria included patients 55 to 85 years of age; standard clinical criteria for probable AD based on the 2011 National Institute on Aging Alzheimer's Association (NIA-AA) guidelines; mild-to-moderate dementia as assessed by the MMSE (range from 0 to 30, with lower scores indicating greater impairment) score between 14 and 24 inclusive, and Clinical Dementia Rating global score (CDR; range from 0 to 3, with higher scores indicating greater impairment) of 1 or 2 at screening.^17–19 Magnetic resonance imaging (MRI) or computerized tomography (CT) scans within 12 months of screening confirmed that there were no other significant comorbid central nervous system pathologies in eligible participants. Participants were tested for apolipoprotein E (APOE) ε4 genotype at screening to inform pre-specified subgroup analyses. Participants were required to have a primary caregiver who met caregiver-specific eligibility criteria (Supplemental Material 1).

Initially, participants receiving concomitant AChEIs (at stable doses for at least 3 months prior to screening), referred to as + AChEIs, were enrolled into the trial. The results from the Phase 2 (ACT-AD) trial suggested a difference in effects on cognition and plasma biomarkers in the group not receiving concomitant AChEI treatment (-AChEIs); therefore, LIFT-AD was amended to stop further enrollment of participants on concomitant AChEIs. Active + AChEIs participants had the option to complete the trial. Herein, the results include a pre-specified comparison of the + AChEI versus -AChEI participants. Other key exclusion criteria were use of memantine; history of significant neurological or psychiatric disorders; and current symptoms of severe major depressive disorder at screening (Supplemental Material 1 and 2).

Outcome measures

Efficacy

The primary efficacy outcome was the Global Statistical Test (GST) score, a composite of the change from baseline z-scores to Week 26 in the 11-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog11; range 0–70, with higher scores indicating greater impairment) and the 23-item Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL23; range 0–78, with lower scores indicating greater impairment).^20,21 This composite approach was used to assess an overall change in disease status. The GST score was defined as a single outcome variable based on standardizing and then combining individual patient-level z-score of change from baseline (CFB) cognition (ADAS-Cog11) and functional (ADCS-ADL23) scores. The between-group difference was calculated by subtracting the mean GST score for placebo from the mean GST score for fosgonimeton. A negative value based on the change from baseline in the composite (fosgonimeton minus placebo) GST scores indicates a favorable response to fosgonimeton while a positive value favors placebo. Secondary efficacy endpoints included change from baseline at Week 26 in ADAS-Cog11 and ADCS-ADL23, individually.

Principal site investigators selected clinical raters, who were trained in a standardized manner and approved to administer the instruments to participants and caregivers. Site staff, including clinical raters, remained blinded to treatment assignments.

Biomarkers

The change from baseline at Week 26 in plasma concentrations of neurofilament light chain (NfL; marker of neurodegeneration) was another secondary endpoint. Other key exploratory endpoints included change from baseline to Week 26 in plasma concentrations of glial fibrillary acidic protein (GFAP), phosphorylated tau at threonine 181 or 217 (p-tau181, p-tau217), and the Aβ_42/40 ratio. Plasma concentrations of NfL, GFAP, p-tau181, p-tau217, Aβ₄₂, and Aβ₄₀ were assessed by ultrasensitive biomarker detection technology, using commercially available Quanterix Simoa assays (Quanterix^®, Billerica, MA; Product#103670, NfL, GFAP, Aβ₄₂, and Aβ₄₀; Product#104111, p-tau181; Product#104371, p-tau217).

P-tau217 is recognized as a blood-based biomarker for AD pathology; advancements in plasma p-tau217 immunoassays allow for accurate and reliable detection of Aβ positive pathology with reproducible cut-offs of plasma p-tau217.²² P-tau217 plasma levels at baseline established which participants had confirmed AD pathophysiology (Aβ positive; p-tau217 ≥ 0.63 pg/mL) and which participants did not have AD pathophysiology (Aβ negative or required further confirmatory testing; < 0.62 pg/mL). This cut off was used for post-hoc subgroup analyses.

Safety

Safety assessments were performed at each visit, including the incidence and severity of treatment-emergent adverse events, clinical laboratory test results, findings on 12-lead electrocardiography, physical and neurologic examinations, as well as scores on the Columbia Suicide Severity Rating Scale and Geriatric Depression Scale.

Sample size calculation

The original protocol planned for 300 participants to be randomized to fosgonimeton 70 mg, fosgonimeton 40 mg, or placebo (1:1:1 ratio). Results of the ACT-AD (Phase 2) study informed changes to LIFT-AD specifically regarding the use of concomitant AChEI therapy for the primary analysis population and a prespecified interim analysis for futility or a sample size increase based on conditional power using the promising zone approach was implemented.²³ The interim analysis was conducted on -AChEI participants (N = 102) who completed or early terminated the trial across the three treatment arms. An independent unblinded data monitoring committee reviewed the results under a prespecified decision framework and recommended for LIFT-AD to continue as planned, with an increase of sample size. No changes were made to the randomization scheme because of the interim analysis.

The fosgonimeton 70 mg dose was also studied in ACT-AD; clinical and biomarker endpoints did not consistently favor 70 mg when compared to fosgonimeton 40 mg. Also, those assigned to fosgonimeton 40 mg showed better tolerability when compared to fosgonimeton 70 mg. Based on these results, a subsequent amendment to LIFT-AD was implemented to discontinue randomization to fosgonimeton 70 mg. These amendments resulted in a revised sample size for the primary analysis population to 298 participants randomized to fosgonimeton 40 mg or placebo (1:1 ratio) and was calculated to provide at least 85% power in detecting differences in GST score at a 2-sided alpha level of 0.05, assuming a mean between-group treatment difference (standard deviation) for change from baseline to Week 26 of 1.8 (6.0) in ADAS-Cog11 and 2.7 (9.0) in ADCS-ADL23 with a correlation coefficient of 0.5. The power calculation also assumed a 20% discontinuation rate. No individual treatment assignments were unblinded, following the interim analysis outcomes and discontinued randomization to fosgonimeton 70 mg. Amendments impacting the sample size calculation are detailed in Supplemental Material 3.

Statistical methods

Efficacy endpoints were evaluated in the mITT population (N = 510) and the primary analysis population (N = 287). The mITT population included all randomized participants who took at least one dose of the study drug (fosgonimeton 40 mg or 70 mg, or placebo) and who had baseline and at least one post-baseline visit with both ADAS-Cog11 and ADCS-ADL23 assessments completed. The primary analysis population was defined as a subset of mITT, which only included participants who were not receiving AChEI at least 28 days before the first dose of study drug and who were randomized to either fosgonimeton 40 mg or placebo.

The primary efficacy endpoint, GST score, was analyzed using a mixed model for repeated measures (MMRM). The model included the following fixed terms: baseline GST score, treatment arm, visit, treatment by visit interaction, APOE ε4 carrier status, baseline age (continuous), and baseline MMSE stratification factor. Study site pooling was also included as a fixed effect factor in the MMRM model. The correlations among repeated observations within a patient were accounted for by specifying an unstructured covariance matrix. A predefined gatekeeping plan and multiplicity adjustment for the sample size increase were used to control the overall Type I error rate for primary and secondary endpoints at a two-sided 0.05 level.

Secondary and exploratory endpoints were analyzed using MMRM as defined for the primary analysis. Safety was analyzed for all randomized participants (N = 549) who received at least one dose of the study medication.

Results

Study participants and characteristics

A total of 1284 participants were screened, of whom 554 were randomized (Figure 2). The safety population included 549 randomized participants who received at least 1 dose of study drug (224 fosgonimeton 40 mg, 107 fosgonimeton 70 mg, 218 placebo). The mITT population included 510 participants (204 fosgonimeton 40 mg, 99 fosgonimeton 70 mg, 207 placebo group). The primary analysis population included 287 participants not receiving concomitant AChEIs (143 fosgonimeton 40 mg, 144 placebo group).

Figure 2.

Trial participant disposition. ^aParticipants may have more than one reason for exclusion from analysis population(s) and therefore the reason for exclusion will not necessarily add up to the number of participants excluded. AChEI: acetylcholinesterase inhibitor; ADAS-Cog11: Alzheimer's Disease Assessment Scale–Cognitive Subscale; ADCS-ADL23: Alzheimer's Disease Cooperative Study–Activities of Daily Living; ITT: intent to treat; mITT: modified intent to treat; mg: milligram.

In the safety population, 78% in the fosgonimeton 40 mg group, 64% in the fosgonimeton 70 mg group, and 84% in the placebo group completed the study. The study had a 22% early termination rate. More participants in the fosgonimeton group (10.7% fosgonimeton 40 mg, 21.5% fosgonimeton 70 mg) discontinued from the study due to Treatment Emergent Adverse Events (TEAEs) compared with placebo (4.6%), mostly due to injection site reactions (ISRs).

Baseline characteristics were generally balanced between groups across the primary analysis population (Table 1), as well as the mITT and safety population dataset (data not shown). In the primary analysis population, mean age was 73.0 years; 55.1% were women; 54.0% had mild and 45.6% had moderate dementia as assessed by MMSE; and 51.6% were APOE ε4 carriers.

Table 1.

Baseline characteristics (primary analysis population).

Characteristics	Placebo(N = 144)	Fosgonimeton 40 mg(N = 143)	Overall(N = 287)
Mean (SD) age, y	73.4 (7.1)	72.6 (6.9)	73.0 (7.0)
Female, n (%)	82 (56.9)	76 (53.1)	158 (55.1)
White, n (%)	118 (81.9)	116 (81.1)	234 (81.5)
Mean (SD) body mass index, kg/m²	26.4 (4.9)	26.5 (4.3)	26.4 (4.6)
Mean (SD) years since AD Dx	3.1 (2.9)	2.8 (2.3)	2.9 (2.6)
Education level, n (%)
High school	55 (38.2)	50 (35.0)	105 (36.6)
Post high school	89 (61.8)	93 (65.0)	182 (63.4)
Clinical assessment language
English	118 (81.9)	117 (81.8)	235 (81.9)
Spanish	26 (18.1)	26 (18.2)	52 (18.1)
APOE ε4 carriers, n (%)	74 (51.4)	74 (51.7)	148 (51.6)
Heterozygotes	59 (41.0)	59 (41.3)	118 (41.1)
Homozygotes	15 (10.4)	15 (10.5)	30 (10.5)
Concomitant AChEI, n (%)	0 (0)	0 (0)	0 (0)
Mean (SD) MMSE score	19.3 (3.4)	19.9 (3.5)	19.6 (3.5)
MMSE ≥20 (mild), n (%)	74 (51.4)	81 (56.6)	155 (54.0)
MMSE <20 (moderate), n (%)	70 (48.6)	61 (42.7)	131 (45.6)
CDR Score, n (%)
0.5	1 (0.7)	1 (0.7)	2 (0.7)
1	123 (85.4)	122 (85.3)	245 (85.4)
2	19 (13.2)	20 (14.0)	39 (13.6)
Mean (SD) ADAS-Cog₁₁	22.3 (7.6)	20.7 (7.8)	21.5 (7.8)
Mean (SD) ADCS-ADL23	62.3 (10.0)	62.5 (9.9)	62.4 (10.0)
Mean (SD) NfL, pg/mL	27.7 (16.4)	26.3 (25.5)	27.0 (21.5)
Mean (SD) p-tau217, pg/mL	1.0 (0.6)	0.8 (0.8)	0.9 (0.7)

AChEI: acetylcholinesterase inhibitor; AD: Alzheimer's disease; ADAS-Cog₁₁: Alzheimer's Disease Assessment Scale–Cognitive Subscale 11; ADCS-ADL23: Alzheimer's Disease Cooperative Study–Activities of Daily Living 23; APOE ε4: apolipoprotein E ε4; CDR: Clinical Dementia Rating; MMSE: Mini-Mental State Examination; NfL: neurofilament light chain; p-tau: phosphorylated tau; SD: standard deviation.

Clinical efficacy outcomes

Primary analysis population

Between-group difference in the least-square mean (LSM) change (SE) were not statistically significant for any of the primary and secondary clinical endpoints: −0.08 (0.10) (p = 0.70) in the GST score, −0.70 (0.77) (p = 0.35) in ADAS-Cog11, and +0.67 (0.92) (p = 0.61) in ADCS-ADL23 (Table 2). Unexpectedly, both placebo and fosgonimeton groups showed improvements in ADAS-Cog11 as early as Week 2, reaching a peak at Week 6, and gradually returning towards baseline levels at Week 26 (Figure 3). However, non-significant (NS) differences favoring fosgonimeton remained consistent throughout the 26-week study. ADCS-ADL23 also showed a small improvement in both groups up to Week 12 (NS); although the placebo group returned to baseline levels at Week 26, the fosgonimeton group continued to show modest improvements through Week 26 (NS). Differences between fosgonimeton and placebo also remained consistent throughout the 26-week study for ADCS-ADL23 (NS).

Figure 3.

Change in (a) Cognition (ADAS-Cog₁₁) and (b) Activities of Daily Living (ADCS-ADL23) (Primary Analysis Population). Arrow indicates direction of improvement. ADAS-Cog₁₁: Alzheimer’s Disease Assessment Scale–Cognitive Subscale 11; ADCS-ADL23: Alzheimer’s Disease Cooperative Study–Activities of Daily Living 23; CFB: change from baseline; LS mean: least squares mean; pts: points; SD: standard deviation; SE: standard error.

Table 2.

Summary of primary and secondary endpoints (primary analysis population).

Outcome MeasureLS Mean (SE)	Placebo(N = 144)	Fosgonimeton 40 mg(N = 143)	Difference vs. Placebo(N = 287)
GST Score ↓	−0.13 (0.07)	−0.21 (0.07)	−0.08 (0.10)p = 0.70
ADAS-Cog₁₁ ↓	−0.39 (0.54)	−1.09 (0.56)	−0.70 (0.77)p = 0.35
ADCS-ADL23 ↑	−0.02 (0.65)	0.65 (0.67)	0.67 (0.92)p = 0.61
NfL (pg/mL) ↓	2.95 (2.49)	−0.96 (2.48)	−3.91 (3.46)p = 0.26*

*Weighted model p-value not reported due to lack of model convergence; non-weighted analysis p-value = 0.26. Arrow indicates direction of improvement. ADAS-Cog₁₁: Alzheimer's Disease Assessment Scale–Cognitive Subscale 11; ADCS-ADL23: Alzheimer's Disease Cooperative Study–Activities of Daily Living 23; GST: Global Statistical Test; LS mean: least squares mean; MMSE: Mini-Mental State Examination; NfL: neurofilament light chain; SE: standard error.

Subgroups: MMSE severity and APOE ε4 status

In the primary analysis population, pre-specified subgroup analyses were performed on the following subgroups: AD severity defined by MMSE at baseline (mild ≥20, N = 155; moderate <20, N = 131), and APOE ε4 status (carriers, N = 148; non-carriers, N = 138).

Participants with moderate AD or who were APOE ε4 carriers maintained cognitive and functional performance when treated with fosgonimeton for 26 weeks; the participants in the placebo group declined throughout the duration of the trial. As a result, the magnitude of difference between fosgonimeton and placebo is greater in these two subgroups compared to participants with mild AD and APOE ε4 non-carriers. This subgroup analysis showed non-significant between-group differences (LSM [SE]) in change from baseline at Week 26 in ADAS-Cog11 of −1.16 (1.33) points (p = 0.39) among participants with moderate dementia and −1.07 (1.09) points (p = 0.33) among APOE ε4 carriers. For ADCS-ADL23, differences of +0.56 (1.68) points (p = 0.74) were observed among participants with moderate dementia and +0.74 (1.34) points (p = 0.58) among APOE ε4 carriers compared with placebo (Figure 4). Results in these subgroups were directionally consistent with the overall primary analysis results in cognition and function.

Figure 4.

Change in (a-d) cognition (ADAS-Cog₁₁) and (e-h) activities of daily living (ADCS-ADL23) (MMSE and APOE ε4 status subgroups). Arrow indicates direction of improvement. ADAS-Cog₁₁: Alzheimer’s Disease Assessment Scale–Cognitive Subscale 11; ADCS-ADL23: Alzheimer’s Disease Cooperative Study–Activities of Daily Living 23; APOE ε4: apolipoprotein E ε4; CFB: change from baseline; LS mean: least squares mean; MMSE: Mini-Mental State Examination; pts: points; SE: standard error.

Non-significant improvements in cognition and functional outcomes for both fosgonimeton and placebo groups were observed in participants with mild AD and APOE ε4 non-carrier participants; within each subgroup, no discernable between-group differences were observed at Week 26 (Figure 4).

mITT population: +/-AChEI therapy, pooled fosgonimeton versus placebo

The primary analysis population excluded concomitant AChEIs. Therefore, a pre-specified subgroup analysis performed on the mITT population compared the effects of fosgonimeton with or without AChEI therapy. There were 173 participants in the + AChEI subgroup; 110 were assigned to fosgonimeton 40 mg or 70 mg and 63 were assigned to placebo. There were no discernible baseline characteristic differences within the AChEI subgroups (Table 3).

Table 3.

Baseline characteristics of subgroups with or without concomitant AChEI therapy (+AChEI versus -AChEI subgroups, mITT population) fosgonimeton group reports pooled 40 mg and 70 mg results.

Baseline Characteristic, Mean (SD)	– AChEI		+AChEI
Baseline Characteristic, Mean (SD)	Placebo (N = 144)	Fosgonimeton (N = 193)	Placebo (N = 63)	Fosgonimeton (N = 110)
Age, years	73.4 (7.1)	72.3 (7.0)	73.0 (7.6)	72 (7.2)
MMSE Score	19.3 (3.4)	19.9 (3.5)	19.2 (4.1)	18.8 (3.4)
ADAS-Cog₁₁	22.3 (7.6)	20.9 (7.5)	23.9 (9.1)	23.1 (8.1)
ADCS-ADL23	62.3 (10.0)	62.6 (9.4)	59.5 (10.1)	62.6 (8.7)
NfL, pg/mL	27.7 (16.4)	26.6 (23.1)	28.3 (14.7)	27.3 (12.0)
GFAP, pg/mL	247.9 (118.7)	232.6 (125.5)	276.0 (115.1)	288.9 (113.8)
p-tau217, pg/mL	1.0 (0.6)	0.9 (0.9)	1. 2 (0.7)	1.2 (0.7)

AChEI: acetylcholinesterase inhibitor; ADAS-Cog₁₁: Alzheimer's Disease Assessment Scale–Cognitive Subscale 11; ADCS-ADL23: Alzheimer's Disease Cooperative Study–Activities of Daily Living 23; GFAP: glial fibrillary acidic protein; MMSE: Mini-Mental State Examination; NfL: neurofilament light chain; pg/mL: picogram/milliliter; p-tau: phosphorylated tau; SD: standard deviation.

Both placebo and fosgonimeton participants in the + AChEI subgroups experienced a worsening in cognition and function, as measured by the ADAS-Cog11 and ADCS-ADL23 at Week 26. (Table 4).

Table 4.

Change from baseline to Week 26 ADAS-Cog₁₁ and ADCS-ADL23 (+/- AChEI subgroups, mITT population) Fosgonimeton group reports pooled 40 mg and 70 mg results.

Clinical Endpoint, LS Mean (SE)	–AChEI			+AChEI
Clinical Endpoint, LS Mean (SE)	Placebo (N = 144)	Fosgonimeton (N = 193)	Difference vs. Placebo	Placebo (N = 63)	Fosgonimeton (N = 110)	Difference vs. Placebo
ADAS-Cog₁₁	−0.38 (0.55)	−0.48 (0.49)	−0.11 (0.73)P = 0.89	1.46 (0.71)	2.34 (0.57)	0.88 (0.90)p = 0.33
ADCS-ADL23	−0.07 (0.63)	0.60 (0.57)	0.67 (0.85)P = 0.43	−2.24 (0.93)	−4.29 (0.73)	−2.05 (1.15)p = 0.08

Plasma biomarker outcomes

Primary analysis population

Changes in plasma biomarkers of AD pathology showed evidence of decrease in measures of inflammation, protein pathology and neurodegeneration (Figure 5). The LSM (SE) change from baseline at Week 26 in plasma neurofilament light chain (NfL) concentrations, a biomarker of neurodegeneration and a secondary endpoint, was −0.96 (2.48) pg/mL in the fosgonimeton group and +2.95 (2.49) pg/mL in the placebo group (percent difference of −14.3% versus placebo; p = 0.26; Figure 5).

Figure 5.

Change from baseline to Week 26 in biomarkers of (a) Neurodegeneration (NfL), (b) Neuroinflammation (GFAP), and (c–e) Protein Pathology in Alzheimer’s Disease (p-tau181, p-tau217, Aβ42/40) (Primary Analysis Population). *Weighted model p-value not reported due to lack of model convergence; Non-weighted analysis p-value = 0.26. Arrow indicates direction of improvement. Aβ: amyloid-β; GFAP: glial fibrillary acidic protein; LS mean: least squares mean; NfL: neurofilament light chain; pg/mL: picogram/milliliter; p-tau: phosphorylated tau; SE: standard error.

The percent change from baseline at Week 26 was non-significant when compared to placebo in glial fibrillary acidic protein (GFAP), a biomarker of neuroinflammation (−9.4%; p = 0.21), and p-tau181, a biomarker of tau burden (−5.6%; p = 0.13). A nominally significant percent change from baseline at Week 26 was observed in p-tau217 when compared to placebo, a biomarker associated with Aβ burden (−13.7%; p < 0.01) (Figure 5).

Subgroups: MMSE severity, APOE ε4 status, and p-tau217 reference ranges

In the subgroups with moderate dementia or APOE ε4 carrier status, a modest decrease in plasma NfL concentrations was observed in the fosgonimeton group, in contrast to an increase in concentration observed in the placebo group, likely due to the natural progression of aging and neurodegeneration over the treatment period.^24,25 Subgroup biomarker outcomes also reflect the directional changes observed in the primary analysis. The percent change from baseline at Week 26 plasma NfL is −27.3% (LSM (SE); −8.01 (7.02) pg/mL; p = 0.26)) among participants with moderate dementia, and −22.3% (LSM (SE) −1.68 (1.97) pg/mL; p = 0.40)) among APOE ε4 carriers (Table 5) compared with placebo. Generally, change from baseline in plasma GFAP levels demonstrated a similar pattern of response in both moderate dementia and APOE ε4 subgroups (Table 5).

Table 5.

Change from baseline to Week 26 in plasma biomarkers of neurodegeneration (NfL) and neuroinflammation (GFAP) in a) MMSE subgroups and b) APOE ε4 Status subgroups.

a)
Plasma Biomarker, LS Mean (SE)	Mild Baseline MMSE (20–24)			Moderate Baseline MMSE (14–19)
	Placebo (N = 54)	Fosgonimeton 40 mg (N = 68)	Difference vs. Placebo	Placebo (N = 56)	Fosgonimeton 40 mg (N = 47)	Difference vs. Placebo
NfL, pg/mL	−0.14 (1.41)	0.37 (1.30)	0.52 (1.89) p = 0.79	6.77 (4.90)	−1.24 (5.34)	−8.01 (7.02) p = 0.26
CFB, %	−0. 6	1.5	2.1	23.1	−4.2	−27.3
GFAP, pg/mL	−8.24 (8.42)	−4.12 (7.78)	4.12 (11.27) p = 0.72	26.24 (23.13)	−30.04 (25.37)	−56.28 (33.90) p = 0.10
CFB, %	−3.6	−1.9	1.7	9.8	−12.6	−22.3

b)
Plasma Biomarker, LS Mean (SE)	APOE ε4 Non-Carrier			APOE ε4 Carrier
	Placebo (N = 54)	Fosgonimeton 40 mg (N = 55)	Difference vs. Placebo	Placebo (N = 56)	Fosgonimeton 40 mg (N = 59)	Difference vs. Placebo
NfL, pg/mL	7.29 (4.88)	1.03 (4.90)	−6.26 (6.87) p = 0.36	−1.70 (1.56)	−3.38 (1.44)	−1.68 (1.97) p = 0.40
CFB, %	28.7	4.6	−24.1	−5.7	−11.1	−5.4
GFAP, pg/mL	2.00 (8.54)	−11.64 (8.53)	−13.65 (11.81) p = 0.25	9.51 (22.40)	−17.63 (22.13)	−27.13 (30.87) p = 0.38
CFB, %	0.8	−5.6	−6.4	3.8	−7.2	−11.0

APOE ε4: apolipoprotein E ε4; CFB: change from baseline; GFAP: glial fibrillary acidic protein; LS mean: least squares mean; MMSE: Mini-Mental State Examination; NfL: neurofilament light chain; pg/mL: picogram/milliliter; SE: standard error.

A post-hoc analysis was conducted on participants with baseline plasma p-tau217 levels above and below the cutoff associated with Aβ positive pathology. Participants with baseline plasma p-tau217 levels ≥0.63 pg/mL were retrospectively classified as Aβ positive (N = 136); participants with baseline plasma p-tau217 levels <0.63 pg/mL were classified as Aβ negative, including those requiring further confirmatory testing (N = 85). These subgroups were analyzed for change from baseline at week 26 in plasma NfL and GFAP. Notably, the Aβ positive subgroup was older by about 2 years of age and had greater mean concentrations of plasma NfL and GFAP compared to the Aβ negative subgroup (Table 6). The fosgonimeton group (N = 63) and placebo group (N = 73) were well balanced within the Aβ positive subgroup.

Table 6.

Baseline characteristics of Aβ+ versus Aβ-subgroups based on plasma p-tau217 concentrations.

Baseline Characteristic, Mean (SD)	Aβ – Cutoff<0.63 pg/mL plasma p-tau217		Aβ + Cutoff≥0.63 pg/mL plasma p-tau217
Baseline Characteristic, Mean (SD)	Placebo (N = 34)	Fosgonimeton 40 mg (N = 51)	Placebo (N = 73)	Fosgonimeton 40 mg (N = 63)
Age, y	72.6 (6.8)	71.5 (6.6)	74.1 (6.9)	73.5 (7.1)
MMSE Score	20.1 (3.4)	20.6 (3.0)	19.0 (3.4)	19.6 (3.9)
ADAS-Cog₁₁	21.0 (7.5)	19.3 (6.4)	22.9 (6.8)	22.1 (7.0)
ADCS-ADL23	62.3 (12.2)	62.4 (8.8)	62.2 (9.5)	63.8 (9.9)
NfL, pg/mL	24.2 (23.1)	20.7 (14.3)	28.7 (12.0)	31.0 (31.3)
GFAP, pg/mL	153.6 (95.0)	172.8 (133.9)	289.6 (101.6)	271.5 (97.7)
p-tau217, pg/mL	0.3 (0.1)	0.3 (0.1)	1.3 (0.4)	1.3 (0.8)

Aβ-: amyloid-β negative; Aβ+: amyloid-β positive; ADAS-Cog₁₁: Alzheimer's Disease Assessment Scale–Cognitive Subscale 11; ADCS-ADL23: Alzheimer's Disease Cooperative Study–Activities of Daily Living 23; GFAP: glial fibrillary acidic protein; MMSE: Mini-Mental State Examination; NfL: neurofilament light chain; pg/mL: picogram/milliliter; p-tau: phosphorylated tau; SD: standard deviation.

Aβ positive participants showed reductions of plasma NfL and GFAP concentrations with fosgonimeton. The percent change from baseline at week 26 in plasma NfL was −13.0% (p = 0.49) and in plasma GFAP was −14.9% (p = 0.14) compared with placebo. Participants without confirmed Aβ positivity showed no notable change in plasma NfL and GFAP concentrations at week 26 (Table 7).

Table 7.

Change from baseline to week 26 in biomarkers (Aβ+ versus Aβ- subgroups).

Plasma Biomarker, LS Mean (SE)	Aβ – Cutoff<0.63 pg/mL plasma p-tau217			Aβ + Cutoff≥0.63 pg/mL plasma p-tau217
Plasma Biomarker, LS Mean (SE)	Placebo (N = 34)	Fosgonimeton 40 mg (N = 51)	Difference vs. Placebo	Placebo (N = 73)	Fosgonimeton 40 mg (N = 63)	Difference vs. Placebo
NfL, pg/mL	1.05 (1.60)	1.19 (1.29)	0.14 (1.80) p = 0.94	2.42 (3.88)	−1.40 (4.20)	−3.82 (5.56) p = 0.49
CFB, %	4.4	5.8	1.4	8.4	−4.5	−13.0
GFAP, pg/mL	0.53 (8.71)	5.31 (7.06)	4.77 (10.19) p = 0.64	13.67 (18.85)	−27.45 (21.08)	−41.17 (27.78) p = 0.14
CFB, %	0.3	3.1	2.7	4.7	−10.1	−14.9

Aβ-: amyloid-β negative; Aβ+: amyloid-β positive; ADAS-Cog₁₁: Alzheimer's Disease Assessment Scale–Cognitive Subscale 11; ADCS-ADL23: Alzheimer's Disease Cooperative Study–Activities of Daily Living 23; CFB: change from baseline; MMSE: Mini-Mental State Examination; NfL: neurofilament light chain; pg/mL: picogram/milliliter; p-tau: phosphorylated tau; SE: standard error.

For participants with confirmed AD pathology based on plasma p-tau217 concentrations, the decrease in plasma NfL and GFAP concentrations at week 26 favored the effect of fosgonimeton versus placebo, although non-significant.

Safety

The safety analysis evaluated 549 dosed participants, including those who received either fosgonimeton 70 mg, 40 mg, or placebo. Fosgonimeton was generally well-tolerated with an acceptable safety profile (Table 8). Treatment-emergent adverse events (TEAEs) were reported in 60.6% of the placebo group, 78.1% of the fosgonimeton 40 mg group, and 87.9% of the fosgonimeton 70 mg group; most were mild-to-moderate in severity. There were no deaths reported in the study. Serious TEAEs were reported in 15/218 (6.9%) participants in the placebo group, 11/224 (4.9%) participants in the fosgonimeton 40 mg group, and 3/107 (2.8%) participants in the fosgonimeton 70 mg group. Most serious TEAEs were generally consistent with findings in clinical trials and/or in an elderly population and appeared generally balanced between placebo and pooled fosgonimeton groups. Among serious TEAEs, 5 (1.5%) were suspected to be related to fosgonimeton (3 in the 40 mg group [fecaloma, pyrexia, and angioedema] and 2 in the 70 mg group [diarrhea and angioedema]) compared with none in the placebo group.

Table 8.

Summary of adverse events (safety population).

Participant incidence, n (%)	Placebo (N = 218)	Fosgonimeton 40 mg (N = 224)	Fosgonimeton 70 mg (N = 107)
Any adverse events	136 (62.4)	177 (79.0)	94 (87.9)
Treatment-emergent adverse events (TEAEs)	132 (60.6)	175 (78.1)	94 (87.9)
TEAEs occurring in ≥ 4% in any group
Injection site reactions (high-level term)^a	31 (14.2)	128 (57.1)	78 (72.9)
Fall	9 (4.1)	10 (4.5)	5 (4.7)
COVID-19	12 (5.5)	10 (4.5)	2 (1.9)
Eosinophilia	0	16 (7.1)	8 (7.5)
Pruritus	4 (1.8)	10 (4.5)	6 (5.6)
Headache	9 (4.1)	6 (2.7)	3 (2.8)
Urinary tract infection	9 (4.1)	5 (2.2)	2 (1.9)
Treatment-related TEAEs	54 (24.8)	155 (69.2)	86 (80.4)
Serious TEAEs	15 (6.9)	11 (4.9)	3 (2.8)
Treatment-related serious TEAEs	0	3 (1.3)	2 (1.9)
TEAEs leading to study drug withdrawal	9 (4.1)	24 (10.7)	23 (21.5)
TEAEs leading to study drug interruption	9 (4.1)	29 (12.9)	11 (10.3)
TEAEs leading to study withdrawal	10 (4.6)	24 (10.7)	23 (21.5)
Deaths	0	0	0

High-level term includes the following preferred terms: injection site reaction, injection site pruritus, injection site pain, injection site nodule, injection site erythema, injection site swelling, injection site mass, injection site induration, injection site bruising, injection site hemorrhage, injection site vesicles, injection site rash, injection site paresthesia, injection site urticaria, injection site oedema, injection site warmth, injection site discomfort, injection site extravasation, injection site hematoma, injection site irritation, injection site papule. Preferred terms reported for TEAEs occurring in ≥ 4% in any group. All values presented as n (%); % = (n/N) * 100. MedDRA: Medical Dictionary for Regulatory Activities Terminology (MedDRA version 24.0); mg: milligram; TEAE: treatment-emergent adverse event.

More participants in the fosgonimeton group (10.7% fosgonimeton 40 mg, 21.5% fosgonimeton 70 mg) discontinued from the study due to TEAEs compared with placebo (4.6%). Most of the discontinuations due to TEAEs in the fosgonimeton groups were attributed to injection site reactions (ISRs) (Table 8). ISRs were reported in 14.2% of the placebo group, 57.1% of the fosgonimeton 40 mg group, and 72.9% of the fosgonimeton 70 mg group; ISRs were mostly mild-to-moderate in severity. Transient, asymptomatic, and reversible increases in absolute eosinophil count were observed with fosgonimeton. Based on safety reports, 16 (7.1%) participants receiving fosgonimeton 40 mg and 8 (7.5%) participants receiving fosgonimeton 70 mg reported TEAEs of eosinophilia, compared with none in the placebo group. Overall, 20/24 (83%) participants with TEAEs of eosinophilia also reported concurrent TEAEs of ISRs. Most of the elevations stayed below 3 × 10³/μL and resolved without intervention. A few participants (2.2%) experienced elevations above 5 × 10³/μL (6 participants each in the 40 mg and 70 mg groups). No clinically significant transaminase elevations were reported. A few participants had elevations in alanine transaminase >3–5× the upper limit of normal during the study, but these were balanced between groups: placebo (1 [0.5%] participant), fosgonimeton 40 mg (0 [0%]), and fosgonimeton 70 mg (1 (0.9%]).

Discussion

LIFT-AD did not achieve statistical significance in the primary endpoint, composite GST score, or its secondary efficacy endpoints of ADAS-Cog11 and ADCS-ADL23. At Week 26, a small difference was seen in ADAS-Cog11; non-significant LSM change of −1.09 was observed in the fosgonimeton group and −0.39 in the placebo group. A similar difference was also observed in ADCS-ADL23; non-significant LSM change of +0.65 in the fosgonimeton group versus −0.02 in the placebo group.

The lack of decline in cognition and function in the placebo group was unexpected. Historically, in clinical trials of mild-to-moderate AD, a worsening in ADAS-Cog11 and in ADCS-ADL23 was seen in the placebo group over a 6-month period.^26–29 The lack of decline in LIFT-AD may be attributed to a trial population with milder disease progression than those in the historical trials. In recent AD clinical trials with monoclonal antibody therapies, trial populations had earlier stages of AD and required 18 months to observe a separation between treatment and placebo. In the context of a milder disease population, LIFT-AD is limited by a shorter study duration of 26 weeks, which may not have allowed for enough time to observe the progression of the disease. Although approximately half of the population was screened as having moderate disease severity based on the MMSE, baseline data showed that the majority (85%) had mild dementia based on the CDR global score (CDR = 1) and an overall baseline mean ADAS-Cog11 score of 21.5. In addition, daily subcutaneous injections of the investigational drug may have biased participant and caregiver responses to the clinical questionnaires as reflected in the large placebo effect. This may have contributed to the trending improvement seen in the first 6 weeks of the study across both the placebo and fosgonimeton groups. In this study, the inclusion of participants was based on a pre-established diagnosis of AD, referring to the 2011 NIA-AA criteria for “probable AD”.¹⁸ When the study started in 2020, the 2018 NIA-AA Research Framework provided a binary classification system based on biomarkers, but there were no definitive cut points to apply to this study's patient population.³⁰ The AD diagnostic criteria were revised in 2024 to provide a biological definition of AD and enabled the utility of plasma biomarkers, as such, a diagnosis of AD may now be confirmed based on plasma p-tau217 levels.^22,31 The absence of biomarker confirmed AD biology may have further contributed to the selection of a trial population less prone to decline.

To determine whether the neuroprotective effects of fosgonimeton observed in various preclinical models would translate into the clinic, plasma biomarkers of neurodegeneration, inflammation, and AD pathophysiology were assessed. In LIFT-AD, an increase in plasma NfL and GFAP in the placebo group at Week 26 were observed, while plasma NfL and GFAP did not increase in the fosgonimeton group at Week 26, which is consistent with the expected neuroprotective and pleotropic effects of fosgonimeton. The non-significant decreases in markers of neurodegeneration and neuroinflammation were observed in the fosgonimeton group in both the primary analysis population and the subgroup with confirmed AD pathophysiology based on plasma p-tau217 levels.

To assess the study design limitations seen by the milder trial population, analyses of prespecified subgroups with either greater cognitive impairment or with certain genetic risk factors at baseline (e.g., moderate MMSE, APOE ε4 carriers) showed a placebo decline over 26 weeks. Among these subgroups, for both cognition and function, the difference of fosgonimeton versus placebo was greater than that observed in subgroups of milder cognitive impairment and APOE ε4 non-carriers. Participants in these subgroups also showed a larger separation in NfL and GFAP levels compared with placebo. These results suggest that a trial population of participants with advanced dementia or greater risk factors may demonstrate a larger effect size for fosgonimeton, with a placebo group declining as expected. Fosgonimeton was generally well tolerated, with a favorable safety profile. Participants treated with fosgonimeton for 26 weeks showed a higher incidence of TEAEs compared with placebo, mainly driven by ISRs.

In summary, while LIFT-AD did not achieve its primary or secondary endpoints, the consistent non-significant improvements favoring fosgonimeton treatment across multiple endpoints suggest that positive modulation of HGF signaling may have a positive impact on neuronal health in patients with AD.

Supplemental Material

sj-docx-1-alr-10.1177_25424823251405817 - Supplemental material for Fosgonimeton in mild-to-moderate Alzheimer's disease

Supplemental material, sj-docx-1-alr-10.1177_25424823251405817 for Fosgonimeton in mild-to-moderate Alzheimer's disease by Anton P Porsteinsson, Marwan Sabbagh, Pierre N Tariot, Kevin J Church, Javier San Martin, Kai-Bin C Ooi, Simon Daggett, Michael D Hale, Richard Holub and Hans J Moebius in Journal of Alzheimer's Disease Reports

Footnotes

Acknowledgements

We thank the trial participants, their families, and caregivers, and trial investigators and site staff who made the trial possible; members of the data safety monitoring committee; Athira Pharma staff; staff of our vendors; Toshio Kimura of SSI Consulting for statistical programming support; John Harrison for rater training and oversight support; Alexandra Murphy and Eileen McIver of ApotheCom, and Ting Chang and Maya Kneip of Athira Pharma for medical writing and editorial support.

We would like to thank Dr Leen Kawas for her support of the research teams involved in these studies and acknowledge her contributions to the conceptualization, design, and work on several Athira Pharma studies, including the study underlying this publication.

ORCID iDs

Anton P Porsteinsson

Marwan Sabbagh

Pierre N Tariot

Kevin J Church

Javier San Martin

Kai-Bin C Ooi

Simon Daggett

Michael D Hale

Hans J Moebius

Ethical considerations

This study was approved by relevant institutional review board or independent ethics committee at each site. All participants (or their LAR) provided written informed consent prior to enrollment in the study. This research was conducted ethically in accordance with the World Medical Association Declaration of Helsinki.

Consent to participate

All participants (or their LAR) and caregivers provided written informed consent prior to participating.

Author contribution(s)

Anton P Porsteinsson: Investigation; Resources; Writing – original draft; Writing – review & editing.

Marwan Sabbagh: Conceptualization; Writing – review & editing.

Pierre N Tariot: Conceptualization; Writing – review & editing.

Kevin J Church: Conceptualization; Writing – review & editing.

Javier San Martin: Conceptualization; Supervision; Writing – original draft; Writing – review & editing.

Kai-Bin C Ooi: Conceptualization; Visualization; Writing – review & editing.

Simon Daggett: Conceptualization; Supervision; Writing – review & editing.

Michael D Hale: Formal analysis; Methodology; Writing – review & editing.

Richard Holub: Investigation; Resources; Writing – review & editing.

Hans J Moebius: Conceptualization; Methodology; Writing – review & editing.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Funded by Athira Pharma, Inc.; LIFT-AD ClinicalTrials.gov number, NCT04488419

Declaration of conflicting interests

The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr Anton P Porsteinsson reports consulting fees from Acadia Pharmaceuticals, Athira Pharma, Axsome, Biogen, BMS, Cognitive Research Corp, Cognition Therapeutics, Eisai, IQVIA, Lundbeck, MapLight Therapeutics, Novartis, Novo Nordisk, ONO Pharmaceuticals, Otsuka, WCG, WebMD, and Xenon; grants to his institution from Alector, Athira Pharma, Biogen, Cassava, Eisai, Eli Lilly, Genentech/Roche, Vaccinex, NIA, NIMH, and DOD.

Dr Marwan Sabbagh reports consulting fees from Athira Pharma, Eisai, Lilly, Synaptogenix, NeuroTherapia, Signant Health, Novo Nordisk, Anavex, Cognito Therapeutics, GSK, and Abbvie; ownership interests (stock or stock options) in Optimal Cognitive Health Company, uMethod Health, Versanum, Athira Pharma, TransDermix, Seq BioMarque, NeuroReserve, Lighthouse Pharmaceuticals, Alzheon, and Reservoir Neuroscience; board of director member of EIP Pharma/Cervo Med; grants to his institution from the NIA and the Lewy Body Dementia Association Research Centers of Excellence. Dr Sabbagh is an Editorial Board Member of this journal but was not involved in the peer-review process of this article nor had access to any information regarding its peer-review.

Dr Pierre N Tariot reports consulting fees from AbbVie, AC Immune, Acadia, Athira Pharma, Axsome, Bristol Myers Squibb, Cognition Therapeutics, Cognito, Corium, CuraSen, Eisai, Immunobrain, Janssen, Lundbeck, MapLight, Merck, Novartis, Novo Nordisk, Otsuka, Roche, T3D Therapeutics.

Dr Kevin J Church, Dr Javier San Martin, Dr Michael D Hale, Simon Daggett, and Kai-Bin C Ooi are employees or ex-employees and stockholders of Athira Pharma.

Dr Richard Holub reports grants to his institution from Athira Pharma.

Dr Hans J Moebius served as Chief Medical Officer of Athira Pharma between 2019 and 2024, and since as Senior Scientific Advisor, and is a stockholder of Athira Pharma.

Data availability statement

Athira Pharma, Inc. is committed to clinical trial data sharing and will make reasonable efforts to share anonymized data from our clinical trials without compromising the privacy of trial participants. Data requests must be for legitimate medical/scientific research purposes from qualified researchers and may be sent by email to info@athira.com. Proposed analyses that demonstrate scientific merit will be considered. Athira Pharma, Inc. intends to share data from clinical studies that have completed, and the product/indication is approved at minimum in the U.S. and EU.

Supplemental material

Supplemental material for this article is available online.

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