A bittersweet moment for Athira Pharma as they unravel the outcomes of the Phase 2/3 LIFT-AD trial, where the coveted primary endpoint of GST and essential secondary endpoints of cognition (ADAS-Cog11) and function (ADCS-ADL23) eluded their grasp.

Yet, in the crevices of this setback, faint glimmers of optimism emerge. Within subsets of patients with moderate Alzheimer’s disease or those carrying the APOE4 gene, fosgonimeton, the hepatocyte growth factor (HGF) positive modulator, hinted at a more substantial treatment effect.

Signs of change reverberated across all Alzheimer’s disease-related biomarkers, reflecting alterations from fosgonimeton treatment that resonate with the profound neuroprotective spectrum of HGF modulation.

Athira braces for a digital congregation today at 4:30 PM Eastern time, a moment of reflection and synthesis in the wake of the trial’s denouement.

BOTHELL, Wash., Sept. 03, 2024 (GLOBE NEWSWIRE) — Athira Pharma, Inc. ATHA, a late clinical-stage biopharmaceutical entity tireless in its pursuit of small molecules to rekindle neuronal vitality and impede neurodegeneration, unfurled the curtain on the topline results from its Phase 2/3 LIFT-AD clinical exploration of fosgonimeton, an HGF positive modulator, in individuals grappling with mild-to-moderate Alzheimer’s disease (AD).

The epilogue unveiled a narrative where neither the trial’s protagonist, the Global Statistical Test (GST), a fusion of cognition (ADAS-Cog11) and function (ADCS-ADL23), nor its pivotal supporters – ADAS-Cog11 and ADCS-ADL23 – could claim statistical victory over the placebo cohort at the 26-week juncture. Nevertheless, within the labyrinth of GST, the realms of cognition (ADAS-Cog11) and function (ADCS-ADL23) tilted favorably towards fosgonimeton treatment, particularly amid subgroups characterized by hastened disease progression (moderate AD and APOE4 carriers). In a dance with biomarkers of protein pathology (Aβ42/40, p-Tau181, and p-Tau217), inflammation (GFAP), and neurodegeneration (NfL), fosgonimeton choreographed directional strides that harmonized with the overarching symphony of HGF modulation’s neurodefensive opus.

“In this tale of outcomes, the expected course was upended. As the placebo arm bucked the trend of clinical descent, coupled with the brevity of our study’s duration, the stage may have been dimmed for fosgonimeton to showcase its transformative prowess,” articulated Javier San Martin, M.D., Athira’s Chief Medical Officer. “Yet, amidst this chiaroscuro, the holistic data tableau persistently whispers of the potential of HGF pathway modulation to unfurl into enhancements in neuronal well-being, potentially curbing the disease’s advancing shadows.”

“Though the ultimate crescendo of the trial’s primary objective remained elusive, the symphony of biomarker and subgroup insights beckons us to a riveting encore. Not only do these observations paint a multifaceted mural across endpoints, but they also harmonize seamlessly with our comprehension of fosgonimeton’s neural shield modus operandi,” appended Anton P. Porsteinsson, M.D., luminary of the University of Rochester Alzheimer’s Disease Care, Research, and Education Program (AD-CARE) and a bard in the LIFT-AD saga.

Phase 2/3 LIFT-AD Clinical Trial Design and Topline Results

LIFT-AD (NCT04488419) unfurled as a randomized, placebo-piloted, veiled study scrutinizing the efficacy and safety of daily subcutaneous infusions of 40 mg of fosgonimeton across 312 mild-to-moderate AD voyagers bereft of acetylcholinesterase inhibitors (AChEIs) in comparison to the placebo passage over a 26-week navigation. LIFT-AD’s summit was marked by the Global Statistical Test (GST), a measure fusing cognition (ADAS-Cog11) and function (ADCS-ADL23) alterations post a 26-week sojourn. Supplementary waypoints included cognition (ADAS-Cog11), function (ADCS-ADL23), and a plasmic marker of neuronic decay, neurofilament light chain (NfL). The expedition traversed additional plasmic markers like glial fibrillary acidic protein (GFAP), an emissary of neuroinflammation, and the venerable emissaries of AD pathology, amyloid beta, and phosphorylated tau (pTau).

Primary Analysis Population

Leaping from the pages of the LIFT-AD chronicle in the account of mild-to-moderate AD frequenters after 26 weeks, the divulgence was thus:

• A -0.08 metamorphosis in GST veering towards fosgonimeton that failed to attain statistical eminence (p=0.70)
• The cognition shift from baseline, as gauged by ADAS-Cog11, revealed a -0.39 parry for the placebo ensemble and a -1.09 stance for the fosgonimeton fellowship, a -0.70 delta (p=0.35) nudging in favor of fosgonimeton
• Within the fosgonimeton fold, a propulsion (betterment) of 0.65 in function quantified by ADCS-ADL23 emerged versus a droop of -0.02 in the placebo parade, albeit sans ceremonial statistical laurels (p=0.61)

Prespecified Biomarker Analyses

The ballads of plasma biomarkers escorting neuronic decay (NfL), inflammation (GFAP), and protein pathology (p-Tau181, p-Tau217, and amyloid beta 42/40 ratio) resonated cohesively towards fosgonimeton in preference to the placebo at the 26-week milestone. Noteworthy was fosgonimeton’s maneuver to diminish plasma tiers of pTau217, a stalwart of AD, by -0.12 pg/mL in contrast to placebo (p<0.01).

Prespecified Subgroup Analyses

Within a predesignated subgroup scrutiny of robust AD wayfarers, the fosgonimeton facet mirrored a superior numerical maneuver in clinical denouements in the fosgonimeton faction juxtaposed to placebo post 26 weeks:

• The cognitive realignment from baseline viewed through the lens of ADAS-Cog11 in moderate AD denizens, where a descent from the origin signified betterment, unraveled the fosgonimeton narrative (n=61) surpassing the placebo poise (n=70), with a delta of -1.16 (p=0.39)
• For AD sojourners bearing the APOE4 insignia, the anticipated ebb in cognition witnessed by the placebo contingent (n=74) over the 26-week odyssey, found a tranquil state within the fosgonimeton realm (n=74), with a delta of -1.07 (p=0.33)

Post Hoc Subgroup Analyses

Embarking on post hoc ruminations delineated by disease severity demarcated by baseline ADAS-Cog11 (>30) and Clinical Dementia Rating (CDR) 2, fosgonimeton showcased a grander effulgence chiefly propelled by a cognitive enhancement at week 26.

• Travelers with the loftiest baseline ADAS-Cog11 (>30) embracing fosgonimeton (n=42) juxtaposed against placebo (n=52) unfurled a -2.51 uplift in cognition quantified by ADAS-Cog11 (p=0.16), where a diminished number heralded improvement
• A meager enclave of CDR 2 wayfarers (moderate dementia) immersed in the fosgonimeton realm (n=20) in contrast to the placebo enclave (n=19) illumined a -3.74 rise in cognition assessed by ADAS-Cog11 (p=0.21)

Safety and Tolerability

Fosgonimeton waltzed along the realms of tolerability with a benevolent safety veneer. Pioneers exposed to fosgonimeton (40 mg) for 26 weeks manifested a heightened instance of emergent adverse events in comparison to the placebo fold, primarily steered by the infusion