AAN 2024 Poster - INTERCEPT-AD, a Phase 1 Study of Sabirnetug (ACU193): Safety, Target Engagement, and Biomarker Changes

INTERCEPT-AD, a Phase 1 Study of Sabirnetug (ACU193): Safety, Target Engagement, and Biomarker Changes

Eric Siemers1, Erika Cline2, Todd Feaster1, Vladimir Skljarevski1, Karen Sundell1, Daniel Antwi-Berko3, Marleen Koel-Simmelink3, Charlotte Teunissen3, Hao Zhang2, Gopalan Sethuraman1, Jerome Moore2, Hugo Vanderstichele2, June Kaplow2, Robert Dean2, Jasna Jerecic2

1. Clinical Research, Acumen Pharmaceuticals 2. Bioanalytical Methods, Acumen Pharmaceuticals 3. Amsterdam UMC

Introduction

Figure 1. Sabirnetug Binding

Target Engagement Assay Methods

Figure 4. Target Engagement Assay (MSD S-Plex [Turbo] Immunoassay)

Novel assay configuration tailored to selectively detect sabirnetug-AβO complex in CSF as

direct measure of target engagement

RESEARCH HIGHLIGHTS	INTERCEPT-AD: NCT04931459
• Sabirnetug has a favorable safety and tolerability profile	ALTITUDE-AD: NCT06335173

• • Rates of ARIA-E were relatively low
  • Lack of ARIA-E in APOE Ɛ4 homozygotic participants was of interest
• Dose-dependenttarget engagement of Aβ oligomers was demonstrated in CSF
• Sabirnetug significantly lowered CSF neurogranin (-13.9%) and pTau181 (-13.0%) concentrations and numerically increased Aβ 42/40 after 3 administrations of sabirnetug 60 mg/kg Q4W
• Reduction of the synaptic marker neurogranin correlated significantly with sabirnetug engagement with AβO target
• Effects on biomarkers may be both duration- and dose-dependent
• Long-termchanges in clinical cognitive outcomes, biomarkers, and safety will be evaluated in the ongoing, placebo-controlled phase 2 ALTITUDE-AD study over 18 months.
• Based on safety, target engagement, and biomarker changes, sabirnetug doses in ALTITUDE-AD will be 35 mg/kg Q4W and 50 mg/kg Q4W

Soluble amyloid ß oligomers (AßOs) instigate neurodegeneration in Alzheimer's disease (AD). Sabirnetug (ACU193) is a humanized IgG2 subclass monoclonal antibody raised against soluble AßOs. The objective of the INTERCEPT-AD phase 1 study was to investigate safety, pharmacokinetics, target engagement, and biomarker effects of sabirnetug in a phase 1 trial of participants with early AD.

Study Design

INTERCEPT-AD (NCT04931459) was a double-blind,placebo-controlled study incorporating four single ascending dose (SAD) cohorts with doses ranging from 2 mg/kg to 60 mg/kg and three multiple-ascending dose (MAD) cohorts receiving three doses of sabirnetug (10 or 60 mg/kg every four weeks [Q4W] or 25 mg/kg every two weeks [Q2W] or placebo; Figure 2). Participants had mild cognitive impairment or mild dementia and amyloid positivity was confirmed by florbetapir PET. Safety assessments included regular MRI. Target engagement was assessed in cerebrospinal fluid (CSF) and CSF and plasma were used for biomarker assessments. CSF was collected pre-dose and 7-21 days post-dose.

Figure 2. Study Design

Arrows indicate reviews conducted on data from one cohort by safety review team before initiation of treatment in the next cohort.

Figure 3. Key Biofluid Biomarkers Associated with Alzheimer's Disease Pathology

Astrocytic

Activation:

GFAP

Biomarker Assay Methods

Biomarkers were measured in CSF and EDTA-plasma, before and after drug administration, at ADx NeuroSciences (CSF pTau217) and Amsterdam UMC (all other biomarkers). Participants were excluded from all biomarker analyses for the following reasons: baseline and/or endpoint lumbar puncture not done (n=9); 10 mg/kg Q4W cohort participant who received only one of three infusions (n=1). Participants were excluded from some analyses for the following reasons: values below measurable range and/or limited CSF volume (n=3); and values outside mean ± 2 standard deviations and outside published correlations with other biomarkers (n=2). P-values were calculated for differences in means using unpaired, 2-sided Student's t test and for correlations using Pearson's r test.

Results

Figure 5. Amyloid Related Imaging Abnormalities - Edema/Effusion (ARIA-E)

Five of 48 sabirnetug-treated participants experienced amyloid related imaging abnormalities - edema/effusion (ARIA-E). Only one instance, in a participant in the 60 mg/kg Q4W cohort, was symptomatic. None of the six apolipoprotein Ɛ4 homozygotic participants experienced ARIA-E. Four cases of ARIA-E were in Ɛ4 heterozygotes. One (at 60 mg/kg) was a non-carrier.

Figure 6. Target Engagement in Single and Multiple Dose Cohorts

Sabirnetug target engagement increased with increasing dose with both single and multiple dose treatment.

*One 10 mg/kg Q4W participant received only 1 dose and was therefore excluded.

Figure 7.Target Engagement Emax Model

Central target engagement (sabirnetug-AβO complex) approached maximum at the higher sabirnetug doses in

INTERCEPT-AD.

Target Engagement, continued

Figure 8. Simulated Target Engagement to Aid Dose Selection for Phase 2 ALTITUDE-AD Study: 35 and 50 mg/kg Q4W

CSF target engagement was simulated at steady state for a list of doses administered Q4W.

Doses were selected with variation in participant PK/PD in mind; select doses based on participants at 50th percentile and 10th percentile.

Doses were selected with peak- trough variation in mind; select doses based on trough (end of dosing interval) CSF engagement. Notable diminishing differentiation was observed as doses increased.

Biomarkers

Figure 9. Changes in CSF Biomarker Concentrations During Sabirnetug Treatment

p = 0.049

n=8 for		Significant
p = 0.037	normalizing
sabirnetug-
treated		changes were
n=8 for		observed for
pooled		pTau181, VAMP2,
placebo		and neurogranin
group
		after 3 doses of

sabirnetug.

Figure 10. Duration- and Dose-Dependence of Changes in CSF Neurogranin and pTau181

Normalizing changes of CSF neurogranin & pTau181 were positively correlated with

duration of drug exposure ("time drug on board"), defined as time between first sabirnetug

dose and lumbar puncture (LP). Dose (magnitude & number) is another contributing factor, further substantiating observations in Figure 9.

Biomarkers, continued

Figure 11. Post-Dose Changes in Plasma Biomarker Concentrations

After 1-6 weeks drug washout, median levels of glial fibrillary acidic protein (GFAP), pTau181, and pTau217 in 10 mg/kg Q4W & 60 mg/kg Q4W groups were lower than placebo.

After 10-20 weeks drug washout, median levels remained lower than placebo; note that placebo levels also increased at this time point.

Figure 12. Effect of Sabirnetug on Amyloid Plaque Load

Nearly all sabirnetug-treated participants in the high dose MAD cohorts showed reductions in plaque load after three doses at 63 or 70 days.

Acknowledgments

The authors acknowledge with gratitude the individuals who enrolled in the INTERCEPT-AD trial as well as the family, study partners, and friends who supported them. We would also like to acknowledge the site staff, CRO, and all study team members who were vital to the successful completion of this trial.

Site investigators: Kimball Johnson (iResearch Atlanta), Diana Kerwin (Kerwin Research Center), Jeffrey Norton (Charter Research), Mohammad Reza Bolouri (Alzheimer's Memory Center), Alida Reinoso (Columbus Clinical Services), Shirley Valdez-Arroyo (Santos Research Center), Eric Carbonelli (Combined Research), David Weisman (Abington Neurological), Alexander White (Progressive Medical Research), Beth Safirstein (MD Clinical), Lawrence Honig (Columbia University Hospital), Nelson Berrios (Clinical Trial Network), Steve Sitar (Orange County Research Institute), Nida Laurin (Clinical Endpoints), Sanjiv Sharma (CenExel), Gustavo Alva (Hoag Memorial Hospital Presbyterian) and Maria Johnson (ACMR)

Medical writing assistance provided by Jennie G. Jacobson of Jacobson Medical Writing.

The authors also acknowledge Erik Stoops and Eugeen Vanmechelen at ADx NeuroSciences for analysis of CSF pTau217 levels.

References: 1. Lacor et al 2004 2. Lacor et al 2007 3. Townsend et al 2006 4. Batistia et al 2018 5. De Felice et al 2008 6. Zemple et al 2010. 7. Clearly et al 2005 8. Poling et al 2008 9. Cline et al 2019 10. Gobom J et al. 2021