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EXPEDITION-1 Solanezumab

Year of Publication: 2014

Journal: New England Journal of Medicine

Link: https://doi.org/10.1056/NEJMoa1312889

PDF: https://www.nejm.org/doi/pdf/10.1056/NEJMoa1312889

Clinical Question

Does solanezumab, an anti-amyloid-beta monoclonal antibody targeting soluble Aβ, improve cognition (ADAS-cog) or function (ADCS-ADL) in mild-to-moderate Alzheimer's disease?

Bottom Line

In EXPEDITION-1 (N=1012) and EXPEDITION-2 (N=1040) parallel phase 3 trials, solanezumab 400 mg IV q4w for 80 weeks did not meet primary cognitive or functional endpoints in mild-to-moderate AD. Pooled mild-AD subgroup showed a 1.7-point ADAS-cog14 benefit (95% CI -3.5 to 0.1; p=0.06) that informed EXPEDITION-3 (also negative) and ultimately led to discontinuation of solanezumab. Established that targeting soluble Aβ with this antibody at this dose was insufficient — shifted the field toward protofibril and plaque-targeting antibodies.

        Major Points
        Two parallel phase 3 multicenter randomized double-blind placebo-controlled trials, EXPEDITION-1 (N=1012) and EXPEDITION-2 (N=1040) (Doody NEJM 2014)
Mild-to-moderate probable AD per NINCDS-ADRDA, MMSE 16-26; ~88% on ChEI/memantine; ~60% APOE ε4+
1:1 randomization to solanezumab 400 mg IV vs placebo every 4 weeks for 80 weeks
Co-primary endpoints ADAS-cog11 and ADCS-ADL; EXPEDITION-2 revised pre-unblinding to ADAS-cog14 in mild-AD
EXPEDITION-1 primary missed: ADAS-cog11 diff -0.8 (p=0.24); ADCS-ADL diff -0.4 (p=0.64)
EXPEDITION-2: ADAS-cog11 diff -1.3 (p=0.06); ADCS-ADL diff +1.6 (p=0.08) — trends only
Pooled mild-AD subgroup (MMSE 20-26): ADAS-cog14 diff -1.7 (95% CI -3.5 to 0.1); p=0.06
Target engagement confirmed: plasma Aβ40/42 rose 3-10x; CSF total Aβ rose (p<0.001)
Favorable safety: ARIA-E 0.9% (vs 0.4% placebo); ARIA-H 4.9% vs 5.6% — no excess
Hypothesis generating for EXPEDITION-3 in mild AD (also negative, 2016)
Led to Eli Lilly discontinuing solanezumab
Shifted field toward protofibril/plaque-targeting antibodies (aducanumab, lecanemab, donanemab)

      

Design

Study Type: Two parallel phase 3 multicenter randomized double-blind placebo-controlled trials

Randomization: 1

Blinding: Double-blind

Follow-up Duration: 80 weeks

Sample Size: 2052

Analyzed: 2052

Analysis: MMRM; ITT population

Baseline Characteristics

Characteristic	Control	Active
N	506	506
Age mean	74.4 ± 8.0	75.0 ± 7.9
MMSE	21 ± 3	21 ± 4
ADAS-cog11	22 ± 9	22 ± 8
APOE ε4 carrier	61.3%	57.3%
On ChEI or memantine	~88%	~88%

Arms

Field	Control	Solanezumab
N	506	506
Intervention	Placebo IV every 4 weeks	Solanezumab 400 mg IV every 4 weeks
Duration	80 weeks	80 weeks

Outcomes

Outcome	Type	Control	Intervention	HR / OR / RR	P-value
Change in ADAS-cog11 and ADCS-ADL from baseline to week 80 (EXPEDITION-1); revised to ADAS-cog14 in mild-AD (EXPEDITION-2)	Primary	ADAS-cog11 +4.5 (3.3-5.8); ADCS-ADL -8.7 (-10.4 to -7.0)	ADAS-cog11 +3.8 (2.5-5.0); ADCS-ADL -9.1 (-10.9 to -7.4)		p=0.24 ADAS-cog11; p=0.64 ADCS-ADL — both not significant
EXPEDITION-2 ADAS-cog11 diff	Secondary	+6.6	+5.3	Diff -1.3 (95% CI -2.5 to 0.3)	p=0.06
EXPEDITION-2 ADCS-ADL diff	Secondary	-10.9	-9.3	Diff +1.6 (95% CI -0.2 to 3.3)	p=0.08
Mild-AD (MMSE 20-26) ADAS-cog14 diff	Secondary	Reference	Favored solanezumab	Diff -1.7 (95% CI -3.5 to 0.1)	p=0.06
Moderate-AD (MMSE 16-19) ADAS-cog14 diff	Secondary	Reference	Similar	Diff -1.5 (95% CI -4.1 to 1.1)	p=0.26
CDR-SB (EXPEDITION-1)	Secondary	+1.8	+2.0	Diff +0.1 (95% CI -0.3 to 0.6)	p=0.51
MMSE (EXPEDITION-2)	Secondary	-2.8	-2.1	Diff +0.8 (95% CI 0.2-1.4)	p=0.01 favoring solanezumab
Plasma Aβ40 and Aβ42	Secondary	Unchanged	Sustained 3-10x increase through week 80		p<0.001 (target engagement)
CSF total Aβ40 and Aβ42	Secondary	Unchanged	Increased		p<0.001 (target engagement)
ARIA-E (amyloid-related imaging abnormalities-edema)	Adverse	0.4%	0.9%		p=0.27
ARIA-H (amyloid-related imaging abnormalities-hemorrhage)	Adverse	5.6%	4.9%		p=0.49 (no excess)
Cardiac arrhythmias	Adverse	3.7%	5.0%		Slightly higher with solanezumab
Fall	Adverse	10.4%	9.0%		Similar
Infections (total)	Adverse	36.8%	32.2%		Lower with solanezumab
Urinary tract infection	Adverse	8.1%	6.9%		Similar
Cerebral microhemorrhage	Adverse	5.5%	4.9%		No excess
Discontinuation for AE	Adverse	~7.5%	~7%		Similar
Death	Adverse	19 (EXPEDITION-2: 12)	24 (EXPEDITION-2: 13)		No imbalance

Subgroup Analysis

Predefined mild-AD subgroup (MMSE 20-26) in EXPEDITION-2 showed consistent directional benefit across ADAS-cog, ADCS-ADL, and MMSE, though without statistical significance. This subgroup observation became the primary hypothesis for EXPEDITION-3 (also negative in 2016). APOE ε4 carriers and noncarriers showed similar responses. The pattern suggested that earlier-stage disease might be a better target — hypothesis pursued by the A4 and DIAN trials in preclinical/genetic AD.

Criticisms

Target (soluble Aβ) rather than insoluble plaque may have been incorrect mechanism — later antibodies (aducanumab, lecanemab, donanemab) target protofibrils and plaque with greater success
Dose of 400 mg q4w may have been inadequate to achieve sufficient CNS exposure; subsequent antibodies use higher doses
80-week duration and mild-to-moderate inclusion may have captured disease too late — Aβ pathology precedes symptoms by 15+ years
Primary endpoint change mid-trial (to ADAS-cog14 in mild AD, post-EXPEDITION-1 analysis) raised concerns about multiplicity
Biomarker engagement (plasma, CSF Aβ rise) did not translate to clinical benefit — cautioned about sole reliance on biomarkers
Cognitive improvement on MMSE (p=0.01) in EXPEDITION-2 without ADAS-cog improvement suggested possibly scale-specific effects

Funding

Eli Lilly and Company

Based on: EXPEDITION-1 Solanezumab (New England Journal of Medicine, 2014)

Content summarized and formatted by NeuroTrials.ai.

EXPEDITION-1 Solanezumab

(2014)

Objective

Solanezumab 400 mg IV every 4 weeks — humanized monoclonal antibody that preferentially binds soluble amyloid-beta — to evaluate cognitive and functional benefit in mild-to-moderate Alzheimer's disease.

Study Summary

• EXPEDITION-1 and -2 both failed to meet primary cognitive (ADAS-cog) and functional (ADCS-ADL) endpoints in mild-to-moderate AD.
• EXPEDITION-1 ADAS-cog11 difference -0.8 (95% CI -2.1 to 0.5; p=0.24); ADCS-ADL -0.4 (95% CI -2.3 to 1.4; p=0.64).
• EXPEDITION-2 ADAS-cog11 -1.3 (p=0.06); ADCS-ADL +1.6 (p=0.08) — trends but not significant.
• Mild-AD subgroup (MMSE 20-26): ADAS-cog14 -1.7 (95% CI -3.5 to 0.1; p=0.06) — hypothesis-generating.
• Target engagement confirmed: plasma Aβ40/42 rose 3-10x; CSF total Aβ rose (p<0.001).
• ARIA-E 0.9% (vs 0.4% placebo); ARIA-H 4.9% vs 5.6% — favorable safety relative to subsequent anti-Aβ antibodies, but efficacy insufficient.

Intervention

Solanezumab 400 mg IV or placebo every 4 weeks for 18 months (week 80 primary endpoint). Two parallel phase 3 RCTs (EXPEDITION-1 and EXPEDITION-2). Concurrent ChEI/memantine allowed.

Inclusion Criteria

Adults ≥55 years with mild-to-moderate AD (MMSE 16-26), NINCDS-ADRDA criteria, no significant depression. Mild AD subgroup defined post hoc as MMSE 20-26.

Study Design

Arms: Solanezumab 400 mg IV q4w vs Placebo

Patients per Arm: EXPEDITION-1: 506 + 506 (total 1012); EXPEDITION-2: 521 + 519 (total 1040)

Outcome

• EXPEDITION-1 primary: ADAS-cog11 diff -0.8 (95% CI -2.1 to 0.5; p=0.24); ADCS-ADL diff -0.4 (95% CI -2.3 to 1.4; p=0.64) — not significant
• EXPEDITION-2 primary: ADAS-cog11 diff -1.3 (p=0.06); ADCS-ADL diff +1.6 (p=0.08) — trends only
• Mild-AD subgroup (revised analysis): ADAS-cog14 diff -1.7 (95% CI -3.5 to 0.1; p=0.06); moderate-AD -1.5 (NS)
• ADCS-ADL in mild-AD subgroup favored solanezumab (+2.3; 95% CI 0.2-4.4; p=0.04) — nominal only
• Biomarker engagement: plasma and total CSF Aβ40/42 significantly elevated with solanezumab (p<0.001)

Bottom Line

Major Points

Two parallel phase 3 multicenter randomized double-blind placebo-controlled trials, EXPEDITION-1 (N=1012) and EXPEDITION-2 (N=1040) (Doody NEJM 2014)
Mild-to-moderate probable AD per NINCDS-ADRDA, MMSE 16-26; ~88% on ChEI/memantine; ~60% APOE ε4+
1:1 randomization to solanezumab 400 mg IV vs placebo every 4 weeks for 80 weeks
Co-primary endpoints ADAS-cog11 and ADCS-ADL; EXPEDITION-2 revised pre-unblinding to ADAS-cog14 in mild-AD
EXPEDITION-1 primary missed: ADAS-cog11 diff -0.8 (p=0.24); ADCS-ADL diff -0.4 (p=0.64)
EXPEDITION-2: ADAS-cog11 diff -1.3 (p=0.06); ADCS-ADL diff +1.6 (p=0.08) — trends only
Pooled mild-AD subgroup (MMSE 20-26): ADAS-cog14 diff -1.7 (95% CI -3.5 to 0.1); p=0.06
Target engagement confirmed: plasma Aβ40/42 rose 3-10x; CSF total Aβ rose (p<0.001)
Favorable safety: ARIA-E 0.9% (vs 0.4% placebo); ARIA-H 4.9% vs 5.6% — no excess
Hypothesis generating for EXPEDITION-3 in mild AD (also negative, 2016)
Led to Eli Lilly discontinuing solanezumab
Shifted field toward protofibril/plaque-targeting antibodies (aducanumab, lecanemab, donanemab)

Study Design

Study Type: Two parallel phase 3 multicenter randomized double-blind placebo-controlled trials
Randomization: Yes
Blinding: Double-blind
Sample Size: 2052
Follow-up: 80 weeks

Primary Outcome

Definition: Change in ADAS-cog11 and ADCS-ADL from baseline to week 80 (EXPEDITION-1); revised to ADAS-cog14 in mild-AD (EXPEDITION-2)

Control	Intervention	HR/OR	P-value
ADAS-cog11 +4.5 (3.3-5.8); ADCS-ADL -8.7 (-10.4 to -7.0)	ADAS-cog11 +3.8 (2.5-5.0); ADCS-ADL -9.1 (-10.9 to -7.4)	- (ADAS-cog11 -2.1 to 0.5; ADCS-ADL -2.3 to 1.4)	p=0.24 ADAS-cog11; p=0.64 ADCS-ADL — both not significant

Limitations & Criticisms

Target (soluble Aβ) rather than insoluble plaque may have been incorrect mechanism — later antibodies (aducanumab, lecanemab, donanemab) target protofibrils and plaque with greater success
Dose of 400 mg q4w may have been inadequate to achieve sufficient CNS exposure; subsequent antibodies use higher doses
80-week duration and mild-to-moderate inclusion may have captured disease too late — Aβ pathology precedes symptoms by 15+ years
Primary endpoint change mid-trial (to ADAS-cog14 in mild AD, post-EXPEDITION-1 analysis) raised concerns about multiplicity
Biomarker engagement (plasma, CSF Aβ rise) did not translate to clinical benefit — cautioned about sole reliance on biomarkers
Cognitive improvement on MMSE (p=0.01) in EXPEDITION-2 without ADAS-cog improvement suggested possibly scale-specific effects

Citation

View Original Publication →

EXPEDITION-1 Solanezumab

Clinical Question

Bottom Line

Major Points

Design

Baseline Characteristics

Arms

Outcomes

Subgroup Analysis

Criticisms

Funding

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