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DIAN-TU

Q: What were the key findings of the DIAN-TU trial?

High-dose gantenerumab significantly removed amyloid plaques over 3 years (PiB-PET SUVR −0.71, p<0.0001), with 45% of the longest-treated subgroup achieving amyloid-normal status. While clinical endpoints were not statistically significant overall, the longest-treated group (~8.4 years) showed a clinically meaningful but statistically uncertain ~50% slowing of CDR-SB progression (HR 0.57). CSF biomarkers of amyloid and tau pathology normalized. These findings provide preliminary evidence that early, sustained amyloid removal may delay symptom onset in DIAD, though the study was underpowered and stopped early.

Safety and efficacy of long-term gantenerumab treatment in dominantly inherited Alzheimer's disease: an open label extension of the phase 2/3 multicentre, randomised, double-blind, placebo-controlled platform DIAN-TU Trial

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Year of Publication: 2025

Authors: Randall J. Bateman, Yan Li, Eric M. McDade, ..., David B. Clifford

Journal: medRxiv (preprint)

Citation: medRxiv 2025.01.29; doi: 10.1101/2024.10.29.24316289

Link: https://doi.org/10.1101/2024.10.29.24316289

PDF: https://www.medrxiv.org/content/medrxiv/...316289.full.pdf

Clinical Question

Does long-term high-dose gantenerumab treatment remove brain amyloid plaques and delay the onset of clinical symptoms in asymptomatic carriers of dominantly inherited Alzheimer's disease mutations?

Study Overview

Objective

To assess whether long-term high-dose gantenerumab treatment removes amyloid plaques and delays clinical symptom onset in asymptomatic carriers of dominantly inherited Alzheimer's disease (DIAD) mutations.

Study Summary

High-dose gantenerumab significantly reduced amyloid plaques (PiB-PET SUVR −0.71 at 3 years, p<0.0001)
30% of participants converted from amyloid-abnormal to normal; 45% in longest-treated subgroup
Longest-treated group (~8.4 years) showed non-significant ~50% slowing of CDR-SB progression (HR 0.57, 95% CI 0.31–1.07)
CSF Aβ42/40 and p-tau181 significantly improved toward normal levels
ARIA-E incidence 30%; ARIA-H (microhemorrhage) 47%; no deaths from ARIA
Study stopped early by sponsor due to lack of regulatory path for gantenerumab

Intervention

Open-label extension of phase 2/3 DIAN-TU-001 platform trial. 73 DIAD mutation carriers received gantenerumab up to 1500 mg SC every 2 weeks for up to 3 years. Compared to external (DIAN Observational Study) and internal (prior placebo-treated) controls. Primary endpoint: PiB-PET SUVR change. Key secondary: CDR-SB and CDR global progression.

Patients per Arm

Gantenerumab OLE: 73 (55 mITT for primary); Any Gant: 53 asymptomatic; Longest Gant: 22; Main controls: 74; Extended controls: 86

Bottom Line

High-dose gantenerumab significantly removed amyloid plaques over 3 years (PiB-PET SUVR −0.71, p<0.0001), with 45% of the longest-treated subgroup achieving amyloid-normal status. While clinical endpoints were not statistically significant overall, the longest-treated group (~8.4 years) showed a clinically meaningful but statistically uncertain ~50% slowing of CDR-SB progression (HR 0.57). CSF biomarkers of amyloid and tau pathology normalized. These findings provide preliminary evidence that early, sustained amyloid removal may delay symptom onset in DIAD, though the study was underpowered and stopped early.

        Major Points
        Primary endpoint met: PiB-PET SUVR decreased by −0.71 (95% CI −0.88 to −0.53, p<0.0001) from OLE baseline to year 3, confirming substantial amyloid plaque removal
Amyloid removal was dose-dependent: 3-fold higher doses produced 3-fold greater annual SUVR reduction (0.35 vs 0.06 per year)
At OLE end, 15% converted amyloid-abnormal to normal; in the longest-treated group, 45% achieved amyloid-normal status
Any Gant group (n=53 asymptomatic): CDR-SB HR 0.83 (0.50–1.36) and CDR global HR 0.84 (0.40–1.77) — not significant
Longest Gant group (n=22, ~8.4 years treatment): CDR-SB HR 0.57 (0.31–1.07), CDR global HR 0.41 (0.14–1.20) — suggestive of ~50% slowing but not significant
CSF Aβ42/40 improved significantly (−42 CentiMarker at year 3, p<0.0001), approaching normal levels in asymptomatic participants
CSF p-tau181/tau181 improved significantly (−21 CentiMarker at year 3, p<0.0001)
No significant treatment effect on Tau-PET, cognitive composite, MMSE, or FAS
ARIA incidence: ARIA-E 30% (22/73), ARIA-H microhemorrhage 47% (34/73); higher with APOE ε4 carriers. No ARIA-related deaths. Higher doses produced ~33% more ARIA-E than double-blind period
Study stopped early by sponsor (Roche) due to lack of regulatory path for gantenerumab, after most participants completed ~2 years of OLE treatment

      

Design

Study Type: Open-label extension of randomized, double-blind, placebo-controlled phase 2/3 platform trial

Randomization: 1

Blinding: Open-label (OLE); assessors blinded to prior treatment assignment

Follow-up Duration: Median 2.64 years OLE (IQR 1.99–2.90); longest-treated subgroup ~8.4 years total

Centers: 18

Countries: Australia, Canada, France, Ireland, Puerto Rico, Spain, UK, USA

Sample Size: 73

Inclusion Criteria

Prior participation in DIAN-TU-001 double-blind period
Known carrier of PSEN1, PSEN2, or APP mutation causing dominantly inherited Alzheimer's disease
Willing to know mutation status
Original enrollment: −15 to +10 years from estimated symptom onset
CDR global 0 (cognitively normal) to 1 (mild dementia) at original enrollment

Exclusion Criteria

Major or unstable illness preventing trial participation
Volumetric MRI contraindications
Required anticoagulation therapy
Screen failure due to inability to receive drug or complete safety assessments

Baseline Characteristics

Characteristic	Control	Active
Group		Gantenerumab OLE (n=73)
Age (mean±SD)		~40 years (estimated from EYO data)
Female		~55%
APOE ε4 carriers		~36%
Mutations		PSEN1 (majority), PSEN2, APP
Asymptomatic at baseline		~73%
Mean EYO at OLE baseline		~−2.5 years

Arms

Field	Gantenerumab OLE	Control	Control
Intervention	Gantenerumab titrated from 120 mg Q4W up to 1020–1500 mg SC Q2W; average titration to max dose ~19 months; 78% reached highest dose	External controls from DIAN Observational Study plus internal controls (placebo-treated in double-blind phase)	Main set controls plus OLE baseline values for participants who were placebo/solanezumab-treated in double-blind and entered OLE
Duration

Outcomes

Outcome	Type	Intervention	HR / OR / RR	P-value
PiB-PET SUVR change from OLE baseline to year 3: −0.71 (95% CI −0.88 to −0.53, p<0.0001) \| PiB-PET SUVR at year 1: −0.12 (p=0.012); year 2: −0.47 (p<0.0001) \| 15% converted abnormal to normal; 15% remained normal; 70% remained abnormal \| Longest-treated group: 45% achieved amyloid-normal status	Primary			p<0.0001
CDR global time to first progression (Any Gant vs main controls): HR 0.84 (0.40–1.77)	Secondary		0.84
CDR-SB recurrent progression (Any Gant vs main controls): HR 0.83 (0.50–1.36)	Secondary		0.83
Longest Gant CDR global vs main controls: HR 0.41 (0.14–1.20)	Secondary		0.41
Longest Gant CDR-SB vs main controls: HR 0.57 (0.31–1.07)	Secondary		0.57
Longest Gant CDR-SB vs extended controls: HR 0.52 (0.30–0.92, p=0.024)	Secondary		0.52	p=0.024
CSF Aβ42/40 at year 3: −42 CentiMarker (95% CI −52 to −31, p<0.0001)	Secondary			p<0.0001
CSF p-tau181/tau181 at year 3: −21 CentiMarker (95% CI −25 to −17, p<0.0001)	Secondary			p<0.0001
No significant differences in cognitive composite, MMSE, FAS, or Tau-PET between treated and controls	Secondary
ARIA-E	Adverse	30% (22/73); higher in APOE ε4 homozygotes (67%) vs heterozygotes (26%) vs non-carriers (29%)
ARIA-H microhemorrhage	Adverse	47% (34/73)
Combined ARIA (E+H)	Adverse	53% (39/73)
Most common TEAEs	Adverse	injection-site reactions (70%), upper respiratory infections (59%), upper respiratory symptoms (45%)
SAEs	Adverse	12% (9/73); 4 nervous system SAEs
Treatment discontinuation due to AE	Adverse	3% (2/73)
No deaths during OLE; no cerebral macrohemorrhages	Adverse	No deaths during OLE; no cerebral macrohemorrhages

Subgroup Analysis

Longest Gant subgroup (n=22, ~8.4 years total treatment) showed the most favorable clinical trends: CDR-SB HR 0.57, CDR global HR 0.41, FAS HR 0.59, MMSE HR 0.54. APOE ε4 homozygotes had highest ARIA-E rates (67%). Prior gantenerumab-treated participants showed greater amyloid reduction from double-blind baseline (−0.44 SUVR) vs prior placebo (−0.07 SUVR, NS).

Criticisms

Study stopped early by sponsor, limiting statistical power and duration of follow-up
Small sample size (n=73 OLE, n=22 longest-treated) insufficient for definitive clinical conclusions
Open-label design introduces potential measurement and selection bias despite blinding of assessors
Use of external controls from observational study introduces confounding
Only 18% completed the planned 3-year treatment; 64% stopped due to sponsor termination
Incomplete amyloid removal — 70% of overall group remained amyloid-abnormal at study end
No significant effect on tau PET, cognitive composite, MMSE, or functional measures in overall group
~1 year treatment gap between double-blind and OLE periods may have reduced treatment effect
Results in dominantly inherited AD may not generalize to sporadic late-onset AD

Funding

National Institute on Aging (NIA), Alzheimer's Association, GHR Foundation, F. Hoffmann-La Roche Ltd/Genentech

Based on: DIAN-TU (medRxiv (preprint), 2025)