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AFFINITY

Safety and efficacy of opicinumab in participants with relapsing multiple sclerosis (AFFINITY Part 1): A randomized, controlled, phase 2 trial

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Year of Publication: 2025

Authors: Calabresi PA, Giovannoni G, Hartung HP, ..., Fox RJ

Journal: Multiple Sclerosis Journal

Citation: Mult Scler. 2026 Jan;32(1) (Epub 2025 Dec 26). doi:10.1177/13524585251396433

Link: https://doi.org/10.1177/13524585251396433

Bottom Line

Opicinumab 750 mg IV q4w did not meet its primary endpoint (Overall Disability Response Score) at 72 weeks, although a multicomponent CDI endpoint that incorporated SDMT and a prespecified subgroup with baseline EDSS ≥3.0 favored opicinumab; the safety profile was generally similar to placebo.

        Major Points
        Phase 2, 72-week, multicenter (95 sites, 15 countries), randomized, double-blind, placebo-controlled trial in relapsing MS.
Patients were enriched by screening MRI markers of remyelination potential (T2-lesion MTR ≤−0.17 nMTRu and DTI-RD ≤0.98 ×10⁻³ mm²/s).
263 participants randomized 1:1 (132 opicinumab, 131 placebo) on top of stable interferon beta, dimethyl fumarate, or natalizumab.
Primary endpoint (ODRS over 72 weeks) NOT met: adjusted mean difference 0.15 (95% CI −0.05 to 0.35; p=0.148).
Multicomponent Confirmed Disability Improvement including SDMT favored opicinumab (75% vs 63%; OR 1.78; p=0.042); EDSS-only CDI did not (37% vs 39%; p=0.768).
Prespecified subgroups with baseline EDSS ≥3.0, age ≥40 years, or disease duration ≥6 years showed significant ODRS benefit with opicinumab.
Adverse events were balanced (any AE 86% vs 85%); weight gain >7% was more common with opicinumab (37% vs 21%); one death (road traffic accident, unrelated).
Study was funded by Biogen.

      

Design

Study Type: Randomized Controlled Trial — Phase 2

Randomization: 1

Blinding: Double-blind (participants and study staff blinded; pharmacy unblinded)

Enrollment Period: First patient November 15, 2017; primary outcome data lock February 12, 2021

Follow-up Duration: 72 weeks (19 infusions q4w)

Centers: 95

Countries: USA, United Kingdom, Germany, and 12 other countries (15 total)

Sample Size: 263

Analysis: Modified intention-to-treat with mixed-effects model for ODRS; multiple imputation for missing data

Inclusion Criteria

Age 18–58 years
Relapsing MS (RRMS or SPMS with relapses) by 2010 McDonald criteria
EDSS 2.0–6.0 at screening
Disease duration ≤20 years from first symptom
Clinical relapse or new/enlarging T2 or Gd-enhancing lesion within 24 months before screening
Stable background DMT (interferon beta, dimethyl fumarate, or natalizumab) for ≥6 months
Screening MRI eligibility: T2-lesion magnetization transfer ratio ≤−0.17 normalized MTR units
Screening MRI eligibility: T2-lesion diffusion tensor imaging radial diffusivity ≤0.98 ×10⁻³ mm²/s

Exclusion Criteria

Primary progressive MS
Timed 25-Foot Walk >30 seconds
MS relapse within 6 months of screening
Prior chemotherapy or cell-depleting antibodies within 1 year
Systemic corticosteroids within 30 days of screening
Contraindication to MRI

Baseline Characteristics

Characteristic	Placebo	Opicinumab
N	131	132
Median Age (IQR)	38 (31–45)	40 (32–47)
Sex - Female	60% (79/131)	68% (90/132)
Median Weight kg (IQR)	74.0 (63–88)	76.2 (64–95)
RRMS	99% (130/131)	99% (131/132)
SPMS	<1% (1/131)	<1% (1/132)
Median EDSS (IQR)	2.5 (2.0–3.0)	2.5 (2.0–4.0)
Median T25FW sec (IQR)	5.2 (4.4–6.5)	5.7 (4.6–6.8)
Median 9HPT-Dominant sec (IQR)	20.8 (18.2–24.0)	20.7 (18.9–24.3)
Median 9HPT-Non-dominant sec (IQR)	22.4 (19.3–26.2)	22.0 (20.0–25.7)
Median Time Since MS Onset years (IQR)	6.0 (3.0–13.0)	6.0 (4.0–11.0)
Median Time Since Recent Relapse months (IQR)	16.3 (11.0–22.8)	16.6 (11.6–23.9)
Mean Relapses Past 2 Years (SD)	1.2 (0.93)	1.2 (0.91)
IFN-β background	22% (29/131)	21% (28/132)
Dimethyl fumarate background	33% (43/131)	33% (43/132)
Natalizumab background	45% (59/131)	46% (61/132)
Mean T1 hypointense lesion volume mL (SD)	2.6 (3.1)	2.7 (3.4)
Mean T2 lesion volume mL (SD)	10.3 (10.2)	10.2 (10.8)

Arms

Field	Opicinumab	Control
Intervention	Opicinumab 750 mg IV every 4 weeks (19 infusions) on background DMT	Sterile normal saline IV every 4 weeks (19 infusions) on background DMT
Duration	72 weeks	72 weeks

Outcomes

Outcome	Type	Control	Intervention	HR / OR / RR	P-value
Overall Disability Response Score (ODRS) over 72 weeks — multicomponent composite of EDSS, T25FW, 9HPT-dominant, 9HPT-non-dominant, and SDMT scored as improved/stable/worsened with confirmation visits	Primary	Adjusted mean −0.04	Adjusted mean 0.11		0.148
ODRS at Week 72	Secondary	−0.04	0.19		0.120
Confirmed Disability Improvement (EDSS+T25FW+9HPT-D+9HPT-ND, 15% threshold)	Secondary	37% (49/131)	39% (52/132)	1.08	0.768
Confirmed Disability Improvement (multicomponent including SDMT, 20% threshold)	Secondary	63% (83/131)	75% (99/132)	1.78	0.042
Confirmed Disability Worsening (20% threshold)	Secondary	22% (29/131)	20% (27/132)	0.83	0.566
Any AE	Adverse	86% (113/132) opicinumab vs 85% (111/131) placebo
Mild AE	Adverse	30% vs 31%
Moderate AE	Adverse	49% vs 50%
Severe AE	Adverse	6% vs 4%
Treatment-related AE	Adverse	30% (39/132) vs 20% (26/131)
Nasopharyngitis	Adverse	20% vs 23%
Upper respiratory tract infection	Adverse	23% (31/132) vs 15% (20/131)
MS relapse	Adverse	17% vs 15%
Headache	Adverse	14% vs 18%
Urinary tract infection	Adverse	14% vs 15%
Fall	Adverse	13% vs 9%
Fatigue	Adverse	11% vs 11%
Serious AE	Adverse	7% (9/132) vs 5% (6/131)
Treatment-related SAE	Adverse	0 in both arms
Treatment discontinuation due to AE	Adverse	<1% (1/132) vs 2% (3/131)
Weight increase >7%	Adverse	37% (48/131) vs 21% (27/131)
Weight decrease >7%	Adverse	9% (12/131) vs 15% (20/131)
Deaths	Adverse	1 in opicinumab (road traffic accident, unrelated); 0 in placebo

Subgroup Analysis

Prespecified subgroups favoring opicinumab on ODRS over 72 weeks: baseline EDSS ≥3.0 (0.36, 95% CI 0.05–0.68; p=0.025); age ≥40 years at Week 72 (0.52, 95% CI 0.08–0.96; p=0.021); disease duration ≥6 years at Week 72 (0.49, 95% CI 0.11–0.86; p=0.011); on DMF background with EDSS ≥2.5 over 72 weeks (0.65, 95% CI 0.06–1.25; p=0.031).

Criticisms

Primary endpoint NOT met — borderline non-significant result; subgroup and component analyses are exploratory and should be interpreted cautiously.
Strict MRI enrichment criteria (MTR and DTI-RD thresholds) limit generalizability outside this lesion phenotype.
Trial enrolled patients on three different background DMTs with heterogeneous mechanisms (interferon beta, DMF, natalizumab) which complicates interpretation of remyelination signal.
Sponsor-funded (Biogen) with several Biogen employees as co-authors on the manuscript.
Only 72-week follow-up; durability of any signal and effect on long-term disability is unknown.

Funding

Biogen (Cambridge, MA, USA). Biogen funded medical writing support and participated in the decision to submit for publication.

Based on: AFFINITY (Multiple Sclerosis Journal, 2025)

Authors: Calabresi PA, Giovannoni G, Hartung HP, ..., Fox RJ

Citation: Mult Scler. 2026 Jan;32(1) (Epub 2025 Dec 26). doi:10.1177/13524585251396433

Content summarized and formatted by NeuroTrials.ai.

AFFINITY

(2025)

Objective

Evaluate whether opicinumab (anti-LINGO-1 monoclonal antibody) added to background DMT improves disability outcomes in relapsing MS participants enriched by MRI lesion markers of remyelination potential.

Study Summary

• Primary outcome (Overall Disability Response Score, ODRS, over 72 weeks) was not met: adjusted mean difference 0.15 (95% CI −0.05 to 0.35; p=0.148) favoring opicinumab
• Confirmed Disability Improvement on the multicomponent endpoint including SDMT favored opicinumab: 75% vs 63% (OR 1.78, 95% CI 1.02–3.11; p=0.042)
• Prespecified subgroup with baseline EDSS ≥3.0 showed significant ODRS benefit: 0.36 (95% CI 0.05–0.68; p=0.025)
• Safety profile was comparable: any AE 86% vs 85%; SAE 7% vs 5%; one death (road traffic accident, unrelated)
• Weight increase >7% more common with opicinumab (37% vs 21%)

Intervention

Opicinumab 750 mg IV every 4 weeks (19 infusions over 72 weeks) added to background interferon beta, dimethyl fumarate, or natalizumab

Inclusion Criteria

Adults 18–58 years with relapsing MS, EDSS 2–6, disease duration ≤20 years, clinical or MRI activity within 24 months, stable background DMT ≥6 months, and protocol-defined MRI markers (T2-lesion MTR ≤−0.17 nMTRu and DTI-RD ≤0.98 ×10⁻³ mm²/s)

Study Design

Arms: Opicinumab 750 mg IV q4w vs matching placebo (saline) IV q4w, both on top of background DMT

Patients per Arm: 132 opicinumab vs 131 placebo (n=263 randomized; 237 [90%] completed)

Outcome

• Primary ODRS endpoint NOT met: 0.15 (95% CI −0.05 to 0.35; p=0.148) over 72 weeks
• Multicomponent CDI including SDMT: 75% vs 63% (OR 1.78; p=0.042)
• EDSS-only CDI: 39% vs 37% (OR 1.08; p=0.768) — not significant
• Confirmed Disability Worsening: 20% vs 22% (OR 0.83; p=0.566) — not significant
• Subgroup EDSS ≥3.0 ODRS: 0.36 (p=0.025)

Clinical Question

Does opicinumab (anti-LINGO-1 monoclonal antibody) added to background disease-modifying therapy improve a multicomponent disability response score over 72 weeks in MRI-enriched relapsing MS?

Bottom Line

Major Points

Phase 2, 72-week, multicenter (95 sites, 15 countries), randomized, double-blind, placebo-controlled trial in relapsing MS.
Patients were enriched by screening MRI markers of remyelination potential (T2-lesion MTR ≤−0.17 nMTRu and DTI-RD ≤0.98 ×10⁻³ mm²/s).
263 participants randomized 1:1 (132 opicinumab, 131 placebo) on top of stable interferon beta, dimethyl fumarate, or natalizumab.
Primary endpoint (ODRS over 72 weeks) NOT met: adjusted mean difference 0.15 (95% CI −0.05 to 0.35; p=0.148).
Multicomponent Confirmed Disability Improvement including SDMT favored opicinumab (75% vs 63%; OR 1.78; p=0.042); EDSS-only CDI did not (37% vs 39%; p=0.768).
Prespecified subgroups with baseline EDSS ≥3.0, age ≥40 years, or disease duration ≥6 years showed significant ODRS benefit with opicinumab.
Adverse events were balanced (any AE 86% vs 85%); weight gain >7% was more common with opicinumab (37% vs 21%); one death (road traffic accident, unrelated).
Study was funded by Biogen.

Study Design

Study Type: Randomized Controlled Trial — Phase 2
Randomization: Yes
Blinding: Double-blind (participants and study staff blinded; pharmacy unblinded)
Sample Size: 263
Follow-up: 72 weeks (19 infusions q4w)
Centers: 95
Countries: USA, United Kingdom, Germany, and 12 other countries (15 total)

Primary Outcome

Definition: Overall Disability Response Score (ODRS) over 72 weeks — multicomponent composite of EDSS, T25FW, 9HPT-dominant, 9HPT-non-dominant, and SDMT scored as improved/stable/worsened with confirmation visits

Control	Intervention	HR/OR	P-value
Adjusted mean −0.04	Adjusted mean 0.11	- (−0.05 to 0.35)	0.148

Limitations & Criticisms

Primary endpoint NOT met — borderline non-significant result; subgroup and component analyses are exploratory and should be interpreted cautiously.
Strict MRI enrichment criteria (MTR and DTI-RD thresholds) limit generalizability outside this lesion phenotype.
Trial enrolled patients on three different background DMTs with heterogeneous mechanisms (interferon beta, DMF, natalizumab) which complicates interpretation of remyelination signal.
Sponsor-funded (Biogen) with several Biogen employees as co-authors on the manuscript.
Only 72-week follow-up; durability of any signal and effect on long-term disability is unknown.

Citation

Mult Scler. 2026 Jan;32(1) (Epub 2025 Dec 26). doi:10.1177/13524585251396433

View Original Publication →

AFFINITY

Safety and efficacy of opicinumab in participants with relapsing multiple sclerosis (AFFINITY Part 1): A randomized, controlled, phase 2 trial

Bottom Line

Major Points

Design

Inclusion Criteria

Exclusion Criteria

Baseline Characteristics

Arms

Outcomes

Subgroup Analysis

Criticisms

Funding

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