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ADHERE

Safety, tolerability, and efficacy of subcutaneous efgartigimod in patients with chronic inflammatory demyelinating polyradiculoneuropathy (ADHERE): a multicentre, randomised-withdrawal, double-blind, placebo-controlled, phase 2 trial

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Year of Publication: 2024

Authors: Allen JA, Lin J, Basta I, ..., van Doorn PA; ADHERE Study Group

Journal: Lancet Neurology

Citation: Lancet Neurol 2024; 23: 1013–24

Link: https://clinicaltrials.gov/study/NCT04281472

Clinical Question

In adults with CIDP who respond to open-label subcutaneous efgartigimod PH20, does continued weekly treatment reduce the risk of relapse compared with placebo?

Bottom Line

Subcutaneous efgartigimod PH20 significantly reduces the risk of relapse (HR 0.39, 95% CI 0.25–0.61; p<0.0001) versus placebo in adults with CIDP who demonstrated confirmed clinical improvement, supporting FcRn blockade as an effective therapeutic strategy for CIDP.

Major Points

  • In the open-label induction (stage A), 66% (214/322) of participants achieved confirmed evidence of clinical improvement (ECI) with weekly subcutaneous efgartigimod PH20
  • In the randomised-withdrawal phase (stage B), efgartigimod reduced relapse risk by 61% versus placebo (HR 0.39, 95% CI 0.25–0.61; p<0.0001)
  • Relapse occurred in 27.9% of efgartigimod-treated participants versus 53.6% of placebo participants
  • Safety profile was favorable — TEAE and serious TEAE rates were similar between efgartigimod and placebo in stage B
  • Results support the hypothesis that IgG autoantibodies play a key pathogenic role in CIDP and validate FcRn blockade as a therapeutic target

Design

Study Type: Multicentre, multistage, open-label (stage A) and randomised-withdrawal, double-blind, placebo-controlled (stage B) phase 2 trial

Randomization: 1

Blinding: Double-blind in stage B (investigators, CRO, and participants masked); stage A was open-label

Allocation: 1:1 in stage B via interactive response technology, stratified by aINCAT change during stage A and most recent CIDP medication within 6 months of screening

Enrollment Period: April 15, 2020 to May 11, 2023

Follow-up Duration: Stage A up to 12 weeks (with optional additional week); Stage B up to 48 weeks or until 88 relapse events

Centers: 146

Countries: Asia-Pacific region, Europe, North America

Sample Size: 322

Analyzed: 221

Analysis: Stage A primary endpoint evaluated in stage A safety population; stage B primary endpoint evaluated in modified intention-to-treat population

Power Calculation: Planned enrollment up to 360 participants in stage A; stage B continued until 88 relapse events accrued

Registration: ClinicalTrials.gov NCT04281472; EudraCT 2019-003076-39

Inclusion Criteria

  • Adults aged ≥18 years
  • Definite or probable CIDP per 2010 EFNS–PNS criteria, confirmed by independent expert CIDP Confirmation Committee
  • CDAS (CIDP Disease Activity Status) score ≥2 at screening
  • INCAT score ≥2 at first run-in visit or stage A baseline (score of 2 must be exclusively from leg disability)
  • Either off treatment or receiving CIDP treatment (corticosteroids, IVIg, or SCIg) willing to discontinue
  • Off-treatment participants with documented aINCAT worsening within 3 months of screening (vs a prior aINCAT within 6 months) could skip the run-in and enter stage A directly; all other participants (off-treatment without recent active disease, or those discontinuing CIDP treatment) entered the run-in and were required to demonstrate evidence of clinically meaningful deterioration (ECMD: ≥1 point aINCAT increase, ≥4 point I-RODS centile decrease, or ≥8 kPa grip strength decrease) to enter stage A

Exclusion Criteria

  • Pure sensory CIDP variant
  • Polyneuropathies of other causes
  • Total IgG concentration less than 6 g/L at screening

Baseline Characteristics

0:

  • Characteristic: Age, years — mean (SD)
  • Stage A (N=322): 54.0 (13.92)
  • Stage B Efgartigimod (N=111): 54.5 (13.18)
  • Stage B Placebo (N=110): 51.3 (14.47)

1:

  • Characteristic: Male — n (%)
  • Stage A (N=322): 208 (65%)
  • Stage B Efgartigimod (N=111): 73 (66%)
  • Stage B Placebo (N=110): 69 (63%)

2:

  • Characteristic: Female — n (%)
  • Stage A (N=322): 114 (35%)
  • Stage B Efgartigimod (N=111): 38 (34%)
  • Stage B Placebo (N=110): 41 (37%)

3:

  • Characteristic: White — n (%)
  • Stage A (N=322): 211 (66%)
  • Stage B Efgartigimod (N=111): 73 (66%)
  • Stage B Placebo (N=110): 71 (65%)

4:

  • Characteristic: Asian — n (%)
  • Stage A (N=322): 89 (28%)
  • Stage B Efgartigimod (N=111): 33 (30%)
  • Stage B Placebo (N=110): 34 (31%)

5:

  • Characteristic: Typical CIDP — n (%)
  • Stage A (N=322): 268 (83%)
  • Stage B Efgartigimod (N=111): 97 (87%)
  • Stage B Placebo (N=110): 95 (86%)

6:

  • Characteristic: Time since diagnosis, years — mean (SD)
  • Stage A (N=322): 4.9 (6.09)
  • Stage B Efgartigimod (N=111): 3.7 (4.40)
  • Stage B Placebo (N=110): 3.8 (4.68)

7:

  • Characteristic: Total INCAT score — mean (SD)
  • Stage A (N=322): 4.6 (1.67)
  • Stage B Efgartigimod (N=111): 3.1 (1.51)
  • Stage B Placebo (N=110): 3.3 (1.57)

8:

  • Characteristic: I-RODS score — mean (SD)
  • Stage A (N=322): 40.1 (14.67)
  • Stage B Efgartigimod (N=111): 53.6 (17.91)
  • Stage B Placebo (N=110): 51.2 (15.37)

9:

  • Characteristic: Grip strength, dominant hand, kPa — mean (SD)
  • Stage A (N=322): 38.5 (24.18)
  • Stage B Efgartigimod (N=111): 54.9 (23.64)
  • Stage B Placebo (N=110): 58.0 (25.09)

10:

  • Characteristic: Previous corticosteroids within 6 months — n (%)
  • Stage A (N=322): 63 (20%)
  • Stage B Efgartigimod (N=111): 24 (22%)
  • Stage B Placebo (N=110): 23 (21%)

11:

  • Characteristic: Previous IVIg or SCIg within 6 months — n (%)
  • Stage A (N=322): 165 (51%)
  • Stage B Efgartigimod (N=111): 48 (43%)
  • Stage B Placebo (N=110): 48 (44%)

12:

  • Characteristic: Off treatment — n (%)
  • Stage A (N=322): 94 (29%)
  • Stage B Efgartigimod (N=111): 39 (35%)
  • Stage B Placebo (N=110): 39 (36%)

13:

  • Characteristic: CDAS score 5 (unstable, active disease) — n (%)
  • Stage A (N=322): 197 (61%)
  • Stage B Efgartigimod (N=111): 74 (67%)
  • Stage B Placebo (N=110): 76 (69%)

Arms

FieldStage A: Open-label subcutaneous efgartigimod PH20Stage B: Subcutaneous efgartigimod PH20Control
N322111110
InterventionSubcutaneous efgartigimod PH20 1000 mg weekly by subcutaneous abdominal injection (30–90 s)Subcutaneous efgartigimod PH20 1000 mg weeklyPlacebo containing 2000 U/mL PH20, weekly subcutaneous injection
DurationUp to 12 weeks (optional additional week for ECI confirmation)Up to 48 weeks or until relapseUp to 48 weeks or until relapse

Outcomes

OutcomeTypeControlInterventionHR / OR / RRP-value
Stage A: Confirmed evidence of clinical improvement (ECI) — ≥1 point aINCAT decrease, ≥4 point I-RODS increase (centile metric), or ≥8 kPa grip strength increase after four injections and two consecutive visits. Stage B: Risk of relapse (time to first aINCAT increase of ≥1 point) in modified intention-to-treat population.PrimaryStage B placebo: 59/110 (53.6%, 95% CI 44.3–63.0) relapsedStage A: 214/322 (66%, 95% CI 61.0–71.6) achieved confirmed ECI. Stage B efgartigimod: 31/111 (27.9%, 95% CI 19.6–36.3) relapsed0.39<0.0001
Stage B: I-RODS deterioration ≥4 pointsSecondaryEfgartigimod: 40/111 (36%) · Placebo: 57/110 (52%) · Effect: HR 0.54 (95% CI 0.35–0.81); nominal p=0.0034
Stage B: I-RODS improvement ≥4 pointsSecondaryEfgartigimod: 50/111 (45%) · Placebo: 40/110 (36%) · Effect: OR 1.44 (95% CI 0.81–2.57); nominal p=0.23
Stage B: Mean change from baseline in aINCAT scoreSecondaryEfgartigimod: 0.1 (SE 0.1) · Placebo: 0.9 (SE 0.19) · Effect: Descriptive
Stage B: Mean change from baseline in I-RODS scoreSecondaryEfgartigimod: 0.8 (SE 1.17) · Placebo: -7.0 (SE 1.84) · Effect: Descriptive
Stage B: Mean change in grip strength, dominant hand (kPa)SecondaryEfgartigimod: 2.1 (SE 1.26) · Placebo: -8.2 (SE 1.98) · Effect: Descriptive
Stage B: Mean change in grip strength, non-dominant hand (kPa)SecondaryEfgartigimod: 2.0 (SE 1.64) · Placebo: -6.9 (SE 2.04) · Effect: Descriptive
Stage B: Mean change in MRC sum scoreSecondaryEfgartigimod: -0.3 (SE 0.43) · Placebo: -3.0 (SE 0.86) · Effect: Descriptive
Stage B: Mean change in TUG test score (s)SecondaryEfgartigimod: 0.8 (SE 0.36) · Placebo: 1.9 (SE 0.60) · Effect: Descriptive
Stage A TEAEsSafety204/322 (63%) participants
Stage A severe TEAEs (grade ≥3)Safety25/322 (8%) participants
Stage A serious TEAEsSafety21/322 (7%) participants
Stage A treatment-related TEAEsSafety101/322 (31%) participants
Stage A injection site reactionsSafety62/322 (19%) participants
Stage A infectionsSafety44/322 (14%) participants
Stage A discontinued due to TEAEsSafety22/322 (7%) participants
Stage B TEAEs (efgartigimod vs placebo)Safety71/111 (64%) vs 62/110 (56%)
Stage B severe TEAEs grade ≥3 (efg vs placebo)Safety7/111 (6%) vs 7/110 (6%)
Stage B serious TEAEs (efg vs placebo)Safety6/111 (5%) vs 6/110 (5%)
Stage B treatment-related TEAEs (efg vs placebo)Safety27/111 (24%) vs 22/110 (20%)
Stage B injection site reactions (efg vs placebo)Safety16/111 (14%) vs 7/110 (6%)
Stage B infections (efg vs placebo)Safety35/111 (32%) vs 37/110 (34%)
Stage B discontinued due to TEAEs (efg vs placebo)Safety3/111 (3%) vs 1/110 (1%)
DeathsSafety3 total: 2 in stage A (cardiac arrest during COVID-19 infection deemed not treatment-related, and CIDP deterioration during follow-up deemed unlikely related) and 1 in stage B placebo group (pneumonia)
AdverseEvent: Any TEAE · Stage A (N=322): 204 (63%) · Stage B Efgartigimod (N=111): 71 (64%) · Stage B Placebo (N=110): 62 (56%)
AdverseEvent: Any severe TEAE (grade ≥3) · Stage A (N=322): 25 (8%) · Stage B Efgartigimod (N=111): 7 (6%) · Stage B Placebo (N=110): 7 (6%)
AdverseEvent: Any serious TEAE · Stage A (N=322): 21 (7%) · Stage B Efgartigimod (N=111): 6 (5%) · Stage B Placebo (N=110): 6 (5%)
AdverseEvent: Any treatment-related TEAE · Stage A (N=322): 101 (31%) · Stage B Efgartigimod (N=111): 27 (24%) · Stage B Placebo (N=110): 22 (20%)
AdverseEvent: Injection site reaction · Stage A (N=322): 62 (19%) · Stage B Efgartigimod (N=111): 16 (14%) · Stage B Placebo (N=110): 7 (6%)
AdverseEvent: Headache · Stage A (N=322): 16 (5%) · Stage B Efgartigimod (N=111): 4 (4%) · Stage B Placebo (N=110): 2 (2%)
AdverseEvent: Infections · Stage A (N=322): 44 (14%) · Stage B Efgartigimod (N=111): 35 (32%) · Stage B Placebo (N=110): 37 (34%)
AdverseEvent: Discontinued due to TEAEs · Stage A (N=322): 22 (7%) · Stage B Efgartigimod (N=111): 3 (3%) · Stage B Placebo (N=110): 1 (1%)
AdverseEvent: Death · Stage A (N=322): 2 (1%) · Stage B Efgartigimod (N=111): 0 · Stage B Placebo (N=110): 1 (1%)

Subgroup Analysis

Stage B relapse rates by prior CIDP treatment (efgartigimod vs placebo): previous corticosteroids 5/24 (21%) vs 15/23 (65%); previous IVIg/SCIg 14/48 (29%) vs 28/48 (58%); off-treatment 12/39 (31%) vs 16/39 (41%). Treatment benefit (placebo minus efgartigimod relapse rate) was largest in the corticosteroids subgroup (44%) and IVIg/SCIg subgroup (29%) and narrowest in the off-treatment subgroup (10%); the benefit of efgartigimod could not be seen in the off-treatment subgroup, which had the highest relapse rate on efgartigimod and the lowest relapse rate on placebo despite all subjects having responded in stage A. This subgroup finding may reflect the heterogeneous nature of the off-treatment population. The study was not powered to detect differences between subgroups and no formal statistical testing was performed.

Criticisms

  • Enriched randomised-withdrawal design only tests responders, potentially overestimating benefit in the general CIDP population
  • No active comparator against currently available treatments (IVIg, SCIg, corticosteroids)
  • Longer-term efficacy and safety data beyond 48 weeks not available
  • Absence of a known pathogenic autoantibody in most CIDP patients limits mechanistic confirmation
  • Treatment benefit was not seen in the off-treatment subgroup, raising questions about efficacy in patients not currently on immunotherapy

Funding

argenx

Based on: ADHERE (Lancet Neurology, 2024)

Authors: Allen JA, Lin J, Basta I, ..., van Doorn PA; ADHERE Study Group

Citation: Lancet Neurol 2024; 23: 1013–24

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