ALKIVIA met its primary endpoint with a 15.4-point greater improvement in mean Total Improvement Score at Week 52 versus placebo (p=0.0011) in combined immune-mediated necrotizing myopathy and dermatomyositis, with a 14.8-point advantage in the IMNM subgroup (p=0.0048), positioning efgartigimod Hytrulo for a Supplemental Biologics License Application for IMNM by end of 2026 under Breakthrough Therapy Designation as a potential first approved treatment. The Phase 3 RCT tier outweighs indication-matched but mechanistically distinct peers: Octagam 10% IVIG in ProDERM Phase 3 (79% vs 44% TIS ≥20 at 16 weeks, p<0.001), dazukibart randomized Phase 2 in dermatomyositis, and a 10-patient open-label tofacitinib pilot, while rituximab, abatacept and complement inhibitors carry very low-certainty Cochrane signals. [1][2] Payer precedent is adverse: NICE did not recommend efgartigimod in generalized myasthenia gravis with ICERs substantially above £20,000-£30,000 per QALY, Denmark did not recommend citing temporary effect and unreasonable price, France granted ASMR V with no added benefit, and the Netherlands required price parity to eculizumab/ravulizumab at €345,510 per patient per year. [3][4] No responder distributions, muscle or skin subscales, steroid-sparing, background therapy, or quantified safety were disclosed, and no closely comparable FcRn-in-myositis precedent exists to anchor approval odds.
Phase 3 ALKIVIA met mean TIS at Week 52 in combined and IMNM populations, but without responder distributions, background therapy or quantified safety and with negative gMG HTA precedents. [5]
| Indication | Immune-mediated necrotizing myopathy (IMNM) |
| Drug | Efgartigimod |
| Mechanism of Action | FcRn blocker |
| Company | argenx SE |
| Trial Phase | Phase 3 |
| Trial Acronym | ALKIVIA |
| Category | Clinical Trial Event |
| Sub Category | Topline Results Positive |
| Therapeutic Area | Immunology |
| Conference Name | ACR Convergence 2026 |
| Presentation Date | November 11, 2026 |
| Primary Endpoint | Mean Total Improvement Score (TIS) at Week 52 |
| Statistical Significance (Combined IMNM/DM) | p=0.0011 |
| Patient Population Size (Phase 3) | 175 |
| Follow-up Duration | 52 weeks |
| Regulatory Submission Type | Supplemental Biologics License Application (sBLA) |
| Regulatory Agency | U.S. Food and Drug Administration (FDA) |
| Regulatory Designation | Breakthrough Therapy Designation |
| Submission Timeline | By the end of 2026 |
argenx's Efgartigimod Shows Rapid, Sustained Improvement in Autoimmune Myositis
argenx announced positive Phase 3 ALKIVIA study data for VYVGART Hytrulo (efgartigimod) in autoimmune myositis, presented at ACR Convergence 2026. The study met its primary endpoint in the combined immune-mediated necrotizing myopathy (IMNM) and dermatomyositis (DM) population, demonstrating a statistically significant 15.4-point greater improvement in mean Total Improvement Score (TIS) at Week 52 versus placebo (p=0.0011). In the IMNM subgroup, efgartigimod showed a clinically meaningful 14.8-point greater TIS improvement (p=0.0048), supporting its potential as the first approved treatment for IMNM. The drug was generally well tolerated, with a safety profile consistent with previous studies. argenx plans to submit a Supplemental Biologics License Application (sBLA) to the FDA for IMNM by the end of 2026, leveraging its Breakthrough Therapy Designation.
- The ALKIVIA study successfully met its primary endpoint in the combined immune-mediated necrotizing myopathy (IMNM) and dermatomyositis (DM) patient population. Patients treated with efgartigimod achieved a statistically significant and clinically meaningful 15.4-point greater improvement in mean Total Improvement Score (TIS) at Week 52 compared to placebo (48.0 vs 32.6, p=0.0011). This robust outcome was further supported by positive results across key secondary endpoints, including response rate, time to response, muscle strength, and overall disease activity, highlighting the broad therapeutic potential of FcRn inhibition.
- Efgartigimod demonstrated particularly strong and clinically meaningful results within the immune-mediated necrotizing myopathy (IMNM) subgroup, showing a 14.8-point greater improvement in mean TIS versus placebo (p=0.0048). IMNM patients experienced rapid and sustained improvements in muscle strength, measured by a 5.4-point increase in Manual Muscle Testing-8 (MMT-8), and a significant reduction in the muscle injury biomarker creatine kinase (CK), with a 43.5 percentage-point greater reduction from baseline. These findings are critical as IMNM currently lacks approved targeted therapies, positioning efgartigimod as a potential first-in-class treatment.
- While statistical significance was not reached in the smaller dermatomyositis (DM) cohort (p=0.1093), efgartigimod still showed a clinically meaningful 14.5-point greater TIS improvement and clear improvements in skin disease severity, as measured by the Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI). The overall safety profile of efgartigimod was consistent with prior studies. Based on these compelling results, argenx intends to submit a Supplemental Biologics License Application (sBLA) to the FDA for efgartigimod in IMNM by the end of 2026, a process expedited by its existing Breakthrough Therapy Designation.
The High Burden of IMNM and Current Treatment Gaps
Immune-mediated necrotizing myopathy is characterized by rapidly progressive proximal muscle weakness, markedly elevated creatine kinase levels, and myofiber necrosis with minimal lymphocytic infiltration. There are currently no approved therapies for IMNM and many patients experience active disease despite off-label treatment with intravenous immunoglobulin, glucocorticoids, and immunosuppressants.
Resistance to corticosteroids and multiple immunotherapies: Most cases are refractory to high-dose steroids in combination with multiple immunotherapies. In a review of 34 patients treated with rituximab after prior immunotherapies, 64.7% (22/34) showed no improvement after previous treatments, and 61.8% (21/34) presented a response to rituximab.
High relapse rate during tapering and dependence on combination therapy: Relapse occurred in 25-35% of cases, most often after tapering corticosteroids or immunosuppressants. In the same 34-patient review, 35.3% (12/34) relapsed when attempting to wean steroids or other immunosuppressive agents, and patients frequently require combination therapy to achieve disease control.
Antibody-defined severity with early irreversible damage: Anti-signal recognition particle IMNM presented at younger ages with more severe and treatment-refractory disease, with higher odds of loss of motor independence (OR=4.22) and relapse (OR = 14.4) than anti-3-hydroxy-3-methylglutaryl-CoA reductase IMNM. Muscle atrophy and irreversible fatty replacement happen early in the disease course, and delayed treatment initiation from symptom onset was correlated with prolonged treatment time until the first remission, with an average diagnostic delay of 233 days reported in anti-HMGCR-positive IMNM.
Lack of prospective controlled data to define optimal strategies: Optimal management strategies remain uncertain, with a need for more prospective trials to inform optimal treatment strategies and for further validation by large-scale and randomized controlled studies. Overall certainty of evidence is moderate, underscoring the need for standardized diagnostic criteria and prospective multicenter studies.
Failure of complement C5 inhibition: In IMNM01, a phase 2, multicentre, randomised, double-blind, placebo-controlled study (NCT04025632) of daily subcutaneous zilucoplan (0·3mg/kg) or placebo for eight weeks in 27 participants, there were no clinically relevant or statistically significant differences between arms in mean percent change of CK levels versus baseline (-9·86% [26·06] versus -20·72% [31·22] in zilucoplan [n=10] and placebo arms [n=14], p=0·46, respectively). C5 inhibition does not appear to be an effective treatment modality for IMNM.
ALKIVIA: Trial Design and Efgartigimod's Efficacy in IMNM and DM
Recent IMNM trials span retrospective case series, open-label pilot studies, and randomized controlled evaluation, with creatine kinase dynamics, muscle strength, and 2016 ACR/EULAR response criteria as central efficacy measures. Interventions include intravenous immunoglobulin, tocilizumab, and complement C5 inhibition with zilucoplan, assessed over 8 weeks to 6 months with safety and steroid-sparing endpoints.
| Trial / Intervention | Design | Population | Endpoints / Assessments |
|---|---|---|---|
| Intravenous immunoglobulin (IVIg), University of Pittsburgh 2014 to 2019 | Case series longitudinally evaluated 4 of the 6 myositis core set measures at baseline and at 3 and 6 months after IVIg | 20 adult IMNM patients | Improvement in core set measures, prednisone dose, adverse effects, and by the "limited" ACR/EULAR 2016 myositis response criteria; mean differences in CK and manual muscle testing (MMT-8) compared using a paired t test; clinically significant response defined as a >10% absolute improvement in the MMT-8 and a >50% absolute reduction in serum CK at 6 months of IVIg |
| Tocilizumab (TCZ) open-label pilot observational study | Open-label pilot observational study with intravenous TCZ treatment; muscle biopsies and serum and muscle biomarker analyses | 11 patients with refractory IMNM, including 3 anti-3-hydroxy-3-methylglutaryl-CoA reductase- and 8 anti-signal recognition particle-positive patients | Clinical response assessed after 6 months of TCZ treatment according to the 2016 American College of Rheumatology-European League Against Rheumatism (ACR-EULAR) response criteria for adult dermatomyositis and polymyositis; muscle fiber regeneration by immunohistochemical staining of CD56; serum levels of interleukin (IL)-6 measured using a multiplex bead-based flow fluorescent immunoassay; levels of muscle IL-6 mRNA detected by real-time polymerase chain reaction |
| Zilucoplan IMNM01 (NCT04025632) | Phase 2, multicentre, randomised, double-blind, placebo-controlled study at 15 sites (four countries); participants randomised 1:1 to receive daily subcutaneous zilucoplan (0·3mg/kg) or placebo for eight weeks; with optional enrolment in the study open-label extension | 27 participants (13 female and 14 male) with anti-HMGCR or anti-SRP autoantibody-positive IMNM who received zilucoplan (n=12) or placebo (n=15) | Primary efficacy endpoint was percent change from baseline to Week 8 in CK levels; secondary endpoints included safety |
| IVIg (Privigen) first-line monotherapy (Netherlands Trial Register NTR6160) | Investigator-initiated phase 2 open-label study; standard treatment regimen consisted of IVIg monotherapy for 9 weeks: a loading dose (2 g/kg body weight) and two subsequent maintenance doses (1 g/kg body weight) with a 3-week interval | 20 adults with a newly diagnosed, biopsy-proven idiopathic inflammatory myopathy, and a disease duration of less than 9 months, including DM (n=9), immune-mediated necrotizing myopathy (n=6), non-specific myositis/overlap myositis (n=4) and anti-synthetase syndrome (n=1); patients with IBM and prior use of immunosuppressants were excluded | Primary outcome was the number of patients with at least moderate improvement on the 2016 ACR/EULAR Total Improvement Score; secondary outcomes included time to improvement, the number of patients requiring rescue medication and serious adverse events |
Efgartigimod's FcRn Mechanism: Expanding Its Therapeutic Reach
Efgartigimod, a human IgG1 antibody Fc fragment, blocks the neonatal Fc receptor, decreasing IgG recycling and reducing both healthy and pathogenic IgG autoantibody levels. This FcRn blockade is being evaluated across multiple IgG-mediated autoimmune diseases, with trial designs ranging from randomised placebo-controlled studies to open-label extensions and retrospective observational studies.
| Indication | Representative Trial / Study | Intervention Model / Design |
|---|---|---|
| Generalized myasthenia gravis (gMG) | ADAPT (NCT03669588) | Randomised, double-blind, placebo-controlled, phase 3 trial, efgartigimod (10 mg/kg) or matching placebo administered as four infusions per cycle (one infusion per week), repeated as needed |
| Generalized myasthenia gravis (gMG) | ADAPT+ (NCT03770403) | Open-label, single-arm, multicenter, up to 3-year extension of ADAPT, treatment cycles of 4 intravenous infusions (one 10 mg/kg infusion per week) |
| Generalized myasthenia gravis (gMG) | ADAPT-SC (NCT04735432) and ADAPT-SC+ (NCT04818671) | Phase 3 randomized noninferiority study and long-term open-label extension study, 4 once-weekly administrations of efgartigimod PH20 SC 1000 mg or efgartigimod IV 10 mg/kg |
| Chronic inflammatory demyelinating polyneuropathy (CIDP) | ADHERE | Multistage, randomised-withdrawal, double-blind, placebo-controlled, phase II trial, open-label efgartigimod weekly for ≤12 weeks (Stage A) then double-blind efgartigimod or placebo weekly for ≤48 weeks (Stage B) |
| Primary immune thrombocytopenia (ITP) | Phase 2 study in adult patients with primary immune thrombocytopenia | Randomized 1:1:1 to four weekly intravenous infusions of placebo (N = 12) or efgartigimod 5 mg/kg (N = 13) or 10 mg/kg (N = 13) |
| Pemphigus vulgaris (PV) and pemphigus foliaceus (PF) | ADDRESS (NCT04598451) | Global, phase III, prospective, multicentre, randomised, double-blinded, placebo-controlled study, weekly subcutaneous efgartigimod PH20 or placebo with concomitant prednisone starting at 0.5 mg kg-1 daily |
| Pemphigus vulgaris and pemphigus foliaceus | Phase 2 study (NCT03334058) | Efgartigimod in combination with prednisone; Not reported |
| Seronegative myasthenia gravis | Open-label study in seronegative myasthenia gravis (NCT06587867) | Open-label 6-month prospective study, efgartigimod weekly for 4 weeks and then biweekly for 5 months followed by observation period |
| Morvan Syndrome with LGI1 and CASPR2 antibodies | Retrospective study of 2 cases | Retrospective review, intravenous efgartigimod (800 mg, once a week for 4 times and 400 mg, once a week for 4 times) |
| Stiff person syndrome, Guillain-Barre syndrome, inflammatory myositis, idiopathic inflammatory myopathies (IIM), Sjögren's disease (SjD), systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) | Clinical development described across reviews | Not reported |
Efgartigimod's Potential to Transform the IMNM Treatment Landscape
Immune-mediated necrotizing myopathy (IMNM) is characterized by proximal muscle weakness, markedly elevated creatine kinase (CK) levels, and myofiber necrosis with minimal lymphocytic infiltration, with anti-3-hydroxy-3-methylglutaryl-CoA reductase (anti-HMGCR) and anti-signal recognition particle (anti-SRP) autoantibodies defining distinct phenotypes. The cornerstone treatment for IMNM is a combination of glucocorticoids and steroid-sparing agents, with intravenous immunoglobulin (IVIG) and rituximab showing promise as powerful treatments. Intravenous immunoglobulin treatment was associated with marked improvement in IMNM patients, with 85% of patient meeting clinically significant response, and the median (interquartile range) relative percent improvement in CK level was 96% (85%-98%) and in MMT was 29% (14%-36%) at 6 months. Patients treated with IVIG (n=40) had higher odds of CK normalization at 6 months (OR 9.44, 95% CI 1.19-74.89, p=0.03) compared to patients not treated with IVIG (n=13), and subgroup analysis of patients on IVIG monotherapy (n=15) showed a median CK reduction of 84.5% at 3 months (p<0.001) and 95.7% at 6 months (p<0.001), with 76.9% had normal/near-normal proximal strength by 6 months. For rituximab, the overall pooled response rate was 70% (95% confidence interval [CI]: 57%-82%; I2 = 74%, p < 0.001) across idiopathic inflammatory myositis, with immune-mediated necrotizing myopathy 86%, and in a literature review of 34 patients with IMNM, 61.8% (21/34) of patients presented a response to RTX.
Previous studies suggested that complement dysregulation may be involved in the pathogenesis of IMNM, leading to evaluation of zilucoplan, a complement component 5 (C5) inhibitor, in IMNM01, a phase 2, multicenter, randomised, double-blind, placebo-controlled study (NCT04025632) at 15 sites (four countries) in adult participants with anti-HMGCR or anti-SRP autoantibody-positive IMNM randomised 1:1 to receive daily subcutaneous zilucoplan (0·3mg/kg) or placebo for eight weeks. Between 07 November 2019 and 07 January 2021, 27 participants (13 female and 14 male) received zilucoplan (n=12) or placebo (n=15) and completed the 8-week main study. At Week 8 there were no clinically relevant or statistically significant differences, despite target engagement based on mode of action, between treatment arms in mean percent change (standard deviation) of CK levels versus baseline (-9·86% [26·06] versus -20·72% [31·22] in zilucoplan [n=10] and placebo arms [n=14], p=0·46, respectively) and no clinically relevant improvement over time within the treatment arm. Treatment emergent adverse events (TEAEs) and serious TEAEs were reported in n=9 (75·0%) vs n=13 (86·7%) and n=0 (0%) and n=3 (20·0%) participants, respectively, with the most frequent TEAEs were headache (n=4 in both groups [33·3% and 26·7%, respectively]) and nausea (n=3 in both groups [25·0% and 20·0%, respectively]). The interpretation was that C5 inhibition does not appear to be an effective treatment modality for IMNM.
Efgartigimod is an engineered human IgG1 Fc fragment that antagonizes the neonatal Fc receptor (FcRn), thereby preventing recycling and promoting lysosomal degradation of IgG, including autoantibodies. Administration of efgartigimod rapidly reduced total IgG levels, including the level of pathogenic anti-HMGCR aAbs, in both serum (P<0.0001) and muscle (P<0.001) in a humanized murine model of IMNM, prevented myofibre necrosis (P<0.05) in the preventive setting, and prevented further necrosis and allowed muscle fibre regeneration (P<0.05) in the therapeutic setting with muscle strength returned to normal (P<0.01). Early application of efgartigimod in combination with methylprednisolone for the treatment of anti-SRP-IMNM led to a substantial decrease in CK values and effectively improved muscle strength in three patients with positive anti-signal recognition particle (SRP) antibodies following one cycle of efgartigimod treatment (administered at a dosage of 10 mg/kg, once a week for a total of 4 injections in one period), where CK values decreased by 79.30, 95.80, and 93.62%, respectively, and MMT score increased from 232, 156, and 169 to 242, 258, and 229, respectively, with no serious adverse events observed during the efgartigimod treatment.
Frequently Asked Questions
References
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