Dazukibart for dermatomyositis: expanding the therapeutic arsenal

In a landmark study, Dr. Greenberg and colleagues uncovered a striking overactivation of the type I interferon (IFN) pathway in the muscles of patients with dermatomyositis (1). Follow-up research from the same group revealed that IFN-β, rather than IFN-α, was the predominant type I IFN elevated in the blood (2) and skin (3) of these patients, closely correlating with increased expression of type I IFN-related genes.

Subsequent investigations demonstrated that the autoantibodies characteristic of classical dermatomyositis (anti-Mi2, anti-NXP2, anti-TIF1γ, and anti-MDA5) were each associated with comparable levels of type I IFN activation in the muscle of affected patients (4). In contrast, muscles from those with the anti-synthetase syndrome—which can present with dermatomyositis-like skin features—exhibited intermediate IFN pathway activation that was markedly higher than that observed in immune-mediated necrotizing myositis or inclusion body myositis (4).

More recent studies confirmed that IFN-β is also the predominant type I IFN in dermatomyositis muscle (5). Moreover, disease pathogenesis appears to be driven by the ability of autoantibodies to penetrate muscle cells where they disrupt their target autoantigens—many of which are key regulators of the IFN-β pathway (5). For example, MDA5 activates the type I interferon pathway by interacting with mitochondrial antiviral-signaling proteins (MAVS) (6). Similarly, the antigens targeted by anti-TIF1γ (TRIM33) and anti-NXP2 (MORC3) autoantibodies act as nuclear inhibitors of IFNB1 gene expression (7,8).

These discoveries identified the type I IFN pathway as a compelling therapeutic target for dermatomyositis. Among the available approaches, JAK/STAT inhibitors were the first to be implemented, with increasing evidence supporting the efficacy of ruxolitinib, tofacitinib, and baricitinib, while additional compounds—including brepocitinib—are currently undergoing evaluation (9-12). Additionally, inhibitors of the type I IFN receptor (IFNAR1) have shown promise in case reports and small case series (13,14).

However, the most direct approach to targeting IFNB1 is through neutralization of the cytokine itself. Recognizing this potential, researchers behind the initial discoveries of IFNB1’s role in dermatomyositis developed a humanized IgG1-neutralizing monoclonal antibody, originally designated PF-06823859 and later named dazukibart (15).

In a groundbreaking study, dazukibart was evaluated in a multicenter, double-blind, placebo-controlled phase 2 trial for moderate-to-severe dermatomyositis (16). Conducted across 25 sites in Europe and the USA, the study enrolled adults with either skin-predominant or muscle-predominant dermatomyositis, who were randomized to receive dazukibart (150 or 600 mg) or placebo. Notably, the study incorporated three separate stages (1, 2, and 2a) for skin-predominant disease and one stage (3) for patients with moderate muscle involvement. The primary endpoint for skin-predominant stages was the change in the Cutaneous Dermatomyositis Disease Area and Severity Index Activity (CDASI-A) score from baseline, while the muscle-predominant cohort was evaluated for safety (16).

At week 12, study subjects on the 600 mg dose of dazukibart had significantly reduced CDASI-A scores compared to those taking placebo in both the full analysis set (stage 1) and the pooled skin full analysis set (stages 1, 2, and 2a), demonstrating a marked decrease in disease activity (both P<0.0001; CDASI-A reduction of 19%). In the muscle-predominant cohort, there was a non-significant improvement in muscle strength as measured by MMT-8, accompanied by a significant reduction in serum creatine kinase levels. Treatment-emergent adverse events were reported in approximately 80% of both the treatment and placebo groups. The most common adverse events were infections and infestations, with serious events occurring in 11% of the 150 mg group and 4% of the placebo group. One death was reported due to hemophagocytic lymphohistiocytosis in a patient in stage 3 receiving 600 mg/day. Overall, dazukibart was generally well tolerated and showed significant therapeutic potential by inhibiting IFN-β in dermatomyositis patients (16).

This is an exciting time for dermatomyositis patients, as new treatments are continuously being developed, validated, and approved. Currently, two primary therapeutic approaches are emerging: (I) targeting pathogenic autoantibodies by reducing their half-life with (IVIG) (17), inhibiting their production with monoclonal antibodies against CD20, CD19 or BCMA (18), or resetting the B cell pool with B cell-depleting CAR-T cell therapy (19); and (II) blocking key cytokine pathways that drive the downstream pathogenic effects of these autoantibodies, particularly through inhibition of type I interferon via receptor blockade (13,14), JAK/STAT signaling (9-12), or, now, direct cytokine neutralization with dazukibart (16).

Moving forward, the critical challenge will be to determine the optimal treatment strategy. With multiple effective therapeutic options available but no direct comparative studies, clinicians must navigate complex decisions to tailor therapies to individual patients. This is particularly relevant in specific clinical scenarios. For instance, published data suggest that JAK/STAT inhibitors can prevent the development of rapidly progressive ILD in patients with anti-MDA5 autoantibodies (20). However, it remains unknown whether dazukibart or anifrolumab could provide similar protection or whether these therapies might not only prevent but also treat patients with established rapidly progressive interstitial lung disease.

Until head-to-head studies become available, insights from monogenic interferonopathies may help guide treatment selection in dermatomyositis. For instance, a patient with SAVI due to a de novo STING1 mutation experienced the most favorable clinical response with anifrolumab after sequential treatment with baricitinib, dazukibart, and anifrolumab (21). Similarly, patients with SAVI (STING-associated vasculopathy with onset in infancy) and CANDLE (chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperatures) who had previously received baricitinib also showed positive outcomes with anifrolumab (22). These observations suggest that receptor blockade provides stronger IFN inhibition, which may offer greater clinical benefit but also carries a higher risk of viral infections (21,22). Conversely, JAK/STAT inhibition may be insufficient for some patients, while dazukibart could serve as an intermediate option, potentially offering greater efficacy than JAK/STAT inhibitors but less than anifrolumab (21,22).

Another important question remains: To what extent do autoantibody-defined dermatomyositis subtypes (23) respond differently to these therapies? Growing evidence suggests that not all toxicity in dermatomyositis is driven by the type I IFN pathway (5). For instance, anti-Mi2 autoantibodies are associated with the derepression of genes related to the NuRD complex, likely contributing to direct cellular toxicity and the characteristic muscle cell necrosis observed in patients with these autoantibodies (5,24,25). Addressing these uncertainties will require further studies to determine the most effective therapeutic strategies for different autoantibody subsets.

In conclusion, this study adds dazukibart to the expanding arsenal of drugs targeting the interferon pathway in dermatomyositis. Over the coming years, the relative efficacy of different treatment approaches will be tested, refined, and compared, further shaping the therapeutic landscape for this complex disease.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Annals of Translational Medicine. The article has undergone external peer review.

Peer Review File: Available at https://atm.amegroups.com/article/view/10.21037/atm-25-44/prf

Funding: This study was funded, in part, by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health.

Conflicts of Interest: The authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-25-44/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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References

1. Greenberg SA, Pinkus JL, Pinkus GS, et al. Interferon-alpha/beta-mediated innate immune mechanisms in dermatomyositis. Ann Neurol 2005;57:664-78. [Crossref] [PubMed]
2. Huard C, Gullà SV, Bennett DV, et al. Correlation of cutaneous disease activity with type 1 interferon gene signature and interferon β in dermatomyositis. Br J Dermatol 2017;176:1224-30. [Crossref] [PubMed]
3. Liao AP, Salajegheh M, Nazareno R, et al. Interferon β is associated with type 1 interferon-inducible gene expression in dermatomyositis. Ann Rheum Dis 2011;70:831-6. [Crossref] [PubMed]
4. Pinal-Fernandez I, Casal-Dominguez M, Derfoul A, et al. Identification of distinctive interferon gene signatures in different types of myositis. Neurology 2019;93:e1193-204. [Crossref] [PubMed]
5. Pinal-Fernandez I, Muñoz-Braceras S, Casal-Dominguez M, et al. Pathological autoantibody internalisation in myositis. Ann Rheum Dis 2024;83:1549-60. [Crossref] [PubMed]
6. Rehwinkel J, Gack MU. RIG-I-like receptors: their regulation and roles in RNA sensing. Nat Rev Immunol 2020;20:537-51. [Crossref] [PubMed]
7. Gaidt MM, Morrow A, Fairgrieve MR, et al. Self-guarding of MORC3 enables virulence factor-triggered immunity. Nature 2021;600:138-42. [Crossref] [PubMed]
8. Ferri F, Parcelier A, Petit V, et al. TRIM33 switches off Ifnb1 gene transcription during the late phase of macrophage activation. Nat Commun 2015;6:8900. [Crossref] [PubMed]
9. Ma C, Liu M, Cheng Y, et al. Therapeutic efficacy and safety of JAK inhibitors in treating polymyositis/dermatomyositis: a single-arm systemic meta-analysis. Front Immunol 2024;15:1382728. [Crossref] [PubMed]
10. Sevim E, Kobrin D, Casal-Dominguez M, et al. A comprehensive review of dermatomyositis treatments - from rediscovered classics to promising horizons. Expert Rev Clin Immunol 2024;20:197-209. [Crossref] [PubMed]
11. Casal-Dominguez M, Pinal-Fernandez I, Mammen AL. Inhibiting interferon pathways in dermatomyositis: rationale and preliminary evidence. Curr Treatm Opt Rheumatol 2021;7:258-71. [Crossref] [PubMed]
12. Paik JJ, Lubin G, Gromatzky A, et al. Use of Janus kinase inhibitors in dermatomyositis: a systematic literature review. Clin Exp Rheumatol 2023;41:348-58. [PubMed]
13. Shaw KS, Hashemi KB, Castillo RL, et al. Anifrolumab in recalcitrant cutaneous dermatomyositis: A multicenter retrospective cohort study. J Am Acad Dermatol 2024;91:1217-9. [Crossref] [PubMed]
14. Ang PS, Ezenwa E, Ko K, et al. Refractory dermatomyositis responsive to anifrolumab. JAAD Case Rep 2024;43:27-9. [Crossref] [PubMed]
15. Neelakantan S, Oemar B, Johnson K, et al. Safety, Tolerability, and Pharmacokinetics of PF-06823859, an Anti-Interferon β Monoclonal Antibody: A Randomized, Phase I, Single- and Multiple-Ascending-Dose Study. Clin Pharmacol Drug Dev 2021;10:307-16. [Crossref] [PubMed]
16. Fiorentino D, Mangold AR, Werth VP, et al. Efficacy, safety, and target engagement of dazukibart, an IFNβ specific monoclonal antibody, in adults with dermatomyositis: a multicentre, double-blind, randomised, placebo-controlled, phase 2 trial. Lancet 2025;405:137-46. [Crossref] [PubMed]
17. Aggarwal R, Charles-Schoeman C, Schessl J, et al. Trial of Intravenous Immune Globulin in Dermatomyositis. N Engl J Med 2022;387:1264-78. [Crossref] [PubMed]
18. Hagen M, Bucci L, Böltz S, et al. BCMA-Targeted T-Cell-Engager Therapy for Autoimmune Disease. N Engl J Med 2024;391:867-9. [Crossref] [PubMed]
19. Müller F, Taubmann J, Bucci L, et al. CD19 CAR T-Cell Therapy in Autoimmune Disease - A Case Series with Follow-up. N Engl J Med 2024;390:687-700. [Crossref] [PubMed]
20. Chen Z, Wang X, Ye S. Tofacitinib in Amyopathic Dermatomyositis-Associated Interstitial Lung Disease. N Engl J Med 2019;381:291-3. [Crossref] [PubMed]
21. Alehashemi S, Buehring B, de Jesus AA, et al. Sustained Interferon Signature Suppression With Anifrolumab in a Patient With STING-Associated Vasculopathy with Onset in Infancy Refractory to JAK Inhibitor and Dazukibart Therapy. Arthritis Rheumatol 2025; Epub ahead of print. [Crossref] [PubMed]
22. Kretzschmar G, Páez LP, Tan Z, et al. Normalized Interferon Signatures and Clinical Improvements by IFNAR1 Blocking Antibody (Anifrolumab) in Patients with Type I Interferonopathies. J Clin Immunol 2024;45:31. [Crossref] [PubMed]
23. Casal-Dominguez M, Pinal-Fernandez I, Pak K, et al. Performance of the 2017 European Alliance of Associations for Rheumatology/American College of Rheumatology Classification Criteria for Idiopathic Inflammatory Myopathies in Patients With Myositis-Specific Autoantibodies. Arthritis Rheumatol 2022;74:508-17. [Crossref] [PubMed]
24. Pinal-Fernandez I, Milisenda JC, Pak K, et al. Transcriptional derepression of CHD4/NuRD-regulated genes in the muscle of patients with dermatomyositis and anti-Mi2 autoantibodies. Ann Rheum Dis 2023;82:1091-7. [Crossref] [PubMed]
25. Pinal-Fernandez I, Mecoli CA, Casal-Dominguez M, et al. More prominent muscle involvement in patients with dermatomyositis with anti-Mi2 autoantibodies. Neurology 2019;93:e1768-77. [Crossref] [PubMed]