A study published in The New England Journal of Medicine has provided the first clinical evidence that enzymatic degradation of neutrophil extracellular traps (NETs) may reduce disease activity in severe systemic lupus erythematosus (SLE), offering proof of concept for a new therapeutic approach targeting a key driver of autoimmune disease.

The report describes the compassionate-use treatment of a patient with severe, treatment-refractory SLE caused by congenital DNASE1L3 deficiency using Neutrolis’ investigational DNASE1L3 analogue, NTR-441. Researchers observed rapid clinical improvement alongside biomarker changes consistent with NET degradation, supporting the biological mechanism behind the treatment.

NETs are web-like structures released by neutrophils during immune responses. While they play an important role in trapping pathogens, excessive or persistent NET formation has been linked to chronic inflammation, tissue damage and autoimmune diseases including lupus. DNASE1L3 is an enzyme responsible for clearing these structures, and inherited deficiency of the enzyme can lead to severe, early-onset autoimmune disease.

The publication, Targeted Degradation of NETs in Lupus with DNASE1L3 Deficiency, reports on a 16.5-year-old patient whose disease had failed to achieve sustained remission despite extensive immunosuppressive treatment. The patient experienced recurrent vasculitic rash, polyarthritis, episcleritis, inflammatory bowel disease, autoimmune hepatitis and persistent systemic inflammation before receiving weekly intravenous infusions of NTR-441.

Clinical symptoms improved within six hours of the first infusion. Although a temporary recurrence of rash and episcleritis occurred within 24 hours, these symptoms subsequently improved. Over four weeks, investigators reported a reduction in vasculitic rash from 76% to 20% of body surface area, resolution of joint inflammation and episcleritis, and improvements across multiple disease activity measures.

Researchers also reported pharmacodynamic evidence supporting the proposed mechanism of action. Plasma DNASE1L3 levels increased rapidly following treatment, while circulating DNA and myeloperoxidase-DNA complexes increased in a manner consistent with NET degradation. According to the authors, these biomarker changes closely tracked the patient’s clinical improvement.

Andreas Reiff, chief medical officer of Neutrolis, said: “Patients with DNASE1L3 deficiency can experience severe, early-onset autoimmune disease with limited treatment options. The speed and extent of improvement for this patient after NTR-441 treatment are an important proof-of-concept for how NET-degrading therapy can benefit patients across autoimmune and inflammatory indications.”

During the fifth infusion, the patient developed an infusion reaction associated with anti-drug antibodies, which investigators attributed to the patient’s congenital lack of exposure to native DNASE1L3. Treatment continued using a desensitisation protocol and clinical benefit was maintained until therapy was discontinued after the eighth infusion because of reduced drug exposure.

Although the findings are limited to a single compassionate-use patient, the publication represents the first reported clinical evidence that directly degrading NETs may alter disease activity in humans. The results also provide mechanistic support for Neutrolis’ broader exDNASE platform, including NTR-1011, an improved DNASE1L3 fusion protein that has completed a Phase 1a study and is now entering Phase 1b evaluation in patients with SLE and rheumatoid arthritis through the Liberty-I study.

Tobias Fuchs, co-founder and chief scientific officer of Neutrolis, said: “The pharmacodynamic biomarker data in this publication confirm that restoring DNASE1L3 activity degrades NETs as designed. The tight temporal link between NET degradation and clinical response supports our strategy of targeting NETs as a non-immunosuppressive approach to directly target the trigger of disease inflammation in the tissue for the first time in a patient.”

The findings add to growing evidence that NETs play a central role in autoimmune and inflammatory diseases and suggest that therapies designed to remove these structures, rather than suppress the immune system more broadly, may represent a new treatment strategy. Larger clinical studies will now be needed to determine whether the approach can be replicated across wider patient populations.