Neutrolis publishes NEJM case report on NET-degrading SLE therapy
Neutrolis has announced publication in The New England Journal of Medicine of a clinical case report showing that its investigational DNASE1L3 analog, NTR-441, produced rapid and substantial improvement in a teenager with severe, treatment-refractory systemic lupus erythematosus (SLE) arising from a congenital loss-of-function variant in DNASE1L3.
The 16.5-year-old patient had experienced disease onset at 18 months and, despite extensive prior immunosuppressive therapy, had not achieved sustained remission. Manifestations included recurrent vasculitic rash covering 76% of body surface area, polyarthritis, episcleritis, inflammatory bowel disease and autoimmune hepatitis. Clinical symptoms began to resolve within six hours of the first weekly intravenous infusion of NTR-441. Over four weeks, rash coverage fell to 20% of body surface area, joint inflammation and episcleritis resolved, and disease-activity scores on the SLEDAI-2K and BILAG scales improved alongside patient-, parent- and physician-reported assessments.
Mechanism and pharmacodynamic evidence
NTR-441 is designed to enzymatically degrade neutrophil extracellular traps (NETs) by dismantling their DNA backbone, restoring a function normally performed by DNASE1L3, a DNase secreted by macrophages and dendritic cells. Plasma DNASE1L3 levels rose rapidly after each infusion, confirming systemic exposure. Target engagement was supported by increases in circulating DNA and myeloperoxidase-DNA complexes, biomarker changes consistent with in-tissue NET degradation that correlated closely with clinical response.
"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," said Tobias Fuchs, co-founder and chief scientific officer of Neutrolis.
An infusion reaction accompanied by anti-drug antibodies emerged at the fifth dose, attributed to the patient's immune system having had no prior exposure to native DNASE1L3. Doses were adjusted under a desensitisation protocol and clinical benefit was maintained until treatment was discontinued after the eighth infusion due to shortened drug exposure.
Platform and next steps
Neutrolis is positioning the case report as proof-of-concept for its broader exDNASE platform. An improved fusion protein, NTR-1011, completed a Phase 1a study demonstrating favourable safety and tolerability in April 2026. The company is now initiating a Phase 1b study, LIBERATE-I (NCT07237659), in SLE and rheumatoid arthritis, with the aim of establishing proof-of-concept across a wider autoimmune population.
The case carries significance beyond the rare DNASE1L3-deficiency population. NETs have been implicated as pathological drivers in a range of autoimmune and inflammatory conditions, including antiphospholipid syndrome, ANCA-associated vasculitis and certain forms of RA, making a non-immunosuppressive NET-clearing approach of potential interest well beyond the monogenic indication studied here. Several other groups are investigating anti-NET strategies, including PAD4 inhibitors and DNase-based approaches in early clinical development, though none has yet reached late-stage trials or secured regulatory approval for an autoimmune indication.
The Neutrolis data should be read carefully in light of its limitations. The entire human evidence base currently rests on a single compassionate-use patient, a fact the company acknowledges in its own forward-looking statement disclosures. Broader generalisability, optimal dosing intervals, long-term immunogenicity management and efficacy in patients without a monogenic DNASE1L3 variant all remain open questions that LIBERATE-I must begin to address. Investors and clinicians will be watching the Phase 1b readout for safety signals, pharmacodynamic consistency and early efficacy signals in a genetically heterogeneous cohort.