NTR-441 is an emerging treatment option for rheumatological conditions

NTR-441, a DNase1L3-albumin fusion protein, demonstrated acceptable safety in a phase 1 trial, with preliminary clinical efficacy observed in a patient with systemic lupus erythematosus (SLE) who had a deficiency in DNase1L3.

Dr Tobias Fuchs (Neutrolis Inc., MA, USA) reported the results from a first-in-humans study (NCT04941183) evaluating NTR-441 as a therapeutic approach to inactivate Neutrophil Extracellular Traps (NETs) [1]. The phase 1a part assessed single doses in healthy participants (n=35), followed by a phase 1b part involving single and multiple ascending doses in hospitalised participants with COVID-19 (n=16). Additionally, 1 SLE participant with systemic lupus erythematosus and congenital DNase1L3 deficiency received NTR-441 at 3.0 mg/kg weekly for 3 months under compassionate use.

Pharmacodynamic analyses revealed that NTR-441 results in rapid and supraphysiological DNase1L3 levels shortly after infusion. NTR-441 was overall well tolerated, with most adverse events reported at the highest dose (10 mg). Infusion-related reactions were observed in 1 healthy volunteer and in the SLE participant, which were linked to the development of anti-drug antibodies.

In the lupus participant, clinical improvement across multiple organs was observed within 6 hours of the first administered dose, although partial recurrence of rash and episcleritis occurred before subsequent administrations. After 3 months, treatment was discontinued due to anti-drug antibodies, which affected clinical response. Notably, clinical improvement correlated with markers of NET degradation.

“These first-in-humans studies validate DNase1L3 analogues as a therapeutic strategy to inactivate NETs rapidly,” concluded Dr Fuchs, “and the temporal association between NET clearance and clinical improvement implicates NETs as a key pathogenic driver.”

A phase 2 trial is planned to evaluate NTR-441 in patients with anti-dsDNA-positive SLE and anti-citrullinated protein antibody-positive rheumatoid arthritis.

1. Reiff A, et al. Early evidence of proof-of-concept of an albumin-DNASE1L3 fusion protein (NTR-441) for the rapid enzymatic inactivation of NETs in SLE with DNASE1L3-deficiency. ACR Convergence, 24–29 October 2025, Chicago, IL, USA.

Medical writing support was provided by Mihai Surducan, PhD.

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Posted on 31 October 2025