Phase 1a/b Tolerability of NTR-1011 in Healthy Adults and Adult Patients With SLE and RA

Summary

The goal of this clinical trial is to inform the safety and tolerability of NTR-1011 in treating adult patients diagnosed with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). It will also learn about the safety of NTR-1011 in healthy adult volunteers. The main questions it aims to answer are: * What is the highest dose of NTR-1011 that is safe and well tolerated, when given under the skin or into a vein? * How does the body process NTR-1011, and how does NTR-1011 affect the body? * Does the body develop an immune response to NTR-1011? * Are there early signs that NTR-1011 may benefit patients with SLE or RA when added to their current standard-of-care treatment? In the first part of the study (Phase 1a, now complete), researchers compared single doses of NTR-1011 to a placebo (a look-alike substance that contains no drug) in 48 healthy volunteers to see how the body tolerates and processes the drug. In the current part of the study (Phase 1b, actively recruiting), all participants receive NTR-1011 in addition to their usual SLE or RA treatment; there is no placebo group. Up to 24 participants with moderate-to-severe SLE or RA will: * Receive five weekly doses of NTR-1011 given directly into a vein (intravenous) * Continue their current standard-of-care treatment throughout the study * Be monitored for 4 weeks after their last dose * Be assigned to either the SLE group or the RA group (up to 12 patients each)

Detailed Description

This is a Phase 1a/1b, first-in-human study (LIBERATE-I) designed to characterize the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity, and preliminary efficacy of NTR-1011 in healthy adults and in adult patients with systemic lupus erythematosus (SLE) or rheumatoid arthritis (RA). Mechanism of Action NTR-1011 is a recombinant fusion protein combining human serum albumin (HSA) with DNASE1L3, an enzyme the body normally uses to break down neutrophil extracellular traps (NETs). NETs are web-like structures released by immune cells that help fight infection, but when they build up excessively or aren't cleared properly, they can contribute to tissue damage and inflammation in autoimmune diseases such as SLE and RA. NTR-1011 is designed to clear NETs systemically, with the goal of reducing this inflammatory process. Phase 1a (completed, no longer enrolling) The Phase 1a portion was a randomized, double-blind, placebo-controlled, single-ascending-dose study conducted in healthy adult volunteers, intended to establish an initial safety and tolerability profile and characterize single-dose PK and PD prior to dosing in patients. * Forty-eight (48) adult participants were enrolled across three ascending dose cohorts. * Within each cohort, participants were randomized to a single dose of NTR-1011 or placebo, given either intravenously or subcutaneously (8 participants per route per cohort; 6 active : 2 placebo). * A sentinel-dosing approach was used: a sentinel pair was dosed first in each cohort/route, followed by a Principal Investigator safety review before the remaining participants were dosed. * All participants were followed for 4 weeks after dosing to monitor safety, PK, and PD. Phase 1b (actively recruiting) The Phase 1b portion is an open-label, multiple-dose study in adult patients with moderate-to-severe SLE or RA, in addition to their standard-of-care treatment. Its purpose is to evaluate the safety, tolerability, PK, PD, and immunogenicity of repeated intravenous dosing in the intended patient population, and to explore preliminary signals of clinical benefit. * Up to 24 adult participants are planned for enrollment, in two disease cohorts (SLE and RA), balanced up to 12 patients per cohort. * Each participant will receive five weekly intravenous administrations of NTR-1011 (over a 4-week treatment period), in addition to their current standard-of-care medication. * Dosing is adaptive: an initial cohort of 6 patients per disease group will receive our starting dose level. A Safety Monitoring Committee (SMC) then reviews accumulated safety, tolerability, PK, and efficacy data before determining the dose for the next 6 patients per disease group. * There is no placebo group in Phase 1b; all enrolled participants receive active treatment. * Participants are followed for 4 weeks after their final dose to assess safety, PK, PD, immunogenicity, and early markers of clinical response. Assessments Across both portions, safety is assessed through physical examinations, laboratory testing, vital signs, and monitoring for adverse events, including hypersensitivity reactions as an adverse event of special interest. Blood samples are collected at scheduled visits to measure drug levels (PK), NET-related biomarkers (PD, including cell-free DNA measures and calprotectin), and antibodies against NTR-1011 (immunogenicity). In Phase 1b, exploratory clinical efficacy measures are also collected: for SLE, these include the SRI-4 composite response, SLEDAI-2K, BILAG-2004, and patient-reported outcomes; for RA, these include DAS28-CRP, ACR20/50/70 response rates, and patient-reported outcomes. Findings from this study, including the maximum tolerated dose and PK/PD relationships, are intended to support dose selection for future clinical development of NTR-1011 in autoimmune disease.

Eligibility Criteria

Interventions