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

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.

Phase 1a - Healthy Volunteers (Completed, No Longer Enrolling)

Key Inclusion Criteria

• Healthy men and women, 18-55 years of age
• Body mass index (BMI) between 17.0 and 30.0 kg/m²
• Good general health, confirmed by medical history, physical exam, vital signs, ECG, and lab testing
• Willing and able to use highly effective contraception during and after the study

Key Exclusion Criteria

• Pregnant or breastfeeding
• History of drug allergies or anaphylaxis to human, murine, or yeast proteins, monoclonal antibodies, or other allergens
• Use of an investigational drug within 30 days (or 5 half-lives) before dosing
• Positive test for hepatitis B, hepatitis C, or HIV
• Clinically significant heart, lung, digestive, blood, autoimmune, psychiatric, or other medical condition
• Clinically significant abnormal lab values (e.g., liver enzymes, blood counts) or ECG findings
• Uncontrolled high blood pressure
• Poor venous access

Phase 1b - Adult Patients with SLE and RA (Actively Recruiting)

General Inclusion Criteria (All Patients)

• Men and women, 18-75 years of age
• Able to understand and sign informed consent, and comply with study visits
• Willing and able to use highly effective contraception during and after the study

Additional Inclusion Criteria - SLE Patients

• Diagnosis of SLE for at least 6 months, meeting 2019 EULAR/ACR classification criteria
• Active disease at screening
• Positive lupus-related antibodies (e.g., anti-dsDNA, anti-Smith) and low complement (C3/C4)
• On stable standard-of-care background therapy (e.g., antimalarials, low-dose corticosteroids, and at least one conventional DMARD)
• Up to date on age-appropriate vaccinations Additional Inclusion Criteria - RA Patients
• Diagnosis of RA for at least 3 months, meeting 2010 ACR/EULAR classification criteria
• Moderate-to-severe active disease
• Seropositive for rheumatoid factor and/or anti-CCP antibodies
• On stable standard-of-care background therapy (e.g., low-dose corticosteroids and at least one conventional DMARD)

Key Exclusion Criteria (All Patients)

• Pregnant or breastfeeding
• Known allergy or reaction to NTR-1011, placebo components, or related products
• Use of an investigational drug within 30 days (or 5 half-lives) before dosing, or concurrent enrollment in another clinical trial
• History of cancer within the past year (with limited exceptions)
• Significant kidney impairment, severe liver dysfunction, or severe lung disease
• Uncontrolled high blood pressure or significant cardiovascular disease (e.g., recent heart attack or stroke, certain arrhythmias)
• Active, recurrent, or high-risk infection, including active or latent tuberculosis without appropriate treatment, opportunistic infections, or chronic hepatitis B
• Recent symptoms of COVID-19 without a documented negative test
• Receipt of a live vaccine within 4 weeks before screening or planned within 4 weeks after last dose
• Significant central nervous system disease or pain-amplification conditions (e.g., epilepsy, fibromyalgia) that could interfere with study assessments
• Major surgery within 8 weeks before screening or planned within 6 months after baseline
• History of bone marrow, stem cell, or solid organ transplant (except cornea)
• Uncontrolled diabetes within the past 12 months (with some exceptions)
• History of a blood clot within the past 12 months (with some exceptions)
• Clinically significant abnormal lab values (e.g., liver enzymes, blood counts) at screening