EF-M2 (Immutalon) Multiple Ascending Dose Study in Moderate-to-Severe Rheumatoid Arthritis

This phase I/IIa, open-label, multicenter, multiple ascending dose (MAD) study evaluates EF-M2 (Immutalon) administered subcutaneously to adults with moderate-to-severe rheumatoid arthritis. The trial is designed primarily to characterize safety/tolerability and immunogenicity and to describe pharmacodynamic (PD) evidence of macrophage M2 polarization rather than to demonstrate definitive clinical efficacy.

Participants are enrolled into sequential dose cohorts. Each participant receives EF-M2 for 4 weeks: Cohorts 1-4 receive 1, 3, 5, or 7 mcg twice weekly (8 injections total). If needed, expanded PD cohorts may evaluate 3 mcg or 5 mcg administered three times weekly (12 injections total) to better understand whether increased dosing frequency strengthens the M2 PD signature and where a plateau may begin. Dose escalation is sequential and occurs only after DSMB review of safety and PD data; sentinel dosing is used in each new cohort (the first 2 participants receive initial dosing with an observation period before full cohort enrollment continues).

Key assessments include adverse event monitoring, physical examinations and vital signs at visits, laboratory safety testing at scheduled time points, and immunogenicity testing (anti-drug antibodies, with neutralizing antibodies assessed if antibodies are detected). Pharmacodynamic assessments are based on blood markers measured over time (e.g., soluble cytokines and macrophage/monocyte markers), with PD endpoints including change in ARG1/iNOS and IL-10/TNF-α ratios and changes in M2-associated cell phenotypes.

Study timing includes screening up to 28 days, 4 weeks of treatment, and an off-drug follow-up period of 8-12 weeks (total participation up to 16 weeks). Example follow-up assessments extend through Day 112. The planned sample size is approximately 32 participants (8 per cohort across four dose levels), with up to 48 participants if both expanded PD cohorts are activated.

Inclusion criteria

• Age 18 to 70 years.
• Diagnosis of rheumatoid arthritis according to the 2010 American College of - Rheumatology and European Alliance of Associations for Rheumatology classification criteria for at least 6 months.
• Moderate-to-severe active disease, defined as:
• Disease Activity Score in 28 joints using C-reactive protein at least 3.2 and not more than 6.0; and
• At least 6 tender joints and at least 6 swollen joints based on the 28-joint count.
• Inadequate response to at least one conventional synthetic disease-modifying antirheumatic drug (for example, methotrexate or leflunomide); and either:
• No prior biologic or targeted synthetic disease-modifying antirheumatic drug therapy; or
• No more than one prior line of biologic or targeted synthetic disease-modifying antirheumatic drug therapy, discontinued at least 12 weeks before screening.
• Stable background therapy:
• Conventional synthetic disease-modifying antirheumatic drug at a stable dose for at least 8 weeks; and
• Glucocorticoids at a dose not exceeding 10 milligrams per day of prednisone (or equivalent) at a stable dose for at least 4 weeks; and
• Nonsteroidal anti-inflammatory drugs and/or analgesics on a stable regimen for at least 2 weeks.
• Willingness and ability to comply with study visits, biospecimen collection, and contraception requirements (for women and men).

Exclusion criteria

• Current severe infection; active or latent tuberculosis without completed preventive therapy.
• Chronic hepatitis B, chronic hepatitis C, or human immunodeficiency virus infection with high viral load.
• Active malignancy or history of malignancy within 5 years, except adequately treated carcinoma in situ of the cervix or skin.
• History of severe opportunistic infections.
• Uncontrolled cardiovascular disease (including New York Heart Association class III or IV heart failure, acute coronary syndrome within the past 6 months, or uncontrolled arterial hypertension), decompensated diabetes mellitus, or severe liver or kidney disease.
• Pregnancy, breastfeeding, or planning pregnancy within 6 months.
• Prior treatment with cellular therapies, chimeric antigen receptor T-cell therapy, or profound immunosuppressive therapies with incomplete immune reconstitution.
• Any condition that, in the investigator's opinion, increases the risk of study participation.