Cabaletta Bio announces updated clinical data on CABA-201

Cabaletta Bio (CABA) announced new and updated clinical data on CABA-201 demonstrating the potential to achieve drug-free, compelling clinical responses based on eight patients dosed across the ongoing Phase 1/2 RESET-Myositis, RESET-SLE and RESET-SSc clinical trials. These data were presented in oral and poster presentations at the American College of Rheumatology Convergence 2024, which is being held at the Walter E. Washington Convention Center in Washington, D.C. from November 14-19, 2024. Cabaletta designed CABA-201, a 4-1BB-containing fully human CD19-CAR T cell investigational therapy, to deeply and transiently deplete CD19-positive B cells following a one-time infusion that may enable a reset of the immune system with the potential for durable remission without chronic immunosuppressive therapies in patients with autoimmune diseases. Cabaletta is currently evaluating CABA-201 in the RESET clinical development program across five company-sponsored clinical trials that each have disease-specific cohorts with six patients per cohort. All cohorts are evaluating the same single, weight-based dose of CABA-201 at 1 x 106 cells/kg without a dose escalation requirement. Treatment with CABA-201 in each clinical trial includes a preconditioning regimen of fludarabine and cyclophosphamide, consistent with the dosing regimen used in the third-party academic studies, except for the RESET-PV trial which is evaluating CABA-201 without preconditioning. New and Updated Clinical Data Summary: As of the data cut-off date of November 1, 2024, eight patients had been dosed with CABA-201 with sufficient follow-up to be evaluable across the RESET clinical development program. In the RESET-Myositis trial, one patient in the immune-mediated necrotizing myopathy cohort completed six months of follow-up and two patients, one in the IMNM cohort and one in the dermatomyositis cohort, each completed one month of follow-up. In the RESET-SLE trial, one patient in the non-renal systemic lupus erythematosus cohort completed six months of follow-up, one patient in the lupus nephritis cohort completed four months of follow-up and two patients in the non-renal SLE cohort each completed one month of follow-up. Translational assessments from the third patient in the non-renal SLE cohort were not available for inclusion at the time of the data cut-off. In the RESET-SSc trial, one patient in the severe skin cohort completed six weeks of follow-up. Across these eight patients treated with CABA-201, patients were administered a one-time infusion of CABA-201 at 1 x 106 cells/kg, following a preconditioning regimen of fludarabine and cyclophosphamide. The primary endpoint of each trial is safety and tolerability within 28 days of infusion. Secondary endpoints include translational assessments and clinical outcomes. Safety and Tolerability Profile: CABA-201 has shown a favorable risk-benefit profile in patients with active and refractory autoimmune disease. Through 28 days of follow-up, no evidence of cytokine release syndrome of any grade was observed in five of the eight patients. Low-grade CRS was observed in three patients, all of which recovered following standard care. Tocilizumab was not administered for any cases of CRS. No evidence of immune effector cell-associated neurotoxicity syndrome of any grade has been observed in any patient since reporting the initial safety data on the first LN patient in August 2024. This patient had acute inflammatory events shortly before CABA-201 treatment and demonstrated an abnormal, pro-inflammatory cytokine profile prior to infusion that continued after CABA-201 infusion, suggestive of a possible occult infection. Translational Assessments: CABA-201 induced consistent and complete B cell depletion, with early naive B cell repopulation suggesting the potential to generate an immune system reset CAR T cell expansion associated with CABA-201 reached its peak between day 8 and day 15. Translational assessments from the first patient in the LN cohort indicated a second peak at day 29. Complete B cell depletion was observed by day 22 after CABA-201 infusion. B cell repopulation occurred in the first two patients treated with CABA-201 as early as 8 weeks and exhibited a transitional naive phenotype, reflecting the production of new B cells after deep systemic depletion. Two of the three patients with follow-up beyond three months demonstrated a reduction in disease-associated antibodies. Clinical responses in all three of these patients were observed independent of autoantibody levels. Vaccine and infectious pathogen antibodies remained generally stable. Clinical Outcomes: CABA-201 provided compelling signs of early efficacy, supporting the potential for drug-free clinical responses Initial clinical responses in the RESET-Myositis trial were consistent with published data with response kinetics appearing to differ between myositis subtypes. The first known adult DM patient dosed with CAR T in the form of CABA-201 demonstrated an improvement in muscle strength to normal and a major total improvement score response off all immunosuppressants at one month of follow-up. The Cutaneous Dermatomyositis Disease Area and Severity Index – Activity improved from 25 to 9. At six months of follow-up, the first IMNM patient demonstrated a continued and improved clinical response off immunosuppressants and without flares. At one month of follow-up, the second IMNM patient demonstrated a total improvement score consistent with the first IMNM patient at one month after CABA-201 infusion off immunosuppressants. All four patients in the RESET-SLE trial demonstrated clinical responses off immunosuppressants. All three patients in the non-renal SLE cohort demonstrated no clinical symptoms on SLEDAI-2K as of the latest follow-up and the first patient has completed a prednisone taper to discontinuation. The first patient in the LN cohort, who experienced the previously reported ICANS event, had a SLEDAI that improved from 22 at baseline to 8 at month four of follow-up. The patient’s proteinuria improved more than 90%, approaching normal levels, while off all immunosuppressants and with an ongoing prednisone taper. The first patient in the severe skin cohort in the RESET-SSc trial demonstrated early clinical improvements after discontinuation of disease-specific therapy. The modified Rodnan Skin Score of the first patient in the severe skin cohort improved from 42 at baseline to 36 at day 42, suggesting the potential emergence of a drug-free clinical response.