Cabaletta Bio has reported promising initial results from its RESET-PV trial, demonstrating that its investigational CAR-T cell therapy rese-cel can achieve meaningful clinical responses in pemphigus vulgaris patients without the need for preconditioning chemotherapy. The data, presented at the 2025 European Society of Gene & Cell Therapy Annual Congress in Seville, Spain, represents the first evaluation of rese-cel without cyclophosphamide and fludarabine preconditioning agents.
Clinical Efficacy Without Preconditioning
Three evaluable patients with pemphigus vulgaris received rese-cel at 1 x 10⁶ cells/kg without preconditioning. All patients demonstrated substantial B cell depletion within the first month post-infusion, with two patients achieving complete peripheral B cell depletion. These same two patients experienced rapid reduction in autoantibodies to desmoglein and near-complete resolution of clinical symptoms.
Clinical responses were measured using the Pemphigus Disease Area Index (PDAI) activity scores, which form the basis for recent regulatory approvals in pemphigus vulgaris. The improvements from baseline to latest follow-up were substantial:
- Patient 1 (4 months): PDAI score decreased from 24 to 10
- Patient 2 (3 months): PDAI score decreased from 83 to 3
- Patient 3 (1 month): PDAI score decreased from 22 to 2
"These data provide preliminary evidence that a single infusion of rese-cel without preconditioning can achieve complete B cell depletion and meaningful early clinical responses with a simplified regimen that can expand access to patients who may desire a treatment option without preconditioning," said David J. Chang, M.D., Chief Medical Officer of Cabaletta.
Comparable CAR-T Cell Performance
Despite the absence of preconditioning, rese-cel exhibited similar CAR-T cell expansion and contraction kinetics compared to translational data from other RESET trials that used preconditioning. This finding suggests that the therapeutic mechanism remains intact without the preparatory chemotherapy regimen typically used in CAR-T treatments.
The increase in peak B cell activating factor (BAFF) was within the range observed in patients who received rese-cel with preconditioning, indicating deep B cell depletion in tissue compartments. This biomarker response supports the biological activity of the treatment approach.
Safety Profile and Treatment Burden
The therapy was generally well tolerated with no immune effector cell-associated neurotoxicity syndrome (ICANS) reported across the three patients. Patient 1 experienced transient fever classified as grade 1 cytokine release syndrome. Patient 2 required steroids for a disease flare in the first two weeks following infusion after discontinuing immunomodulators, but this steroid course was less intense than previous treatment for flares and the patient tapered to below pre-infusion baseline doses by three months.
Notably, all three patients remained off immunomodulators as of the data cut-off date of September 11, 2025, and were either off steroids or tapering their steroid doses.
Implications for Autoimmune Disease Treatment
The RESET-PV trial represents the first study within Cabaletta's broader RESET clinical development program to evaluate rese-cel without preconditioning. The company is now planning to expand patient enrollment in the RESET-PV trial at the current dose and potentially evaluate higher doses as warranted.
Based on these results, Cabaletta is pursuing the incorporation of no preconditioning regimens in certain other RESET clinical trial program cohorts. The company has fully enrolled all adult Phase 1/2 cohorts within trials for myositis, lupus, scleroderma, and myasthenia gravis as of September 30, 2025.
About Rese-cel Technology
Rese-cel (resecabtagene autoleucel) is an investigational autologous CAR-T cell therapy engineered with a fully human CD19 binder and a 4-1BB co-stimulatory domain, designed specifically for autoimmune diseases. The therapy is administered as a single, weight-based infusion intended to transiently and deeply deplete CD19-positive cells, with the goal of resetting the immune system and achieving durable clinical responses without chronic therapy requirements.
The simplified approach without preconditioning could potentially expand access to CAR-T therapy for autoimmune patients who may not be candidates for or may prefer to avoid the intensive preparatory chemotherapy typically required for such treatments.
