Background: B-cell maturation antigen (BCMA) is a member of the tumor necrosis factor receptor superfamily with selective expression on benign and malignant plasma cells. Signaling through BCMA mediates survival and proliferation of multiple myeloma (MM) cells. BCMA is a validated clinical target with multiple BCMA-directed therapies approved or in development for patients with relapsed and/or refractory (r/r) MM. Bispecific antibodies (BsAbs) offer a convenient alternative to chimeric antigen receptor–modified T-cell (CAR-T) therapies targeting BCMA and are demonstrating high response rates in patients with MM. Here we describe the discovery of WVT078, a novel BCMA-CD3 BsAb and report initial clinical data from the ongoing phase 1 study (NCT04123418) evaluating ascending doses of WVT078 in patients with r/r MM.
Aims: To evaluate the safety and tolerability of the novel BCMA-CD3 BsAb WVT078 in patients with r/r MM.
Methods: Multiple BCMA-CD3 BsAb candidates were characterized in vitro and in vivo for T cell activation and anti-MM activity. The activity and tolerability of prioritized candidates were further assessed in an integrated pharmacology study in cynomolgus monkeys. WVT078 was selected for the phase 1 clinical study and is being tested in patients with MM who are r/r to ≥2 standard of care regimens including an immunomodulatory drug, a proteasome inhibitor, and an anti-CD38 agent (if available). Patients who have received a prior BCMA CAR-T or BCMA-antibody-drug conjugates therapy are included, whereas those with prior treatment with BCMA-CD3 bispecifics are excluded.
Results: WVT078, a BCMA-CD3 BsAb with high affinity binding to BCMA (with subnanomolar KD), was selected to effectively target MM cells with a low BCMA expression, an emerging mechanism of resistance to BCMA-targeted therapies. WVT078 demonstrated potent anti-MM activity and efficient T-cell activation in preclinical models, and was well tolerated in cynomolgus monkeys. As of December 08, 2021, a total of 33 patients with r/r MM were treated with intravenous WVT078 once weekly at the following dose levels: 3, 6, 12, 24, 48, 64, 96, 192, and 250 µg/kg of body weight. Twenty-five patients (75.8%) discontinued treatment due to progressive disease (n=22), physician decision (n=2) or adverse event (AE, n=1). The most frequent (≥20%) treatment-related AEs (TRAEs) of all grades across all doses included cytokine release syndrome (CRS, 60.6%), pyrexia (39.4%), increased alanine aminotransferase (ALT, 30.3%), increased aspartate aminotransferase (AST) and anemia (24.2% each), and the most common grade ≥3 TRAEs (≥10%) included increased AST, lymphopenia (18.2% each), increased ALT (15.2%), CRS and neutropenia (12.1% each). Clinical activity was observed starting at the dose of 48 µg/kg. At the active doses of 48-250 µg/kg (n=26), the overall response rate (partial response or better) was 34.6% (n=9; 90% CI, 19.4-52.6) and the complete response rate (stringent complete response+complete response) was 11.5% (n=3; 90% CI, 3.2-27.2). The maximum tolerated dose has not been reached. Pharmacokinetic data showed a trend towards dose-proportional relationship and no evidence of accumulation.
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Summary/Conclusion: WVT078, a novel BCMA-CD3 BsAb, demonstrated potent anti-MM activity and favorable tolerability in preclinical models. In the phase 1 study, WVT078 exhibited an acceptable safety profile and preliminary evidence of clinical activity. Clinical evaluation of WVT078 as a single agent and in combination with a gamma secretase inhibitor is ongoing.