A Phase 1b, Randomized, Double-Blind, Placebo-Controlled, Multiple-Ascending Dose Study to Investigate the Safety, Tolerability, and Pharmacokinetics of DSTA4637S in Patients with Complicated Staphylococcus aureus
Loren G Miller, Vance G Fowler, Jose M Miro, Juan Pablo Horcajada Gallego, Nicholas Lewin-Koh, Tom Chu, Sharon Rymut, Johnny Gutierrez, Carrie M Rosenberger, Wouter L W Hazenbos, Sara Glickstein, Jessica A Couch, Melicent C PeckAbstract
Background
Safe and effective therapies are needed for hospitalized patients with complicated Staphylococcus aureus infections, including approaches capable of eradicating intracellular bacterial reservoirs that contribute to treatment failure. This study evaluated the safety, tolerability, and pharmacokinetics of DSTA4637S, an antibody-antibiotic conjugate combining an anti-S. aureus antibody with a rifamycin-class antibiotic, in patients with complicated S. aureus bacteremia.
Methods
In this phase 1b, randomized, double-blind, placebo-controlled study, 25 patients with methicillin-sensitive (MSSA, 68%) or -resistant (MRSA, 32%) complicated S. aureus bacteremia received weekly intravenous doses of DSTA4637S at 15, 45, or 100 mg/kg in combination with at least 4 weeks of standard-of-care anti-staphylococcal antibiotics.
Results
Most patients (92%) experienced ≥1 treatment-emergent adverse event (TEAE), of which 44% were considered treatment-related. Grade ≥3 TEAEs and serious adverse events occurred in 72% and 56% of patients, respectively. The most common grade ≥3 TEAEs were infusion-related reactions (IRRs), pneumonia, anemia, and respiratory failure. Four patients (21%) receiving DSTA4637S discontinued study treatment due to treatment-related IRRs. Systemic exposure of DSTA4637S in patients increased approximately dose-proportionally from 15 to 100 mg/kg but was 30–60% lower than previously observed in healthy volunteers.
Conclusion
The safety profile of DSTA4637S, characterized by unpredictable IRRs, and its pharmacokinetic behavior in patients differed substantially from those observed in healthy volunteers, highlighting the critical importance of conducting early-phase studies in the target patient population.