Safety and efficacy of monoclonal antibody therapy in patients with chronic herpes simplex virus-2 genital infections: MATCH-2, a randomized double-blinded, parallel-group phase 2 multi-center trial.

Frequent anogenital recurrences in Herpes-Simplex-Virus type 2 (HSV-2) infected individuals remain a global health challenge. Nucleoside analogues, with limited clinical efficacy, have been the standard treatment for decades. The humanized antibody HDIT101 is a first-in-class biologic under clinical development for HSV-related diseases. In this randomized, double-blinded, phase 2 multi-center parallel-group trial, HSV-2 seropositive patients with ≥ 4 annual anogential recurrences were enrolled. Following an initial pre-treatment observation phase in which anogenital swabs were taken for a maximum of 28 days patients were randomly assigned (2:1) at the occurrence of an outbreak to either receive a single 2 g intravenous dose of HDIT101 or infusional HDIT101 buffer placebo solution. At each recurrence during the 180-day trial period patients in the HDIT101 arm received episodic oral valacyclovir placebo (twice daily for 3 days) or valacyclovir (500 mg twice daily for 3 days) in the control arm. Post-treatment viral shedding was monitored by daily anogenital swabbing for 28 consecutive days starting immediately after infusional treatment and at day 150. Ordered statistical testing was applied to control for multiplicity. From 122 patients (full-analysis-set, FAS), 36/41 in the VAL arm and 67/81 in the HDIT101 arm completed the trial per-protocol (per-protocol-set, PPS). Adverse events were mild/moderate and similar between treatment arms. The primary endpoint, percentage of days with lesions after treatment, did not differ between the two treatment arms (PPS mean: HDIT101 14.6 vs VAL 14.9). However, independent of peak drug exposure, a longer "time to first recurrence", defined as key secondary endpoint of the trial, (PPS median: HDIT101 47.0 days vs VAL 39.0 days, p = .11), and a lower "recurrence rate" (PPS mean: HDIT101 2.7 vs VAL 3.8, p = .01) in favour of the HDIT101 group were observed. The results demonstrate that HDIT101 is well tolerated as an infusion therapy. Although no superiority was observed in the primary endpoint, HDIT101 may provide improved prevention of recurrences in chronic HSV-2 disease. Meanwhile, complementary studies confirming immunomodulatory effects mediated by the HDIT101 antibody as its key mode of action support the rationale for further clinical investigation. (CinicalTrials.gov NCT04165122).