VIR-5818: PRO-XTENTM Initial Proof-of-Concept and Potential First-in-Class HER2 Immunotherapy
Despite availability of HER2-targeting therapies, there remains a significant unmet need for treatments with novel mechanisms of action to improve tolerability
and extend survival. Currently, no HER2-directed immunotherapies are approved for solid tumors. The preliminary safety and efficacy data of VIR-5818 support the tumor-specific activation of PRO-XTENTM dual-masked TCEs and the potential of this technology to broaden the therapeutic index of TCEs.
VIR-5818 is being evaluated in a Phase 1 clinical trial (NCT05356741) designed to study its safety and
pharmacokinetics alone, and in combination with pembrolizumab, in participants with a variety of HER2-expressing cancers, including breast and colorectal cancer (CRC). The study has enrolled 79 heterogeneous and heavily pretreated participants in
monotherapy cohorts.
Early efficacy data indicate that 50% (10/20) of participants receiving VIR-5818 doses
≥400 µg/kg experienced dose-dependent tumor shrinkage across multiple HER2-positive tumor types. This includes participants who had received up to 9 prior lines of therapy. Strong anti-tumor activity was observed in a subset of
participants with HER2-positive CRC who have exhausted standard of care. In this subset, confirmed partial responses (cPRs) were seen in 33% (2/6) of participants at early doses, and one patient continued in cPR for more than 18 months as of the
data cut-off.
Preliminary safety data demonstrate that VIR-5818 is
generally well-tolerated, with minimal grade 1 or 2 CRS (20% and 10%, respectively) and no grade 3 or greater CRS observed in any of the 79 participants across doses up to 1000 µg/kg. Most treatment-emergent adverse events (TEAEs) were low
grade, reversible and manageable. The MTD has not yet been reached. Preliminary pharmacokinetics and safety data indicate low systemic unmasking of the TCE, suggesting tumor-specific activation. Dual masking results in a half-life of approximately 6
days, which may enable a less frequent dosing regimen. As a result, Vir Biotechnology is currently evaluating a Q3W dosing regimen.
VIR-5500: First Dual-Masked PSMA-Targeting TCE
Prostate cancer is the second most diagnosed cancer in men1. Despite advancements, there is still a significant unmet need for efficacious, well-tolerated treatments that can extend survival and improve quality of life.
VIR-5500 is being evaluated in a Phase 1 clinical trial (NCT05997615) designed to assess its safety, pharmacokinetics,
and preliminary efficacy in participants with mCRPC. The study has enrolled 18 participants with significant disease burden who have received 3 to 6 prior lines of therapy.
Early efficacy data show encouraging signs of prostate-specific antigen (PSA) responses, and PSA reductions were observed in 100% (12/12) of participants
after an initial dose ≥120 µg/kg. PSA50 response was confirmed in 58% (7/12) of participants receiving a first dose ≥120 µg/kg.
Preliminary data show a promising safety profile, with no dose-limiting toxicities observed up to 1000 µg/kg without prophylactic corticosteroids.
Safety findings showed minimal grade 1 or 2 CRS (17% and 11%, respectively) and no grade 3 or greater CRS at any dose. Most TEAEs were low grade. No hearing loss has been reported, suggesting safety benefits of dual masking in preventing on-target, off-tumor toxicities. Dose escalation is ongoing, and the MTD for VIR-5500 has not yet been reached. Preliminary
pharmacokinetics and safety data indicate tumor-specific activation with minimal unmasking outside the tumor. The dual-masked TCE shows a desirable half-life of 8-10 days, which is enabling Vir Biotechnology
to evaluate a Q3W dosing regimen. The safety and tolerability profile observed for VIR-5500 in ongoing dose escalation, together with the observed signs of early anti-tumor activity at low doses, may
enable a wide therapeutic index.
