Baseline sequencing data are available for 611 of the patients in the BLAZE-4 (Arms 9-14) study. Of these, 552 (90.3%) were infected with a variant of interest or concern, as designated by the World Health Organization (WHO). No subject was infected with virus of the Omicron lineage or sub-lineages.1

The majority of patients in the trial were infected with Delta (49.9%) and Alpha (28.6%).1 These were distributed across the treatment groups with Delta and Alpha infection rates of

• 60.2% and 23.1% in placebo
• 31.3% and 41.8% in bebtelovimab alone arms, and
• 58.3% and 21.9% in the bebtelovimab, bamlanivimab and etesevimab arms.1

Gamma and Mu infections comprised 5.6% and 3.8% of the total infections respectively.1

Patients infected with other WHO-classified variants were the minority of the total infections with

• Beta comprising 0.5%
• Delta +K417N comprising 0.8%
• Iota comprising 0.7%, and
• Lambda comprising 0.5%.1

All other patients in the trial had SARS-CoV-2 infections from either non-WHO classified viruses (3.3%), or the lineage was not able to be determined based on the baseline sequence data (6.4%).1

Detection of viral variants with a ≥5-fold reduction in susceptibility to bebtelovimab at baseline has been rare, with only one G446V substitution (8-fold shift) observed transiently out of 611 patients in the BLAZE-4 (Arms 9-14) study that had baseline sequencing available (0.2%, 1/611).1

Analysis of treatment-emergent variants focused on changes at amino acid positions with known phenotypically confirmed bebtelovimab-associated variations (ie, K444, V445, G446, and P499) in serial viral samples obtained in the BLAZE-4 (Arms 9-14) bebtelovimab Phase 2 Study.1

Treatment-emergent substitutions detected at ≥15% or ≥50% allele fractions at these positions included K444E/N, V445G, G446V, and P499H/R. These substitutions resulted in a 5-fold or greater reduction in susceptibility to bebtelovimab in pseudotyped VLP assays: K444E (>862), K444N (>1,901-fold), V445G (>730-fold), G446V (8-fold), P499H (>1,606-fold), and P499R (>1,870-fold). Additional treatment-emergent substitutions detected at ≥15% or >50% allele fractions outside the epitope in at least 2 subjects included C379F (n=2) and G404C (n=2), seen in bebtelovimab in combination with bamlanivimab and etesevimab arms.1

Considering all substitutions detected at ≥15% allele fraction at positions K444, V445, G446, and P499, 5.5% (11/199) of patients treated with bebtelovimab alone harbored a variant that was treatment-emergent. This was more frequent than observed in placebo arm (0%, 0/112) or when bebtelovimab was administered together with bamlanivimab and etesevimab (0.3%, 1/312).1

The appearance of these treatment-emergent bebtelovimab resistance-associated substitutions was associated with higher viral loads in the subjects in whom they were detected, but none of these patients were hospitalized.1 The majority of the variants were first detected on Day 5 (n=3) and Day 7 (n=6) following treatment initiation.1