Thread by @DrJLi

BA.2 is a sublineage of Omicron that's replacing the original BA.1 version in the U.S. I'll break down what we know about its effects on current antivirals and the facts behind #bebtelovimab, the newest anti-SARS-CoV-2 monoclonal antibody (mAb) that received FDA EUA. a🧵 1/

Compared to BA.1, BA.2 has quite a few changes to ORF1ab and the NTD region of Spike. Luckily, I don't see any mutations in nsp5 or 12 that would affect Paxlovid, remdesivir, or molnupiravir activity 2/

The other good news pertains to Evusheld (tix/cil). It took a hit vs BA.1/BA.1.1, but based on data from David Ho's group (biorxiv.org/content/10.110…), BA.2 has almost no effect on cilgavimab (CoV2-2130, blue box). This is great news for Evusheld and for our immunosuppressed pts 3/

From that same paper above, the data on sotrovimab is concerning as there is a 27-fold drop in activity vs BA.2 (S309, black box in figure above). Vir's press release suggests that sotrovimab could still be active despite this finding (investors.vir.bio/news-releases/…) 4/

Translating in vitro data into loss of clinical efficacy can be complicated as it depends on combo of IC90s, lung penetration of mAb, and pharmacokinetics. The big Q is whether sufficient sotrovimab serum levels can be achieved to overcome this resistance. Will need more data 5/

In David Ho's figure above, notice that there's a new mAb (LY-CoV1404, red arrow) that is active against all of the Omicron lineages. This is Lily's new mAb bebtelovimab that just received FDA EUA yesterday in the absence of phase 3 efficacy results (fda.gov/news-events/pr…) 6/

Here's a preprint of its in vitro characteristics (biorxiv.org/content/10.110…). It's an RBD-specific IgG1 mAb and binds to similar epitope as sotrovimab/imdevimab. Importantly, it appears to neutralize all known variants of concern as outlined in EUA (fda.gov/media/156152/d…) 7/

The limited clinical data supporting bebtelovimab is from the small ph 2 BLAZE-4 trial showing decreased median day 5 viral loads and a 2 day faster improvement in symptoms vs placebo (6 vs 8 d), in low-risk pts in pre-Omicron era. There were very few hospitalizations overall 8/

BLAZE-4 also enrolled a small number of high risk pts into Bam/Ete/Beb (N=50) vs Beb (N=100) alone that showed a 4% vs 3% hospitalization, respectively, but absolute numbers are tiny (N=2, N=3). No unexpected safety concerns reported 9/

The FDA authorization of betelovimab without ph3 results is astounding and raises lots of Qs. Is this a paradigm shift that opens the door wide for more mAb authorization without ph3 studies or a 1-off due to Qs surrounding sotrovimab vs BA.2 + limited supplies of paxlovid? 10/

How should clinicians be using bebtelovimab and under what circumstances? FDA authorization specifically states that this mAb is "for whom alternative COVID-19 treatment options approved or
authorized by FDA are not accessible or clinically appropriate" 11/

On the one hand, clinical data on bebtelovimab is scant, but on the other, it's active against all VOCs and from a therapeutic class that has proven its mettle time and again. It's great that we have another option for our pts, but lots of thorny questions remain. 12/12