Efficacy and safety of ZX-7101A, an inhibitor of influenza cap-dependent endonuclease, in adults with uncomplicated influenza: a randomised, double-blind, placebo-controlled phase 2/3 Trial.

OBJECTIVES: To evaluate the efficacy and safety of ZX-7101A: an inhibitor of influenza viral cap-dependent endonuclease, in adults with uncomplicated influenza and explore treatment-emergent resistance. METHODS: We conducted a randomized, double-blind, placebo-controlled, adaptive-design phase 2 and phase 3 studies (ZX-7101A-202) in adults with uncomplicated influenza. Eligible patients were randomised 1:1:1 to receive a single dose of 40 or 80mg ZX-7101A or placebo, stratified by body weight and baseline composite symptom score. The primary efficacy endpoint was time to alleviation of influenza symptoms (TTAS) in intention-to-treat infected (ITTI) population. RESULTS: The phase 2 trial suggested a significantly shorter in TTAS for ZX-7101A compared to placebo: the median TTAS of 40 or 80mg ZX-7101A was 34.7 hours (95% confidence interval [CI], 22.8-43.4; p=0.005) and 45.8 hours (95%CI, 32.0-66.3; p=0.020), compared with 63.6 hours (95%CI, 43.9-93.4) in the placebo group. In the phase 3 trial, the TTAS of both ZX-7101A dose groups was significantly shortened relative to the placebo: the median TTAS was shortened to 48.4 hours (95%CI, 40.5-55.6) for 40mg and 39.4 hours (95%CI, 35.8-49.3) for 80mg, compared with 62.9 hours (95%CI, 56.4-69.3) for placebo (p=0.003 and p<0.001, respectively). In the safety population, ZX-7101A treatment was associated with fewer adverse events (AEs), with 41.8% (100/239) in the 40mg group, 44.2% (106/240) in the 80mg group, and 53.8% (129/240) in the placebo group. The majority of AEs were mild or moderate. Emergence of resistance to ZX-7101A through I38T amino acid substitution was detected in 5/122 (4.1%) patients. CONCLUSIONS: ZX-7101A was an effective treatment for influenza with a single dose of either 40mg or 80mg, with more rapid alleviation of influenza symptoms versus placebo. No safety concerns were identified with single-dose treatment of ZX-7101A.

Potent and broadly neutralizing antibodies against sarbecoviruses induced by sequential COVID-19 vaccination.

The current SARS-CoV-2 variants strikingly evade all authorized monoclonal antibodies and threaten the efficacy of serum-neutralizing activity elicited by vaccination or prior infection, urging the need to develop antivirals against SARS-CoV-2 and related sarbecoviruses. Here, we identified both potent and broadly neutralizing antibodies from a five-dose vaccinated donor who exhibited cross-reactive serum-neutralizing activity against diverse coronaviruses. Through single B-cell sorting and sequencing followed by a tailor-made computational pipeline, we successfully selected 86 antibodies with potential cross-neutralizing ability from 684 antibody sequences. Among them, PW5-570 potently neutralized all SARS-CoV-2 variants that arose prior to Omicron BA.5, and the other three could broadly neutralize all current SARS-CoV-2 variants of concern, SARS-CoV and their related sarbecoviruses (Pangolin-GD, RaTG13, WIV-1, and SHC014). Cryo-EM analysis demonstrates that these antibodies have diverse neutralization mechanisms, such as disassembling spike trimers, or binding to RBM or SD1 to affect ACE2 binding. In addition, prophylactic administration of these antibodies significantly protects nasal turbinate and lung infections against BA.1, XBB.1, and SARS-CoV viral challenge in golden Syrian hamsters, respectively. Importantly, post-exposure treatment with PW5-5 and PW5-535 also markedly protects against XBB.1 challenge in these models. This study reveals the potential utility of computational process to assist screening cross-reactive antibodies, as well as the potency of vaccine-induced broadly neutralizing antibodies against current SARS-CoV-2 variants and related sarbecoviruses, offering promising avenues for the development of broad therapeutic antibody drugs.