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BackgroundCamostat inhibits severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in vitro. We studied the safety and efficacy of camostat in ACTIV-2/A5401, a phase 2/3 platform trial of therapeutics for COVID-19 in nonhospitalized adults.MethodsWe conducted a phase 2 study in adults with mild-to-moderate COVID-19 randomized to oral camostat for 7 days or a pooled placebo arm. Primary outcomes were time to improvement in COVID-19 symptoms through day 28, proportion of participants with SARS-CoV-2 RNA below the lower limit of quantification (LLoQ) from nasopharyngeal swabs through day 14, and grade ≥3 treatment-emergent adverse events (TEAEs) through day 28.ResultsOf 216 participants (109 randomized to camostat, 107 to placebo) who initiated study intervention, 45% reported ≤5 days of symptoms at study entry and 26% met the protocol definition of higher risk of progression to severe COVID-19. Median age was 37 years. Median time to symptom improvement was 9 days in both arms (P = .99). There were no significant differences in the proportion of participants with SARS-CoV-2 RNA ConclusionsIn a phase 2 study of nonhospitalized adults with mild-to-moderate COVID-19, oral camostat did not accelerate viral clearance or time to symptom improvement, or reduce hospitalizations or deaths. Clinical Trials Registration. ClinicalTrials.gov identifier: NCT04518410.

It has been reported that many receptors and proteases are required for SARS-CoV-2 infection. Although angiotensin-converting enzyme2 (ACE2) is the most important of these receptors, little is known about the contribution of other genes. In this study, we examined the roles of neuropilin-1, basigin, transmembrane serine proteases (TMPRSSs), and cathepsins (CTSs) in SARS-CoV-2 infection using the CRISPR interference system and ACE2-expressing human iPS cells. Double-knockdown of TMPRSS2 and CTSB reduced the viral load to 0.036±0.021%. Consistently, the combination of the CTPB inhibitor CA-074 methyl ester and the TMPRSS2 inhibitor Camostat reduced the viral load to 0.0078±0.0057%. This result was confirmed using four SARS-CoV-2 variants (B.1.3, B.1.1.7, B.1.351, and B.1.1.248). The simultaneous use of these two drugs reduced viral load to less than 0.01% in both female and male iPS cells. These findings suggest that compounds targeting TMPRSS2 and CTSB exhibit highly efficient antiviral effects independent of gender and SARS-CoV-2 variant.

金沢大学 医 第2外科, 分化度の異なる5種類のヒト膵癌培養細胞を用いて検討した. 1)mRNAレベル及び蛋白レベルにおいて,u-PAは分化度とは関係なく全種類に発現が認められたのに対し,膵トリプシノーゲンは分化型であるCapan-1,BxPC-3及びAsPC-1の3種類にのみ発現がみられた. 2)ヌードマウスの脾内移植法による肝転移発生率はCapan-1では56%,BxPC-3では50%,AsPC-1では89%と,分化型の癌で高率であったのに対し,Panc-1ならびにMIAPaCa-2の分化度の低い癌では転移が全くみられなかった.即ち,膵癌細胞の肝転移発生率は分化度ならびに膵トリプシノーゲンの発現とよく相関した. 3)インベージョンアッセイにおけるCapan-1細胞の浸潤細胞数はFOY-305により0.1μM以上で濃度依存性に減少した. 4)Capan-1細胞の脾内移植法による肝転移発生率は,FOY-305非投与群の62%に対し投与群では14%と,FOY-305投与により有意に低下した