During the COVID-19 pandemic, variants of theBetacoronavirusSARS-CoV-2, the etiologic agent of COVID-19 disease, progressively decreased in pathogenicity up to the Omicron strain. However, the case fatality rate has increased from Omicron through each major Omicron subvariant (BA.2/BA.4, BA.5, XBB.1.5) in the United States of America. World data also mirror this trend. We show that the rise of Omicron pathogenicity is exponential, and we have modeled the case fatality rate of the next major subvariant as 0.0413, 2.5 times that of the Alpha strain and 60% of the original Wuhan strain which caused the greatest morbidity and mortality during the pandemic. Small-molecule therapeutics have been developed, and some of these, such as chlorpheniramine maleate, may be useful in the event of an Omicron subvariant of higher risk.