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The company was founded in 1986 by Charles E. Bugg and John A. Montgomery. In March 1994, BioCryst became a public company when it completed an initial public offering by listing its shares on the NASDAQ stock exchange. In 2008, the company was named one of the fastest growing companies by Deloitte & Touche in its 2008 list of Technology Fast 500.
In October 2010, BioCryst announced its headquarters would move to Durham, North Carolina, where the company has had an office since 2006. In January 2018, BioCryst signed a definitive merger agreement with Idera Pharmaceuticals, with plans for the combined company to change its name and move to Pennsylvania. However, BioCryst shareholders voted down the merger in July.