Material Event (Form 8-K)

On November 6, 2025, Lexicon Pharmaceuticals, Inc., a Delaware corporation (the "Company"), in connection with its previously announced Open Market Sale Agreement^SM, dated December 29, 2023 (the "Agreement"), with Jefferies LLC, as sales agent, pursuant to which the Company may offer and sell, from time to time, through Jefferies, shares of its common stock, par value $0.001, having an aggregate sales price of up to $75,000,000 (the "Shares"), filed a prospectus supplement to its Registration Statement on Form S-3filed with the Securities and Exchange Commission (the "SEC") on August 2, 2024, and declared effective by the SEC on August 15, 2024 (File No. 333-281208)with the SEC with respect to the offer and sale of the Shares from time to time pursuant to the Agreement. As of November 6, 2025, no sales have been made by the Company pursuant to the Agreement.

Vinson & Elkins L.L.P., counsel to the Company, has issued a legal opinion relating to the validity of the Shares being offered pursuant to the Agreement. A copy of such legal opinion, including the consent included therein, is filed as Exhibit 5.1 to this Current Report on Form 8-Kand is incorporated herein by reference.

This Current Report on Form 8-Kshall not constitute an offer to sell or the solicitation of an offer to buy any Shares under the Agreement nor shall there be any sale of such Shares in any state in which such offer, solicitation or sale would be unlawful prior to registration or qualification under the securities laws of any such state.