MADRIGAL PHARMACEUTICALS, INC.

Except as set forth below, there have been no material changes to the risk factors included in detail in the “Risk Factors” section appearing in Part I, Item 1A of our Annual Report on Form 10-K for the year ended December 31, 2025, filed with the SEC on February 19, 2026 (the “Annual Report”). We encourage you to read and carefully consider all of the risk factors disclosed in our Annual Report, in addition to the risk factors presented below, for a more complete understanding of the risks and uncertainties material to our business.

If clinical trials or regulatory approval processes are prolonged, delayed or suspended, we may be unable to advance the development of or commercialize our product candidates on a timely basis, which would require us to incur additional costs and delay our receipt of any revenue from potential product sales.

We cannot predict whether we will encounter problems with any of our completed, ongoing or planned clinical trials that will cause us or any regulatory authority to delay, suspend, or terminate those clinical trials or delay the analysis of data derived from them. A number of events, including, but are not limited to, any of the following, could delay or impede completely the completion of our ongoing and planned clinical trials and negatively affect our ability to obtain regulatory approval for, and to market and sell, a particular product candidate:

•conditions imposed on us by the FDA, the EMA or other regulatory authorities regarding the scope or design of our clinical trials;

•insufficient supply of our product candidates or other materials necessary to conduct and complete our clinical trials;

•slow enrollment and retention rate of subjects in our clinical trials;

•challenges in identifying or recruiting sufficient trial sites or investigators for clinical trials; and

•serious and unexpected drug-related side effects related to the product candidate being tested.

Commercialization of any future product candidates may be delayed by the imposition of additional conditions on our clinical trials by the FDA or any other applicable foreign regulatory authority or the requirement of additional supportive trials by the FDA or such foreign regulatory authority.

We do not know whether our ongoing clinical trials will need to be restructured, will enroll an adequate number of patients on time, or will be completed on schedule, if at all, or whether future clinical trials will begin as planned or have similar future challenges. Certain clinical trials evaluate the accrual of events in the patients enrolled. Outcomes-based trials are subject to delays stemming from patient withdrawal and from lower-than-expected event rates. Actual event accrual rates may differ from our assumptions. Accordingly, the precise timing for completion of these trials is difficult to predict with any certainty and may occur at a different time than currently expected. Delays in the initiation, enrollment or completion of our clinical trials may result in increased development costs for our product candidates. In addition, if our clinical trials are delayed, our competitors may be able to bring products to market before we do and the commercial viability of our product candidates could be limited.

We have a history of operating losses and may never achieve or maintain consistent profitability.

As of September 30, 2026, we had an accumulated deficit of $2,187.4 million. Losses have principally resulted from costs incurred from our commercialization efforts, in our preclinical studies and clinical trials, research and development programs and from our selling, general and administrative expenses. As of September 30, 2026, we had cash, cash equivalents, restricted cash and marketable securities of $961.8 million. Despite generating net income of $55.4 million for the three months ended September 30, 2026, we may experience significant fluctuations in our operating results, including incurring net losses in future periods, as we:

•continue to support our sales and marketing efforts for Rezdiffra;

•fulfill our post-marketing commitments and clinical trials of Rezdiffra, as required by the FDA;

•initiate or continue clinical trials of any future product candidates;

•seek to acquire or in-license additional product candidates;

•seek regulatory approvals and, if approved, commercialize Rezdiffra in foreign markets;

•add operational, financial and management information systems and personnel, including personnel to support commercialization of Rezdiffra and pipeline development and to help us comply with our obligations as a public company; hire and retain additional personnel, such as clinical, quality control, scientific, commercial and administrative personnel;

•maintain, expand and protect our intellectual property portfolio; and

•add equipment and physical infrastructure to support our research and development.

As a result, we may report net income in certain quarterly periods and net losses in certain other quarterly periods, and profitability in any particular quarter should not be considered indicative of our ability to achieve or sustain profitability in future periods. Due to the numerous risks and uncertainties associated with developing and commercializing Rezdiffra and any future product candidates, we are unable to predict the extent of any future losses or if we will be able to achieve and sustain consistent profitability.