Crinetics Pharmaceuticals, Inc.

We do not believe that there have been any material changes to the risk factors set forth in Part I, Item 1A of our Annual Report on Form 10-K for the year ended December 31, 2024 except as relates to the Risks related to our limited operating history, financial position and capital requirements, with the following paragraph replaced in its entirety:

We have a limited operating history, have incurred significant operating losses since our inception and expect to continue to incur losses. We may never generate enough revenue or become profitable or, if we achieve profitability, we may not be able to sustain it.

Pharmaceutical product development is a highly speculative undertaking and involves a substantial degree of risk. We are a global pharmaceutical company with a limited operating history upon which you can evaluate our business and prospects. We commenced operations in 2010 and we have focused primarily on organizing and staffing our company, business planning, raising capital, discovering potential product candidates, conducting preclinical studies and clinical trials; more recently, commercial launch activities for PALSONIFY. While we have obtained FDA regulatory approval, we have not yet demonstrated that we can commercialize PALSONIFY.

We are not profitable and have incurred significant operating losses since our inception. Our prospects are highly dependent on the successful launch and commercialization of PALSONIFY and other late stage clinical drug candidates. The commercial success of PALSONIFY will depend on the degree of market acceptance by physicians, patients, third-party payors and others in the health care community. To the extent that we cannot generate enough revenue from commercial sales of PALSONIFY, our business, financial condition and results of operations may be materially adversely affected and the price of our securities may decline. Regarding our other late stage clinical drug candidates, if those product candidates are not successfully developed and approved, we may never generate revenue from commercial sales or successfully commercialize those drug candidates. We have incurred cumulative net losses since our inception and, as of September 30, 2025, we had an accumulated deficit of $1.3 billion. Our losses have primarily resulted from expenses incurred in connection with our research and development programs and from selling, general and administrative costs associated with our operations. More recently, we have begun to incur losses associated with pre-commercialization and commercial activities for PALSONIFY associated with its U.S. approval, EMA submission, and pre-commercialization activities in other jurisdictions. In addition, all of our product candidates will require substantial additional development time and resources before we would be able to apply for or receive regulatory approvals and begin generating revenue from product sales. We expect to continue to incur losses, and we anticipate these losses will increase substantially as we continue our preclinical discovery programs and to develop, seek regulatory approval for PALSONIFY outside of the U.S. and potentially commercialize it or any other approved products.

To become and remain profitable, we must succeed in developing and commercializing products that generate significant revenue. This will require us to be successful in a range of challenging activities, including completing preclinical studies and clinical trials of our product candidates, discovering additional product candidates, obtaining regulatory approval for our product candidates and manufacturing, marketing and selling any products for which we may obtain regulatory approval. We are in different stages of these activities across the various drug candidates in our pipeline. Other than the FDA approval of PALSONIFY, we have not yet demonstrated an ability to successfully overcome many of the risks and uncertainties frequently encountered by companies in new and rapidly evolving fields, particularly in the biopharmaceutical industry. Because of the numerous risks and uncertainties associated with pharmaceutical product development, commercialization and revenue realization, we are unable to accurately predict the timing or amount of any increased expenses or when, or if, we will be able to achieve profitability. Even if we do achieve profitability, we may not be able to sustain or increase profitability on a quarterly or annual basis. Our failure to become and remain profitable would depress the value of our company and could impair our ability to raise capital, expand our business, maintain our research and development efforts, diversify our product candidates or even continue our operations, any of which could materially and adversely affect our business, prospects, results of operations and the trading price of our common stock.