Crinetics Pharmaceuticals, Inc.

Business Overview

We are a pharmaceutical company committed to transforming the treatment of endocrine diseases and endocrine-related tumors through science rooted in patient needs. We are focused on discovering, developing, and commercializing novel therapies, with a core expertise in targeting GPCRs with small molecules that have specifically tailored pharmacology and properties.

Our lead product, PALSONIFY (paltusotine), is the first once-daily, oral treatment approved by the FDA for the treatment of adults with acromegaly who had an inadequate response to surgery and/or for whom surgery is not an option. Paltusotine is also in clinical development for CS associated with NETs. Our deep pipeline of 10+ disclosed programs includes late-stage investigational candidate atumelnant, which is currently in development for CAH and ADCS, and CRN09682, a NDC candidate that is being developed to treat SST2 expressing NETs and other SST2 expressing solid tumors. Additional discovery programs address a variety of endocrine conditions such as NETs, Graves’ disease (including Graves’ hyperthyroidism and Graves’ orbitopathy, or TED), polycystic kidney disease, hyperparathyroidism, diabetes, obesity, and GPCR-targeted oncology indications.

Approved Product

•On September 25, 2025, the FDA approved PALSONIFY as the first and only once-daily oral somatostatin receptor ligand for the treatment of adults with acromegaly who had an inadequate response to surgery and/or for whom surgery is not an option.

Key Pipeline Updates

Paltusotine

•The first patient was enrolled in the Phase 3 study of paltusotine for CS in November 2025.

•In February 2026, the CHMP of the EMA adopted a positive opinion, recommending the marketing authorization of PALSONIFY for the medical treatment of adult patients with acromegaly. The CHMP opinion will be reviewed by the EC, consistent with a timeline for a potential decision in the first half of 2026.

Atumelnant

•In January 2025, we reported positive results from the first three cohorts of the Phase 2 TouCAHn open-label study of atumelnant in CAH. In January 2026, we provided an update, including data on the fourth cohort of the Phase 2 TouCAHn study and data from the separate OLE study. Participants in all four cohorts were eligible to enroll in the OLE.

•In May 2025, we announced the design of our Phase 3 CALM-CAH study. The first participant in the CALM-CAH study was randomized in December 2025.

•In August 2025, we announced our pediatric trial design in CAH, BALANCE-CAH. BALANCE-CAH is designed as an operationally seamless Phase 2/3 study. The first participant in the BALANCE-CAH study was dosed in January 2026.

•We expect to initiate an operationally seamless Phase 2/3 study of atumelnant in ADCS (EQUILIBRIUM-ADCS) in the first half of 2026.

CRN09682

•In April 2025, we received IND clearance for CRN09682, the first candidate from the NDC platform. In November 2025, the first patient received CRN09682 in the dose escalation phase of a Phase 1/2 study.

Our Strategy

Our mission is to build the world’s leading endocrine company that pioneers new therapeutics to help patients better control their disease and improve their daily lives. To achieve this mission, we are pursuing the following strategy:

•Commercialize our product candidates. PALSONIFY became the first oral nonpeptide SST2-agonist approved by the FDA for the treatment of acromegaly in September 2025 and was commercially available in October 2025 in the U.S. We are establishing a highly specialized and focused commercial organization, including sales, marketing and market access expertise to support the launch of PALSONIFY in the U.S. We continue to execute our launch strategy by educating healthcare providers and patients on the diagnosis and appropriate clinical management of acromegaly and the potential clinical benefits and appropriate use of PALSONIFY.

•We are also activating patients to request PALSONIFY, educating HCPs on PALSONIFY to drive breadth and depth of prescribers and engaging with payers to support patient access to therapy and formulary inclusion of PALSONIFY. We believe PALSONIFY's profile as a once-daily, oral SST2R agonist that is approved to offer biochemical and symptom control and convenience will provide meaningful differentiation in the acromegaly competitive landscape.

•We are building the structure and expertise to commercialize our product candidates in additional markets, including the EU, where we believe we can do this efficiently and effectively, if approved by regulators. In February 2022, we entered into the SKK License pursuant to which SKK has the exclusive right to commercialize paltusotine in Japan. In the future, we may seek relationships with additional global licensing, distribution or other partners for our product candidates where we determine this to be an effective approach.

•Focus on endocrine diseases and endocrine-related tumors with significant unmet medical need. There are numerous endocrine diseases and endocrine-related tumors for which currently available pharmacological therapies (when they exist) have significant limitations in efficacy, safety and/or tolerability. Patients living with these diseases often experience significant morbidity, mortality and/or poor quality of life. We are focused on discovering, developing, and commercializing therapies for multiple indications across endocrinology to advance the standard of care for these patients.

•Rapidly advance multiple product candidates in parallel to clinical proof-of-concept and late-stage development by targeting diseases that employ validated biomarkers as clinical endpoints. Phase 1 clinical trials for endocrine diseases and endocrine-related tumors can often measure predictive biomarkers in healthy volunteers and lower the technical risk by providing a predictive measure of efficacy early in clinical development.

•Continue to expand our therapeutic pipeline for endocrine diseases and endocrine-related tumors by leveraging the capabilities of our experienced discovery team in the area of peptide hormone GPCRs. Our discovery team has significant expertise in understanding and creating product candidates to influence the dynamic behavior of GPCRs and has developed a number of proprietary methods, techniques and tools that we believe will enable us to efficiently and reliably evaluate newly synthesized molecules. We employ an iterative strategy where compounds are designed, synthesized, and rapidly characterized for pharmacologic and pharmaceutical properties. This approach has led to our current pipeline, and we will continue to invest in creating additional product candidates acting at this important class of targets. Peptide hormone GPCRs regulate many aspects of physiology and are attractive drug targets for treating a broad range of diseases. There are more than 80 known peptide hormones acting at more than 120 known different receptors. With each of our drug discovery programs, our goal is to specifically tailor a product candidate with pharmacologic and pharmaceutical properties highly optimized for its interaction with its specific GPCR target that we anticipate will translate to downstream benefits in our chosen therapeutic applications. For example, the SST2R ligand in paltusotine is designed to disfavor internalization of SST2R, while the SST2R ligand in CRN09682 is designed to promote internalization.

•Maintain an entrepreneurial, scientifically rigorous, and inclusive corporate culture where employees are fully engaged and strive to bring improved therapeutic options to patients. The patients we seek to treat often have limited treatment options with significant drawbacks and often limited efficacy, safety and/or tolerability. We are passionate about developing new pharmacological therapies to help these patients better control their diseases and to reduce the impact of these diseases on their daily lives. We believe that building a successful and sustainable endocrine company requires not just specific expertise in multiple areas of drug discovery, development, and commercialization, but a team-oriented culture that integrates and harnesses the creative energy, scientific insights and passion of the entire organization.

The Endocrine System

Overview

The endocrine system regulates most of the body’s physiological activities through the actions of hormones, which are chemical and biochemical messengers secreted from different organs that influence growth, gastrointestinal function, maturation and development, reproduction, stress, metabolism and nearly all aspects of homeostasis. Hormonal dysregulation can arise from endocrine organ defects, including injury, inflammation, genetic abnormalities, or the growth of tumors derived from endocrine cells. These insults can result in the under-secretion or over-secretion of one or more hormones, disrupting homeostasis and causing disease. For example, several serious clinical disorders, including acromegaly and Cushing’s disease, result from pituitary tumors secreting excess hormones.

Peptide hormone GPCRs

Various GPCRs are expressed in every type of cell in the body and their function is to transmit signals from outside the cell across the membrane to signaling pathways within the cell, between cells and between organ systems. Because of these critical actions, the GPCR superfamily is the largest and single most important family of drug targets as highlighted by the large number of approved therapeutics targeting this class. However, most currently available GPCR-targeting drugs act as receptors for which the native ligands are small molecules, such as histamine, adrenaline, and neurotransmitters.

Most peptide hormones bind selectively to specific receptors located on the surface of cells in the target tissue. Receptors for peptide hormones are often GPCRs, which play a central role in many biological processes and are linked to a wide range of disease areas. There are more than 80 known peptide hormones acting at more than 120 known different receptors. Historically, it was assumed that small molecules could not replicate or compete with the complex interactions between peptides and their cognate GPCRs. As such, most drugs developed for peptide GPCRs have been and continue to be peptides themselves, which present manufacturing and formulation difficulties and force patients to undergo frequent injections because peptides generally are not orally bioavailable. We believe our approach to developing novel small molecule product candidates that uniquely engage peptide hormone GPCRs will enable us to generate orally bioavailable, and potentially more selective, effective and better tolerated therapeutics for patients.

GPCRs were originally thought to function as simple on-off switches responding to hormones and neurotransmitters but have since been shown to exhibit complex and diverse molecular and cellular behaviors. Many lines of structural and mechanistic research demonstrate that distinct signaling cascades and feedback mechanisms create multi-dimensional pathways with distinct physiological responses. These different responses are based on ligand binding kinetics, receptor regulation and trafficking. Some transduce signals into the cell interior to regulate various cellular functions. Other responses attenuate hormonal signals to prevent overstimulation and include receptor internalization (a removal of the GPCR from the cell surface, which makes it unavailable for external ligands), desensitization and downregulation. We believe our understanding of these different signaling pathways enables us to develop oral, small molecule product candidates that not only are highly selective for specific receptor subtypes but also are further custom-tailored to activate specific GPCR properties and ultimately improve patient outcomes.

Product Pipeline Summary

All of our product candidates have been discovered and developed internally and we have retained global rights to commercialize our product candidates and have no royalty or licensing obligations, other than the licenses and collaborations discussed under “Our Strategic Collaborations” herein.

The following table summarizes our current product candidate pipeline.

Our Products and Product Candidates

We focus on the discovery and development of nonpeptide therapeutics that target peptide GPCRs with well-understood biological functions, validated biomarkers and the potential to substantially improve the treatment of endocrine diseases and endocrine-related tumors.

Paltusotine (SST2 Agonist Program)

Acromegaly Disease Background

Acromegaly is a serious chronic endocrine disorder typically caused by a pituitary tumor that secretes excess GH. Pituitary tumors are generally benign adenomas that, in addition to GH secretion, also express membrane receptors for somatostatin. Increased GH secretion results in excess downstream secretion of IGF-1 from the liver. GH and IGF-1 promote tissue growth and have other metabolic effects throughout the body.

The consequences of chronically elevated GH and IGF-1 can be severe, including changes in facial features, enlargement of the hands and feet, and carpal tunnel syndrome. Enlargement of the heart can lead to congestive heart failure and these excess hormones also induce insulin resistance, hypertension, and other negative clinical consequences.

From the perspective of someone living with acromegaly, the physical changes in their appearance, not to mention the sweating and skin changes, can be alarming and socially isolating. Severe headaches, fatigue, joint pain, and peripheral neuropathies can be debilitating. Additional symptoms can include thick, coarse, oily skin, skin tags, excessive sweating and skin odor, fatigue and weakness, headaches, goiter, decreased libido, menstrual abnormalities in women and erectile dysfunction in men. As the tumor grows, it can impinge on the nerves in the optic chiasm leading to visual problems and potentially vision loss. Compression of the surrounding normal pituitary tissues can decrease production of other pituitary hormones, resulting in hypopituitarism. Acromegaly patients experience increased mortality rates, principally due to cardiovascular diseases (diabetes, hypertension), respiratory disease and cerebrovascular diseases.

Acromegaly is often suspected when the patient exhibits enlargement of extremities and an alteration of facial features. Pituitary tumors are also often found during clinical workup for severe headaches, vision changes or incidentally on cranial imaging initiated for other reasons. Elevation of serum IGF-1 levels confirms the suspicion of acromegaly, but a formal diagnosis requires lack of suppression of serum GH levels in response to an oral glucose tolerance test. A magnetic resonance imaging (MRI) or computerized tomography (CT) scan of the pituitary is then used to locate the tumor, determine its size and assess the potential for surgical intervention. Unfortunately, for many patients, it can take 5 to 10 years to reach a diagnosis.

Our research suggests that there are approximately 36,000 people living with acromegaly in the U.S., of which 17,000 or more are undiagnosed, 7,500 are not in active follow-up for treatment, and 11,500 are actively managed. Our research further suggests that of the 11,500 actively managed patients in the U.S., 40% are treatment naïve, 25% are on injectable somatostatin receptor ligands, 20% are on other therapies, and 15% have discontinued treatment. Our research also indicates that there are approximately 1,500 newly diagnosed patients per year, 500 of which are candidates to initiate pharmaceutical treatment.

Acromegaly Clinical Development Program

PALSONIFY, is the first once-daily, oral treatment approved by the FDA in the U.S. for the first-line treatment of adults with acromegaly who had an inadequate response to surgery and/or for whom surgery is not an option. Paltusotine is also in clinical development for CS associated with neuroendocrine tumors.

Paltusotine establishes a new class of oral selective nonpeptide SST2 agonists designed for the treatment of adults with acromegaly and CS due to well-differentiated neuroendocrine tumors. Somatostatin is a neuropeptide hormone that broadly inhibits the secretion of other hormones, including GH from the pituitary gland.

Our Phase 3 development program for paltusotine in acromegaly consisted of two placebo-controlled clinical trials, PATHFNDR-1 and PATHFNDR-2. The PATHFNDR-1 trial was designed as a double-blind, placebo-controlled, nine-month clinical trial of paltusotine in acromegaly patients with average IGF-1 levels less than or equal to 1.0 times the ULN and who had been on stable doses of somatostatin receptor ligand monotherapy (octreotide LAR or lanreotide depot). We also conducted a second study, the PATHFNDR-2 trial, which was designed as a double-blind, placebo-controlled, six-month clinical trial of acromegaly patients who were not on pharmacological treatment and had elevated IGF-1 levels. The primary endpoint of both PATHFNDR studies was the proportion of patients with IGF-1 ≤ 1.0 ×ULN at the end of the treatment period on paltusotine as compared to placebo.

Positive topline data from the randomized controlled portion of the PATHFNDR-1 study was reported in September 2023, where the primary endpoint and all secondary endpoints of the study were achieved. Additionally, in the PATHFNDR-1 study, paltusotine was well tolerated and no serious or severe adverse events were reported in participants treated with paltusotine.

In March 2024, we reported positive topline results from the PATHFNDR-2 study. The study met statistical significance (p<0.0001) on the primary endpoint, and all secondary endpoints. Additionally, in PATHFNDR-2, paltusotine was generally well-tolerated and no serious adverse events were reported in participants treated with paltusotine.

The OLE phases of both PATHFNDR trials are ongoing. In July 2025, we presented open-label extension data from both the pivotal PATHFNDR-1 and PATHFNDR-2 trials in two presentations, showing the long-term clinical profile of PALSONIFY in people with acromegaly.

Data from the PATHFNDR-1 OLE demonstrated that mean insulin-like IGF-1 levels remained stable with IGF-1 (mean ± SE) of 0.93 ± 0.22 at OLE baseline and 0.81 ± 0.21 times the ULN at Week 96, demonstrating durable biochemical control over this time span. Symptom control, as measured by the ASD, and GH level also remained stable at Week 96. PALSONIFY was generally well tolerated.

Data from the PATHFNDR-2 OLE demonstrated that patients with placebo during the RC portion of the study and then transitioned to paltusotine experienced sustained reductions in IGF-1, with a mean change from baseline of –0.81 × ULN at Week 84 (n=39). Direct-to-OLE participants (n=9) showed similar reductions (–0.75 × ULN), while those who had been treated with PALSONIFY during the RC phase (n=40) maintained control (mean change –0.01 × ULN). GH, ASD symptom scores and pituitary tumor size were durably controlled over the study period. PALSONIFY was generally well tolerated.

On September 25, 2025, the FDA approved PALSONIFY for the first-line treatment of adults with acromegaly who had an inadequate response to surgery and/or for whom surgery is not an option. The FDA has granted orphan drug designation for paltusotine for the treatment of acromegaly. We believe that the results of the clinical trials of paltusotine could support marketing applications outside the U.S. for the use of paltusotine for all acromegaly patients who require pharmacotherapy, including untreated patients and those switching from other therapies.

In February 2025, the EMA, granted paltusotine orphan drug designation for the treatment of acromegaly. Designation was given following a positive recommendation from the EMA Committee for Orphan Medicinal Products, highlighting the potential impact of paltusotine for acromegaly patients in the European Union. The EMA validated the MAA in March 2025. The EMA also granted ODD for paltusotine for the treatment of acromegaly, further highlighting the level of unmet need and the potential for paltusotine to offer significant benefit to patients. In February 2026, CHMP of the EMA adopted a positive opinion, recommending the marketing authorization of PALSONIFY for the medical treatment of adult patients with acromegaly. The CHMP opinion will be reviewed by the EC, consistent with a timeline for a potential decision in the first half of 2026. Paltusotine is also in development for acromegaly in Japan through our licensing agreement with SKK.

To date, our clinical trials have shown that paltusotine was generally well tolerated among healthy adults and patients with acromegaly.

CS Disease Background

NENs are comprised of NECs, which are poorly differentiated and highly proliferative, with rapid disease progression; and NETs, which are well differentiated and generally slow-growing. NETs represent 80-90% of NENs and include tumors with a broad range of disease characteristics depending on site, grade and other features. NETs most commonly originate from the gastrointestinal tract, lungs and pancreas, and approximately 75% of NETs express SST2 receptors, with higher rates of expression in well-differentiated NETs.

Many NETs are well differentiated and exhibit indolent growth, frequently remaining asymptomatic for prolonged periods. As a result, a significant proportion of patients are diagnosed at an advanced or metastatic stage, often with liver metastases that can drive morbidity and mortality. A subset of NETs are functional, meaning they secrete hormones or other biologically active substances and are associated with corresponding symptoms. Approximately one-fifth of NETs cases are associated with excess serotonin secretion, leading to CS. The key debilitating symptoms of CS are cutaneous flushing (>90% of cases) and chronic diarrhea (60-80% of cases). Patients with CS may also present with related systemic symptoms, including mesenteric fibrosis, abdominal pain, carcinoid heart disease and other symptoms.

We estimate that 28,000-51,000 adults diagnosed with NETs are undergoing medical management. Of these, it is estimated that approximately 18,000-34,000 are candidates for treatment with paltusotine, if it is approved for the treatment of CS.

CS Clinical Development Program

In March 2024, we reported positive topline results from our randomized, open-label, parallel group, multi-center Phase 2 study to assess safety, tolerability, pharmacokinetics, and efficacy of paltusotine in people living with CS. A total of 36 participants were randomized to receive either 40 mg (n=18) or 80 mg (n=18) of paltusotine for eight weeks, with the ability to adjust dose based on tolerability or inadequate control of symptoms during the first four weeks of treatment. Results demonstrated that administration of paltusotine resulted in rapid and sustained reductions in bowel movement frequency and flushing episodes. Paltusotine was generally well-tolerated with a safety profile consistent with prior clinical studies, with no treatment-related severe or serious adverse events.

Patients from the Phase 2 study were eligible to enroll in an open-label extension study of paltusotine in CS. In November 2025, we shared one-year investigator-assessed PFS data from the open-label study, which showed a PFS rate of 74% following one year of treatment.

The Phase 3 CAREFNDR study is designed to evaluate the safety and efficacy of paltusotine in patients with CS. The first patient in the CAREFNDR study was dosed in November 2025 and we continue to activate additional sites. CAREFNDR is designed as a double-blind, placebo-controlled, sixteen-week clinical trial to enroll CS patients (who may or may not be on pharmacological treatment at baseline) and are actively symptomatic. The primary endpoint of the CAREFNDR trial is the percentage change from baseline in the frequency of flushing episodes at week 12. In addition, a key secondary endpoint measures the change from baseline in bowel movement frequency at week 12. The CAREFNDR trial is designed to capture other efficacy endpoints including severity of flushing and urgency of bowel movements. Following the 16-week randomized controlled period, the trial will include a 104-week OLE to evaluate long-term efficacy, safety and additional clinical outcomes. The OLE will include an exploratory assessment of tumor control.

To date, our clinical trials have shown that paltusotine was generally well tolerated among healthy adults and patients with CS.

Atumelnant (ACTH Antagonist)

Atumelnant is our investigational, orally available, nonpeptide product candidate designed to block the action of ACTH on the ACTH receptor. It is intended for the treatment of diseases caused by excess ACTH, including CAH and ADCS, which includes patients with either Cushing's disease or EAS.

We conducted a double-blind, randomized, placebo-controlled Phase 1 study of atumelnant in healthy volunteers to assess the safety and tolerability of single and multiple doses of atumelnant. In addition, the study was designed to measure the effect of atumelnant on suppression of cortisol, cortisol precursors, and adrenal androgens following exogenous ACTH stimulation. In May 2022, we announced positive topline data from the Phase 1 study in healthy volunteers which showed atumelnant was well tolerated and demonstrated dose-dependent increases in atumelnant plasma concentrations. We believe atumelnant demonstrated pharmacologic proof-of-concept, as the Phase 1 results showed dose-dependent reductions of both basal cortisol and elevated cortisol following an ACTH challenge. All adverse events were considered mild to moderate and there were no serious adverse events.

CAH encompasses a set of disorders that are caused by genetic mutations that result in impaired cortisol synthesis. A lack of cortisol leads to a breakdown of feedback mechanisms and results in persistently high levels of ACTH, which, in turn, causes overstimulation of the adrenal cortex. The resulting adrenal hyperplasia and over-secretion of other steroids (particularly androgens) and steroid precursors can lead to a variety of effects from improper gonadal development to life-threatening dysregulation of mineralocorticoids. We estimate that approximately 17,000 patients are potential candidates for treatment with atumelnant, 12,000 of which are adults and 5,000 of which are pediatric.

Cushing’s disease results from a pituitary tumor that secretes excess ACTH, and EAS results from non-pituitary ectopic tumors which secrete ACTH. The excess secretion of ACTH causes the downstream synthesis and over-secretion of cortisol by the adrenal glands. Cortisol is the body’s main stress hormone and excess amounts can cause significant increases in mortality and morbidity. We estimate there are over 11,000 patients with Cushing’s disease in the U.S., of which approximately 5,000 patients are potential candidates for treatment with atumelnant.

CAH Disease Background

CAH encompasses a set of disorders that are caused by genetic mutations that result in impaired cortisol synthesis. This lack of cortisol leads to a breakdown of feedback mechanisms and results in persistently high levels of ACTH, which in turn causes overstimulation of the adrenal cortex. The resulting adrenal hyperplasia and over-secretion of other steroids (particularly androgens) and steroid precursors can lead to a variety of effects from improper gonadal development to life-threatening dysregulation of mineralocorticoids. CAH patients have a two-fold risk of bone fractures compared to the general population and commonly suffer from hypercholesterolemia, insulin resistance, and hypertension. Compared to the general population, CAH patients have a diminished life expectancy of 7 years, and more than 20% of CAH patients will die of a condition complicated by adrenal crisis.

Treatment goals for adults with CAH include:

•Reduce A4 and other androgens to address hyperandrogenism, which can manifest as excessive facial hair, acne and polycythemia;

•Restore normal menstrual cycles and fertility in women;

•Shrink testicular adrenal rest tumors, alleviate pain and restore fertility in men; and

•Eliminate excessive exposure to glucocorticoids to minimize steroid therapy related adverse effects including weight gain, cardiovascular issues, diabetes, and osteoporosis.

CAH is an orphan indication with an estimated prevalence of approximately 17,000 patients in the U.S., of which 12,000 are adult and 5,000 are pediatric.

CAH Clinical Development Program

We conducted the TouCAHn Phase 2 study of atumelnant in adult CAH patients. This open-label study was designed to evaluate the safety, efficacy, and pharmacokinetics of different doses of atumelnant. In addition, biomarkers, including serum A4 and 17 hydroxyprogesterone (17-OHP), were measured to evaluate the potential efficacy of atumelnant. We reported positive initial findings from our Phase 2 study in June 2024 and topline data from 28 patients in January 2025. Atumelnant administration was shown to result in rapid, substantial and sustained statistically significant reduction in A4 levels, the key biomarker for disease control, and demonstrated significant clinical improvements. Atumelnant demonstrated statistically significant reductions of A4 at the first 2-week time point in all dose groups (40 mg, 80 mg, and 120 mg). These effects were sustained through the 12-week prespecified primary endpoint where the degree of suppression was dose dependent and statistically significant. The data showed that atumelnant was well-tolerated with no treatment-related severe or serious adverse events.

We have continued progress on the development program for atumelnant across multiple trials. In January 2026, we presented additional data from the Phase 2 study of atumelnant in adults with CAH. The update included data from the fourth cohort (n=10, 12-week study); two participants withdrew consent for administrative reasons. The participants received atumelnant (80 mg) once daily in the morning and underwent GC dose reduction toward physiologic levels (<11 mg/m 2/day HC or equivalent) in weeks 2 to 10. Treatment with atumelnant resulted in rapid, sustained lowering of A4 (in all 8 patients that completed the fourth cohort). Seven out of these 8 patients continued to maintain lower A4 after glucocorticoid doses were reduced to physiologic levels. Atumelnant was well-tolerated with no serious adverse events and no treatment-related severe adverse events. No participants discontinued due to adverse events. No patients experienced hepatic transaminase adverse events. Participants from this study were given the option to enroll in our open-label extension study.

We have initiated a Phase 3 study (CALM-CAH) in adult CAH patients, with first participant randomized in December 2025. The study has an uncompromising primary endpoint to demonstrate atumelnant’s potential ability to normalize A4 levels while patients are on physiological doses of GC replacement. CALM-CAH is designed as a Phase 3 double-blind, placebo-controlled, thirty two-week clinical trial to enroll patients with CAH. The primary endpoint of the CALM-CAH trial is the proportion of participants with A4 ≤ULN (upper limit of normal) who are on physiologic GC replacement at week 32. The CALM-CAH trial is also designed to evaluate the impact of atumelnant on the clinical signs, symptoms, co-morbidities and outcomes of CAH. The participants in the CALM-CAH can roll into the open-label extension study referenced above.

In January 2026, we presented a data snapshot with limited source data verification from the first 7 patients in the OLE to have completed at least 13 weeks. Those data showed both serum A4 reductions and GC dose reductions that were in line with those seen in Cohort 4. Additionally, investigators have not observed any serious adverse events or any treatment-related severe adverse events, and have not observed any hepatic transaminase adverse events to date with 25 patients enrolled and with 7 participants who have completed over 20 weeks of treatment in the study.

The BALANCE-CAH pediatric study is a seamlessly-operational Phase 2/3 study, and the first patient was dosed in January 2026. The Phase 2 is an open-label, semi-sequential cohort study to evaluate the safety, efficacy, and PK of atumelnant treatment in pediatric participants with classic CAH. The Phase 3 is a double-blind, placebo-controlled confirmatory portion of the study to evaluate the safety and efficacy of atumelnant in pediatric participants with classic CAH. Pediatric participants that completed participation in either Phase 2 or Phase 3 of this study will be eligible to enroll in the OLE, a single-arm, open-label, long-term safety and efficacy study. The primary endpoint in the Phase 2 portion is change from baseline in morning serum A4 at Week 8, and the primary endpoint in the Phase 3 portion is the percent change from baseline in GC daily dose at Week 28 while serum early morning A4 is less than the upper limit of normal.

ACTH-Dependent Cushing's Syndrome Disease Background

Cushing’s syndrome results from a prolonged exposure to elevated levels of glucocorticoids, particularly cortisol. Common signs include growth of fat pads (above the collarbone and on back of the neck), abdominal obesity, facial fat accumulation, excessive sweating, dilation of capillaries, thinning of the skin, muscle weakness, hirsutism, depression/anxiety, hypertension, osteoporosis, insulin resistance and hyperglycemia, heart disease and a range of other metabolic disturbances resulting in high morbidity. While excessive synthetic steroid administration or adrenal tumors can cause ACTH-independent forms of the disease, ACTH dependent Cushing’s syndrome (which includes Cushing’s disease and Ectopic ACTH Syndrome) is the most common form, accounting for 60-80% of all cases. Cushing’s disease is caused by tumors of pituitary corticotroph cells that secrete excess ACTH. EAS is caused by tumors outside the pituitary gland that secrete excess ACTH.

EAS is a rare disorder that results from non-pituitary tumors that secrete excessive amounts of ACTH. The supraphysiological degree of ACTH secretion in EAS can vary with effects that range from cushingoid to acutely life-threatening. Treatment options for EAS are limited, with the first goal being surgical removal of the tumors, if possible. If surgery is not an option, medical therapy may be used to block cortisol production. And in some cases, adrenalectomy is required if the tumor cannot be located and medical therapy does not fully block the cortisol.

Cushing’s disease is an orphan indication with a prevalence of approximately 11,000 patients in the U.S. It presents more commonly in women, and usually between 30 and 50 years of age. Cushing’s disease often takes many years to diagnose and may well be under-diagnosed in the general population as many of its symptoms such as lethargy, depression, obesity, hypertension, hirsutism and menstrual irregularity can be incorrectly attributed to other more common disorders.

ACTH-Dependent Cushing’s Syndrome Clinical Development Program

Atumelnant is currently being studied in patients with ADCS, including those with Cushing's disease and Ectopic ACTH Syndrome, in an open-label, multiple-ascending dose Phase 1b/2a trial. This single-center, in-patient study is in collaboration with the NIDDK of the NIH. The ten-day study is designed to evaluate safety, tolerability, and pharmacokinetics of different doses of atumelnant in patients with ADCS as well as to measure 24-hour urinary-free cortisol and serum cortisol as indicators of efficacy. We reported positive initial findings from the study in June 2024, and the study remains ongoing. We expect to initiate an operationally seamless Phase 2/3 study of atumelnant in ADCS (EQUILIBRIUM-ADCS) in the first half of 2026. The Phase 2 is a double-blind, placebo-controlled study, and will inform dose selection for the Phase 3 double-blind placebo-controlled part of the study. Participants that participate in either the Phase 2 or Phase 3 portion will be eligible to enroll in the OLE, a single-arm, open-label, long-term safety and efficacy part of the study.

CRN09682 (non-peptide drug conjugate for SST2 positive solid tumors)

We have developed a first-in-class, non-peptide, non-radioactive NDC linking an SST2 agonist with the cytotoxic drug MMAE, via a spacer and a cleavable linker for the treatment of NETs and potentially for use in other solid tumors that express SST2, or SST2+ tumors. CRN09682 is designed to selectively deliver MMAE to SST2-expressing tumor cells, such that the delivery of MMAE is directed to the SST2 expressing tumors to drive antitumor activity, while minimizing the uptake of the conjugate in other tissues that do not express or express low levels of SST2.

Measurement of CRN09682 and MMAE levels in tumor tissues from mice bearing small-cell lung cancer (NCI-H524 SCLC CDX) demonstrated high tumor uptake for CRN09682 and prolonged MMAE tumor exposure, relative to MMAE in plasma and CRN09682 in plasma. These in vitro data suggest that CRN09682 inhibits cancer cell proliferation upon selective SST2 activation and internalization of CRN09682.

SST2-Positive Solid Tumor Disease Background

NENs arise across multiple organs and vary widely in behavior, with treatment guided by tumor grade and differentiation. Disease severity ranges from well‑differentiated, indolent NETs to poorly differentiated, highly aggressive NECs, including SCLC. Well‑differentiated tumors generally exhibit higher SST2 expression and are often associated with better outcomes. Approximately 75% of NET patients express SST2, with higher, more consistent expression in well-differentiated, low-grade, and GEP-NETs. Poorly differentiated NECs typically exhibit lower SST2 expression and are linked to more aggressive disease and poorer prognoses.

NENs often present at advanced, incurable stages, with more than half of cases metastatic, typically to the liver. They are classified as functional or nonfunctional based on symptoms or hormone hypersecretion; for example, CS results from excess serotonin production.

Patients with locoregional and resectable tumors often undergo surgery as a first step. Those with metastatic or unresectable tumors may undergo medical management for symptom and/or tumor control. Medical management may commonly include SSAs, PRRT, chemotherapy, or kinase / mTOR inhibitors.

We estimate that 28,000 to 51,000 patients with NENs receive medical management, of which an estimated 11,000 to 21,000 seek treatment for tumor control and represent the initial addressable population for CRN09682. Additional SST2‑expressing tumors—such as SCLC, meningioma, head and neck cancer, and breast cancer—may further expand the number of patients who could benefit from CRN09682.

SST2-Positive Solid Tumors Clinical Development Program

We received IND clearance for CRN09682, the first candidate from our NDC platform, along with a “Study May Proceed” letter authorizing initiation of a Phase 1/2 study in metastatic or locally advanced SST2‑positive neuroendocrine tumors and other SST2‑expressing solid tumors. In November 2025, the first patient was dosed in our BRAVESST2 Phase 1/2 study.

During the Phase 1 dose‑escalation stage, we plan to enroll 3–6 patients per ascending dose cohort until the maximum tolerated dose is established. Results from this stage will guide selection of the recommended expansion dose for Phase 2 and determine the tumor sub‑types to include in the expansion cohorts. Across both phases, we expect to enroll up to 150 participants.

Early Stage Product Pipeline Summary

In addition to our clinical stage pipeline, we have several preclinical candidates in development. We may provide updates on these molecules from time to time or if and when they have received IND clearance.

Research Discovery

Patients with many other debilitating endocrine diseases and endocrine related tumors await new therapeutic options, and we continuously evaluate and prioritize where to deploy our drug discovery efforts. We plan to continue to expand our drug discovery efforts and leverage our expertise in the evaluation of additional unmet medical needs. Our drug discovery and development efforts are focused on endocrine, metabolism, and targeted therapies.

Endocrine: Our deep understanding of endocrine systems and patient needs have produced a robust pipeline of transformative novel molecules that are purposefully designed to meet the needs of patients. We focus on developing innovative nonpeptide drug candidates with unique methods of action, targeting particular endocrine pathways, including non-traditional ones, where modulating irregular hormone secretion can lead to improving conditions that significantly impact patients’ lives.

Metabolism: Metabolic disorders including diabetes, obesity, and others impact the lives of hundreds of millions of people across the world and their effects on patients are significant and varied. Many of these disorders are a result of the dysregulation of key metabolic hormones, including insulin, glucagon, glucagon-like peptide-1, gastric inhibitory polypeptide, and others. Crinetics’ understanding of these hormonal pathways and the GPCRs that control them coupled with our expertise in developing nonpeptides with specific pharmacologies allows us to create new molecules with the chance to improve the lives of patients with metabolic diseases.

Targeted Therapies: Our efforts in precision oncology began with developing nonpeptide, GPCR-targeted radioligands for the imaging and treatment of a broad range of endocrine receptor-driven cancers, ultimately leading to the formation of Radionetics in 2021. Our continued dedication to this concept has led to our latest novel development program that is exploring a new modality known as NDCs, a unique therapeutic approach that leverages endocrine receptors for highly selective targeting of anti-tumor agents.

Product Competition for Clinical Stage Candidates

The commercialization of new drugs is competitive, and we could face competition from a number of pharmaceutical or biotechnology companies around the world. Our commercial opportunity could be reduced or eliminated if our competitors develop and commercialize products that are safer, more effective, have fewer or less severe side effects or are more convenient than any products that we may develop. Our competitors also may obtain FDA or other regulatory approval for their products more rapidly than we do. The key competitive factors affecting the success of all of our programs are likely to be their efficacy, safety and convenience. See "Risk Factors – Risks related to commercialization of PALSONIFY and our product candidates."

Acromegaly

The major goals of treatment are to reduce serum GH and normalize IGF-1 levels, ameliorate symptoms, and reduce or stabilize the pituitary tumors that cause acromegaly. Surgical removal of the pituitary tumor is usually the first treatment and can result in long-term remission if the tumor is fully resected. For those for whom surgery is not an option and those whose tumors are not able to be completely removed, standard pharmacotherapy has historically consisted of peptide somatostatin receptor ligands, a GH receptor antagonist, and off-label use of dopamine agonists.

There are three injected somatostatin analogs approved for the treatment of acromegaly: octreotide (marketed by Novartis AG), lanreotide (marketed by Ipsen Biopharmaceuticals, Inc.) and pasireotide (marketed by Recordati Rare Diseases Inc.). Oral octreotide (marketed by Chiesi Farmaceutici) is approved in the U.S. for long-term maintenance treatment in acromegaly patients who have responded to and tolerated treatment with octreotide or lanreotide. Pegvisomant (marketed by Pfizer Inc.) is a daily injectable GHRA and is generally used in patients not fully controlled on somatostatin analogs. Orally administered dopamine agonists, such as bromocriptine and cabergoline, are also used. In December 2021, the FDA approved a biosimilar of lanreotide injection, followed by the approval of a generic lanreotide injection in May 2024 for the treatment of acromegaly, CS, and GEP-NETs. Both products are manufactured by Cipla Ltd. Additionally, in December 2023, the FDA approved an octreotide acetate injectable suspension for treating acromegaly and CS. Other products in clinical development include new formulations of peptide somatostatin agonists (Camurus AB), GH receptor antagonists (Alexion Pharmaceuticals, Inc./AstraZeneca PLC) and anti-GHRA monoclonal antibodies (Marea Therapeutics).

NETs/CS

Long-acting injectable formulations of peptide SSAs are also routinely used in the treatment of NETs to control symptoms associated with hormone hypersecretion and to slow tumor growth in patients with well-differentiated disease. For adults with CS whose symptoms are inadequately controlled by somatostatin therapy alone, telotristat ethyl (marketed by TerSera Therapeutics, Inc.) is available as an orally administered add-on therapy to reduce serotonin-mediated symptoms.

For patients with advanced or metastatic NETs, additional systemic treatment options include peptide receptor radionuclide therapy (PRRT), cytotoxic chemotherapy, and targeted therapies such as mTOR inhibitors and tyrosine kinase inhibitors. However, there is no established consensus regarding optimal treatment sequencing. PRRT is constrained by a limited number of lifetime treatment cycles and is associated with manufacturing, logistical, and administration complexities. Chemotherapy agents lack tumor specificity and generally produce transient responses with cumulative toxicity. Targeted therapies typically provide modest and largely cytostatic clinical benefit, with limited durability of response and the development of treatment resistance during chronic administration.

More recent approvals for the treatment of NETs include FDA approval of Novartis’ Lutathera for the treatment of somatostatin receptor-positive GEP-NETs in 2018, and Exelexis’ Cabometyx for the treatment of previously treated NETs in 2025. Other companies developing NETs therapeutics that target somatostatin receptors include Oranomed/RadioMedix, ASCIL Biopharm, RayzeBio, Molecular Targeting Technologies Inc., Perspective Therapeutics, and Immunwork Inc. Camurus, Chiesi Farmaceutici, POINT Biopharma Global Inc., RayzeBio, and ITM Isotopen Technologien Munchen are currently engaged in Phase 3 trials of new compounds for use in the treatment of NETs.

CAH

The current treatment algorithm for CAH consists of lifelong daily glucocorticoid supplementation which attempts to address the body's inability to synthesize cortisol as well as its over-production of androgens that results from misregulated steroidogenesis. The inability to precisely dose glucocorticoids can often lead to enduring cycles of over- or under-treatment. Under-treatment can result in adrenal crisis and intramuscular stress doses of glucocorticoid for acute illness are common.

In December 2024, the FDA approved an oral CRF1 receptor antagonist, crinecerfont (marketed by Neurocrine Biosciences) as an adjunctive treatment of classic congenital adrenal hyperplasia. Neurocrine Biosciences is also developing a peptide CRF receptor antagonist for CAH. Other companies developing products for potential use in CAH include Lundbeck Pharmaceuticals, and OMass Therapeutics.

ACTH-Dependent Cushing's Syndrome

As with acromegaly, first-line therapy for Cushing’s disease is surgery to remove the pituitary tumor if possible. The use of adrenal enzyme inhibitors (metyrapone, ketoconazole and more recently levoketoconazole which gained FDA approval in December 2021 and is marketed by Xeris Pharmaceuticals) prevent the synthesis of cortisol and can improve symptoms. Mifepristone (marketed by Corcept Therapeutics, Inc.), a glucocorticoid receptor antagonist, is approved for control of hyperglycemia in Cushing’s syndrome. A generic form of mifepristone has been approved for the treatment of endogenous Cushing’s syndrome. Osilodrostat (marketed by Recordati Rare Diseases Inc.), a cortisol synthesis inhibitor, is approved for the treatment of endogenous Cushing’s syndrome. The somatostatin agonist pasireotide is also approved for Cushing’s disease. Other companies developing products for potential use in Cushing’s disease include Corcept Therapeutics, Inc., Sparrow Pharmaceuticals, and Lundbeck Pharmaceuticals.

Earlier Stage Clinical Programs

There may be other earlier-stage clinical programs that, if approved, would compete with our products. Many of our competitors have substantially greater financial, technical and human resources than we have. Additional mergers and acquisitions in the pharmaceutical industry may result in even more resources being concentrated on our competitors. Competition may increase further as a result of advances made in the commercial applicability of technologies and greater availability of capital for investment in these fields. Our success will be based in part on our ability to build and actively manage a portfolio of drugs that address unmet medical needs and create value in patient therapy.