The annual meeting of the Endocrine Society, ENDO 2026, held in Chicago, served as a pivotal stage for the global biotechnology and pharmaceutical industries to unveil transformative data across a spectrum of rare and chronic endocrine disorders. This year’s assembly was characterized by a distinct shift toward oral therapeutic alternatives for conditions traditionally managed by burdensome injectables, alongside the emergence of high-precision monoclonal antibodies designed to address the root causes of hormonal dysregulation. From congenital adrenal hyperplasia and acromegaly to Cushing’s syndrome and hyperinsulinism, the clinical updates presented underscore a new era of endocrine medicine focused on long-term disease stabilization and improved patient quality of life.
Crinetics Pharmaceuticals Advances Oral ACTH Antagonism for CAH
A primary highlight of the conference was the presentation by Crinetics Pharmaceuticals regarding its investigational compound, atumelnant (CRN04894). As a first-in-class, once-daily oral adrenocorticotropic hormone (ACTH) receptor antagonist, atumelnant is being developed to treat classic congenital adrenal hyperplasia (CAH) and ACTH-dependent Cushing’s syndrome (ADCS). The data presented from the Phase 2 TouCAHn study provided evidence that the drug can effectively block the effects of excess ACTH, which is the primary driver of androgen excess in CAH patients.
In the newly revealed results from Cohort 4, participants received 80 mg of atumelnant once daily. A critical component of this cohort was the mandatory reduction of glucocorticoid (GC) doses. Standard treatment for CAH has long relied on high doses of glucocorticoids to suppress ACTH and adrenal androgens; however, chronic steroid use often leads to severe side effects, including metabolic dysfunction, bone loss, and cardiovascular issues. The TouCAHn trial demonstrated that even as GC doses were lowered to a target of less than 11 mg/m²/day of hydrocortisone equivalents, atumelnant maintained a sustained reduction in key biomarkers such as androstenedione (A4), 11-hydroxyandrostenedione (11-OHA4), and 11-ketotestosterone (11-KT).
The chronology of the atumelnant program shows a steady progression: initial Phase 2 findings for Cohorts 1-3 (where GC doses remained stable) were presented at ENDO 2025, showing A4 reductions ranging from 58% at a 40 mg dose to 80% at a 120 mg dose. The 2026 data confirms that the drug’s efficacy is not dependent on high steroid levels, paving the way for the ongoing Phase 3 CALM-CAH trial. Dr. Alan Krasner, Chief Endocrinologist at Crinetics, noted that the drug’s design to selectively target the melanocortin type 2 receptor (MC2R) on the adrenal gland allows for a "simple to use oral therapy" that could fundamentally change the standard of care.
Long-Term Stability in Acromegaly Management with Paltusotine
Crinetics further solidified its position in the endocrine market by presenting two-year data for PALSONIFY (paltusotine), its once-daily oral somatostatin receptor ligand (SRL) for acromegaly. Following its commercial launch in late 2025, the medical community has closely watched for long-term durability data. The pooled results from the PATHFNDR-1 and PATHFNDR-2 open-label extension (OLE) trials presented at ENDO 2026 confirmed that paltusotine provides consistent biochemical control.
In PATHFNDR-1, which transitioned patients from injectable SRLs to oral paltusotine, mean IGF-1 levels remained stable at 0.81x the upper limit of normal (ULN) after 96 weeks of treatment. Similarly, in PATHFNDR-2, which included medically untreated patients with high baseline IGF-1 (1.64x ULN), levels dropped significantly to 0.96x ULN by week 72. Beyond biochemical markers, the study highlighted that pituitary tumor volumes remained stable in the vast majority of patients, with some even experiencing a reduction of over 20%.
The implications of these findings are significant for patient adherence. Current standard-of-care treatments for acromegaly often involve painful monthly intramuscular or subcutaneous injections. The transition to an oral daily pill that maintains the same level of tumor and symptom control represents a major shift in the treatment paradigm. Furthermore, data from the ACROBAT Advance study suggested that for patients not fully controlled by monotherapy, the combination of paltusotine with oral cabergoline was both well-tolerated and effective in further normalizing IGF-1 levels.
Marea Therapeutics and the Next Generation of GHR Blockade
While Crinetics focuses on oral SRLs, Marea Therapeutics presented a different approach to acromegaly with its first-in-human Phase 1 study of MAR002. This candidate is a first-in-class allosteric monoclonal antibody targeting the growth hormone receptor (GHR). Unlike somatostatin analogs that inhibit GH secretion from the pituitary, MAR002 blocks GH signaling at the receptor level in peripheral tissues, specifically the liver, to reduce IGF-1 production.
The Phase 1 data demonstrated a profound suppression of IGF-1, with reductions reaching up to 64%. Most notably, the pharmacokinetic profile of MAR002 suggests it could be administered as infrequently as once every two weeks via subcutaneous injection. This compares favorably to current GHR antagonists like pegvisomant, which require daily injections. Dr. Shlomo Melmed of Cedars-Sinai commented that the depth of suppression seen with MAR002 exceeds levels reported with previous therapies, potentially offering a solution for the 65% of acromegaly patients who fail to achieve optimal control on first-line medical therapy. Marea Therapeutics is expected to initiate Phase 2/3 trials in the coming weeks.
Recordati Rare Diseases: Sustained Efficacy in Cushing’s Syndrome
Recordati Rare Diseases utilized the ENDO 2026 platform to present comprehensive data from its LINC clinical program, focusing on ISTURISA (osilodrostat) for the treatment of Cushing’s syndrome. Osilodrostat is a potent cortisol synthesis inhibitor that targets 11-beta-hydroxylase.
The presentations included four distinct analyses:
- LINC CARE: A Phase 4 study evaluating the drug’s impact on hypertension caused by hypercortisolemia.
- LINC 7: A retrospective study demonstrating effectiveness in adrenal and ectopic Cushing’s syndrome, which are often more difficult to manage than pituitary-derived disease.
- LINC 6: Three-year real-world data confirming long-term safety and maintenance of biochemical control.
- LINC 3 & 4: Patient-reported outcomes showing meaningful improvements in physical and mental quality of life.
The consensus among the Recordati presenters was that as the body of evidence for osilodrostat grows, its role is expanding from a secondary treatment to a cornerstone of long-term management. The ability to achieve rapid normalization of urinary free cortisol (UFC) levels while improving comorbidities like hypertension and psychological distress remains the primary clinical goal for this patient population.
Precision Medicine for Thyroid Eye Disease and Graves’ Disease
Ethyreal Bio introduced its lead program, ETHY-001, reporting preclinical data that suggests a "best-in-class" potential for treating Graves’ disease (GD) and thyroid eye disease (TED). ETHY-001 is a half-life-extended monoclonal antibody designed to block the thyroid-stimulating hormone receptor (TSHR).
The preclinical results were particularly striking for their consistency; the antibody achieved complete signaling blockade across all tested patient sera samples. In models of TED, ETHY-001 showed superior activity compared to IGF-1R antagonism, which is the current mechanism of the only FDA-approved therapy for TED (teprotumumab). By targeting TSHR—the shared pathogenic driver of both the thyroid and orbital manifestations of the disease—Ethyreal Bio aims to provide a single-agent solution. The company plans to move ETHY-001 into first-in-human clinical trials in the second half of 2026, with an emphasis on the convenience of subcutaneous administration and an extended half-life.
Addressing the Burden of Rare Hyperinsulinism
Rezolute, Inc. rounded out the pharmaceutical updates with a focus on congenital and tumor-related hyperinsulinism (HI). The company highlighted results from its ersodetug (formerly RZ358) clinical program. Ersodetug is a monoclonal antibody that works by partially blocking insulin receptors, thereby dampening the effect of excess insulin without completely eliminating its metabolic function.
In an oral presentation, investigators reviewed the Phase 3 sunRIZE study, which demonstrated that ersodetug significantly reduced the frequency and severity of hypoglycemia in patients with congenital HI. Additionally, Rezolute presented a case series of nine patients with malignant insulinomas (tumor HI) who were experiencing refractory hypoglycemia. In this group, 75% of those requiring intravenous dextrose or total parenteral nutrition were able to discontinue these intensive supports after receiving ersodetug through an expanded access program.
To support the future commercialization and health-economic arguments for the drug, Rezolute also presented natural history studies. These analyses quantified the severe neurological and health-economic burdens of congenital HI, emphasizing the urgent need for treatments that can prevent the brain damage associated with frequent, severe low blood sugar episodes in infants and children.
Conclusion and Industry Implications
The data presented at ENDO 2026 reflects a broader trend in endocrinology toward precision and patient-centricity. The success of oral therapies like atumelnant and paltusotine signals a transition away from "injection fatigue," a major factor in patient non-compliance for chronic conditions. Simultaneously, the development of targeted antibodies like MAR002, ETHY-001, and ersodetug illustrates a move toward "mechanistic" medicine, where the therapy addresses the specific molecular receptor or pathway responsible for the disease rather than merely managing symptoms.
As these compounds move through the final stages of clinical development and into the market, the endocrine landscape is likely to become increasingly competitive. For clinicians, these advancements offer a more diverse toolkit to tailor treatments to individual patient needs, particularly for those with rare diseases who have historically had few, if any, effective options. The focus now shifts to the upcoming Phase 3 results and regulatory filings expected throughout 2027 and 2028.
