The ENDO 2026 annual meeting served as a pivotal platform for the global endocrinology community, unveiling a series of clinical breakthroughs that promise to reshape the treatment landscape for rare and chronic endocrine disorders. From the introduction of novel oral therapies for Congenital Adrenal Hyperplasia (CAH) to long-term data confirming the efficacy of oral treatments for acromegaly, the presentations underscored a broader industry shift toward improving patient quality of life through reduced treatment burden and precision pharmacology. Leading the charge were several biotechnology and pharmaceutical firms, including Crinetics Pharmaceuticals, Marea Therapeutics, Recordati Rare Diseases, Ethyreal Bio, and Rezolute, each presenting data that address significant unmet needs in hormone-related conditions.
Crinetics Pharmaceuticals Advances Atumelnant for Congenital Adrenal Hyperplasia
On June 14, Crinetics Pharmaceuticals presented highly anticipated data from its Phase 2 TouCAHn trial, evaluating atumelnant (CRN04894), an investigational once-daily oral adrenocorticotropic hormone (ACTH) receptor antagonist. Designed to target the melanocortin type 2 receptor (MC2R) on the adrenal gland, atumelnant seeks to block the effects of excess ACTH, which is the primary driver of the androgen excess and systemic complications associated with classic CAH and ACTH-dependent Cushing’s syndrome.
The findings presented at ENDO 2026 focused on Cohort 4 of the study, which involved adult participants with classic CAH receiving an 80 mg once-daily morning dose. Unlike previous cohorts where glucocorticoid (GC) doses remained static, Cohort 4 participants underwent a stepwise reduction of their GC intake by 5-10 mg hydrocortisone (HC) equivalents. The goal was to reach a target dose of less than 11 mg/m²/day.
The clinical results were significant: atumelnant enabled a substantial reduction in GC doses while maintaining suppressed levels of androstenedione (A4), a key biomarker of disease control. Historically, CAH patients have been forced to rely on supra-physiological doses of GCs to manage androgen excess, a practice that leads to long-term complications such as obesity, type 2 diabetes, osteoporosis, and cardiovascular disease. The ability of atumelnant to decouple androgen control from high-dose steroid therapy represents a potential paradigm shift in CAH management.
Supporting data from Cohorts 1-3, which were previously reported, showed a clear dose-response relationship in A4 reduction without GC adjustment:
- 40 mg dose (n=11): 58% mean reduction in A4.
- 80 mg dose (n=11): 70% mean reduction in A4.
- 120 mg dose (n=6): 80% mean reduction in A4.
Dr. Alan Krasner, Chief Endocrinologist at Crinetics, emphasized that these results validate the mechanism of atumelnant as a potent and selective blocker of ACTH effects. The company has already moved into late-phase development, with Phase 3 trials (CALM-CAH) currently enrolling both adult and pediatric populations.
Long-Term Stability in Acromegaly: The PALSONIFY (Paltusotine) Data
In a second major presentation, Crinetics Pharmaceuticals unveiled long-term data for PALSONIFY (paltusotine), its oral, once-daily somatostatin receptor ligand (SRL) for the treatment of acromegaly. Following its commercial launch in late 2025, the new data from the PATHFNDR open-label extension (OLE) studies provided evidence of the drug’s durability over a two-year period.
Acromegaly is characterized by the overproduction of growth hormone (GH), usually due to a pituitary tumor, which in turn stimulates the liver to produce excess insulin-like growth factor-1 (IGF-1). The standard of care has long involved painful monthly injections of depot SRLs. The PATHFNDR-1 trial focused on patients who were biochemically controlled on these injections before switching to oral paltusotine, while PATHFNDR-2 focused on medically untreated patients with uncontrolled disease.
The pooled OLE data revealed:
- PATHFNDR-1: In 53 participants, baseline mean IGF-1 levels were 0.91x the Upper Limit of Normal (ULN). After 96 weeks, these levels remained stable at 0.81x ULN. Pituitary tumor volumes remained stable in all patients.
- PATHFNDR-2: In 114 participants who entered the OLE with uncontrolled levels (mean 1.64x ULN), IGF-1 levels dropped to 1.06x ULN at 48 weeks and further to 0.96x ULN at 72 weeks.
- Symptom Control: Median Acromegaly Symptom Diary (ASD) scores remained stable across both studies, indicating that the transition to oral therapy did not result in a "breakthrough" of symptoms.
Furthermore, Crinetics presented data on the combination of paltusotine with oral cabergoline for patients who did not achieve full normalization on monotherapy. This combination was well-tolerated and resulted in further improvements in IGF-1 levels, suggesting a flexible oral-only pathway for refractory cases.
Marea Therapeutics and the Next Generation of Acromegaly Biologics
While Crinetics focuses on oral small molecules, Marea Therapeutics presented a different approach to acromegaly with MAR002, a first-in-class allosteric monoclonal antibody targeting the growth hormone receptor (GHR). At ENDO 2026, the company shared Phase 1 first-in-human data that could position MAR002 as a "best-in-disease" biological option.
The Phase 1 study demonstrated that MAR002 provides deep and durable suppression of IGF-1, with reductions of up to 64% observed. One of the most significant advantages of MAR002 is its pharmacokinetic profile, which may allow for dosing as infrequently as once every two weeks. This contrasts sharply with the daily subcutaneous injections required by current GHR antagonists like pegvisomant.
Dr. Rebecca Juliano, Chief Development Officer at Marea, noted that by directly blocking GH signaling at the receptor level, MAR002 could provide biochemical control for patients who are resistant to somatostatin-based therapies. The company is preparing to initiate a Phase 2/3 study in the coming weeks, aiming to establish MAR002 as a new standard of care for patients seeking more convenient and effective biological treatments.
Recordati Rare Diseases: Expanding Evidence for Osilodrostat in Cushing’s Syndrome
Recordati Rare Diseases utilized ENDO 2026 to present a comprehensive update on ISTURISA (osilodrostat), a potent cortisol synthesis inhibitor. Through four poster presentations, the company highlighted data from the LINC clinical program, which encompasses a wide range of Cushing’s syndrome populations.
Cushing’s syndrome, characterized by chronic hypercortisolism, leads to severe metabolic and cardiovascular morbidity. The LINC 7 retrospective study presented by Dr. Antoine Tabarin confirmed the effectiveness of osilodrostat in adrenal and ectopic Cushing’s syndrome, populations that are often harder to treat than those with pituitary-based Cushing’s disease.
Key highlights from the Recordati presentations included:
- Long-term Efficacy: Analysis of the LINC 6 study showed that osilodrostat maintained biochemical control and safety over three years of routine clinical practice.
- Quality of Life: Data from the LINC 3 and LINC 4 trials demonstrated significant improvements in patient-reported outcomes, focusing on the reduction of physical and psychological symptoms associated with high cortisol.
- Hypertension Management: The LINC CARE Phase IV study explored osilodrostat’s role in managing hypertension caused by hypercortisolemia, showing that normalization of cortisol levels directly correlates with better blood pressure control even in patients previously resistant to antihypertensive medications.
Milan Zdravkovic, Head of R&D at Recordati, stated that the growing body of real-world evidence reinforces osilodrostat’s role as a cornerstone of long-term management for Cushing’s syndrome.
Ethyreal Bio: A New Frontier in Thyroid Eye Disease and Graves’ Disease
Ethyreal Bio presented preclinical data for ETHY-001, a half-life-extended monoclonal antibody targeting the thyroid-stimulating hormone receptor (TSHR). TSHR is the shared pathogenic driver behind Graves’ disease (GD) and Thyroid Eye Disease (TED), both of which lack sufficient precision therapies.
The preclinical findings showed that ETHY-001 achieved a complete blockade of TSHR activation across all tested patient sera samples. Notably, the antibody demonstrated differentiated activity compared to existing IGF-1R antagonists (such as teprotumumab), which are currently used for TED. By targeting the TSHR directly, ETHY-001 addresses the root cause of the autoimmune response rather than just the downstream inflammatory symptoms.
The company plans to initiate a first-in-human clinical trial in the second half of 2026. If successful, ETHY-001 could offer a convenient, subcutaneous, single-agent approach to treating both the thyroid and orbital manifestations of these autoimmune conditions.
Rezolute and the Management of Refractory Hypoglycemia
Closing out the week’s major updates, Rezolute, Inc. highlighted its progress in treating hyperinsulinism (HI), a rare condition where the pancreas produces excessive insulin, leading to life-threatening hypoglycemia. The company’s lead candidate, ersodetug, is an investigational monoclonal antibody that binds to the insulin receptor to dampen its activity.
Rezolute presented four data sets, including:
- sunRIZE Phase 3 Results: Reviewing the meaningful therapeutic benefits of ersodetug in congenital HI, particularly its ability to reduce the frequency and severity of hypoglycemic events.
- Tumor HI Success: A case series of nine patients with malignant insulinoma showed that 75% of those receiving ersodetug through an expanded access program were able to completely discontinue intravenous dextrose or total parenteral nutrition (TPN).
- Natural History Studies: These studies quantified the severe neurologic and health-economic burdens of congenital HI, providing a baseline for the clinical and social value of new therapies.
Dr. Brian Roberts, Chief Medical Officer at Rezolute, emphasized that the data from the sunRIZE and upLIFT studies highlight the urgent need for improved treatment options for both congenital and tumor-related hyperinsulinism.
Analysis of Implications for the Endocrinology Market
The data presented at ENDO 2026 signal a transition toward more patient-centric therapeutic modalities. For decades, many rare endocrine disorders were managed with therapies that, while life-saving, carried significant side-effect profiles or administration burdens.
The success of atumelnant in CAH suggests that the "steroid-first" approach may eventually be supplemented or replaced by receptor antagonists that manage hormones more precisely. Similarly, the long-term success of paltusotine in acromegaly proves that oral medications can achieve the same biochemical control as systemic injections, likely leading to higher patient compliance and better long-term outcomes.
For the biotechnology sector, these results demonstrate the value of targeting specific receptors—whether through small molecules like those from Crinetics or advanced antibodies like those from Marea and Ethyreal. As these candidates move into Phase 3 trials and toward regulatory approval, the endocrine market is poised for a period of significant diversification and innovation, ultimately offering clinicians and patients a more robust toolkit for managing complex hormonal diseases.
