Citations

Abstract Disclosure: S. Paknikar: None. J. McHugh: None. K. Rachmasari: None. I. Bancos: None. Introduction: Ectopic secretion of adrenocorticotropic hormone (ACTH) is a rare and severe form of Cushing Syndrome (CS) that requires an urgent specialized approach for diagnosis and management. Clinical Case: A 50-year-old woman was referred to endocrinology due to concern for CS. Over the previous year she had developed progressive weakness, edema, weight gain with abdominal fat redistribution, hypertension, and multiple compression fractures. On exam, she had a profound proximal myopathy, reported 10/10 pain along the spine, and was hypertensive (170/105 mm Hg) with normal other vitals. The patient's sodium was 141mmol/L [reference range 135-145 mmol/ L], potassium 4.1 mmol/L [3.6-5.2 mmol/L] while on spironolactone, and creatinine was 0.57 mg/dL [0.59-1.04 mg/dL]. Due to the severity of her symptoms, she was admitted to the hospital. Hormonal work up was consistent with an ACTH dependent CS: ACTH was 121pg/mL [7.2-63 pg/mL] and 24-hour urine cortisol was 645 mcg/24 hr [3.5-45 mcg/24 hr]. Workup for ACTH secreting tumor included a pituitary MRI which showed a 3 mm area of delayed enhancement in the pituitary gland, felt to be artifactual. A chest computed tomography (CT) showed a 1.3 cm low-density nodule in the right upper lobe concerning for a neuroendocrine tumor. A Gallium-68 DOTATATE Positron emission tomography/CT scan was performed and demonstrated that the nodule was highly DOTATATE avid (Krenning score of 3, scale of 0-4). These findings supported a diagnosis of ectopic CS caused by an ACTH secreting lung neuroendocrine tumor. Management of ectopic CS was twofold: addressing the underlying ACTH secreting lesion and urgent treatment of hypercortisolism and its consequences. In this case, this was achieved with CT-guided cryoablation of the right upper lobe nodule. The ACTH levels were monitored postoperatively, and when decreased (9.3pg/mL [ 7.2-63 pg/mL], glucocorticoid replacement therapy was initiated. As a result of prolonged hypercortisolism, the patient experienced multiple compression fractures and debility. Physical therapy was recommended for recovery from the compression fractures as well as proximal myopathy. Enoxaparin was initiated due to risk of venous thromboembolism from CS. From an osteoporosis standpoint, she was continued on calcium and vitamin-D supplementation and treated with weekly alendronate. Her hypertension improved allowing medication reduction. Postoperatively, she received education on adrenal insufficiency and biochemical monitoring for adrenal insufficiency recovery was implemented. Conclusion: Ectopic ACTH secreting tumors represent a rare cause of CS and effective management requires consideration of medical comorbidities to determine the approach: surgical, cryoablative, or medical therapy alone, mitigation of Cushing syndrome sequelae, and prompt recognition and treatment of glucocorticoid withdrawal. Presentation: Thursday, June 15, 2023

Abstract Disclosure: R. Gregg Garcia: None. I. Bancos: None. Background: Bilateral adrenalectomy (BLA) is a procedure with limited indications, such as bilateral pheochromocytomas and certain cases of Cushing syndrome. Impaired quality of life (QoL) has been reported in patients with primary adrenal insufficiency (PAI) due to autoimmune adrenalitis (AA). We hypothesized that, when compared to AA, patients post-BLA experience worse QoL due to sequelae of Cushing syndrome or pheochromocytoma. Objective: To compare the QoL and burden of disease in patients with PAI due to BLA versus AA. Methods: A cross-sectional study of adults with PAI due to BLA or AA, August 15 - November 26, 2022. Patients were excluded if PAI was diagnosed within one year from the enrollment date or if active malignancy was present. Participants completed a questionnaire about symptoms, burden of disease, adrenal crisis, and QoL (AddiQoL). Results: Of 120 patients with PAI, 49 (41%) had BLA, and 71 (59%) had AA. Median age was 52 years (range 23-80), without subgroup differences, but a higher proportion of women in the post-BLA vs the AA group (86% vs 69%, p=0.04). Reasons for BLA were Cushing syndrome (44, 90%) and bilateral pheochromocytomas (5, 10%). Duration of PAI was higher in patients with AA (median 12 vs 7 years post-BLA, p=0.02). The majority of patients reported wearing a medical bracelet (82%), having injectable glucocorticoid (90%), and comfort injecting (61%), without subgroup differences. Total daily hydrocortisone dose was higher in patients with AA vs patients post-BLA (mean of 23 mg vs 20 mg, p=0.03). A total of 26 (22%) patients reported at least one adrenal crisis within the last year, with a greater proportion in the post-BLA group (33% vs 14% in AA, p=0.02). No subgroup differences were noted in risk factors for adrenal crisis development, such as hydrocortisone equivalent dose, type of glucocorticoid therapy, duration of PAI, having a medic alert bracelet and injectable glucocorticoids, comfort injecting, or physical activity. Compared to AA, patients post-BLA had a similar QoL (median AddiQoL score 86 vs 84, p-value 0.72). Duration of PAI was not associated with QoL. Physical activity ≥3 times/week was associated with a better QoL (median AddiQoL score 90 vs 80 in those with lower level of physical activity, p=0.001); no subgroup differences in physical activity ≥3 times/week were found (57% in BLA vs 62% in AA, p=0.59). Since the initial diagnosis of PAI, more patients with AA reported that PAI was “harder” to manage (23% vs 6% post-BLA, p-value 0.04), with most patients reporting that management was easier (52% in AA and 63% in BLA) or not different (25% in AA and 31% in BLA). Conclusions: Despite a higher prevalence of adrenal crisis, more patients with BLA vs AA found PAI easier to manage. Moreover, patients with BLA and AA had a similar level of comfort and education managing PAI, similar QoL, and engaged in similar levels of physical activity, despite history of Cushing syndrome. Presentation: Saturday, June 17, 2023

AbstractBackgroundIsavuconazole (ISA) is a newer antifungal used in patients with history of hematologic malignancies and hematopoietic transplant and cellular therapies (HM/TCT). Although it has a more favorable side‐effect profile, breakthrough invasive fungal infections (bIFIs) while on ISA have been reported.MethodsIn this single‐center retrospective study evaluating HM/TCT patients who received prophylactic ISA for ≥7 days, we evaluated the incidence and potential risk factors for bIFIs.ResultsWe evaluated 106 patients who received prophylactic ISA. The patients were predominantly male (60.4%) with median age of 65 (range: 21–91) years. Acute myeloid leukemia (48/106, 45.3%) was the most common HM, with majority having relapsed and/or refractory disease (43/106, 40.6%) or receiving ongoing therapy (38/106, 35.8%).Nineteen patients (17.9%) developed bIFIs–nine proven [Fusarium (3), Candida (2), Mucorales plus Aspergillus (2), Mucorales (1), Colletotrichum (1)], four probable invasive pulmonary Aspergillus, and six possible infections. Twelve patients were neutropenic for a median of 28 (8–253) days prior to bIFI diagnosis. ISA levels checked within 7 days of bIFI diagnosis (median: 3.65 μg/mL) were comparable to industry‐sponsored clinical trials.All‐cause mortality among the bIFI cases was 47.4% (9/19).We also noted clinically significant cytomegalovirus co‐infection in 5.3% (1/19). On univariate analysis, there were no significant differences in baseline comorbidities and potential risk factors between the two groups.ConclusionISA prophylaxis was associated with a significant cumulative incidence of bIFIs. Despite the appealing side‐effect and drug‐interaction profile of ISA, clinicians must be vigilant about the potential risk for bIFIs. image

Abstract Disclosure: R. Tora: None. J. Welch: None. J. Sun: None. S.K. Agarwal: None. D.A. Bell: None. M. Merino: None. L.S. Weinstein: None. W.F. Simonds: None. S. Jha: None. Background: Hyperparathyroidism-Jaw Tumor (HPT-JT) syndrome is a heritable form of primary hyperparathyroidism (PHPT) that is associated with tumors in the parathyroid, jaw, kidney, and uterus. We previously presented on the clinical characteristics of primary hyperparathyroidism in our cohort. Methods: We now expand on the report through review of uterine tumors, immunohistochemical staining for parafibromin, sequencing of parathyroid and kidney tumor tissue, and RNA-seq of parathyroid tumors. Results: We identified 68 patients (36 males, 32 females) from 29 kindreds with HPT-JT with median age at last follow-up of 39 [29-53] years. Of these, 7 patients were unaffected (2 males, 5 females). Among females, 12/32 (38%) developed uterine tumors with multiple adenomyomatous polyps, an unusual form of endometrial polyps seen in 10/24 tumors (42%). Given that these types of lesions are very rare in the general population, it is likely that such epithelial-mesenchymal uterine proliferations are a characteristic feature of HPT-JT syndrome.Solid kidney tumors were seen in 4/61 patients (7%). Three had surgery for the tumors - 2/3 were female and had mixed epithelial stromal tumor, while the third patient, a 6-year old male, had metastatic Wilm’s tumor as his initial disease-related manifestation. Among these, two had a germline CDC73 variant at the p.M1 residue while the third patient had the germline variant p.L95P; however, sequencing of his tumor tissue showed a “second hit” at the p.M1 residue resulting in loss of heterozygosity in the tumor. The fourth patient, a female with p.Y55S variant, is being conservatively managed with no kidney surgery yet. All three women with kidney tumors also had a history of uterine tumors. Parafibromin staining of 19 available CDC73 related parathyroid tumors (13 adenomas and 6 carcinoma) did not correlate with histology or genotype. Pathway analysis of 21 parathyroid tumors (8 HPT-JT-related adenomas, 6 HPT-JT-related carcinomas and 7 sporadic parathyroid carcinoma with wild-type CDC73) showed a significant association of HPT-JT-related parathyroid carcinoma with growth, transmembrane receptor protein tyrosine kinase signaling and mesodermal commitment pathways. Conclusion: Multiple, recurrent atypical adenomyomatous uterine polyps appear to be characteristic of HPT-JT syndrome. Our findings support germline testing at a young age in first-degree relatives of patients with HPT-JT given onset of manifestations as early as 6 years. Variants at M1 residue appear to predispose to genitourinary tumors. At present, there are no therapeutic approaches to compensate for CDC73 inactivation. Future research to identify standards of care and therapeutics targets are warranted for this rare disease. Presentation: Friday, June 16, 2023

Abstract Disclosure: M. Moazzami: Grant Recipient; Self; Rochester Epidemiology Project. S. Achenbach: None. E. Atkinson: None. I. Bancos: None. Background: Epidemiology of adrenal insufficiency (AI) is incompletely characterized with most data originating from referral centers and registries. We aimed to determine the incidence, morbidity index, risk of hospitalizations, and mortality in patients with AI living in Olmsted County, Minnesota. Methods: We assessed the standardized incidence rate, morbidity index, risk of hospitalizations and mortality of AI in residents (aged 18+) in Olmsted County, MN, USA, from Jan 1, 2005, to December 31, 2021. The data was collected using the Rochester Epidemiology Project (REP), a database of medical records for all Olmsted County residents since 1966. Incidence rates were standardized for age and sex according to the 2020 US white population. Sex- and age- matched referent subjects were selected from the REP. AI was defined based on presence of oral chronic glucocorticoid therapy (hydrocortisone, prednisone, prednisolone, or dexamethasone) defined as (1) any hydrocortisone use or (2) 6 months of consecutive use of prednisone, prednisolone, or dexamethasone or (3) two AI diagnosis codes 6+ months apart plus at least one glucocorticoid prescription within 1 year of the second diagnosis. Elixhauser morbidity index was used. Findings: Between 2005 and 2021, 5419 patients were diagnosed with AI (median age of 62 years, range 18-103), 56% women). Overall standardized incidence rates for AI increased from 206 (95% CI 174-238) in 2005 to 252 (223-280) per 100 000 person-years in 2021. At baseline, patients with AI had a higher morbidity index (median 3 vs median 1, p <0.001) and a higher history of hospitalizations within 5 years prior to baseline (57% vs 30%; p<0.001) when compared to referent subjects. When comparing patients with AI to referent subjects, and after adjusting for age, sex, morbidity index and prior history of hospitalizations, patients with AI were more likely to be hospitalized during follow-up (aHR 1.4, 95% CI 1.3-1.5). When comparing patients with AI to referent subjects, and after adjusting age, sex, and morbidity index, patients with AI had higher mortality (aHR 1.7, 95% CI 1.6-1.9). Patients with AI demonstrated a higher risk of dying from musculoskeletal disorders (aHR 4.9, 95% CI 2.2-10.8), respiratory disorders (aHR 4.7, 95% CI 3.3-6.6), neoplasms (aHR 2.4, 95% CI 2.0-2.9), and infectious disorders (aHR 2.3, 95% CI 1.2-4.3) than referent subjects. Interpretation: We demonstrate an increase in AI incidence between 2005 and 2021. Surprisingly, even after controlling for morbidity and prior hospitalizations, patients with AI were more likely to be hospitalized. In comparison to referent subjects, mortality was higher in patients with AI, even after adjustment for morbidity index. Presentation: Friday, June 16, 2023

Abstract Disclosure: B. Clarke: Advisory Board Member; Self; Ascendis Pharma, Takeda, Entera-Bio, Extend-Bio, Amolyt. Consulting Fee; Self; Ascendis Pharma, Takeda, Entera-Bio, Extend-Bio, Amolyt. Grant Recipient; Self; Ascendis Pharma, Takeda. Research Investigator; Self; Ascendis Pharma, Takeda. Other; Self; Ascendis Pharma, Takeda, Entera-Bio, Extend-Bio, Amolyt. A.A. Khan: Advisory Board Member; Self; Amgen Inc, Alexion Pharmaceuticals, Inc., Ascendis Pharma, Takeda, Ultragenyx. Consulting Fee; Self; Amgen Inc, Alexion Pharmaceuticals, Inc., Amolyt, Ascendis Pharma, Ultragenyx. Grant Recipient; Self; Amolyt. Research Investigator; Self; Radius Health, Inc, Takeda, Ultragenyx, Amolyt, Ascendis Pharma, Chugai. Speaker; Self; Amgen Inc. Other; Self; Amgen Inc, Alexion Pharmaceuticals, Inc., Ascendis Pharma, Takeda, Ultragenyx. M.R. Rubin: Research Investigator; Self; Chugai Pharma. P.E. Schwarz: Stock Owner; Self; Novo Nordisk, Genmab. T.J. Vokes: Consulting Fee; Self; Takeda, Ascendis Pharma. Research Investigator; Self; Ascendis Pharma, Radius Health, Inc. D.M. Shoback: Research Investigator; Self; Bone Health Tech. C. Gagnon: Advisory Board Member; Self; Novo Nordisk. Grant Recipient; Self; Shire, Takeda, Ascendis Pharma. Research Investigator; Self; Novo Nordisk. Other; Self; Amgen Inc. A. Palermo: Consulting Fee; Self; Theramex, Bruno, Farmaceutici, Amgen Inc. Grant Recipient; Self; Amgen Inc. Research Investigator; Self; Amgen Inc, Shire, Ascendis Pharma. Speaker; Self; UCB, Amgen Inc. L.G. Abbott: Advisory Board Member; Self; Ascendis. Research Investigator; Self; Takeda, Shire, Ascendis Pharma. Speaker; Self; Abbott Laboratories, Clarus. Other; Self; Ascendis. L.C. Hofbauer: Advisory Board Member; Self; Amgen Inc, UCB. Other; Self; Amgen Inc, UCB. L. Kohlmeier: Advisory Board Member; Self; Alexion Pharmaceuticals, Inc., Ascendis Pharma. Research Investigator; Self; Ascendis Pharma. Speaker; Self; Amgen Inc, Radius Health, Inc, Alexion Pharmaceuticals, Inc., Ascendis Pharma. Other; Self; Amgen Inc, Radius Health, Inc, Alexion Pharmaceuticals, Inc., Ascendis Pharma, MediMaps. F. Cetani: None. S. Phil: Employee; Self; Ascendis Pharma. X. An: Employee; Self; Ascendis Pharma. A.R. Smith: Employee; Self; Ascendis Pharma. B. Lai: Employee; Self; Ascendis Pharma. J. Le: Employee; Self; Ascendis Pharma. J. Ukena: Employee; Self; Ascendis Pharma. C. Sibley: Employee; Self; Ascendis Pharma. A. Shu: Employee; Self; Ascendis Pharma. L. Rejnmark: Advisory Board Member; Self; Takeda, Amolyt. Research Investigator; Self; Takeda, Kyowa Kirin International, Ascendis Pharma, Calcilytix Therapeutics. Other; Self; Calcilytix Therapeutics. Objective: Evaluate the long-term efficacy and safety of TransCon PTH as a potential hormone replacement therapy for hypoparathyroidism. Methods: PaTHway is a phase 3 trial of TransCon PTH with a placebo (PBO)-controlled 26-week blinded period and a 156-week open-label extension (OLE) period. Results through Week 52 (26 weeks blinded + 26 weeks OLE) are reported. Three-component efficacy endpoint: normal serum calcium (8.3-10.6 mg/dL) and independence from conventional therapy (≤600 mg/day of elemental calcium and no active vitamin D). Other endpoints: Hypoparathyroidism Patient Experience Scale (HPES); 36-Item Short Form Survey (SF-36); bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA); bone turnover markers (BTM) procollagen type 1 N-terminal propeptide (P1NP) and C-terminal telopeptide of type 1 collagen (CTx). Safety was assessed by 24-hour urine calcium and reported treatment-emergent adverse events (TEAEs). Results: Of the 82 participants given study drug, 79 completed blinded treatment and entered the OLE, and 78 (59 TransCon PTH/TransCon PTH, 19 PBO/TransCon PTH) completed Week 52. Overall at Week 52, 81% (63/78) met the efficacy endpoint, 95% (74/78) achieved independence from conventional therapy, and none required active vitamin D. Mean albumin-adjusted serum calcium was within the normal range at all time points in the OLE (8.9 mg/dL at Week 52). Mean Week 52 HPES scores showed sustained improvement from baseline in disease-related symptoms and the impact of hypoparathyroidism on physical functioning and daily life. Mean Week 52 SF-36 physical functioning scores also remained above baseline. In the TransCon PTH/TransCon PTH group, mean BMD corrected Z-scores trended toward norms from baseline to Weeks 26 and 52:1.5, 0.7, 0.7 at the lumbar spine (L1-L4); 0.8, 0.3, 0.3 at femoral neck; 0.9, 0.5, 0.4 at total hip; and 0.3, 0.3, 0.3 at distal 1/3 radius; P1NP peaked at Week 26 and CTx at Week 12. Smaller incremental changes were seen in BMD and BTM from Weeks 26 to 52 than baseline to Week 26. In the PBO/TransCon PTH group, changes in BMD and BTM from Week 26 to 52 resembled those in the TransCon PTH/TransCon PTH group from baseline to Week 26. Mean 24-hour urine calcium excretion decreased from 376 mg/day at baseline to 195 mg/day at Week 52. Most TEAEs were mild or moderate and none led to discontinuation of the study drug or trial. Conclusions: At Week 52 of the PaTHway trial, TransCon PTH showed a similar sustained efficacy, safety, and tolerability profile to that of Week 26, demonstrating its potential as a hormone replacement therapy for adults with hypoparathyroidism. Indices of skeletal dynamics trended toward age- and sex-matched norms in the TransCon/TransCon PTH group. TransCon PTH treatment in the PBO/TransCon PTH group showed rapid improvement in all outcomes in the first 26 weeks of the OLE consistent with the pattern in the TransCon PTH group during the blinded period. Presentation: Saturday, June 17, 2023

Abstract Disclosure: K.M. Dahir: Consulting Fee; Self; Alexion Pharmaceuticals, Inc., Ultragenyx, Inozyme, AM Pharma. Grant Recipient; Self; Regeneron Pharmaceuticals, Alexion Pharmaceuticals, Inc., AstraZeneca, Ultragenyx. J. McGinniss: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. E. Forleo-Neto: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. S. Mellis: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. R.J. Sanchez: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. M. Di Rocco: Research Investigator; Self; Regeneron Pharmaceuticals, Ipsen. R. Keen: Advisory Board Member; Self; International Clinical Council on FOP and IFOPA Registry. Research Investigator; Self; Ipsen, Regeneron Pharmaceuticals, Clementia. P. Orcel: Research Investigator; Self; Regeneron Pharmaceuticals. C. Roux: Consulting Fee; Self; Alexion Pharmaceuticals, Inc., Amgen Inc. Grant Recipient; Self; Regeneron Pharmaceuticals, Kyowa, Kirin Brewery, Alexion Pharmaceuticals, Inc. J. Tabarkiewicz: Speaker; Self; Merck, Novartis Pharmaceuticals. Other; Self; SoftSystem. J. Bachiller-Corral: Research Investigator; Self; Regeneron Pharmaceuticals. A.M. Cheung: Consulting Fee; Self; Ipsen. Grant Recipient; Self; Ipsen, Incyte, Regeneron Pharmaceuticals. M. Al Mukaddam: Grant Recipient; Self; Ipsen, Clementia, Incyte, Regeneron Pharmaceuticals. K. Mohammadi: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. D. Srinivasan: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. A. Rankin: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. A.N. Economides: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. D. Gonzalez Trotter: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. F.S. Kaplan: Research Investigator; Self; Regeneron Pharmaceuticals, Clementia, Ipsen. M.W. Eekhoff: Grant Recipient; Self; Regeneron Pharmaceuticals, Ipsen, AstraZeneca, IMI, IFOPA. R.J. Pignolo: Grant Recipient; Self; Regeneron Pharmaceuticals, Clementia, Ipsen, Incyte. Background: Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare autosomal dominant disorder driven by missense mutations in ACVR1. This results in inappropriate activation by activin-A. FOP is characterized by progressive heterotopic ossification and painful soft tissue inflammatory events known as flare-ups. Garetosmab, an investigational, fully human monoclonal antibody against activin-A, prevents formation of new heterotopic ossification lesions in FOP. Here we describe the impact of garetosmab on flare-up events in the LUMINA-1 study (NCT03188666). Methods: This was a post hoc analysis of phase 2 LUMINA-1, a randomized double-blind placebo-controlled study that evaluated the safety and efficacy of garetosmab 10 mg/kg/every 4 weeks intravenous vs placebo in adult patients with FOP over 28 weeks (Period 1), followed by a 28-week open-label treatment period (Period 2) and subsequent open-label extension (Period 3). Patient-reported flare-ups were collected via a patient diary and severity of symptoms was reported as mild, moderate, or severe. Clinician-reported flare-ups were collected as adverse events. Results: In Period 1, there was a significant reduction in the proportion of patients reporting one or more flare-ups (35% vs 71%, p=0.032) and clinician-reported flare-ups (10% vs 42%, p=0.039) with garetosmab vs placebo, respectively. The overall number of patient-reported flare-ups (13 vs 34) and mean days experiencing new flare-ups (42.6 days vs 65.4 days) were also reduced with garetosmab vs placebo, respectively. Most flare-ups occurred in the back in garetosmab-treated patients, and most flare-ups occurred in the lower extremities and back for those on placebo. Pain was the most frequent symptom among both cohorts. Flare-up associated joint stiffness and severity of flare-up associated symptoms were nominally reduced at both patient and flare-up level of assessment in those treated with garetosmab. No patients reported severe swelling or severe decrease in movement. One patient reported severe pain and joint stiffness in the garetosmab cohort. In Period 2, there were significant reductions in the proportion of patients experiencing flare-ups (68% vs 14%, p=0.0002) and number of patient-reported flares (31 vs 11) among those who crossed over from placebo in Period 1 to garetosmab. Patients who continued on garetosmab through Period 2 maintained a sustained reduction in number of flare-ups (12 vs 6) and proportion of patients experiencing flare-ups (33.3% vs 22.2%). Reductions were maintained through the open-label extension. Conclusions: Patients treated with garetosmab experienced significant and sustained reductions in the frequency, duration, and severity of flare-ups. The ability of garetosmab to reduce flare-up events may provide a clinically meaningful benefit for patients with FOP. Presentation: Sunday, June 18, 2023

Abstract Disclosure: J. Arguinchona: None. A. Mahajan: None. A. Gonzalez-Estrada: None. E. De Filippis: None. Introduction: Patients with newly diagnosed Graves’ disease often choose treatment with methimazole (MMI) over traditional ablation therapies. However, MMI can result in adverse reactions including skin rash, pruritus, and urticaria. We present a case of Graves’ thyrotoxicosis with a type IV hypersensitivity reaction while on MMI. The patient was successfully treated with a novel, individualized, 27-day desensitization protocol which resulted in tolerance of MMI with subsequent improvement in thyroid indices. Clinical Case: A 42-year-old female presented for abnormal thyroid studies with associated insomnia, heat intolerance, palpitations, resting tremor, and weight loss. Lab work revealed a thyroid-stimulating hormone <0.005 (0.450-4.500 μIU/mL), free thyroxine 3.28 (0.82-1.77 ng/dL), triiodothyronine 310 (71-180 ng/dL), thyroid peroxidase antibody (Ab) 62 (0-34 IU/mL), thyroid-stimulating immunoglobulin 0.67 (0.00 -0.55 IU/L), and thyrotropin receptor Ab of 6.00 (0.00-1.75 IU/L). She was started on MMI, 10 mg daily for Graves’ disease. Three weeks later, T3 and T4 remained elevated prompting an increase in MMI dose to 10 mg twice daily. Two weeks later, she developed a diffuse, pruritic maculopapular exanthema over her trunk, neck, and extremities. Methimazole was discontinued while prednisone was initiated that subsided her rash. Unfortunately, the patient’s symptoms recurred upon repeat MMI exposure. The patient declined propylthiouracil due to concerns of hepatotoxicity and elected to avoid ablation therapy with iodine or surgery. With the assistance of an allergist, a novel, 10-step, 27-day desensitization protocol was developed specifically for her reaction to MMI with plans to taper prednisone once desensitization was completed. The patient underwent desensitization with development of mild lower extremity exanthema that was successfully treated with high dose antihistamines. Three months later, she was tolerating MMI at 15 mg daily without further adverse reactions and tapered off prednisone. While on MMI, her immune titers normalized with euthyroid clinical and biochemical restoration. Conclusion: Many patients and clinicians initially prefer medical management over definitive ablation therapies in the treatment of Graves’ disease. This case demonstrates with the assistance of an allergist, desensitization to MMI is a viable option in the setting of a known hypersensitivity reaction when it is the first line treatment and no equally efficacious alternatives exist. In addition, patient’s preferences should also be considered during medical decision making. Previous literature has offered various rapid desensitization protocols for MMI for immediate type hypersensitivity reactions. However, in non-immediate, type IV hypersensitivity reactions, a slower desensitization protocol can be considered, as demonstrated in this case. Presentation: Thursday, June 15, 2023

Abstract Disclosure: J.P. Frias: Advisory Board Member; Self; Corcept Therapeutics. Consulting Fee; Self; Corcept Therapeutics. Other; Self; Corcept Therapeutics. R.J. Auchus: Consulting Fee; Self; Corcept Therapeutics. Grant Recipient; Self; Corcept Therapeutics. Speaker; Self; Corcept Therapeutics. Other; Self; Corcept Therapeutics. I. Bancos: None. L. Blonde: Advisory Board Member; Self; Corcept Therapeutics. Other; Self; Corcept Therapeutics. R.S. Busch: Consulting Fee; Self; Corcept Therapeutics. Speaker; Self; Bayer, Inc., Novo Nordisk, Amgen Inc, Eli Lilly & Company, AstraZeneca. J.B. Buse: Advisory Board Member; Self; AstraZeneca, Bayer, Inc., Boehringer Ingelheim, Eli Lilly & Company, Jansen Pharmaceuticals, Mannkind Corporation, Sanofi, Alkahest, Altimmune, Anji, Biomea Fusion Inc, CeQur, Cirius Therapeutics Inc, GentiBio, Glycadia, Glyscend, Mellitus Health, Moderna, Pendulum Therapeutics, Praetego, Stability Health, Valo, Zealand Pharma. Consulting Fee; Self; AstraZeneca, Bayer, Inc., Boehringer Ingelheim, Eli Lilly & Company, Janssen, Mannkind Corporation, Sanofi, Alkahest, Altimmune, Anji, Biomea Fusion Inc, CeQur, Cirius Therapeutics Inc, Dasman Diabetes Center (Kuwait), Fortress Biotech, GentiBio, Glycadia, Glyscend, Mediflix, Medscape, Mellitus Health, Moderna, Pendulum Therapeutics, Praetego, ReachMD, Stability Health, Valo, Zealand Pharma. Grant Recipient; Self; Novo Nordisk, Sanofi, VTV Therapeutics, Nanotype, NIH, NovaTarg, Tolerion, Dexcom. Stock Owner; Self; Glyscend, Mellitus Health, Pendulum Therapeutics, PhaseBio, Praetego, Stability Health. Other; Self; AstraZeneca, Boehringer Ingelheim, Eli Lilly & Company, Novo Nordisk, Dasman Diabetes Institute, Zealand, Association for Clinical and Translational Science. R.A. DeFronzo: None. J.W. Findling: Advisory Board Member; Self; Corcept Therapeutics. Consulting Fee; Self; Corcept Therapeutics. V. Fonseca: Advisory Board Member; Self; Corcept Therapeutics. Consulting Fee; Self; Corcept Therapeutics. O. Hamidi: Advisory Board Member; Self; Corcept Therapeutics, Lantheus, Recordati Rare Diseases, Neurocrine Biosciences, Amryt, Novo Nordisk, Strongbridge. Consulting Fee; Self; Corcept Therapeutics. Y. Handelsman: Consulting Fee; Self; Amgen Inc, Applied Therapeutic, AstraZeneca, Bayer, Inc., Boehringer Ingelheim, Corcept Therapeutics, Esperion, Mannkind Corporation, Merck, Pfizer, Inc., Novartis Pharmaceuticals, Novo Nordisk, Sanofi, Vertis. Grant Recipient; Self; Amgen Inc, Applied Therapeutic, Ionis Pharmaceuticals Inc., Regor. Speaker; Self; AstraZeneca, Bayer, Inc., Esperion, Novo Nordisk, Vertis, Amarin. R.E. Pratley: Consulting Fee; Self; Bayer, Inc., Corcept Therapeutics, Gasherbrum Bio, Inc, Hanmi, Hengrui (USA) Ltd, Merck, Novo Nordisk, Pfizer, Inc., Rivus Pharmaceuticals Inc, Sun Pharmaceutical Industries, Sanofi, Scohia Pharma Inc, Dexcom. Grant Recipient; Self; Hanmi, Metavention, Novo Nordisk, Poxel SA. Speaker; Self; Novo Nordisk. J. Rosenstock: Advisory Board Member; Self; Applied Therapeutics, Boehringer Ingelheim, Eli Lilly & Company, Hanmi, Novo Nordisk, Oramed, Sanofi, Structure Therapeutics, Zealand. Consulting Fee; Self; Applied Therapeutics, Boehringer Ingelheim, Eli Lilly & Company, Hanmi, Novo Nordisk, Oramed, Sanofi, Structure Therapeutics, Zealand. Grant Recipient; Self; Applied Therapeutics, AstraZeneca, Boehringer Ingelheim, Eli Lilly & Company, Hanmi, Merck, Oramed, Novartis Pharmaceuticals, Novo Nordisk, Pfizer, Inc., Sanofi. I. Tudor: Employee; Self; Corcept Therapeutics. Stock Owner; Self; Corcept Therapeutics. A.G. Moraitis: Employee; Self; Corcept Therapeutics. D. Einhorn: Employee; Self; Corcept Therapeutics. Studies suggest that the prevalence of hypercortisolism in persons with difficult-to-control type 2 diabetes (T2D) is higher than is currently appreciated. A recently published meta-analysis suggests that the prevalence of hypercortisolism is higher in persons with T2D who require a greater number of antihyperglycemic agents and/or who have more comorbidities. To better understand the prevalence and whether treatment of hypercortisolism may result in better control of diabetes and other hypercortisolism-associated comorbidities, we describe a 2-part phase 4 study in adults with difficult-to-control T2D (HbA1c 7.5-11.5%) despite receiving multiple antihyperglycemic agents. The study will be conducted at approximately 30 sites in the United States. In Part 1, approximately 1000 persons with difficult-to-control T2D will be screened with a 1-mg dexamethasone suppression test. Those responding with serum cortisol >1.8 µg/dL (50 nmol/L) and dexamethasone levels ≥140 ng/dL (3.6 nmol/L) will have adrenocorticotropic hormone (ACTH), dehydroepiandrosterone sulfate, and cortisol measured in fasting blood samples obtained between 7-9 AM and a non-contrast adrenal computed tomography scan. Patients who may have ACTH-dependent hypercortisolism will be discontinued from the study and referred for further evaluation. The primary study endpoint is determining the prevalence of ACTH-independent hypercortisolism and will be evaluated in Part 1. Patients identified to have ACTH-independent hypercortisolism will advance to Part 2, a prospective, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of treatment with the glucocorticoid receptor antagonist mifepristone. Patients will be randomized 2:1 to mifepristone or placebo, stratified by the presence or absence of adrenal adenomas on CT, and receive treatment for 24 weeks. The mifepristone dose will be 300 mg once daily for 4 weeks, then increased to 600 mg daily for 20 weeks based on clinical assessment of tolerability and degree of improvement. There will be an option to increase to mifepristone 900 mg. Placebo will be titrated accordingly from 1 up to 3 tablets. Part 2 will assess the secondary endpoint of change in HbA1c from baseline to 24 weeks, as well as changes in hypercortisolism-related comorbidities (e.g., blood pressure, weight, waist circumference, quality of life). This will be the first prospective study to assess the prevalence of ACTH-independent hypercortisolism in persons with difficult-to-control T2D and the first prospective, randomized, placebo-controlled trial to assess the potential benefits and safety of treatment with mifepristone in this patient population. Presentation: Friday, June 16, 2023

Abstract Disclosure: M. Salama: None. P.J. Tebben: None. Introduction: Hypophosphatasia (HPP) is characterized by defective bone mineralization due to reduced function of tissue non-specific alkaline phosphatase (TNSALP) from pathogenic ALPL gene variants. Initial presentation varies according to the clinical phenotype. Hypercalcemia is more common in the perinatal and infantile forms and may be mitigated or prevented with enzyme replacement therapy asfotase alfa (AA). Here, we report a patient who developed severe hypercalcemia while receiving AA and describe our management strategy. Case: A now three-year-old girl with perinatal hypophosphatasia presented with severe hypercalcemia at 9 months of age. Her prenatal ultrasound was suggestive of a skeletal dysplasia. She was diagnosed with HPP shortly after birth and initiated AA on day two of life. She had normal calcium of 10.5 mg/dl at diagnosis. Phosphorus 9.3 mg/dl, total alkaline phosphatase <5 U/L, pyridoxal 5-phosphata (PLP) 974 mcg/L and phosphoethanolamine (PEA) 1084 nmoL/mg. Calcium dropped to 6.8 mg/dL after starting AA for which calcium supplementation was transiently utilized. At nine months of age, she developed severe hypercalcemia (15.8 mg/dl). Her phosphorus was 5.5 mg/dl, PLP 14 mcg/l and 25 hydroxyvitamin D 28 ng/ml. Parathyroid hormone and calcitriol were appropriately suppressed at <6.0 pg/ml and <8.0 pg/mL respectively. She was receiving 2 mg/kg of Asfotase three times weekly. Initial management included intravenous fluids and a reduction in dietary calcium intake by 50%. Within 2 days, calcium came down to upper normal for age at 11 mg/dL. AA dose was increased to 3 mg/kg three times weekly due to hypercalcemia and mildly worsening radiographs. Hypercalcemia recurred and initially responded to IV fluids and further dietary calcium reduction (low calcium formula (2.9 mg/ 5 fl oz)). Despite these measures, she required a third hospital admission when calcitonin 4 IU/kg every 12 hours was added to her restricted dietary calcium intake and AA therapy. On this regimen, her calcium normalized without recurrence of severe hypercalcemia. Over the subsequent eight months, calcium intake was slowly increased, and calcitonin tapered and discontinued with maintenance of calcium within the normal range. Conclusion: Hypercalcemia is common in infants with untreated, severe HPP and is likely mitigated for most when treated with AA. This case highlights the importance of monitoring calcium concentrations and intake in infants with HPP. Although calcitonin is generally not considered a long-term therapy for hypercalcemia, bisphosphonates may worsen the bone disease of HPP and should be avoided. This case demonstrates the utility of calcitonin therapy added to low calcium intake and maximal AA dosing to treat severe, persistent hypercalcemia in an infant with perinatal HPP. Presentation: Thursday, June 15, 2023