United States

Immune checkpoint inhibitors (ICI) have revolutionized cancer therapy, however, are associated with immune-related adverse events (irAEs). Thyroid dysfunction is among the most common irAEs, yet its mechanism has not been fully elucidated. To further explore the molecular mechanism of ICI-induced thyroid dysfunction, we profiled changes in transcription induced by PD-1/PD-L1 antibody treatment in a non-small cell lung cancer murine model using RNA-seq. We used bioinformatic tools to compare transcriptional changes in our model to previously published transcription data sets of drug-induced thyroiditis. C57BL6/129SvJ mice harboring LKR-M (Lung cancer K-ras metastatic tumor) flank tumors were treated with PD-1 antibody, PD-L1 antibody, or vehicle every 3 days over a period of 7 days when mice were sacrificed, and thyroid glands were removed. The tumor volume increased in the control mice (1.38 ± 0.19) and decreased in the anti PD-1 treated (0.64 ± 0.15; P=0.0001) and PD-L1 treated mice (0.74 ± 0.11; P=0.004). RNA-seq was performed in the LKR-M tumor-bearing control mice and in the anti PD-1/PD-L1 treated mice (n=4 per group). A total of 952 differentially expressed genes (DEGs), including 265 upregulated and 688 downregulated, were identified with anti PD-1 treatment (fold-change ≥1.8, FDR ≤0.05). Only 35 genes were differentially expressed with anti PD-L1 treatment, and we therefore chose to focus on the anti PD-1 treated group alone. Using Ingenuity Pathway Analysis (IPA), we determined that of the DEGs in the PD-1 treatment group, 362 were associated with functions of cell death and survival, with a predicated activation of pathways for apoptosis and necrosis (Z=2.89 and 3.21, respectively) and negative activation of pathways for cell viability and cell survival (Z=-6.22 and -6.45, respectively). When compared to previously published datasets of interleukin-1β and interferon gamma-treated human thyroid cells, the apoptosis pathways were similarly activated. To our knowledge this is the first study to evaluate transcriptomic changes in thyroid tissue following ICI therapy. Our data suggest that there are unique changes in gene expression in the thyroid associated with anti PD-1 therapy. ICI-induced thyroid dysfunction may be mediated by increased tissue apoptosis resulting in destructive thyroiditis.

ENDO 2022

RNA Sequencing Reveals Unique Transcriptomic Signatures of the Thyroid in a Murine Lung Cancer Model Treated with PD-1 and PD-L1 Antibodies

**Program**
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This year’s education program features:
more than 100 in-person and virtual sessions with another 70+ in-person only sessions;
six plenary sessions including plenaries on Envisioning Future Therapies for Type 1 Diabetes and Addressing Challenges in Fertility and Reproduction;
over 20 Meet the Professor sessions presented both in-person and live-streamed virtually and another 20+ presented live in Atlanta;
four Basic Science Pathways, including Diabetes and Metabolism; Neuroendocrinology; Nuclear Receptors and Signaling; and Reproductive Endocrinology; and
more than 30 oral sessions and a robust virtual poster hall for accepted scientific abstracts.

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Product theaters and the Communications and Career Center will also include hybrid content delivery.

**Plenaries**
Spanning the spectrum of science, clinical care, and social implications, an outstanding slate of world-renowned speakers will showcase the most cutting-edge advances on research and medicine.

**Symposia**
Our ENDO 2022 lineup of sessions offers a unique opportunity to dive into topics from nearly every major therapeutic area of endocrinology and hormone science. Listen, learn, and be inspired by world-class faculty who are at the forefront of scientific discovery and high-quality health care.

**Basic Science Pathways**

These special “meeting-within-a-meeting” tracks integrate focused discussions, poster sessions, and networking opportunities to provide you with the latest research in:
Diabetes and Metabolism
Neuroendocrinology
Nuclear Receptors and Signaling
Reproductive Endocrinology

**Meet the Professor & Meet the Scientist**
Discover insights from experts on treating a variety of endocrine conditions and emerging science in the field of endocrinology, and learn the latest in patient care and scientific research.

ENDO’s comprehensive program provides attendees the opportunity to learn about the latest developments in hormone science and medicine from renowned investigators, expert clinicians, and educators from all over the world. 

technical paper

Background. Destructive thyroiditis is the most common endocrine immune related adverse event (iRAEs) in patients treated with anti-PD1/PD-L1 agents. Given its self-limited course, current guidelines recommend no treatment for this iRAE. Nevertheless in patients with enlarged thyroid volume and a poor performance status, thyrotoxicosis may be particularly severe and harmful. Aim of the study is to evaluate if steroid treatment might be useful in improving thyrotoxicosis in subjects with a poor performance status.
Methods. We conducted a case-control study, comparing the course of thyrotoxicosis of 4 patients treated with oral prednisone at the dosage of 25 mg/d (tapered to discontinuation in three weeks) and an enlarged thyroid volume to that of 8 patients with similar thyroid volume who were left untreated.
Results. No difference was found between the two groups at the onset of thyrotoxicosis (time 0) in demographic characteristics and in the levels of thyroid hormones. The levels of thyroid hormones were lower in subjects treated with prednisone compared to those untreated at time 7, 14, 21, 28, 35, 42, 60 and 90 days (P<0.05 at each time). The median time to remission of thyrotoxicosis was 24 days in patients treated with steroids and 92 days in untreated patients (P<0.001). At 6 months, the rate of evolution to hypothyroidism was similar in the 2 groups (4/4 in steroid group vs 7/8 in untreated group, P=0.74) and no difference was found in tumor progression (Progression free survival in treated group 5.1 months vs 5.0 months in untreated patients, P=0.89).
Conclusion. A short period of prednisone therapy is useful to restore more quickly euthyroidism in patients with a poor performance status and a severe destructive thyrotoxicosis induced by PD-1 blockade. This treatment does not impair the efficacy of immunotherapy.

Steroid treatment in the management of destructive thyrotoxicosis induced by PD1 blockade

In vertebrates, thyroglobulin (Tg) is secreted into the lumen of thyroid follicles to enable its iodination for the synthesis of thyroid hormone — defective Tg secretion causes hypothyroidism. A defining step in Tg secretion is export from the endoplasmic reticulum (ER), but Tg structural features needed to meet ER quality control requirements remain poorly defined. Tg primary structure is composed of Regions I, II, III, and ChEL, each engaged in intradomain disuflide bonding. Two major surprises that have recently emerged from the visualization of bovine Tg 3D-structure by cryoEM include the first identified long-range disulfide bond (C408-C608), which appears to tether a boundary separating two halves of region I, as well as the apparent absence of an evolutionarily conserved disulfide bond between C2444 and C2455 in the ChEL domain, which is known to support folding stability of region I. To understand the cell biological importance of these findings, we employed site-directed mutagenesis to determine the impact of these structural features in protein export of recombinant Tg expressed in cultured cells.

To our surprise, we found that mutation of either a single Cys residue or both cysteines that contribute to the C408-C608 disulfide bridge had no discernible impact on the efficiency of Tg export. These data strongly suggest that the proximity of the two-halves of region I in the final Tg structure may be achieved by protein folding of individual repeating units of region I that must take place independently of (and thus presumably prior to) the formation of this interesting long-range disulfide bond.

As ChEL supports Tg region I folding stability, we turned attention to the apparent absence of the C-2444-C2455 disulfide, which is one of the three disulfide bonds that had been thought to exist in every member of the large Cholinesterase-Like gene superfamily. Reported detection of this disulfide within human Tg, but lack of detection in bovine Tg, means either that this bond is 'structurally optional', or that this surface disulfide bond might have been broken by radiolysis under the X-ray beam used for cryoEM. Unequivocally, we found that mutagenesis of either C2444, C2455, or both, blocks Tg secretion and causes a pattern of intracellular misfolding consistent with incomplete Tg compaction indicative of lack of maturation of region I. Moreover, we found that disruption of these same residues causes misfolding and blocks secretion of an expressed isolated secretory ChEL domain, or acetylcholinesterase itself.

Loss of the C2444-C2455 disulfide bridge behaves similarly to the defective folding observed in the mutant Tg encoded within cog/cog mice and rdw/rdw rats, whereas no pathogenic mutations have been reported affecting the long-range disulfide in Tg region I. Together, these results highlight the importance of ChEL domain structure in the maturation and secretion of Tg.

Thyroglobulin Structural Requirements in Protein Trafficking for Thyroid Hormonogenesis

Background More than 50% of adrenocortical carcinomas (ACC) in adults are associated with cortisol excess that makes tumor management challenging and has a negative impact on patient outcome. Abiraterone acetate (AA) is an irreversible inhibitor of the 17α-hydroxylase/C17, 20-lyase (CYP17 enzyme) that is used in patients with prostate cancer, in whom it leads to suppression of cortisol and androgens. Thus, the drug is potentially useful in the medical treatment of steroid-secreting tumors. The aim of this study was to assess the activity of AA to control cortisol excess in patients with advanced ACC and overt Cushing syndrome.
Methods We designed the phase II trial ABACUS (NCT 03145285) whose primary endpoint was normalization of 24-h urinary free cortisol (UFC) excretion within 1 month from treatment start. Inclusion criteria were histologically proven ACC, locally advanced or metastatic disease, and Cushing syndrome confirmed by two 24-h UFC >1.5 times the upper normal limit with suppressed ACTH. No concomitant treatment with mitotane or chemotherapy was allowed for the first 4 weeks of the study. AA was given orally at the daily dose of 1000 mg.
Results From 2017 to 2019, we included 17 patients with ACC (2 stage III, 15 stage IV), 13 women (76%), median age 51 years (18-76), of whom 8 have been heavily pretreated and 9 were treatment naïve.  In 8 patients, multiple steroid secretion was found. Patients were treated with AA for a median of 17 days (7-163). Median 24-h UFC (measured by gas-mass spectrometry) was 368 μg/24h (121-7422) at baseline and 94 μg/24h (20-1793) at end of treatment (p=0.01). Normalization of 24-h UFC was attained in 8 patients (53%) and a >50% decrement in 11 patients (73%). The median time to effect was 21 days and median 24-h UFC reduction 81.8% (-97.7 - +25.9). Androgen and precursor steroids were also significantly reduced by AA treatment. The median Cushing Syndrome Score was 5.0 (2 - 8) at baseline and 3.5 (1 - 6) at the end of treatment, thus confirming clinical improvement. Blood pressure was significantly reduced and hypokalemia was not observed. In 2 patients, treatment was discontinued for toxicity. Seven patients died of ACC progression during follow-up with an overall survival of 5.4 months (0.5-39.3).
Conclusions AA was able to control rapidly cortisol excess in most patients with a good safety profile. The results of this proof-of-concept study show that AA looks promising and may be viewed as an additional weapon to manage Cushing syndrome in patients with ACC. These findings pose the basis for power calculation and implementation of a prospective long-term study to establish AA efficacy in patients with a steroid-secreting ACC.

Activity of Abiraterone Acetate in the management of Cushing syndrome associated to advanced adrenocortical carcinoma: results of the ABACUS trial.

CRN04894 is a potent orally bioavailable MC2R (adrenal cortex specific ACTH receptor) antagonist (Kb=0.34 nM) that is >1000-fold selective for MC2R over other melanocortin receptor subtypes. In rats receiving continuous administration of ACTH via subcutaneously implanted osmotic pumps, oral administration of CRN04894 over 7 days has previously been shown to result in dose-dependent suppression of basal and ACTH stimulated corticosterone levels. This compound is in clinical development for the treatment of diseases of ACTH excess including congenital adrenal hyperplasia (CAH) and Cushing's Disease.
We report initial results from a randomized double-blinded, placebo-controlled single ascending dose study evaluating the safety, pharmacokinetics and pharmacodynamics of CRN04894 in 39 healthy volunteers. After an overnight fast, single doses of CRN04894 were administered at approximately 8 am, 2 hours prior to an IV bolus of ACTH 1-24 (cosyntropin). Serial cortisol over 600 minutes and pharmacokinetics over 168 hours post CRN04894 dose were measured. Two different challenge doses of ACTH 1-24 were studied: 250 μg (supra-pharmacological) and 1 μg (comparable to ACTH concentrations encountered in CAH and Cushing's Disease).
CRN04894 was rapidly orally absorbed (median tmax 0.5-1.5 hour), and demonstrated a dose dependent increase in systemic exposure, with an apparent terminal elimination t1/2 of approximately 20 hours.
Unstimulated (basal) cortisol measured 2 hours after CRN04894 administration fell in a dose-dependent manner, resulting in reduction near the theoretical maximum with the 80 mg dose cohort (‑56.1% [SEM 4.0%, n=12] vs +17.4% in placebo [SEM=18.1%, n=9]). Dose-dependent cortisol suppression following a supra-pharmacological ACTH-stimulated (250 μg) was also observed, with a 41% reduction in the area under the curve (AUC60-600min) post-stimulation at the 80 mg dose. Furthermore, a single dose of 80 mg of CRN04894 reduced the cortisol response (AUC15-120 min) to a disease relevant 1 μg ACTH challenge by 48%, maintaining cortisol concentrations within the normal range seen prior to dosing in a basal unstimulated state. Single doses of CRN04894 were well tolerated with no need for glucocorticoid supplementation. All adverse events (AEs) were considered mild or moderate and there were no serious AEs.
The data from this single-dose, proof-of-concept study show that MC2R antagonist CRN04894 was well tolerated after oral delivery in healthy volunteers and demonstrated dose-dependent increases in exposure with lowering of basal and ACTH-stimulated cortisol secretion, including in the presence of disease relevant excess ACTH exposure. Multiple ascending dose evaluations are underway in anticipation of studies in patients with diseases of ACTH excess.

Inhibition of Basal and ACTH-stimulated Cortisol Secretion in Humans Using an Oral Nonpeptide ACTH Antagonist (CRN04894)

Objective: Primary Bilateral Macronodular Adrenal Hyperplasia (PBMAH) is a heterogeneous disease characterized by adrenal macronodules and variable levels of cortisol excess, with not clearly established clinical diagnostic criteria. PBMAH can be caused by germline inactivating variants of the tumor suppressor gene ARMC5. We aimed to better characterize ARMC5-mutated and wild-type patients and to identify predictive criteria for ARMC5 variants.
Methods: We included 352 consecutive index patients from 12 European centers, sequenced for germline ARMC5alteration because of PBMAH suspicion, regardless their clinical presentation. Clinical, biological and imaging data were collected retrospectively. Sensitivity, specificity, negative and positive predictive values for the prediction of ARMC5variant were calculated for various parameters.
Results: 53 patients (15.1%) carried 40 different ARMC5 germline pathogenic variants and showed a more distinct phenotype than non-mutated patients for cortisol excess (24-hour urinary free cortisol 2.32 vs. 1.11-fold ULN, respectively, p<0.001; plasma cortisol after 1 mg dexamethasone suppression test 337.5 vs. 142.4 nmol/L, respectively, p<0.001) and adrenal morphology (maximal adrenal diameter 104 vs. 83 mm, respectively, p<0.001; 9.8 vs. 3.2 adrenal nodules, respectively, p<0.001), with more frequent metabolic complications such as diabetes (51.0 vs. 35.4%, respectively, p=0.038) and hypertension (88.0 vs. 70.6%, respectively, p=0.014). Thus, ARMC5-mutated patients were more often surgically or medically treated in order to control cortisol excess (67.9 vs. 36.8%, respectively, p<0.001). Among operated patients, a bilateral adrenalectomy was more often performed in those carrying an ARMC5 pathogenic variant than in wild-type patients (56.7 vs. 32.3%, respectively, p=0.019). Even if all patients were more often primarily investigated in front of adrenal incidentaloma than clinical evidence for Cushing's syndrome (73 vs. 27%, respectively), ARMC5 patients were more often referred for Cushing's syndrome than wild-type patients (44 vs. 24%, respectively, p=0.004). To improve the ARMC5 mutation rate, the association of a clear bilateral adrenal involvement with evidence for autonomous cortisol secretion (defined at least by a plasma cortisol after 1 mg dexamethasone suppression test above 50 nmol/L) holds the better yield with a 27% specificity and a 20% positive predictive value, and a 100% sensitivity and negative predictive value, meaning that a useless genotyping could have been avoided for more than 20% of negative patients, without missing any mutated patient.
Conclusion: We report the largest series of index case patients investigated for ARMC5 with clinical characterization and confirm that ARMC5 pathogenic variants are associated with a more severe phenotype. In order to minimize negative ARMC5 screening, genotyping could be limited to clear bilateral adrenal involvement on imaging and autonomous cortisol secretion, with an optimum yield for routine clinical practice. These findings will also help better define PBMAH diagnostic criteria.

Identification of Predictive Criteria for the Primary Bilateral Macronodular Adrenal Hyperplasia Gene ARMC5: A European Series of 352 Unselected Patients.

Background: Patients with adrenal hormone excess demonstrate an increased cardiovascular risk and mortality. We aimed to determine the impact of adrenal hormone excess on the metabolic profile that included plasma lipoproteins, total branched-chain amino acids (BCAA), ketone bodies, and GlycA (a proinflammatory glycoprotein biomarker). Method: We conducted a single-center cross-sectional study of consecutive patients with adrenal adenomas, Cushing syndrome (CS), and pheochromocytoma/paragangliomas (PPGL) between January 2015 and May 2021. Adrenal adenomas comprised nonfunctioning adenomas (NFA), adenomas with mild autonomous cortisol secretion (MACS), and primary aldosteronism (PA). Malignant and other benign tumors were excluded. Collected fasting plasma samples were measured using nuclear magnetic resonance spectroscopy for lipoproteins, BCCA, ketone bodies and GlycA. The results were compared to referent subjects from PREVEND (Prevention of Renal and Vascular End-stage Disease) study. Lipoprotein Insulin Resistance Index (LP-IR) which predicts incident diabetes was calculated based on 6 lipoprotein parameters. Results: NFA (n=166, median age 60.1years, 63.3% women), MACS (n=158 (median age 61.8 years, 62. 0% women), CS (n=101, median age 43.8 years, 85.1% women), PA (n=71 (median age 55.8 years, 31. 0% women), PPGL (n=43, median age 55.5 years, 46.5% women) was diagnosed in 539 patients. Referent subjects (n=6540) were younger with a median age of 48.4, 50.2% women. When compared to referent subjects, and after age and sex-adjustment, GlycA was highest in patients with CS (OR 3.3, 95% CI 2.8-3.8), followed by PPGL (OR 2.3, 95%CI 1.8-2.9), MACS (OR 2, 95%CI 1.7-2.3), NFA (OR 1.9, 95%CI 1.7-2.2), and PA (OR 1.5, 95%CI 1.2-1.8). When compared to referent subjects, and after sex- and age adjustment, all patient groups demonstrated increase in BCAA: CS (OR 2.7 (95%CI 2.3-3.2), PPGL (OR 2.3, 95% CI 1.8-2.9), NFA (OR 2.4, 95% CI 2.1-2.7), PA (OR 2. 0, 95%CI 1.7-2.5), MACS (OR 2.2, 95% CI 1.7-2.6). Total ketone bodies were increased in patients with cortisol excess (OR of 1.4, 95%CI 1.2-1.5 in CS, and OR of 1.2, 95%CI 1-1.3 in MACS) and NFA (OR 1.2, 95%CI 1.1-1.3), but not in PA or PPGL. All patient groups except PPGL were more likely to have a higher LP-IR score. When compared to referent subjects, the highest sex- and age-adjusted LP-IR increase was in patients with CS (OR 1.9 (95%CI 1.5-2.2), followed by MACS (OR 1.4, 95% CI 1.2-1.7), PA (OR 1.4, 95%CI 1.1-1.8), and NFA (OR 1.4, 95% CI 1.2-1.7). Conclusion: Patient with adrenal adenomas and PPGL demonstrate an increase in GlycA, BCAA, and ketone bodies - biomarkers associated with adverse cardiometabolic disorders and mortality. All patients except those with PPGL also demonstrated a higher LP-IR index that was reported to predict incident diabetes. Patients with NFA demonstrated an adverse metabolic profile similar to patients with MACS.

Metabolic Profiling in Adrenal Tumors Demonstrates Enhanced Chronic Inflammation, Branched Chain Amino Acids and Ketone Bodies, Biomarkers that Predict High Cardiometabolic Risk

Background: Pheochromocytoma (Pheo)/Paraganglioma (PGL), together PPGL, are rare but life-threatening tumors, with tumor relapse (TR) rates after initial surgery of 16.5%, and genetic mutations in about 30-40% of patients. Long-term follow-up (FU) and genetic testing in all patients are recommended. Questions remain, however, as to the most suitable duration of FU, the prognostic value of genetic diagnoses and of clinical, biochemical or radiological findings during FU, of the incidence of TR after recommended 10 years FU of low-risk sporadic Pheos, or of TR on morbidity and mortality.
Objective, patients, and methods: We retrospectively determined the overall survival (OAS), progression-free survival (PFS) and tumor-recurrence (TR) in 173 patients with PPGL initially operated and followed-up at a single tertiary referral center from 1988 to 2020 by Kaplan-Meier Estimates, and assessed age, sex, hormonal activity, tumor size, and metastatic spread at first diagnosis, pathohistological PASS score, mutation-positive PPGLs (MP-PPGL), TR, and comorbidities (associated with increased cardiovascular risk) as to independent prognostic markers thereof by multivariate Cox-regression. Certificats of the Austrian death registry were also obtained.
Results: In 8 (5%) PPGLs there was no FU in the charts, but death certified occurring 65±28 (mean±SD, median 2.7) months after first diagnosis. Mean (±SD) age of the remaining 165 (43.9% female) patients (94.5 Pheos, 3.0% multiple PGLs, 2.5% head-and-neck PGLs) was 49(±16) years, mean (range) FU 90(3-537) months. 93 (54%) patients underwent genetic testing, 37 (40%, 21% of entire cohort) had MP-PPGL (mean±SD age 33.8±13.2 yrs, OAS 391 months). 5 of these 37 (13.5%), and 7 of 57 (12%) mutation-negative (MN-PPGL, mean±SD age 53.3±14.8 years, p<0.01 vs. MP-PPGL, OAS 190 months) died during FU (p=0.03). Male sex, higher age, presence of comorbidities, and primary metastatic disease were independent negative prognostic factors for OAS by univariate, but only age and metastatic disease remained significant by multivariate analysis. As to PFS, higher age and no hormonal activity were negatively associated by univariate, but not by multivariate analysis, as were all other tested parameters.
Conclusions: The cohort of our study is the third-largest original report on long-term FU and prognostic markers in PPGL. While others (Ayola-Ramirez et al, JECM 2011) in 371 patients found tumor size and sympathetic PGL independently associated with OAS, we did not. Patients may have harbored more aggressive tumors in that study, as higher primary metastatic spread (25% of Pheos, 60% of sympathetic PGL) was identified. We identified only age and metastatic disease as independent predictors of OAS, in line with data from Korea (Kim J H, et al., Endocrinol Metab. [Seoul]) in 1048 patients (9% with primary metastatis) and with a metaanalysis comprising 703 PPGLs (Crona J, Endocr Relat Cancer, 2019).

Long-term Follow-Up of Pheochromocytoma/Paraganglioma (PPGL) after first diagnosis: a retrospective single-center study of 173 patients

Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome wherein small tumors secrete excess fibroblast growth factor 23 (FGF23) leading to hypophosphatemia, osteomalacia, bone pain, fractures, and muscle weakness. Burosumab is an anti-FGF23 monoclonal antibody approved for treatment of TIO. We report end of study (EOS) data from the open-label phase 2 UX023T-CL201 trial (NCT02304367) of burosumab in adults with TIO.
In UX023T-CL201, participants received burosumab (0.3–2.0 mg/kg) by subcutaneous injection every 4 weeks for 48 weeks with an extension up to 300 weeks (~6 years). Co-primary endpoints were change in serum phosphorus at Week 24 and change in excess osteoid by trans-iliac crest bone biopsy at Week 48. Additional endpoints included changes in bone biomarkers, activity on radionucleotide bone scan representing fractures/pseudofractures, patient-reported outcomes, and safety measures.
This analysis included 14/17 UX023T-CL201 participants; excluding those with other diagnoses (n=3).
Mean (SD) serum phosphorus improved from 1.6 (0.5) mg/dL at baseline to 2.3 (0.5) mg/dL when averaged across the mid-point of the dose interval through Week 24 (co-primary endpoint). Levels further improved (2.6 [0.4] mg/dL; n=7) to within the normal range (2.5–3.6 mg/dL) at Week 240. Most measures of osteomalacia improved at Week 48 (co-primary endpoint), including osteoid/bone volume, osteoid thickness, and mineralization lag time. However, osteoid surface/bone surface showed no change.
Bone biomarkers (P1NP, CTx, BALP) followed similar trends. Upon initiation of burosumab, markers briefly increased by Week 24 as bone healing began, then gradually decreased with further treatment, reaching normal (P1NP, CTx) or near-normal (BALP) ranges by Week 240.
At baseline, 249 areas of increased radionucleotide uptake indicating fracture activity were detected across 14 participants. By Week 144, 36% (72/201) and 13% (26/201) regions of abnormal uptake were fully or partially restored, respectively. By EOS, further reduction of active fractures and fewer new areas of uptake were observed. New fractures at Week 144 were observed in a single participant (considered a burosumab partial responder) and between Week 144 and EOS in another participant unrelated to burosumab (car accident).
Participants reported sustained mean reduction from baseline pain at Week 240 per Brief Pain Inventory and significantly per SF-36 Bodily Pain score. Significant reductions in baseline fatigue at Week 240 were reported per Brief Fatigue Inventory and SF-36 Vitality scores. SF-36 physical health (Role Physical, Bodily Pain, Component Score) and mental health (Social Function, Vitality) significantly improved from baseline at Week 240.
The observed safety profile of long-term burosumab in participants with TIO was consistent with the known safety profile of burosumab and similar to patients with XLH.
Long-term burosumab therapy was associated with improved serum phosphorus, osteomalacia, bone turnover, fracture incidence and healing, health-related quality of life, and reductions in pain and fatigue in adults with TIO.

Long-Term Burosumab Therapy Provides Sustained Benefit in Patients with Tumor-Induced Osteomalacia: End of Study Findings From the Pivotal Phase 2 Study

X-linked hypophosphatemia (XLH) is a rare, heritable disorder wherein excess FGF23 leads to renal phosphate wasting and impaired activation of vitamin D. XLH is characterized by rickets and osteomalacia leading to bone pain, skeletal deformities, and short stature. The XLH Disease Monitoring Program (DMP; NCT03651505) is a prospective, multinational outcomes study of the longitudinal progression of clinical, radiographic, and biochemical features of XLH in children and adults. We assessed the impact of the recombinant human IgG1 monoclonal antibody to FGF23, burosumab, on measures of bone health in children with XLH at Year 1 of the DMP.
As of March 2021, 287 children (<18 years) had completed the Year 1 visit. Participants were grouped by when they first received burosumab: Group 1, prior to DMP enrollment (N=68; mean (SD) age 9.5 (3.6) years); Group 2, during the DMP (N=150; 8.7 (5.0) years); Group 3, never, but receiving conventional therapy (N=69; 8.8 (5.3) years).
Before receiving burosumab, serum phosphorus levels were below normal; after burosumab initiation, serum phosphorus in Groups 1 and 2 rapidly normalized, with sustained improvements up to 3 years of treatment. Serum phosphorus remained low in Group 3. Before burosumab, serum alkaline phosphatase levels were above normal; with continued burosumab therapy, mean levels gradually declined towards normal and were maintained for up to 4 years.
The Radiographic Global Impression of Change (RGI-C) assessed rickets and lower limb deformity from DMP baseline to Year 1, with positive values denoting improvement. Mean (SD) RGI-C rickets global scores were +1.0 (0.9) for Group 1 (n=44), +1.5 (0.7) for Group 2 (n=39), and +0.3 (1.2) for Group 3 (n=3). Lower limb deformity RGI-C scores were +0.3 (0.6) for Group 1 (n=42), +0.4 (0.8) for Group 2 (n=39), and +0.8 (1.1) for Group 3 (n=3). Height Z-score change from DMP baseline at Year 1 was 0.1 (0.3) for Group 1 (n=58), 0.1 (0.4) for Group 2 (n=90), and -0.8 (3.1) for Group 3 (n=18). There were no new safety concerns or reports of hyperphosphatemia.
These real-world data affirm that normalization of serum phosphorus is rapid and sustained following burosumab initiation, resulting in improved serum alkaline phosphatase levels which positively impact bone mineralization. Improvements in rickets, growth, and lower limb deformity occur in the first year of burosumab treatment and continue in those who started burosumab prior to entering the DMP. The absence of new safety concerns or reports of hyperphosphatemia up to 4 years after burosumab initiation is also notable. The 10-year DMP study design will provide understanding of long-term effects in these patients with continued burosumab therapy.

Characterizing the Impact of Burosumab on Bone Health in Children with X-Linked Hypophosphatemia: Results from Year 1 of the Disease Monitoring Program

Introduction: X-linked hypophosphatemia (XLH), a dominant disorder caused by disease-associated variants in the PHEX gene, affects males and females of all ages. Rickets and osteomalacia may be present along with short stature, lower limb deformity, muscle pain and/or weakness/fatigue, bone pain, fractures and poor fracture healing, joint pain/stiffness, hearing difficulty, enthesopathy, osteoarthritis, and dental abscesses. Patients with XLH have below-normal serum phosphate and elevated serum FGF23. The Hypophosphatemia Gene Panel Sponsored Program provides a no-charge genetic test to patients  to confirm a clinical XLH diagnosis or to aid in the diagnosis of suspected genetic hypophosphatemia.
Methods: Individuals aged ≥6 months with either a clinical XLH diagnosis or suspicion of genetic hypophosphatemia, as evidenced by 2 or more clinical signs/ symptoms, were eligible for testing. The next generation sequencing panel includes 17 genes: ALPL, CLCN5, CTNS, CYP2R1, CYP27B1, DMP1, ENPP1, FAH, FAM20C, FGF23, FGFR1, GNAS, OCRL, PHEX, SLC34A1, SLC34A3, and VDR. Copy number variant (CNV) detection was also performed. Variants were interpreted according to the joint consensus from the American College of Medical Genetics and Genomics and the Association for Molecular Pathology using Invitae's proprietary point-based scoring system, Sherloc. In all analyses, data were summarized using descriptive statistics.
Results: One thousand six hundred sixty-eight unrelated individuals, ages 6 months to 87 years (mean = 27.4±21.2 years, median = 22.5 years), were tested between 27 February 2019 and 23 October 2021. The majority of individuals were female (66.6%) and of self-reported White ancestry (54.9%).
Eight hundred seventy-nine (52.7.%) unrelated individuals had a PHEX variant: 825 (93.9%) were either pathogenic or likely pathogenic (P/LP) and 54 (6.1%) were variants of uncertain significance (VUS). Of the 789 (47.3%) cases where no PHEX P/LP or VUS was found, 116 (14.7%) had molecular diagnoses associated with other genes/disorders: ALPL (71 with 1 variant, 12 with 2 variants), FGF23 (8), CYP27B1 (14), SLC34A3 (5), and two or fewer molecular diagnoses for DMP, CTNS, ENPP1, and OCRL.
Four hundred and twenty-eight unique P/LP PHEX variants were detected: 136 deletions, duplications or insertions (<100 bp); 41 copy number variants (>100 bp); 74 splice-site variants; 177 single nucleotide variants. Additional family member testing/clinical information/observation of variants resulted in 25 VUS being reclassified to P/LP (impacting 50 individuals), highlighting the value of cascade family testing/clinical information to resolve VUS. Notably, the frequency of PHEX VUS has decreased from 8.9% in 2019 (41 weeks) to 4.4% in 2021 (44 weeks).
Conclusions: The frequency of any PHEX variant classified as VUS has decreased more than two-fold since 2019. RNA analyses to resolve VUS may further improve molecular diagnostic yield. Program results provide a high molecular diagnostic yield for XLH and other genetic hypophosphatemia disorders and new insight into XLH-associated PHEX variants.

Hypophosphatemia Gene Panel Sponsored Program: A High Yield of Molecular Diagnoses from Clinically Confirmed XLH and Suspected Genetic Hypophosphatemia

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