United States

Background The ESE-ENSAT guidelines on the management of adrenocortical carcinoma (ACC) suggest adjuvant mitotane for patients at high risk of recurrence following radical surgery. This indication has a limited evidence base, lacking results from randomized controlled trials. No suggestion for or against adjuvant mitotane in low-risk patients was given, since studies did not stratify patients for prognosis. The randomized controlled study ADIUVO compared the efficacy of adjuvant mitotane treatment vs. observation in prolonging recurrence-free survival (RFS) in ACC patients at low-intermediate risk of recurrence.?Methods The main inclusion criteria were: stage I-III ACC, R0 surgery, and Ki-67 ≤10%. Patients were randomly assigned 1:1 to adjuvant mitotane (MIT) or observation (OBS). The primary endpoint of the study was RFS. Patients who refused randomization were offered inclusion in the ADIUVO OBSERVATIONAL study. In this prospective, observational study, patients were managed as in the ADIUVO study. A total of 91 patients were enrolled in ADIUVO, 45 in the MIT and 46 in the OBS arm. Baseline characteristics of patients were perfectly matched between the 2 arms: median age, 51 vs. 50.5 years; female, 73% vs. 67%; stage I, 20% vs. 26%; stage II, 67% vs. 63%, stage III, 13% vs. 11%; ACC secretion 44% vs. 36%; Weiss 5 vs. 5; respectively. In ADIUVO OBSERVATIONAL, 42 patients were treated with mitotane and 53 were untreated. Baseline characteristics of patients were matched between the 2 groups and with MIT and OBS groups in ADIUVO. Thus, the ADIUVO OBSERVATIONAL cohorts could be analyzed in parallel to those of ADIUVO.?Results In the ADIUVO study, recurrences were 8 in the MIT and 11 in the OBS arm, while deaths were 2 and 5, respectively. RFS and overall survival (OS) did not significantly differ between the 2 arms. Tumor size was a predictor of RFS in multivariable analysis. In the OBS arm, the HR for recurrence was 1.321 (95%CI, 0.55-3.32, p=0.54) and HR for death 2.171 (95%CI, 0.52-12.12, p=0.29). The survival analysis in the ADIUVO OBSERVATIONAL study confirmed the findings of ADIUVO. Given the outcome of both studies, the NNT is 55.?Conclusions ACC patients at low-intermediate risk of recurrence after surgery are a minority; however, they show a far better prognosis than expected (5-year RFS is about 75%) and do not benefit significantly from adjuvant mitotane. The results of the ADIUVO study do not support routine use of adjuvant mitotane in this subset of patients, who may thus avoid a potentially toxic treatment. This is an important step toward personalization of ACC care.?? 

ENDO 2021

Results of the ADIUVO Study, the First Randomized Trial on Adjuvant Mitotane in Adrenocortical Carcinoma Patients

ENDO is the leading meeting for endocrinology research and clinical care worldwide. 

technical paper

Background: Adrenocortical carcinoma (ACC) has an aggressive but heterogeneous behaviour. ENSAT stage and Ki67 proliferation index are used to predict clinical outcome but are limited in distinguishing patients with different risk of disease progress. We aimed to validate the prognostic role of a previously proposed points-based score (mGRAS) in a large ACC cohort.?Methods: We included ACC patients who underwent adrenalectomy between 2010 and 2019, had complete clinical and histopathological data, and did not participate in our previous studies (Libe et al. Ann Oncol 2015; Lippert et al. JCEM 2018). The mGRAS score was calculated as follows: age (<50yr=0; ≥50yr =1), symptoms (no=0; yes=1), ENSAT stage (1-2=0; 3=1; 4=2), resection status (R0=0; RX=1; R1=2; R2=3), and Ki67 (0-9%=0; 10-19%=1; ≥20%=2 points), generating scores from 0 to 9 and four mGRAS groups (scores 0-1, 2-3, 4-5, and 6-9). Progression-free survival (PFS) and disease-specific survival (DSS) were the primary and secondary endpoints, respectively. The discriminative performance of mGRAS was investigated using the Harrell’s C-index and Royston-Sauerbrei’s R2D statistic.?Results: A total of 942 ACC patients from 14 ENSAT centres were included (38% men; median age 50yrs (interquartile range 38, 61)). The four mGRAS groups showed superior prognostic discrimination compared to the individual clinical and histological parameters for both PFS and DSS (C-index 0.71, R2D=0.30 and 0.77, R2D=0.46, respectively); ENSAT staging was the second best discriminator (C-index 0.67, R2D 0.21 and 0.72, R2D=0.35, respectively). An even better prognostic discrimination was observed using the ten mGRAS scores individually (C-index 0.73, R2D=0.30, and 0.79, R2D=0.45 for PFS and DSS, respectively). The superiority of mGRAS was confirmed when separately considering patients treated or untreated with adjuvant mitotane (n=481 vs 314). In mitotane-treated patients, the four mGRAS groups showed better performance in predicting PFS than Ki67 index (C-index 0.66, R2D 0.18 vs C-index 0.62, R2D 0.12).?Conclusion: The prognostic performance of mGRAS is superior to that of ENSAT staging and Ki67. This simple score may guide personalised treatment decisions in patients with ACC, e.g. regarding the need for adjuvant therapy and frequency of monitoring.?? 

Modified GRAS Score for Prognostic Classification of Adrenocortical Carcinoma: An ENSAT Multicentre Study

Background: High-specific-activity iodine-131 meta-iodobenzylguanidine (HSA I-131 MIBG; AZEDRA®) has been approved for the treatment of adult and pediatric patients (pts) 12 years and older with iobenguane scan positive, unresectable, locally advanced or metastatic PPGL who require systemic anticancer therapy. We have previously presented data showing improved biomarker responses in pts treated with HSA I-131 MIBG. Here we report the impact of biomarker status on the study primary endpoint and objective tumor response. Methods: Pts with iobenguane-avid PPGL who were ineligible for surgery, failed prior therapy or not candidates for chemotherapy, and on a stable antihypertensive medication regimen were treated. Pts received up to two therapeutic doses, each at ~18.5 GBq (or 296 MBq/kg for pts ≤62.5 kg), administered ~90 days apart. Biomarkers were analyzed at baseline and over a 12-month efficacy period. Confirmed biochemical responses (at least ≥ 50% decrease in abnormal tumor marker value for all hypersecreted biomarkers) required subsequent responses to be identical to or better compared with the previous assessment. The primary endpoint was clinical benefit, defined as the proportion of pts with at least 50% reduction of all antihypertensive medication(s) for ≥6 months beginning during the efficacy period. The secondary endpoint, confirmed objective tumor response by RECIST, was also evaluated. Results: 68 pts received at least one therapeutic dose of HSA I-131 MIBG. For all pts with hypersecretory tumors (with a baseline biochemical marker level of ≥1.5× ULN) (n=60), a comparison of biomarker response with antihypertensive therapy yielded a correlation coefficient of 0.35 (P = 0.006; Fisher exact P = 0.012). For pts with norepinephrine only-hypersecreting tumors (n=31), a correlation coefficient of 0.47 (P = 0.008; Fisher exact P = 0.015) was observed. The overall biomarker response also correlated with objective tumor response (n=55) yielding a correlation coefficient of 0.36 (P = 0.007; Fisher exact P = 0.012) for all pts with hypersecreted biomarkers. Pts who were not biochemical hypersecretors for any biomarker (n=6) had only one responder for the primary endpoint and no objective tumor responses. Conclusions: The biomarker data from this study establish a moderate but statistically significant correlation between biomarker response following treatment with HSA I-131 MIBG and objective tumor response and durable reduction of antihypertensive therapy. This correlation was improved with norepinephrine only-hypersecreting tumors in pts with unresectable, locally advanced or metastatic PPGL.?? 

Biochemical Tumor Marker Status and Its Role in Treatment Response in Patients Who Received High-Specific-Activity I-131 MIBG in Advanced Pheochromocytoma and Paraganglioma (PPGL): Results From a Pivotal Phase 2 Clinical Trial

Background: Endogenous Cushing’s syndrome (CS) refers to an inappropriate hypercortisolism usually caused by either Cushing’s disease (CD) or adrenal CS (ACS). CS results in significant morbidity and excess mortality if untreated. Even in treated cases there is often a significant health burden. Due to the rarity of CS (incidence ~ 1/1M population) , single cohort studies have insufficient power for reporting accurate mortality data. Only one previous systematic review and meta-analysis for CS has been reported that limited its scope to the inclusion of specific CD subgroup. Aims: To perform a meta-analysis and meta-regression analysis of all-cause and specific cause -mortality amongst patients with benign endogenous CS.Methods: The protocol was registered in PROSPERO (CRD42017067530). Searches were undertaken of PubMed, EMBASE, CINHAL, web of science and Cochrane Central from start until April 2019. The primary outcomes were proportion of mortality and SMR. The meta-analysis was done with STATA version 16.1 software. The I2 test, subgroup analysis and meta-regression statistics were used to assess heterogeneity among included studies. Results: A total of 11,527 articles, were retrieved. 87 articles with 100 study cohorts containing 17,276 CS patients reporting mortality were included. Fifty-three study cohorts reported Cushing’s disease (CD) patients, 27 study cohorts reported for adrenal CS patients and 20 studies cohorts reported on both types of CS. The overall SMR of all type CS was 2.91 (95% CI 2.41-3.68) with I2 =40.3%. The SMR for CD was 3.27 (95% CI 2.33-4.21) with I2 = 55.6%. The SMR in ACS was 1.62 (95% CI 0.08-3.16) with I2 =0.0%. The overall proportion of death in CS was 0.05 (95% CI 0.03-0.06) with I2 =51.86%; in CD was 0.04 (95% CI 0.03-0.06) with I2 = 62.7% and in ACS 0.06 (95% CI 0.04-0.11) with I2 = 40.3 %. The proportion of death during the 30-day operative period was highest before 1991 at 0.07 and decreased to 0.03 in 1991-2000 to 0.01 in 2001-2010 and zero after 2011. The causes of death reported across 64 studies were cardiac causes (24.7%), infection (14.4%), cerebrovascular diseases (9.4%), malignancy (9.0%), thromboembolism (4.2%), active disease (2.9%), and adrenal insufficiency (2.7%).Conclusion: CS is associated with increase in overall mortality. Advances in operative techniques and care have decreased peri-operative mortality over a 20 year period. The causes of death highlight the need for aggressive management of cardiovascular risk, prevention of thrombo-embolism, infection control and a normalised cortisol level.?? 

Mortality and Specific Causes of Death in Endogenous Cushing’s Syndrome: A Systematic Review, Meta-Analysis and Meta-Regression

Age-induced osteoporosis is characterized by a progressive decline in bone formation and increase in bone resorption with uncoupled activities of osteoblasts and osteoclasts. Parathyroid hormone (PTH) is used in the clinic to treat osteoporosis due to its anabolic actions on bone via binding to the PTH receptor (PPR). The receptor is highly expressed in cells of the osteoblastic lineage, including osteocytes. Osteocytes are the most abundant cells in bone and serve as a key regulator of bone remodeling. Despite the significant role of PPR signaling in skeletal homeostasis, its function in osteocytes during aging remains unclear. We have gathered preliminary data demonstrating that mice lacking PPR predominantly in osteocytes (Dmp1-PPRKO) have marked age-induced bone loss due to increased bone resorption and suppressed bone formation. These mice, with aging, develop characteristics of skeletal senescence: a decrease in osteoprogenitors and an increase in bone marrow adiposity and p16Ink4a/Cdkn2a expression in bone. Since senescence of cells in the bone microenvironment has been reported as a cause of age-induced bone loss, we hypothesized that PPR signaling protects osteocytes from senescence. To test this hypothesis, we generated osteocytes (Ocy454-12H), in which the PPR expression was ablated using CRISPR/Cas9 technique. Ocy454-12H-PPRKO and Ocy454-12H-PPRCtrl cells were treated with PTH followed by an exposure to hydrogen peroxide (H2O2). High levels of intracellular reactive oxygen species (ROS), including H2O2, promote protein and DNA oxidation, resulting in cell death and senescence. PTH treatment significantly suppressed the increase in H2O2-induced cell death, measured by resazurin-based assays, in PPRCtrl but not in PPRKO cells. We analyzed intracellular ROS levels using a fluorescent probe and found that PTH treatment significantly suppressed the increase in ROS upon H2O2 exposure, suggesting an antioxidant function of PTH in osteocytes. To further investigate if PTH prevents osteocytes from oxidative stress-induced senescence, we examined senescence-associated β-galactosidase (SA β-gal) activity in cells that were treated with PTH followed by an exposure to low doses of H2O2. Compared to untreated and PPRKO groups, treatment with PTH significantly decreased the number of SA β-gal positive cells, demonstrating that PPR signaling protects osteocytes, and possibly other osteoblastic cells, from H2O2-induced cellular senescence. PTH treatment reduced mRNA expression of p21/Cdkn1a. Taken together these results demonstrate that PPR signaling is important to protect osteocytes from cellular senescence.?? 

PTH Protects Osteocytes From Oxidative Stress and Cellular Senescence

Opioid use is associated with a three to four-fold increase in fracture risk, which is higher in males compared to females. Although one component of that risk may be falls, there is also evidence of altered bone remodeling. However, the mechanisms of these effects are not entirely clear. Our aim was to develop a mouse model of opioid-induced bone loss and study the impact on bone turnover and potential miRNA-mediated regulatory mechanisms. We evaluated the effects of sustained morphine treatment on the skeleton and metabolism of male and female C57BL/6J mice by treating with vehicle (0.9% saline) (n=9-11) or morphine (18 mg/kg) (n=11) using subcutaneous osmotic minipumps for 25 days. Morphine did not influence body weight or food intake, but did reduce fat mass in both sexes. All mice treated with morphine had higher resting energy expenditure and respiratory quotient, indicating a shift toward carbohydrate metabolism. After 25 days of treatment, microComputed Tomography (µCT) analyses indicated that morphine-treated male mice lost 15% of trabecular bone volume fraction (Tb.BV/TV) and 14% of Tb. bone mineral density (BMD) (p<0.05) in the distal femur compared to vehicle, but there were no changes in cortical bone. Females did not lose bone, suggesting differences may be hormone-related. Despite these sex differences, males and females had similar levels of morphine exposure, measured by LC-MS/MS. Histomorphometric analyses demonstrated that in males, morphine reduced bone formation rate (p<0.05) compared to vehicle, but did not impact osteoclast parameters. Consistent with this, morphine reduced bone formation marker gene expression in the tibia of males (including Bglap and Dmp1). Circulating miRNA profiles were interrogated in serum collected at day 12 from vehicle- and morphine-treated male and female mice. While very few changes were present in females, there were 14 differentially expressed miRNAs in males treated with morphine that reached a threshold of ≥ 2-fold change and p<0.01. After target pathway analysis (DIANA miR Path V.3 using experimentally validated miRNA/mRNA targets (Tarbase V.7)), we found that the four upregulated miRNAs (miR-484, -223-3p, -328-3p, and -3107-3p) were associated with 13 enriched KEGG pathways (p<0.05), including fatty acid metabolism pathways (p<0.001). Fatty acid metabolism has recently been linked to osteoblast function, and suppression of such pathways is consistent with the finding of increased respiratory quotient. In summary, morphine leads to trabecular bone loss due to reduced bone formation in males. miRNA findings indicate this may be due to altered metabolic control of mineralization. Further investigation into hormonal and metabolic dependency of morphine-induced bone formation changes could lead to clinical mitigation strategies for preventing the adverse effects of opioids on bone health.?? 

Sustained Morphine Delivery Suppresses Bone Formation and Alters Metabolic and Circulating miRNA Profiles in Mice

Objective The extraordinarily high bone densities identified in the hypoparathyroidism patients originating from PTH R25C mutation suggested the possibility that this modified protein has unique biologic effects and contributes to the gain of bone volume. Interestingly, western blot of cell lysates stably transfected with PTH R25C construct revealed that Cys25PTH(1-84) formed a dimer, presumably due to disulfide bonding of the cysteine residues. This study aims to study the characteristics of Cys25PTH(1-34) dimeric peptide (Dimer) both in vitro and in vivo for potential therapeutic application of Dimer as a novel anabolic agent. Methods Identity of the chemically synthesized Dimer was confirmed by its molecular weight and purity using MS and HPLC, respectively. Basic characteristics, for example, ability to bind to PTHR and cAMP production were investigated using a variety of cells. In addition, the ligand-receptor internalization was investigated using TMR tagged Dimer. In vivo characteristics, such as calcemic and phosphatemic responses, pharmacokinetics and pharmacodynamics, were assessed in CD1 mice. The osteoanabolic effects of Dimer were assessed using a fracture-healing model, a calvarial-injection model and an OVX mouse model. Results In vivo study showed that Dimer has similar calcemic and phosphatemic responses to PTH(1-34; WT). In cell assays, Dimer showed a similar cAMP production but slightly lower binding affinity compared to WT. Dimer-receptor complex was internalized into the cells. Surprisingly, Dimer showed a potent anabolic effect in the fracture-healing model in mice measured as the callus volume fraction by microCT. We also observed a comparable anabolic effect of Dimer in calvarial-injection model and OVX model. Conclusions Dimeric Cys25PTH(1-84) peptide might play a substantial role in the high bone mass in hypoparathyroidism patients, originating from the PTH R25C mutation. This may be translated into the development of potential therapeutic modality for the treatment of osteoporosis and fracture healing using Dimer.?? 

Therapeutic Potentials of Dimeric Cys25PTH(1-34) Peptide for Osteoporosis and Fracture Healing of the Bones- Buy One, Get One Free

Sarcopenic Obesity Indices Are Major Determinants of Bone Strength in Older Adults With Obesity?Background: The increasing number of older adults with obesity is a growing public health problem because of increased risk of fractures especially at the ankle and upper leg despite normal or high bone mineral density. Among the contributory factors for fracture risk in this population may be aging- and obesity- associated physical frailty and impaired bone quality. However, how the adverse changes in physical function and body composition in this aging and obese population contribute to bone quality as assessed by finite element analyses (FEA) of bone strength has not been determined. Methods: One-hundred sixty-nine older (age ≥ 65 yrs.) adults with obesity (BMI ≥ 30 kg/m2) were recruited to participate in lifestyle intervention trials at our Medical Center. All underwent baseline measurements of bone strength (failure load [N] and stiffness [N.mm-1]) as estimated using FEA from high-resolution peripheral quantitative tomography (HR-pQCT) of the distal radius and tibia. In addition, body composition (appendicular lean mass/BMI [ALMBMI], fat mass/height2 [FMI]) was assessed by dual-energy x-ray absorptiometry (DXA) and physical function by the modified physical performance test (PPT), knee extension strength (isokinetic dynamometry), hand grip strength, and 4-meter gait speed. Results: Bivariate analyses showed that ALMBMI (r=.57 to .58), FMI (r=-.16 to -.17), gait speed (r=.20 to .21), grip strength (.56 to .57), and knee extension strength (r=.40 to .42) correlated with stiffness and failure load at the distal radius (all P<0.05). In addition, ALMBMI (r=.65 to .67), FMI (r=-.22 to .23), gait speed (r+.18 to .19), grip strength (r=.58 to .59), and knee extension strength (r=.44 to .45) correlated with stiffness and failure load at the distal tibia (all P<0.05). Controlling for age and sex, multiple regression analyses revealed that ALMBMI (β=.34 to .35) and grip strength (β=.28 to .29) were the independent predictors of stiffness and failure load at the distal radius, explaining 45% to 46% of the variance in stiffness and failure load (P<0.001). On the other hand, multiple regression analyses revealed that ALMBMI (β=.45 to .52), grip strength (β=.27 to .28), and FMI (β=.17 to .18) were the independent predictors of stiffness and failure load at the distal tibia, explaining 74% to 75% of the variance in stiffness and failure load (P<0.001).Conclusions: These findings suggest the importance of preserving muscle mass while reducing fat mass and improving physical function to maintain bone quality and decrease the risk of fractures when older adults with obesity undergo lifestyle intervention.?? 

Sarcopenic Obesity Indices Are Major Determinants of Bone Strength in Older Adults With Obesity

Anorexia nervosa is complicated by low bone mineral density (BMD) and increased fracture risk associated with low bone formation and high bone resorption. The spine, particularly its trabecular component as measured by lateral spine dual-energy x-ray absorptiometry (DXA), is most severely affected. Low BMD and bone formation are associated with relative insulin-like growth hormone-1 (IGF-1) deficiency. Our objective was to determine whether bone anabolic therapy with off-label recombinant human (rh)IGF-1 followed by antiresorptive therapy with risedronate would increase BMD more than risedronate alone or placebo in women with anorexia nervosa. We conducted a 12-month, randomized, placebo-controlled study of 90 ambulatory women with anorexia nervosa and low areal BMD (aBMD) (Z- or T-score <-1.0). Participants were randomized to 1 of 3 groups: 6 months of rhIGF-1 (starting dose 30 mcg/kg SQ BID) followed by 6 months of risedronate (35mg PO weekly) (“rhIGF-1/Risedronate”) (n=33), 12 months of risedronate (35mg PO weekly) (“Risedronate”) (n=33), or double placebo (“Placebo”) (n=16). Participants received calcium 1200 mg and vitamin D 800 IU daily. rhIGF-1 was titrated to maintain IGF-1 levels within the age-adjusted normal range. Main outcome measures were aBMD at the spine [1° endpoint: postero-anterior (PA) spine BMD], hip, and radius by DXA, and vertebral, tibial, and radial volumetric BMD (vBMD) and estimated strength by multi-detector computed tomography (MDCT) or high-resolution peripheral quantitative CT (HR-pQCT). At baseline, mean age [28 ± 7 y (mean ± SD)], BMI (18.5 ± 1.9 kg/m2), and BMD were similar among groups. At 12 months, mean PA spine aBMD was higher in the rhIGF-1/Risedronate (p=0.03), and trended towards being higher in the Risedronate (p=0.08), group than the Placebo group. Mean lateral spine aBMD was higher in the rhIGF-1/Risedronate than either the Risedronate (p=0.002) or Placebo (p=0.04) groups. From baseline to 12 months, mean PA and lateral spine aBMD increased by 1.9 ± 0.6% and 4.2 ± 1.0% in the rhIGF-1/Risedronate (p<0.05), 1.7 ± 0.8% and 1.7 ± 1.0% in the Risedronate (p=NS), and decreased by 0.3 ± 0.8% and 1.1 ± 1.3% in the Placebo (p=NS), groups, respectively. Areal BMD Z-scores did not normalize in any group. At 12 months, vertebral vBMD by MDCT was higher (p<0.05), and vertebral strength trended towards being higher, in the rhIGF-1/Risedronate than Placebo group. Neither hip or radial BMD, nor radial or tibial estimated strength, by HR-pQCT differed among groups. rhIGF-1 was well tolerated. In conclusion, sequential therapy of 6 months of rhIGF-1 followed by 6 months of risedronate increased lateral spine aBMD, the site most severely affected in women with anorexia nervosa, more than risedronate or placebo. These data suggest that strategies that are anabolic and antiresorptive to bone may be most effective in increasing BMD in women with anorexia nervosa.?? 

Sequential Therapy With Recombinant Human IGF-1 Followed by Risedronate Increases Spine Bone Mineral Density in Women With Anorexia Nervosa

Background Hypoparathyroidism (HP) is characterized by insufficient levels of parathyroid hormone (PTH), resulting in hypocalcemia, hyperphosphatemia, hypercalciuria, and a reduced quality of life (QoL). PTH replacement therapy should restore physiologic levels of PTH and restore downstream physiologic levels of calcitriol, promoting independence from Ca and active vitamin D supplements and normalization of QoL.?TransCon PTH is an investigational long-acting prodrug of PTH(1-34) for the treatment of HP. During the initial 4-week fixed-dose period of the PaTH Forward Trial, TransCon PTH enabled 82% of subjects to achieve independence from standard of care (SoC; no active vitamin D and Ca ≤ 500 mg/day) compared to 15% with placebo. Here, we report 6-month (Week 26) results from the open-label extension (OLE).?Methods PaTH Forward is a phase 2, double-blind, placebo-controlled trial evaluating TransCon PTH in adult HP patients treated with SoC. Subjects received fixed doses of TransCon PTH 15, 18, or 21 µg PTH(1-34)/day or placebo for 4 weeks, followed by an OLE period during which TransCon PTH dose was titrated (6-30 µg PTH[1-34]/day) per individual dosing requirement. Safety and efficacy endpoints were evaluated at predefined timepoints over the OLE. Endpoints were evaluated at Week 26 including 1) sCa, 2) 24-hour uCa, 3) independence from active vitamin D, and 4) independence from therapeutics doses of oral calcium. QoL was assessed by the SF-36 and the Hypoparathyroidism Patient Experience Scales (HPES).?ResultsAll 59 subjects completed the initial 4-week period and continued in the OLE; 58 subjects continue in the OLE beyond 6 months (1 withdrew unrelated to safety or efficacy). TransCon PTH enabled independence from SoC (no active vitamin D and Ca ≤ 500 mg/day) in 91% of subjects and independence from all supplements (no active vitamin D and no Ca) in 76% of subjects by Week 26. Mean 24-hour uCa decreased from a baseline mean of 415 mg/24h to 178 mg/24h by Week 26 (n = 44) while maintaining sCa, and reducing sP and CaxP to fall within the normal range. The mean scores for all SF-36 summary and domains increased from below normal at baseline to within the normal range by Week 26. The HPES Symptom and Impact scores continuously improved through 26 weeks for TransCon PTH and placebo subjects switching to TransCon PTH. TransCon PTH continued to be well-tolerated with no treatment-related serious or severe adverse events.?Conclusions Results from the OLE of the PaTH Forward Trial demonstrated that TransCon PTH continued to enable independence from active vitamin D and Ca supplements for most subjects while maintaining normal sCa, sP, uCa, and demonstrating enhanced quality of life, supporting its potential as a hormone replacement therapy for patients with HP. TransCon PTH will be further evaluated in the phase 3 PaTHway Trial.?? 

TransCon PTH as a Hormone Replacement Therapy for Patients with Hypoparathyroidism: 6-Month Update from the PaTH Forward Open-Label Extension

XLH is the most common heritable rickets. Affected children have high levels of circulating FGF23 that cause hypophosphatemia with consequent rickets and lower limb deformity. Burosumab, a fully human monoclonal antibody that binds FGF23, is FDA-approved for the treatment of XLH in children ≥6 months old and adults. Herein, we report final, 3-year safety and efficacy data from an open-label, phase 2 study of burosumab in children 1 to <5 years old at baseline (NCT02750618).?Eligibility required hypophosphatemia and radiographic evidence of rickets. The primary efficacy endpoint was change from baseline in fasting serum phosphorus (Pi). Secondary endpoints included Rickets Severity Score (RSS) and Radiographic Global Impression of Change (RGI-C). Patients received burosumab subcutaneous Q2W starting at 0.8 mg/kg for 160 weeks (64-week treatment + 96-week treatment extension periods).?All 13 enrolled patients completed the 64-week treatment period; 1 left the study to transition to commercially available burosumab, and 12 completed all 160 weeks. Baseline mean (SD) age was 2.9 (1.1) years; 69% were boys; all had previously received oral phosphate salts and active vitamin D.?Burosumab rapidly corrected fasting serum Pi with mean (SD) levels of 2.5 (0.3) mg/dL at Baseline, 3.7 (0.5) mg/dL at Week 1 (W1), 3.4 (0.5) mg/dL at W64, and 3.4 (0.5) mg/dL at W160 (normal range: 3.2-6.1 mg/dL). Lower RSS indicated improved rickets. Total RSS decreased from 2.9 (1.4) at Baseline to 1.2 (0.5) at W40 and to 0.9 (0.5) at W64 and was maintained through W160 [1.0 (0.6)]. Positive RGI-C scores indicate healing rickets relative to Baseline. Global RGI-C scores indicating substantial healing (≥+2) at W40 [+2.2 (0.3)] and W64 [+2.2 (0.4)] were maintained through W160 [+2.2 (0.4)]. Similarly, lower limb deformity RGI-C scores were +1.2 (0.6) at W40 and +1.5 (0.5) at W64, and sustained healing was evident at W160 [+2.0 (0.3)]. Wrist and knee RSSs and RGI-C scores similarly improved. The upper limit of normal for serum ALP ranged from 297 to 345 U/L depending on the child’s age and sex. Mean ALP was 549 (194) U/L at Baseline, normalized by W40 [335 (88) U/L], and was sustained through W160 [302 (71) U/L].?The burosumab safety profile over 160 weeks resembled previous pediatric studies; no new safety concerns emerged. All patients had ≥1 treatment-emergent adverse event (TEAE). All TEAEs were mild (Grade 1) or moderate (Grade 2) except for one patient with a grade 3 TEAE (food allergy) and one with a grade 3 TEAE (increased serum amylase, 92% salivary/8% pancreatic). One patient had a serious TEAE (dental abscess leading to hospitalization). These grade 3 and serious TEAEs were considered unrelated to study drug.?Burosumab rapidly restored Pi homeostasis, improved rickets, and normalized serum ALP in children with XLH aged 1 to <5 years with no new safety concerns. Improvements were maintained during the 3 years of treatment.?? 

Burosumab Provides Sustained Improvement in Phosphorus Homeostasis and Heals Rickets in Children Aged 1 to 4 Years With X-Linked Hypophosphatemia (XLH)

Results of the ADIUVO Study, the First Randomized Trial on Adjuvant Mitotane in Adrenocortical Carcinoma Patients

Downloads

Next from ENDO 2021

Modified GRAS Score for Prognostic Classification of Adrenocortical Carcinoma: An ENSAT Multicentre Study

Similar lecture

Meet the Scientist: Drugs, Steroids, and Cancer: Bridging the Worlds of Endocrinology, Metabolism, and Oncology

Stay up to date with the latest Underline news!

PRESENTATIONS

CONFERENCES

COMPANY

RESOURCES