Aimee D. Shu

All Publications

• Pharmacodynamics of sustained levels of PTH following palopegteriparatide treatment in adults with hypoparathyroidism JOURNAL OF THE ENDOCRINE SOCIETY Khan, A. A., Rejnmark, L., Jain, R., Pihl, S., Breinholt, V., Zhao, C., Lai, B., Ukena, J., Sibley, C. T., Shu, A. D. 2026; 10 (7)

  View details for DOI 10.1210/jendso/bvag098

  View details for Web of Science ID 001811338600001

• Sustained Improvement in Renal Function with Palopegteriparatide in Adults with Chronic Hypoparathyroidism: 2-Year Results from the Phase 3 PaTHway-Trial. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research Rejnmark, L., Gosmanova, E. O., Khan, A. A., Sprague, S., Shoback, D. M., Kohlmeier, L., Rubin, M. R., Palermo, A., Schwarz, P., Gagnon, C., Tsourdi, E., Takeuchi, Y., Makita, N., Imanishi, Y., Gittoes, N., Díez, J. J., Prot-Bertoye, C., Lai, B., Zhao, C., Ukena, J., Makara, M. A., Sibley, C. T., Shu, A. D. 2026

  Abstract

  The PaTHway clinical trial demonstrated sustained efficacy, safety, and tolerability of daily palopegteriparatide in the treatment of adults with hypoparathyroidism. Palopegteriparatide treatment was also associated with improvements in eGFR over 52 weeks in a post hoc analysis, prompting further exploration of palopegteriparatide in the preservation of renal function. The current post hoc analysis evaluated the impact of palopegteriparatide treatment on renal function in adults with hypoparathyroidism through Week 104; as with prior analysis, changes in renal function were assessed using eGFR. At Week 104, 93% (76/82) of participants remained in the open-label extension. Of those, 82% had albumin-adjusted serum calcium levels in the normal range (8.3-10.6 mg/dL), 97% were independent from conventional therapy (≤ 600 mg/day of elemental calcium and no active vitamin D). Mean (SD) serum phosphate (3.5 (0.7) mg/dL) and albumin-adjusted calcium x phosphate product (30.7(5.1) mg2/dL2) levels were also within normal ranges. Palopegteriparatide treatment resulted in a mean (SD) increase in eGFR of 8.9 (11.0) mL/min/1.73m2 (P<0.0001) from baseline to Week 52, which was sustained through Week 104, where it was 77.8 (14.8) mL/min/1,73m2 with a mean (SD) change from baseline of 9.0 (10.3) mL/min/1.73 m2 (P < 0.0001). By Week 104, 45% and 34% of participants had an increase in eGFR of ≥ 5 mL/min/1.73 m2 and ≥ 10 mL/min/1.73 m2, respectively. Palopegteriparatide treatment normalized mean (SD) 24-hour urine calcium within 26 weeks and maintained levels below 250 mg/day through Week 104 (158.8 (90.5) mg/24 h). Most treatment-emergent adverse events were mild or moderate; no new safety signals or cases of treatment-related nephrolithiasis were reported. These findings demonstrate sustained renal safety of palopegteriparatide and suggest that PTH replacement therapy with palopegteriparatide preserves and may improve renal function in adults with chronic hypoparathyroidism after 104 weeks of treatment.

  View details for DOI 10.1093/jbmr/zjag085

  View details for PubMedID 42166177

• Palopegteriparatide for Adults with Chronic Hypoparathyroidism: Skeletal Dynamics Through 3 yr of the Phase 2 paTH Forward Trial. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research Rubin, M. R., Clarke, B. L., Hofbauer, L. C., Khan, A., Schwarz, P., Vokes, T., Ahmed, I., Palermo, A., Cetani, F., Pagotto, U., Zhao, C., Ominsky, M. S., Lai, B., Ukena, J., Shu, A. D., Rejnmark, L. 2026

  Abstract

  Hypoparathyroidism is an endocrine disease caused by insufficient levels of parathyroid hormone (PTH), which acts directly on bone and kidney and indirectly on the intestine to regulate calcium and phosphate balance. In clinical trials, palopegteriparatide (TransCon PTH) treatment enabled independence from conventional therapy (no active vitamin D, ≤500 mg/d calcium) and maintained serum biochemistries within normal ranges. The current analyses describe patterns of change in bone mineral density (BMD), serum bone turnover markers, and serum and urine calcium in adults with chronic hypoparathyroidism treated with palopegteriparatide through 3 yr of the PaTH Forward trial. Baseline BMD Z-scores for the lumbar spine, total hip, femoral neck, and 1/3 distal radius were above zero, indicating bone mass exceeding age-adjusted normative values. BMD decreased from these elevated baseline levels with palopegteriparatide treatment, with larger reductions during the first 26 wk and modest declines thereafter. Mean BMD Z-scores at week 162 remained above zero for all 4 sites. Participants with lower baseline BMD (Z-scores below -1 and T-scores below -2.5) generally exhibited lesser declines in BMD versus those with higher baseline BMD. Palopegteriparatide treatment was associated with early increases in bone resorption (serum C-terminal telopeptide of type I collagen, CTx) and bone formation (serum procollagen type 1 N-terminal propeptide, P1NP) that peaked at weeks 12 and 26, respectively, followed by declines to levels moderately higher than baseline at week 162. Mean CTx and P1NP in the overall population and the subgroup of postmenopausal women were below their upper limits of normal from weeks 58-162. At week 162, mean serum and median urine calcium remained within normal ranges and 91% of participants were independent from conventional therapy. These results suggest that long-term palopegteriparatide therapy in adults with chronic hypoparathyroidism gradually returns the skeleton toward its natural state thereby enhancing the skeleton's contribution to calcium homeostasis.

  View details for DOI 10.1093/jbmr/zjag013

  View details for PubMedID 41636590

• Efficacy and Safety of Once-Weekly Lonapegsomatropin in Adults With Growth Hormone Deficiency: foresiGHt Trial Results JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Biller, B. M. K., Gilis-Januszewska, A., Doknic, M., Pico, A., Fleseriu, M., Raverot, G., Isidori, A. M., Takahashi, Y., Garcia, J. M., Silverstein, J. M., Bancos, I., Fukuoka, H., Huang, E., Kang, J., Komirenko, A. S., Domrzalski, L., Shu, A. D., Beckert, M., Yuen, K. C. J. 2026

  Abstract

  Adult growth hormone (GH) deficiency (GHD) is characterized by metabolic abnormalities caused by insufficient GH production. Lonapegsomatropin, a prodrug administered once weekly, was designed to provide sustained release of unmodified somatropin to reduce the burden of daily somatropin injections.To evaluate the efficacy and safety of lonapegsomatropin vs placebo as treatment for adults with GHD.The foresiGHt trial was a multicenter, randomized, parallel-arm, placebo-controlled (double-blind) and active-controlled (open-label) trial (NCT04615273).This trial was conducted at 116 centers in North America, Europe, and Asia-Pacific.This trial randomized and dosed 259 adults with GHD.Participants were randomized 1:1:1 to receive once-weekly lonapegsomatropin, once-weekly placebo, or daily somatropin for 38 weeks.The primary efficacy endpoint was change from baseline in trunk percent fat at week 38. Secondary efficacy endpoints included change from baseline in trunk fat mass and total body lean mass.At week 38, lonapegsomatropin significantly reduced trunk percent fat (-1.68% vs +0.37%; LS mean difference -2.04%, P<.001), increased total body lean mass (+1.60 kg vs -0.11 kg; LS mean difference 1.70 kg, P<.0001), and reduced trunk fat mass (-0.48 kg vs +0.22 kg; LS mean difference -0.70 kg, P=.0053) vs placebo. The safety and tolerability profile of lonapegsomatropin was comparable to somatropin.The foresiGHt trial met its primary efficacy endpoint by demonstrating superiority of lonapegsomatropin vs placebo with similar safety and tolerability, supporting its potential as a once-weekly treatment option for adults with GHD.

  View details for DOI 10.1210/clinem/dgaf680

  View details for Web of Science ID 001673053000001

  View details for PubMedID 41420532

• Longitudinal Observation of Children with Achondroplasia: Findings from a Global Natural History Study (ACHieve). Hormone research in paediatrics McDonnell, C., Hove, H. B., Irving, M., White, K. K., Fontecha, C. G., Legare, J. M., Hogler, W., Hoernschemeyer, D. G., Schnabel, D., Unger, S., Bacino, C. A., Hofman, P., Yu, Y., Ma, H., Gong, C., Luo, X., Burrow, T. A., Baujat, G., Mora, S., Fiscaletti, M., Zhao, C., Makara, M. A., Shu, A. D., Savarirayan, R. 2026: 1-12

  Abstract

  INTRODUCTION: The ACHieve study assessed growth velocity, body proportionality, and clinical events in children with achondroplasia not receiving growth-promoting therapy.METHODS: ACHieve was a global, longitudinal, prospective, observational study. Children ≤8 years old with achondroplasia were enrolled and evaluated every 6 months for anthropometric parameters and clinical events.RESULTS: ACHieve enrolled 259 children in 15 countries, including 83 from China. Median follow-up was 21 months; median age of diagnosis was approximately 52 weeks in China and 2 weeks elsewhere. Growth parameters were similar regardless of region. Mean annualized growth velocity was 9.3 cm/year for males and 10.4 cm/year for females at age 1 and decreased to 4.1 cm/year and 4.6 cm/year, respectively, at age 4. Upper-to-lower-body segment ratio was generally consistent across regions. Overall, 77.2% of participants experienced clinical events, 34.0% of which were considered related to achondroplasia. Two deaths occurred (one accident and one cardiac arrest of unknown origin).CONCLUSION: ACHieve was one of the largest longitudinal natural history studies of achondroplasia to date and included the largest prospective Chinese achondroplasia cohort. The results demonstrated common trajectories in growth parameters regardless of region, indicating the generalizability of findings.

  View details for DOI 10.1159/000550169

  View details for PubMedID 41505353

• Patient-Reported Outcomes in Palopegteriparatide-Treated Adults with Hypoparathyroidism: PaTH Forward Trial Extension. The Journal of clinical endocrinology and metabolism Rubin, M., Palermo, A., Vokes, T., Khan, A. A., Schwarz, P., Cetani, F., Pagotto, U., Tsourdi, E., Sikjaer, T., Pfeiffer, K. M., Brod, M., McLeod, L. D., Zhao, C., Noori, W., Shu, A. D., Smith, A. R. 2025

  Abstract

  Individuals with hypoparathyroidism experience a range of physical and cognitive symptoms and reduced quality of life (QoL) despite management with conventional therapy (active vitamin D and calcium).This analysis investigated the long-term impact of parathyroid hormone (PTH) replacement therapy with palopegteriparatide (YORVIPATH®) on symptoms, daily functioning, and well-being in adults with chronic hypoparathyroidism. Associations between patient characteristics and changes in patient-reported outcomes (PROs) were also analyzed.PaTH Forward was a phase 2 clinical trial of palopegteriparatide with a 4-week randomized, double-blind, placebo-controlled period followed by an open-label extension period lasting through trial week 266. PRO measures were collected at baseline, weeks 4, 12, 26, 58, and annually thereafter through the end of the trial. The Hypoparathyroidism Patient Experience Scales (HPES) assess disease-specific symptoms and impacts on functioning and well-being. The Short-Form Health Survey (SF-36v2) measures general health-related QoL. Data were analyzed using descriptive statistics and Mixed Models for Repeated Measures (MMRM).Palopegteriparatide treatment demonstrated significant improvements from baseline in disease-specific symptoms and impacts on daily functioning and well-being at week 12, which were sustained through week 110. Mean changes in PROs met thresholds for clinically meaningful within-patient improvement. Significant improvements in general health-related QoL were also shown in SF-36v2 scores. Results were generally similar across demographics and patient characteristics.Through week 110 of the PaTH Forward trial, PTH replacement therapy with palopegteriparatide was associated with significant improvements in disease-specific symptoms and impacts on daily functioning and well-being, as well as general health-related QoL.

  View details for DOI 10.1210/clinem/dgaf653

  View details for PubMedID 41365829

• Palopegteriparatide in Japanese adults with hypoparathyroidism: 52-week results from the phase 3 PaTHway Japan trial ENDOCRINE JOURNAL Ashida, K., Nomura, M., Makita, N., Imanishi, Y., Kanamoto, N., Zhao, C., Schneider, M., Ukena, J., Lai, B., Shu, A. D., Takeuchi, Y. 2026; 73 (2): 275-289

  Abstract

  PaTHway Japan is an ongoing, phase 3, multicenter, single-arm, open-label trial comprised of a 26-week efficacy period with an extension period through week 182 designed to demonstrate the efficacy, safety, and tolerability of palopegteriparatide in Japanese individuals with hypoparathyroidism. Japanese men and women (≥18 years of age) with hypoparathyroidism of any etiology (≥26 weeks) taking stable doses of active vitamin D were enrolled across five sites in Japan. Once-daily palopegteriparatide was self-administered subcutaneously via a pre-filled pen injector. Titration of palopegteriparatide and conventional therapy was performed according to a protocol-specified algorithm. The main outcomes measures included the proportion of participants at week 26 who achieved albumin-adjusted serum calcium in the normal reference range, independence from active vitamin D, and independence from therapeutic doses of elemental calcium. Thirteen participants were enrolled. Hypoparathyroidism etiology was most commonly idiopathic, followed by postsurgical and genetic causes. After 26 weeks of treatment with palopegteriparatide, 92% (12/13) of participants achieved the primary multi-component endpoint. Of the participants who entered the extension period, 92% (11/12) met the multi-component endpoint at week 52. Adverse events were mild to moderate in severity; none led to discontinuation of palopegteriparatide treatment. These findings in Japanese adults are consistent with results of the pivotal phase 3 and phase 2 North American/European trials and demonstrate the reproducibility of the palopegteriparatide treatment benefit in diverse populations and geographies. Japan Registry of Clinical Trials ID: jRCT2051210058.

  View details for DOI 10.1507/endocrj.EJ25-0376

  View details for Web of Science ID 001621790700001

  View details for PubMedID 41260697

  View details for PubMedCentralID PMC12895123

• Once-Weekly Navepegritide in Children With Achondroplasia: The APPROACH Randomized Clinical Trial. JAMA pediatrics Savarirayan, R., McDonnell, C., Bacino, C. A., Hoernschemeyer, D. G., Legare, J. M., Abuzzahab, M. J., Hofman, P. L., Campeau, P. M., de Bergua Domingo, J. M., Ward, L. M., Smit, K., Smith, A., Mao, M., Ominsky, M. S., Freiberg, L. C., Shu, A. D., Hove, H. B. 2025

  Abstract

  Importance: Historically considered a skeletal dysplasia characterized by disproportionate short stature, achondroplasia is a condition with multisystemic effects due to the widespread expression of the fibroblast growth factor receptor 3 variant throughout the body, impacting muscle, neurological function, cardiorespiratory health, and health-related quality of life.Objective: To evaluate the efficacy, safety, and tolerability of once-weekly navepegritide, an investigational prodrug of C-type natriuretic peptide, while assessing benefits beyond growth that may have important implications for complications and health-related quality of life in children with achondroplasia.Design, Setting, and Participants: Enrollment for this pivotal phase 2b, randomized, double-blind, placebo-controlled trial (APPROACH) was conducted between March and August 2023 at 10 hospitals in Australia, Canada, Denmark, Ireland, New Zealand, Spain, and the US with randomized, blind treatment through 52 weeks and an open-label extension (ongoing). Eligible participants aged 2 to 11 years had achondroplasia confirmed by genetic testing, were naive to treatment with growth-promoting agents, and had their height recorded at least 6 months prior to randomization. Enrolled participants were stratified by age and sex. Those with radiographic evidence of closed growth plates, planned bone surgery, severe untreated sleep apnea, or medical conditions known to affect growth were excluded (n=2 of 86); of 84 participants enrolled, all were analyzed for safety and efficacy outcomes, including 2 who discontinued treatment.Interventions: Navepegritide (100 mug/kg/wk) or placebo administered by once-weekly subcutaneous injection.Main Outcomes and Measures: The primary end point was annualized growth velocity at week 52. Other clinically important secondary measures included radiographically assessed skeletal outcomes and health-related quality of life, evaluated using Achondroplasia Child Experience Measures. Safety assessments included adverse events, clinical laboratory assessments, bone age, and immunogenicity.Results: Eighty-four participants were enrolled and assigned randomly in a 2:1 ratio to receive navepegritide (n=57; mean [SD] age, 5.6 [2.6] years; 31 [54%] male) or placebo (n=27; mean [SD] age, 6.0 [2.7] years; 14 [52%] male). All randomized participants were included in efficacy and safety analyses, although 2 patients in the navepegritide group discontinued treatment (one at week 26 and the other at week 34). The trial met its primary end point, demonstrating superiority of navepegritide in annualized growth velocity at week 52 vs placebo (least-squares mean treatment difference of 1.49 cm/y; 95% CI, 1.05 to 1.93; P<.001). Treatment resulted in improvements (least-squares mean treatment difference [95% CI]) in tibial-femoral angle (-1.81° [-3.16 to -0.47]), mechanical axis deviation (-2.78 mm [-4.71 to -0.86]), fibula to tibia length ratio (-0.016 [-0.024 to -0.008]), and Achondroplasia Child Experience Measures-Physical Functioning (-11.1 [-21.5 to -0.80] in children younger than 5 years). No serious adverse events were treatment-related, and no deaths occurred. Injection site reaction rates were low, and no symptomatic hypotension or fractures were observed.Conclusions: In this randomized clinical trial, navepegritide treatment resulted in statistically significantly higher annualized growth velocity in children with achondroplasia, with a similar safety and tolerability profile vs placebo. Moreover, navepegritide demonstrated additional potential health benefits beyond growth.Trial Registration: ClinicalTrials.gov Identifier: NCT05598320.

  View details for DOI 10.1001/jamapediatrics.2025.4771

  View details for PubMedID 41247754

• Efficacy and Safety of Palopegteriparatide Treatment in Adults With Hypoparathyroidism: 3-Year Results From the Phase 3 PaTHway Trial Khan, A., Clarke, B., Rubin, M., Schwarz, P., Shoback, D., Gagnon, C., Palermo, A., Abbott, L., Kohlmeier, L., Tsourdi, E., Cetani, F., Jain, R., Zhao, C., Lai, B., Makara, M. A., Ukena, J., Sibley, C. T., Shu, A. D., Rejnmark, L., Bertocchio, J. SMW supporting association. 2025

  View details for Web of Science ID 001639841800027

• Long-Term Efficacy and Safety of Palopegteriparatide Treatment in Adults With Chronic Hypoparathyroidism: 4-Year Results From the Phase 2 PaTH Forward Trial Palermo, A., Khan, A., Rubin, M., Schwarz, P., Clarke, B., Pagotto, U., Tsourdi, E., Cetani, F., Jain, R., Zhao, C., Ominsky, M., Lai, B., Ukena, J., Sibley, C. T., Shu, A. D., Rejnmark, L., Bertocchio, J. SMW supporting association. 2025

  View details for Web of Science ID 001639841800051

• TRANSCON CNP (NAVEPEGRITIDE) IMPROVED PHYSICAL FUNCTIONING IN CHILDREN WITH ACHONDROPLASIA (ACH) IN THE APPROACH TRIAL Bacino, C., Savarirayan, R., Hove, H., Hoernschemeyer, D., Legare, J., Abuzzahab, M., Hofman, P., Campeau, P., Domingo, J., Smith, A., Jorgensen, A., Freiberg, L., Ominsky, M., Shu, A., McDonnell, C. KARGER. 2025

  View details for Web of Science ID 001649311400094

• Improvements in Lower Extremity Alignment are Associated with Physical Functioning in Children With Achondroplasia Treated With Navepegritide: 52-Week Results From the ApproaCH Trial Ward, L. M., Hoernschemeyer, D. G., Legare, J. M., Hove, H. B., Bacino, C. A., Campeau, P. M., Hofman, P. L., Domingo, J., Abuzzahab, M., Smit, K., Carsen, S., Tice, A., Jackowski, S. A., Scharke, M., Mao, M., Freiberg, L., Makara, M., Ominsky, M. S., Shu, A. D., Savarirayan, R., McDonnell, C. M. OXFORD UNIV PRESS. 2025

  View details for Web of Science ID 001665519300272

• Improved Skeletal Dynamics in Adults Treated with Palopegteriparatide for Chronic Hypoparathyroidism: 214-Week Results from the Phase 2 PaTH Forward Trial Rubin, M. R., Khan, A. A., Schwarz, P., Palermo, A., Tsourdi, E., Cetani, F., Kohlmeier, L., Jain, R., Clarke, B., Zhao, C., Ominsky, M. S., Lai, B., Ukena, J., Sibley, C. T., Shu, A., Rejnmark, L. OXFORD UNIV PRESS. 2025

  View details for Web of Science ID 001665519300072

• Children with Growth Hormone Deficiency Treated with Lonapegsomatropin Demonstrated Sustained Height Improvements for up to 6 Years: enliGHten Trial Final Results HORMONE RESEARCH IN PAEDIATRICS Maniatis, A. K., Thornton, P. S., Nadgir, U. M., Vlachopapadopoulou, E., Malievskiy, O., Aghajanova, E. M., Korpal-Szczyrska, M., Woods, K. A., Mao, M., Zhao, C., Abdelrahman, S. G., Huang, E. A., Komirenko, A. S., Shu, A. D., Hofman, P. 2025: 1-13

  Abstract

  This international, Phase 3, open-label extension trial evaluated the long-term safety and efficacy of once-weekly lonapegsomatropin in children with growth hormone deficiency (GHD).Conducted across 63 sites (15 countries), the enliGHten trial enrolled children with GHD who previously participated in a Phase 3 lonapegsomatropin trial (heiGHt or fliGHt). Participants received subcutaneous injections of lonapegsomatropin dosed at 0.24 mg hGH/kg/week. Safety was monitored through adverse events, local tolerability, hormone levels, and metabolic parameters. Efficacy was evaluated through annualized height velocity (AHV), change in height standard deviation score (SDS), and IGF-1 SDS.Lonapegsomatropin demonstrated sustained efficacy with mean height SDS (-0.39 at year 4, n = 298) approaching the mean for children of average stature (height SDS = 0) over time. Eighty-one participants completed treatment for pediatric GHD during the trial, and 48 (59.3%) of these met or exceeded their average parental height SDS at their last visit. For the full population, mean values of weekly average IGF-1 remained within 0-2 SDS throughout the trial. Growth was maintained throughout pubertal development and the dose remained stable throughout the trial. Adverse events were mostly mild or moderate and remained consistent with prior reports of daily somatropin with no evidence of accelerated skeletal maturation or safety signals associated with anti-drug antibodies.Treatment of pediatric GHD with lonapegsomatropin in the enliGHten trial provided robust growth outcomes and maintained a safety profile comparable to that of daily GH in a population with a broad range of pubertal statuses.

  View details for DOI 10.1159/000545064

  View details for Web of Science ID 001478918900001

  View details for PubMedID 40049149

  View details for PubMedCentralID PMC12060840

• Palopegteriparatide Improves Skeletal Dynamics in Adults With Chronic Hypoparathyroidism: 3-Year Results From the Phase 2 PaTH Forward Trial Rubin, M. R., Khan, A., Schwarz, P., Ahmed, I., Palermo, A., Tsourdi, E., Cetani, F., Pagotto, U., Jain, R., Zhao, C., Ominsky, M. S., Lai, B., Ukena, J., Shu, A., Rejnmark, L. OXFORD UNIV PRESS. 2024: 369

  View details for Web of Science ID 001361790802230

• Efficacy and Safety of TransCon PTH in Adults with Hypoparathyroidism: 52-Week Results From the Phase 3 PaTHway Trial. The Journal of clinical endocrinology and metabolism Clarke, B. L., Khan, A. A., Rubin, M. R., Schwarz, P., Vokes, T., Shoback, D. M., Gagnon, C., Palermo, A., Abbott, L. G., Hofbauer, L. C., Kohlmeier, L., Cetani, F., Pihl, S., An, X., Smith, A. R., Lai, B., Ukena, J., Sibley, C. T., Shu, A. D., Rejnmark, L. 2024

  Abstract

  Conventional therapy for hypoparathyroidism aims to alleviate symptoms of hypocalcemia but does not address insufficient parathyroid hormone (PTH) levels.Assess the long-term efficacy and safety of TransCon PTH (palopegteriparatide) for hypoparathyroidism.Phase 3 trial with a 26-week double-blind, placebo-controlled period followed by a 156-week open-label extension (OLE).21 sites across North America and Europe.82 adults with hypoparathyroidism were randomized and received study drug and 78 completed week 52.All OLE participants received TransCon PTH administered once daily.Multi-component efficacy endpoint: proportion of participants at week 52 who achieved 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 efficacy endpoints included patient-reported outcomes (PROs) and bone mineral density (BMD). Safety was assessed by 24-hour urine calcium and treatment-emergent adverse events (TEAEs).At week 52, 81% (63/78) met the multi-component efficacy endpoint, 95% (74/78) achieved independence from conventional therapy, and none required active vitamin D. PROs showed sustained improvements in quality of life, physical functioning, and well-being. Mean BMD Z-scores decreased toward age- and sex-matched norms from baseline to week 52. Mean (SD) 24-hour urine calcium excretion decreased from 376 (168) mg/day at baseline to 195 (114) mg/day at week 52. Most TEAEs were mild or moderate and none led to trial discontinuation during the OLE.At week 52 of the PaTHway trial, TransCon PTH showed sustained efficacy, safety, and tolerability in adults with hypoparathyroidism.

  View details for DOI 10.1210/clinem/dgae693

  View details for PubMedID 39376010

• Palopegteriparatide Treatment Improves Renal Function in Adults with Chronic Hypoparathyroidism: 1-Year Results from the Phase 3 PaTHway Trial. Advances in therapy Rejnmark, L., Gosmanova, E. O., Khan, A. A., Makita, N., Imanishi, Y., Takeuchi, Y., Sprague, S., Shoback, D. M., Kohlmeier, L., Rubin, M. R., Palermo, A., Schwarz, P., Gagnon, C., Tsourdi, E., Zhao, C., Makara, M. A., Ominsky, M. S., Lai, B., Ukena, J., Sibley, C. T., Shu, A. D. 2024

  Abstract

  Individuals with chronic hypoparathyroidism managed with conventional therapy (active vitamin D and calcium) have an increased risk for renal dysfunction versus age- and sex-matched controls. Treatments that replace the physiologic effects of parathyroid hormone (PTH) while reducing the need for conventional therapy may help prevent a decline in renal function in this population. This post hoc analysis examined the impact of palopegteriparatide treatment on renal function in adults with chronic hypoparathyroidism.PaTHway is a phase 3 trial of palopegteriparatide in adults with chronic hypoparathyroidism that included a randomized, double-blind, placebo-controlled 26-week period followed by an ongoing 156-week open-label extension (OLE) period. Changes in renal function over 52 weeks (26 weeks blinded + 26 weeks OLE) were assessed using estimated glomerular filtration rate (eGFR). A subgroup analysis was performed with participants stratified by baseline eGFR < 60 or ≥ 60 mL/min/1.73 m2.At week 52, over 95% (78/82) of participants remained enrolled in the OLE and of those, 86% maintained normocalcemia and 95% achieved independence from conventional therapy (no active vitamin D and ≤ 600 mg/day of calcium), with none requiring active vitamin D. Treatment with palopegteriparatide over 52 weeks resulted in a mean (SD) increase in eGFR of 9.3 (11.7) mL/min/1.73 m2 from baseline (P < 0.0001) and 43% of participants had an increase ≥ 10 mL/min/1.73 m2. In participants with baseline eGFR < 60 mL/min/1.73 m2, 52 weeks of treatment with palopegteriparatide resulted in a mean (SD) increase of 11.5 (11.3) mL/min/1.73 m2 (P < 0.001). One case of nephrolithiasis was reported for a participant in the placebo group during blinded treatment; none were reported through week 52 with palopegteriparatide.In this post hoc analysis of the PaTHway trial, palopegteriparatide treatment was associated with significantly improved eGFR at week 52 in addition to previously reported maintenance and normalization of serum and urine biochemistries. Further investigation of palopegteriparatide for the preservation of renal function in hypoparathyroidism is warranted.ClinicalTrials.gov NCT04701203.

  View details for DOI 10.1007/s12325-024-02843-8

  View details for PubMedID 38691316

  View details for PubMedCentralID 8087595

• Once-weekly TransCon CNP (navepegritide) in children with achondroplasia (ACcomplisH): a phase 2, multicentre, randomised, double-blind, placebo-controlled, dose-escalation trial. EClinicalMedicine Savarirayan, R., Hoernschemeyer, D. G., Ljungberg, M., Zarate, Y. A., Bacino, C. A., Bober, M. B., Legare, J. M., Hogler, W., Quattrin, T., Abuzzahab, M. J., Hofman, P. L., White, K. K., Ma, N. S., Schnabel, D., Sousa, S. B., Mao, M., Smith, A., Chakraborty, M., Giwa, A., Winding, B., Volck, B., Shu, A. D., McDonnell, C. 2023; 65: 102258

  Abstract

  Background: TransCon CNP (navepegritide) is an investigational prodrug of C-type natriuretic peptide (CNP) designed to allow for continuous CNP exposure with once-weekly dosing. This 52-week phase 2 (ACcomplisH) trial assessed the safety and efficacy of TransCon CNP in children with achondroplasia.Methods: ACcomplisH is a global, randomised, double-blind, placebo-controlled, dose-escalation trial. Study participants were recruited between June 10, 2020, and September 24, 2021. Eligible participants were prepubertal, aged 2-10 years, with genetically confirmed achondroplasia, and randomised 3:1 to once-weekly subcutaneous injections of TransCon CNP (6, 20, 50, or 100mug CNP/kg/week) or placebo for 52 weeks. Primary objectives were safety and annualised growth velocity (AGV). ACcomplisH is registered with ClinicalTrials.gov (NCT04085523) and Eudra (CT 2019-002754-22).Findings: Forty-two participants received TransCon CNP at doses of 6mug (n=10; 7 female), 20mug (n=11; 3 female), 50mug (n=10; 3 female), or 100mug (n=11; 6 female) CNP/kg/week, with 15 receiving placebo (5 female). Treatment-emergent adverse events (TEAEs) were mild or moderate with no grade 3/4 events reported. There were 2 serious TEAEs that were assessed as not related to TransCon CNP. Eleven injection site reactions occurred in 8 participants receiving TransCon CNP and no symptomatic hypotension occurred. TransCon CNP demonstrated a dose-dependent improvement in AGV. At 52 weeks, TransCon CNP 100mug CNP/kg/week significantly improved AGV vs placebo (least squares mean [95% CI] 5.42 [4.74-6.11] vs 4.35 [3.75-4.94] cm/year; p=0.0218), and improved achondroplasia-specific height SDS from baseline (least squares mean [95% CI] 0.22 [0.02-0·41] vs-0·08 [-0.25 to 0.10]; p=0.0283). All participants completed the randomised period and continued in the ongoing open-label extension period receiving TransCon CNP 100mug CNP/kg/week.Interpretation: This phase 2 trial suggests that TransCon CNP is effective, safe, with low injection site reaction frequency, and may provide a novel, once-weekly treatment option for children with achondroplasia. These results support TransCon CNP at 100mug CNP/kg/week in the ongoing pivotal trial.Funding: Ascendis Pharma, A/S.

  View details for DOI 10.1016/j.eclinm.2023.102258

  View details for PubMedID 37823031

• Improved Skeletal Dynamics in Adults Treated With Palopegteriparatide for Hypoparathyroidism: 52-Week Analysis of Phase 3 PaTHway Trial Khan, A. A., Rubin, M. R., Shoback, D. M., Schwarz, P., Kohlmeier, L., Palermo, A., Clarke, B. L., Eriksen, E., Tsourdi, E., Cetani, F., Jain, R., Zhao, C., Lai, B., Ukena, J., Sibley, C. T., Ominsky, M., Shu, A. D., Rejnmark, L. OXFORD UNIV PRESS. 2023: 432-433

  View details for Web of Science ID 001266167002165

• Content validation of the SF-36v2® Health Survey Acute for use in hypoparathyroidism QUALITY OF LIFE RESEARCH Brod, M., Waldman, L., Shu, A. D., Smith, A. 2023; 32 (6): 1795-1806

  Abstract

  The purpose of this study was to conduct cognitive debriefing (CD) interviews with adults diagnosed with chronic hypoparathyroidism (HP) to assess the content validity of the SF-36v2® Health Survey Acute (SF-36v2) measure in this population.CD interviews were conducted with adults with HP in the United States (US). Interviews were conducted by a trained moderator using a semi-structured interview guide, employing a think-aloud method in conjunction with verbal probing. Participants were asked whether each item was understandable, relevant, important, and sensitive to change in relation to HP. Additionally, comprehension of instructions, response options, and the appropriateness of a 1-week recall period was assessed.Sixteen adults with HP participated in individual CD telephone interviews. All items in the SF-36v2 were reported to be understood, relevant, important, and sensitive to change by at least half, and in most cases, by a strong majority of study participants. Most of the study sample confirmed comprehension of the instructions and the entire sample understood all response options.The study findings show that the items in the SF-36v2® are applicable to adults with HP. The overall high levels of endorsement of items provide strong evidence of the measure's content validity for this population. The SF-36v2 is therefore recommended for usage in clinical trials examining adults with HP, although it is recommended that this generic measure be supplemented with disease-specific instruments such as the recently developed Hypoparathyroidism Patient Experience Scale-Symptom (HPES-Symptom) and Hypoparathyroidism Patient Experience Scale-Impact (HPES-Impact) measures.

  View details for DOI 10.1007/s11136-023-03352-x

  View details for Web of Science ID 000932013500001

  View details for PubMedID 36759379

  View details for PubMedCentralID PMC10172226

• TransCon PTH for Hypoparathyroidism: Skeletal Dynamics Through Week 58 of the Phase 2 PaTH Forward Trial Rubin, M., Clarke, B., Hofbauer, L. C., Khan, A., Schwarz, P., Vokes, T., Ahmed, I., Palermo, A., Marcocci, C., Pagotto, U., Eriksen, E., An, X., Lai, B., Le, J., Ukena, J., Shu, A. D., Rejnmark, L. WILEY. 2023: 27

  View details for Web of Science ID 001008985200080

• Efficacy and Safety of Parathyroid Hormone Replacement with TransCon PTH in Hypoparathyroidism: 26-Week Results From the Phase 3 PaTHway Trial. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research Khan, A. A., Rubin, M. R., Schwarz, P., Vokes, T., Shoback, D. M., Gagnon, C., Palermo, A., Marcocci, C., Clarke, B. L., Abbott, L. G., Hofbauer, L. C., Kohlmeier, L., Pihl, S., An, X., Eng, W. F., Smith, A. R., Ukena, J., Sibley, C. T., Shu, A. D., Rejnmark, L. 2022

  Abstract

  Conventional therapy for hypoparathyroidism consisting of active vitamin D and calcium aims to alleviate hypocalcemia but fails to restore normal parathyroid hormone (PTH) physiology. PTH replacement therapy is the ideal physiologic treatment for hypoparathyroidism. The double-blind, placebo-controlled, 26-week, phase 3 PaTHway trial assessed the efficacy and safety of PTH replacement therapy for hypoparathyroidism individuals with the investigational drug TransCon PTH (palopegteriparatide). Participants (n=84) were randomized 3:1 to once-daily TransCon PTH (initially 18 mug/d) or placebo, both co-administered with conventional therapy. The study drug and conventional therapy were titrated according to a dosing algorithm guided by serum calcium. The composite primary efficacy endpoint was the proportion of participants at week 26 who achieved: normal albumin-adjusted serum calcium levels (8.3-10.6 mg/dL), independence from conventional therapy (requiring no active vitamin D and ≤600 mg/day of calcium), and no increase in study drug over 4weeks prior to week 26. Other outcomes of interest included health-related quality of life measured by the 36-Item Short Form Survey (SF-36), hypoparathyroidism-related symptoms, functioning, and well-being measured by the Hypoparathyroidism Patient Experience Scale (HPES), and urinary calcium excretion. At week 26, 79% (48/61) participants treated with TransCon PTH versus 5% (1/21) placebo met the composite primary efficacy endpoint (p<0.0001). TransCon PTH treatment demonstrated a significant improvement in all key secondary endpoint HPES domain scores (all p<0.01) and the SF-36 Physical Functioning subscale score (p=0.0347) compared to placebo. Additionally, 93% (57/61) of participants treated with TransCon PTH achieved independence from conventional therapy. TransCon PTH treatment normalized mean 24-hour urine calcium. Overall, 82% (50/61) treated with TransCon PTH and 100% (21/21) placebo experienced adverse events; most were mild (46%) or moderate (46%). No study drug-related withdrawals occurred. In conclusion, TransCon PTH maintained normocalcemia while permitting independence from conventional therapy and was well-tolerated in individuals with hypoparathyroidism. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/jbmr.4726

  View details for PubMedID 36271471

• Switching to Weekly Lonapegsomatropin from Daily Somatropin in Children with Growth Hormone Deficiency: The fliGHt Trial HORMONE RESEARCH IN PAEDIATRICS Maniatis, A. K., Nadgir, U., Saenger, P., Reifschneider, K. L., Abuzzahab, J., Deeb, L., Fox, L. A., Woods, K. A., Song, W., Mao, M., Chessler, S. D., Komirenko, A. S., Shu, A. D., Casella, S. J., Thornton, P. S. 2022; 95 (3): 233-243

  Abstract

  The phase 3 fliGHt Trial evaluated the safety and tolerability of once-weekly lonapegsomatropin, a long-acting prodrug, in children with growth hormone deficiency (GHD) who switched from daily somatropin therapy to lonapegsomatropin.This multicenter, open-label, 26-week phase 3 trial took place at 28 sites across 4 countries (Australia, Canada, New Zealand, and the USA). The trial enrolled 146 children with GHD, 143 of which were previously treated with daily somatropin. All subjects received once-weekly lonapegsomatropin 0.24 mg human growth hormone/kg/week. The primary outcome measure was safety and tolerability of lonapegsomatropin over 26 weeks. Secondary outcome measures assessed annualized height velocity (AHV), height standard deviation score (SDS), and IGF-1 SDS at 26 weeks.Subjects had a mean prior daily somatropin dose of 0.29 mg/kg/week. Treatment-emergent adverse events (AEs) reported were similar to the published AE profile of daily somatropin therapies. After switching to lonapegsomatropin, the least-squares mean (LSM) AHV was 8.7 cm/year (95% CI: 8.2, 9.2) at Week 26 and LSM height SDS changed from baseline to Week 26 of +0.25 (95% CI: 0.21, 0.29). Among switch subjects, the LSM for average IGF-1 SDS was sustained at Weeks 13 and 26, representing an approximate 0.7 increase from baseline (prior to switching from daily somatropin therapy). Patient-reported outcomes indicated a preference for weekly lonapegsomatropin among both children and their parents.Lonapegsomatropin treatment outcomes were as expected across a range of ages and treatment experiences. Switching to lonapegsomatropin resulted in a similar AE profile to daily somatropin therapy.

  View details for DOI 10.1159/000524003

  View details for Web of Science ID 000868315100004

  View details for PubMedID 35263755

  View details for PubMedCentralID PMC9501775

• Safety and Efficacy of Lonapegsomatropin in Children With Growth Hormone Deficiency: enliGHten Trial 2-Year Results JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Maniatis, A. K., Casella, S. J., Nadgir, U. M., Hofman, P. L., Saenger, P., Chertock, E. D., Aghajanova, E. M., Korpal-Szczyrska, M., Vlachopapadopoulou, E., Malievskiy, O., Chaychenko, T., Cappa, M., Song, W., Mao, M., Mygind, P., Smith, A. R., Chessler, S., Komirenko, A. S., Beckert, M., Shu, A. D., Thornton, P. S. 2022; 107 (7): E2680-E2689

  Abstract

  The objectives of the ongoing, Phase 3, open-label extension trial enliGHten are to assess the long-term safety and efficacy of weekly administered long-acting growth hormone lonapegsomatropin in children with growth hormone deficiency.Eligible subjects completing a prior Phase 3 lonapegsomatropin parent trial (heiGHt or fliGHt) were invited to participate. All subjects were treated with lonapegsomatropin. Subjects in the United States switched to the TransCon hGH Auto-Injector when available. Endpoints were long-term safety, annualized height velocity, pharmacodynamics [insulin-like growth factor-1 SD score (SDS) values], and patient- and caregiver-reported assessments of convenience and tolerability.Lonapegsomatropin treatment during enliGHten was associated with continued improvements in height SDS through week 104 in treatment-naïve subjects from the heiGHt trial (-2.89 to -1.37 for the lonapegsomatropin group; -3.0 to -1.52 for the daily somatropin group). Height SDS also continued to improve among switch subjects from the fliGHt trial (-1.42 at fliGHt baseline to -0.69 at week 78). After 104 weeks, the average bone age/chronological age ratio for each treatment group was 0.8 (0.1), showing only minimal advancement of bone age relative to chronological age with continued lonapegsomatropin treatment among heiGHt subjects. Fewer local tolerability reactions were reported with the TransCon hGH Auto-Injector compared with syringe/needle.Treatment with lonapegsomatropin continued to be safe and well-tolerated, with no new safety signals identified. Children treated with once-weekly lonapegsomatropin showed continued improvement of height SDS through the second year of therapy without excess advancement of bone age.

  View details for DOI 10.1210/clinem/dgac217

  View details for Web of Science ID 000796682100001

  View details for PubMedID 35428884

  View details for PubMedCentralID PMC9202697

• Sustained Benefit of TransCon PTH, a Potential Hormone Replacement Therapy for Patients with Hypoparathyroidism, at Week 58 in the PaTH Forward Trial Khan, A., Schwarz, P., Rubin, M. R., Vokes, T., Clarke, B. L., Ahmed, I., Hofbauer, L. C., Palermo, A., Marcocci, C., Pagotto, U., Eriksen, E., Markova, D., Pihl, S., Le, J., Beckert, M., Shu, A. D., Rejnmark, L. WILEY. 2022: 350

  View details for Web of Science ID 000778074501484

• Response to Letter to the Editor From Malozowski: "Weekly Lonapegsomatropin in Treatment-Naive Children With Growth Hormone Deficiency: The Phase 3 heiGHt Trial" JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Thornton, P. S., Maniatis, A. K., Aghajanova, E., Chertok, E., Lin, Z., Song, W., Christoffersen, E., Breinholt, V., Giorgadze, E., Korpal-Szczyrska, M., Hofman, P. L., Karpf, D. B., Shu, A. D., Beckert, M. 2022; 107 (5): E2215-E2216

  View details for DOI 10.1210/clinem/dgab879

  View details for Web of Science ID 000783663300087

  View details for PubMedID 34915563

  View details for PubMedCentralID PMC9016423

• Average IGF-1 Prediction for Once-Weekly Lonapegsomatropin in Children With Growth Hormone Deficiency JOURNAL OF THE ENDOCRINE SOCIETY Lin, Z., Shu, A. D., Bach, M., Miller, B. S., Rogol, A. D. 2022; 6 (1): bvab168

  Abstract

  Serum insulin-like growth factor 1 (IGF-1) levels are relatively constant in somatropin-treated children with growth hormone deficiency (GHD), and guide dose adjustments for clinical efficacy and long-term safety. IGF-1 levels following treatment with long-acting growth hormones such as lonapegsomatropin (lonapegsomatropin-tcgd, TransCon hGH), a once-weekly somatropin prodrug, exhibit a characteristic profile over the dosing interval.This study aimed to develop a method to predict average IGF-1 in lonapegsomatropin-treated GHD children to interpret IGF-1 data based on a single sample obtained any time at steady state.A population nonlinear mixed-effect pharmacodynamic model for IGF-1 was developed based on 2 randomized, open-label trials of TransCon hGh in GHD children and used to develop a linear mixed model with Taylor series to fit simulated IGF-1 profiles of lonapegsomatropin-treated children.49 896 IGF-1 sample data simulated from 105 lonapegsomatropin-treated GHD children were utilized for the final prediction model. The dosage range of TransCon hGh was 0.14 to 0.30 hGH mg/kg/week, and weekly average IGF-1 was calculated using IGF-1 profiles simulated from the nonlinear pharmacodynamic model. Predicted average IGF-1 was obtained by linear mixed model with Taylor series.The nonlinear mixed-effect model provided satisfactory model fit. The linear mixed model with Taylor series fit simulated IGF-1 data well, with a relatively straightforward prediction formula. IGF-1 values sampled at ~4.5 days post-dose coincided with weekly average IGF-1 at steady state.A formula to predict average IGF-1 from a single sample of IGF-1 at steady state was established to aid clinicians in interpreting IGF-1 levels in GHD children administered lonapegsomatropin.

  View details for DOI 10.1210/jendso/bvab168

  View details for Web of Science ID 000744315300004

  View details for PubMedID 34913019

  View details for PubMedCentralID PMC8668201

• Response to Letter to the Editor From L. Savendahl et al: "Weekly Lonapegsomatropin in Treatment-Naive Children With Growth Hormone Deficiency: The Phase 3 heiGHt Trial" JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Thornton, P. S., Maniatis, A. K., Aghajanova, E., Chertok, E., Vlachopapadopoulou, E., Lin, Z., Song, W., Christoffersen, E., Breinholt, V., Kovalenko, T., Giorgadze, E., Korpal-Szczyrska, M., Hofman, P. L., Karpf, D. B., Shu, A. D., Beckert, M. 2022; 107 (3): E1333-E1334

  View details for DOI 10.1210/clinem/dgab738

  View details for Web of Science ID 000756897900073

  View details for PubMedID 34626470

  View details for PubMedCentralID PMC8852228

• Psychometric validation of the Hypoparathyroidism Patient Experience Scales (HPES) JOURNAL OF PATIENT-REPORTED OUTCOMES Brod, M., McLeod, L., Markova, D., Gianettoni, J., Mourya, S., Lin, Z., Shu, A., Smith, A. 2021; 5 (1): 70

  Abstract

  Hypoparathyroidism (HP) is a rare endocrine disorder characterized by absent or inappropriately low levels of circulating parathyroid hormone with associated significant physical and cognitive symptoms. This study evaluated the psychometric properties of the Hypoparathyroidism Patient Experience Scales (HPES), which were developed as disease-specific, patient-reported outcome (PRO) measures to assess the symptoms and impacts associated with HP in adults.Data from a non-interventional, observational study (N = 300) and a Phase 2 clinical trial (N = 59) were used in the psychometric evaluation. Observational and trial assessments included: an online validation battery (baseline or screening) and retest (approximately 2 weeks after baseline or screening). In the trial, the primary efficacy endpoint was assessed at week 4 through re-administration of the HPES and validation battery subset. The observational study's larger sample size allowed for evaluation of the HPES descriptive properties, scoring algorithm, test-retest reliability, and construct validity. The trial data examined responsiveness, meaningful within-patient change estimates, and treatment impact on HPES scores.Demographic and self-reported medical characteristics results were similar across the 2 studies. Factor analysis confirmed domains in the HPES-Symptom (n = 2) and HPES-Impact (n = 4). For both measures, total and domain scores demonstrated acceptable reliability and validity for both the observational and trial samples. Internal consistency evidence was strong. Test-retest reliability estimates generally approached the recommended 0.70 threshold. The construct validity correlations with other PRO measures were mainly as hypothesized, thus supporting the HPES scores and constructs. Mean scores for both measures also differed as anticipated and significantly across known-groups, thus providing evidence for the scores discriminating between meaningful groups. Trial results supported both HPES total and domain scores' ability to detect change. The difference in mean total and domain scores for both measures demonstrated statistically significant improvements for TransCon PTH compared to placebo treated subjects despite the small sample and a short 4-week duration on fixed, non-optimized doses.The HPES were found to be conceptually sound with adequate evidence supporting their reliability and validity. Incorporation of the HPES into clinical and research settings will help to further elucidate and assess the patient experience of living with HP and identify treatment differences.

  View details for DOI 10.1186/s41687-021-00320-2

  View details for Web of Science ID 000685102600002

  View details for PubMedID 34374868

  View details for PubMedCentralID PMC8355305

• PaTH Forward: A randomized, double-blind, placebo-controlled phase 2 trial of TransCon PTH in adult hypoparathyroidism. The Journal of clinical endocrinology and metabolism Khan, A. A., Rejnmark, L., Rubin, M., Schwarz, P., Vokes, T., Clarke, B., Ahmed, I., Hofbauer, L., Marcocci, C., Pagotto, U., Palermo, A., Eriksen, E., Brod, M., Markova, D., Smith, A., Pihl, S., Mourya, S., Karpf, D. B., Shu, A. D. 2021

  Abstract

  CONTEXT: Hypoparathyroidism is characterized by insufficient levels of parathyroid hormone (PTH). TransCon PTH is an investigational long-acting prodrug of PTH(1-34) for the treatment of hypoparathyroidism.OBJECTIVE: Investigate the safety, tolerability, and efficacy of daily TransCon PTH in adults with hypoparathyroidism.DESIGN: Phase 2, randomized, double-blind, placebo-controlled 4-week trial with open-label extension.PATIENTS: Enrolled 59 subjects with hypoparathyroidism.INTERVENTIONS: TransCon PTH 15, 18, or 21 g PTH(1-34)/day or placebo for 4 weeks, followed by a 26-week extension where TransCon PTH dose was titrated (6-60 g PTH[1-34]/day).RESULTS: By Week 26, 91% of subjects treated with TransCon PTH achieved independence from standard of care (SoC, defined as active vitamin D = 0 mcg/day and calcium (Ca) ≤ 500mg/day). Mean 24-hour urine Ca (uCa) decreased from a baseline mean of 415mg/24h to 178mg/24h by Week 26 (n=44) while normal serum Ca (sCa) was maintained and serum phosphate (sP) and Ca x P fell within the normal range. By Week 26, mean scores on SF-36 domains increased from below normal at baseline to within the normal range. The Hypoparathyroidism Patient Experience Scale Symptom and Impact scores improved through 26 weeks. TransCon PTH was well-tolerated with no treatment-related serious or severe adverse events.CONCLUSIONS: TransCon PTH enabled independence from oral active vitamin D and reduced Ca supplements (≤ 500mg/day) for most subjects, achieving normal sCa, sP, uCa, CaxP, and demonstrating improved health-related quality of life. These results support TransCon PTH as a potential hormone replacement therapy for adults with hypoparathyroidism.

  View details for DOI 10.1210/clinem/dgab577

  View details for PubMedID 34347093

• Weekly Lonapegsomatropin in Treatment-Naive Children With Growth Hormone Deficiency: The Phase 3 heiGHt Trial JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Thornton, P. S., Maniatis, A. K., Aghajanova, E., Chertok, E., Vlachopapadopoulou, E., Lin, Z., Song, W., Christoffersen, E., Breinholt, V., Kovalenko, T., Giorgadze, E., Korpal-Szczyrska, M., Hofman, P. L., Karpf, D. B., Shu, A. D., Beckert, M. 2021; 106 (11): 3184-3195

  Abstract

  For children with growth hormone deficiency (GHD), treatment burden with daily somatropin injections [human growth hormone (hGH)] is high, which may lead to poor adherence and suboptimal overall treatment outcomes. Lonapegsomatropin (TransCon hGH) is an investigational long-acting, once-weekly prodrug for the treatment of GHD.The objective of this study was to evaluate the efficacy and safety of once-weekly lonapegsomatropin vs daily somatropin.The heiGHt trial was a randomized, open-label, active-controlled, 52-week Phase 3 trial (NCT02781727).This trial took place at 73 sites across 15 countries.This trial enrolled and dosed 161 treatment-naïve, prepubertal patients with GHD.Patients were randomized 2:1 to receive lonapegsomatropin 0.24 mg hGH/kg/week or an equivalent weekly dose of somatropin delivered daily.The primary end point was annualized height velocity (AHV) at week 52. Secondary efficacy end points included change from baseline in height SD scores (SDS).Least squares (LS) mean (SE) AHV at 52 weeks was 11.2 (0.2) cm/year for lonapegsomatropin vs 10.3 (0.3) cm/year for daily somatropin (P = 0.009), with lonapegsomatropin demonstrating both noninferiority and superiority over daily somatropin. LS mean (SE) height SDS increased from baseline to week 52 by 1.10 (0.04) vs 0.96 (0.05) in the weekly lonapegsomatropin vs daily somatropin groups (P = 0.01). Bone age/chronological age ratio, adverse events, tolerability, and immunogenicity were similar between groups.The trial met its primary objective of noninferiority in AHV and further showed superiority of lonapegsomatropin compared to daily somatropin, with similar safety, in treatment-naïve children with GHD.

  View details for DOI 10.1210/clinem/dgab529

  View details for Web of Science ID 000715561700008

  View details for PubMedID 34272849

  View details for PubMedCentralID PMC8530727

• Declining Rates of Inpatient Parathyroidectomy for Primary Hyperparathyroidism in the US. PloS one Kim, S. M., Shu, A. D., Long, J., Montez-Rath, M. E., Leonard, M. B., Norton, J. A., Chertow, G. M. 2016; 11 (8)

  Abstract

  Parathyroidectomy is the only curative therapy for patients with primary hyperparathyroidism. However, the incidence, correlates and consequences of parathyroidectomy for primary hyperparathyroidism across the entire US population are unknown. We evaluated temporal trends in rates of inpatient parathyroidectomy for primary hyperparathyroidism, and associated in-hospital mortality, length of stay, and costs. We used the Healthcare Cost and Utilization Project Nationwide Inpatient Sample (NIS) from 2002-2011. Parathyroidectomies for primary hyperparathyroidism were identified using International Classification of Diseases, Ninth Revision codes. Unadjusted and age- and sex- adjusted rates of inpatient parathyroidectomy for primary hyperparathyroidism were derived from the NIS and the annual US Census. We estimated 109,583 parathyroidectomies for primary hyperparathyroidism between 2002 and 2011. More than half (55.4%) of patients were younger than age 65, and more than three-quarters (76.8%) were female. The overall rate of inpatient parathyroidectomy was 32.3 cases per million person-years. The adjusted rate decreased from 2004 (48.3 cases/million person-years) to 2007 (31.7 cases/million person-years) and was sustained thereafter. Although inpatient parathyroidectomy rates declined over time across all geographic regions, a steeper decline was observed in the South compared to other regions. Overall in-hospital mortality rates were 0.08%: 0.02% in patients younger than 65 years and 0.14% in patients 65 years and older. Inpatient parathyroidectomy rates for primary hyperparathyroidism have declined in recent years.

  View details for DOI 10.1371/journal.pone.0161192

  View details for PubMedID 27529699

• Quality of life and hypertension after hormone therapy withdrawal in New York City MENOPAUSE-THE JOURNAL OF THE NORTH AMERICAN MENOPAUSE SOCIETY Warren, M. P., Richardson, O., Chaudhry, S., Shu, A. D., Swica, Y., Sims, V. R., Sloan, N. L. 2013; 20 (12): 1255-1263

  Abstract

  Many women stopped hormone therapy (HT) or estrogen therapy (ET) after the Women's Health Initiative results were published in 2002. This study assessed the incidence of hypertension, weight gain, and dyslipidemia; conditions that predispose to chronic diseases; medication use; and quality of life in women who used HT/ET for at least 5 years and subsequently stopped its use compared with those who continued its use.A retrospective study was conducted. All consenting eligible women (aged 56-73 y) in physicians' offices were interviewed, and measurements of weight, height, waist-to-hip ratio, and body fat were performed. Standardized quality-of-life and menopausal and medical questionnaires were administered. Three groups were compared: group 1, women who have remained on HT/ET; group 2, women who have resumed HT/ET after stopping for at least 6 months; and group 3, women who have stopped HT/ET and have not resumed.One hundred fifty-nine women were enrolled in group 1, 43 women were enrolled in group 2, and 108 women were enrolled in group 3. Women's characteristics were similar, except that group 3 was 1.5 (0.5) years older and had 4.4 (0.7) years less HT/ET use than groups 1 and 2. Utian Quality of Life scores were significantly lower in group 3 (83.4 [12.5]) than in groups 1 and 2 (87.6 [13.3], P < 0.02), particularly in the occupational satisfaction scale. About 16.6% and 16.3% of women in groups 1 and 2 were on antihypertensive medication, respectively, compared with 27.4% in group 3 (P < 0.04).Discontinuation of HT/ET may predispose some women to the risk of hypertension and may affect their quality of life.

  View details for DOI 10.1097/gme.0b013e31828cfd3b

  View details for Web of Science ID 000330465700007

  View details for PubMedID 23571529

• Trabecular and Cortical Microarchitecture in Postmenopausal HIV-Infected Women CALCIFIED TISSUE INTERNATIONAL Yin, M. T., Shu, A., Zhang, C. A., Boutroy, S., McMahon, D. J., Ferris, D. C., Colon, I., Shane, E. 2013; 92 (6): 557-565

  Abstract

  Our objective was to assess the effects of HIV infection and antiretroviral therapy on trabecular and cortical microarchitecture in postmenopausal minority women. A subgroup of 106 (46 HIV-infected, 60 uninfected) postmenopausal Hispanic and African American women from an established cohort had areal bone mineral density (aBMD) measured by dual-energy X-ray absorptiometry and trabecular and cortical volumetric BMD (vBMD) and microarchitecture measured by high-resolution peripheral quantitative computed tomography (HRpQCT) at the radius and tibia. HIV-infected women were slightly younger (58 ± 1 vs. 61 ± 1 years, p = 0.08), and had lower body mass index (BMI; 28 ± 1 vs. 32 ± 1 kg/m(2), p < 0.01). BMI-adjusted aBMD Z scores were lower in HIV-infected women at the lumbar spine, total hip, and ultradistal radius. Serum N-telopeptide and C-telopeptide levels were also higher in HIV-infected women. Trabecular and cortical vBMD were similar at the radius, but cortical area (105.5 ± 2.4 vs. 120.6 ± 2.0 mm(2), p < 0.01) and thickness (956 ± 33 vs. 1,075 ± 28 μm, p < 0.01) at the tibia were approximately 11-12 % lower in HIV-infected women. Differences remained significant after adjusting for age, BMI, and race/ethnicity. In contrast, cortical porosity was similar in the two groups. Although HIV-infected postmenopausal women had lower aBMD at the spine, total hip, and ultradistal radius and higher levels of bone resorption markers, the only differences detected by HRpQCT were lower cortical thickness and area at the tibia.

  View details for DOI 10.1007/s00223-013-9716-8

  View details for Web of Science ID 000319021400008

  View details for PubMedID 23460340

  View details for PubMedCentralID PMC3656136

• TRABECULAR AND CORTICAL MICROARCHITECTURE IN POSTMENOPAUSAL HIV-INFECTED WOMEN Yin, M. T., Shu, A., Zhang, C. A., Boutroy, S., McMahon, D. J., Ferris, D. C., Colon, I., Shane, E. SPRINGER LONDON LTD. 2012: S211–S212

  View details for Web of Science ID 000309259600305

• Bone structure and turnover in type 2 diabetes mellitus OSTEOPOROSIS INTERNATIONAL Shu, A., Yin, M. T., Stein, E., Cremers, S., Dworakowski, E., Ives, R., Rubin, M. R. 2012; 23 (2): 635-641

  Abstract

  We compared skeletal parameters in type 2 diabetic (T2DM) and non-diabetic postmenopausal women. Bone structure by dual energy x-ray absorptiometry (DXA) and HR-pQCT was not different, although procollagen type 1 amino-terminal propeptide (P1NP) and osteocalcin levels were lower in T2DM.T2DM is associated with increased fracture risk, but, paradoxically, with higher cross-sectional bone density (BMD) as measured by DXA. We sought explanations to this puzzle by investigating detailed structural and biochemical skeletal parameters in T2DM.Cross-sectional comparison of 25 postmenopausal T2DM women and 25 matched controls using DXA, high-resolution peripheral quantitative computed tomography (HR-pQCT) and biochemical bone turnover markers.BMD by DXA did not differ between T2DM and controls. HR-pQCT assessment also did not differ, with the exception of cortical area at the tibia, which tended to be lower in the diabetics (difference of 12 ± 6 [mean ± SD] mm, p = 0.06). P1NP and osteocalcin levels were lower in T2DM as compared to controls (P1NP, 34.3 ± 16 vs. 57.3 ± 28 ng/ml; p = 0.005; osteocalcin, 4.5 ± 2 vs. 6.2 ± 2 nmol/L; p = 0.001).Postmenopausal women with T2DM had lower levels of bone formation markers as compared to controls. Aside from a possible decrease in cortical bone area at a weight-bearing site, bone structure was not altered in T2DM. Lower bone turnover may be a skeletal parameter that is present in T2DM.

  View details for DOI 10.1007/s00198-011-1595-0

  View details for Web of Science ID 000299306300024

  View details for PubMedID 21424265

  View details for PubMedCentralID PMC3690650

• Effect of Estrogen and Hormone Therapy Withdrawal on Health and Quality of Life after Publication of The Women's Health Initiative in New York City Warren, M., Richardson, O., Chaudluy, S., Shu, A., Chua, A., Sloan, N. L. LIPPINCOTT WILLIAMS & WILKINS. 2011: 1342

  View details for Web of Science ID 000297914800043

• Vitamin D deficiency in HIV-infected postmenopausal Hispanic and African-American women OSTEOPOROSIS INTERNATIONAL Stein, E. M., Yin, M. T., McMahon, D. J., Shu, A., Zhang, C. A., Ferris, D. C., Colon, I., Dobkin, J. F., Hammer, S. M., Shane, E. 2011; 22 (2): 477-487

  Abstract

  We evaluated vitamin D status in HIV+ and HIV- postmenopausal African-American (AA) and Hispanic women. Most women (74-78%) had insufficient 25-hydroxyvitamin D (25OHD) levels, regardless of HIV status. 25OHD was lower in AA women and women lacking supplement use, providing support for screening and supplementation. Among HIV+ women, 25OHD was associated with current CD4 but not type of antiretroviral therapy.To evaluate vitamin D status and factors associated with vitamin D deficiency and insufficiency in HIV-infected (HIV+) postmenopausal minority women.In this cross-sectional study, 89 HIV+ and 95 HIV- postmenopausal women (33% AA and 67% Hispanic) underwent assessment of 25OHD, 1,25-dihydroxyvitamin D, parathyroid hormone, markers of bone turnover and bone mineral density by dual energy X-ray absorptiometry.The prevalence of low 25OHD did not differ by HIV status; the majority of both HIV+ and HIV- women (74-78%) had insufficient levels (<30 ng/ml). Regardless of HIV status, 25OHD was significantly lower in AA subjects, and higher in subjects who used both calcium and multivitamins. In HIV+ women on antiretroviral therapy (ART), 25OHD was directly associated with current CD4 count (r=0.32; p<0.01) independent of age, ethnicity, BMI, or history of AIDS-defining illness. No association was observed between 1,25(OH)(2)D and CD4 count or between serum 25OHD, 1,25(OH)(2)D or PTH and type of ART.In postmenopausal minority women, vitamin D deficiency was highly prevalent and associated with AA race and lack of supplement use, as well as lower current CD4 cell count. These results provide support for screening and repletion of vitamin D in HIV+ patients.

  View details for DOI 10.1007/s00198-010-1299-x

  View details for Web of Science ID 000286207800008

  View details for PubMedID 20585939

  View details for PubMedCentralID PMC3105902

• Low Bone Mass and High Bone Turnover in Postmenopausal Human Immunodeficiency Virus-Infected Women JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Yin, M. T., McMahon, D. J., Ferris, D. C., Zhang, C. A., Shu, A., Staron, R., Colon, I., Laurence, J., Dobkin, J. F., Hammer, S. M., Shane, E. 2010; 95 (2): 620-629

  Abstract

  Low bone mineral density (BMD) is commonly reported in young men and women with HIV infection, and fracture rates may be higher. With effective antiretroviral therapy (ART), the HIV population is aging. However, little is known about the skeletal status of postmenopausal women.We aimed to assess the effects of HIV infection and ART on BMD and bone turnover in postmenopausal minority women.A prospective cohort study was performed in 92 HIV+ and 95 HIV- postmenopausal Hispanic and African-American women.We measured BMD by dual-energy x-ray absorptiometry, fracture prevalence, serum levels of inflammatory cytokines (TNFalpha, IL-6), bone turnover markers, calciotropic hormones, and estrone.HIV+ women were younger (56 +/- 1 vs. 60 +/- 1 yr; P < 0.01) and had lower BMI (28 +/- 1 vs. 30 +/- 1 kg/m(2); P < 0.01) and estrone levels. Prevalence of T scores below -1.0 was greater in HIV+ women at the spine (78 vs. 64%; P < 0.05), total hip (45 vs. 29%; P < 0.05), and femoral neck (64 vs. 46%; P < 0.05), and Z scores adjusted for BMI were lower in HIV+ women at the same sites. Serum TNFalpha, N-telopeptide, and C-telopeptide were significantly higher in HIV+ than HIV- women, particularly those receiving ART. HIV+ status was independently and negatively associated with spine and hip BMD after adjustment for age, ethnicity, BMI, and alcohol.The lower BMD, higher prevalence of low BMD, and higher levels of bone turnover markers detected in HIV+ postmenopausal minority women could place them at high risk for future fractures.

  View details for DOI 10.1210/jc.2009-0708

  View details for Web of Science ID 000274298200022

  View details for PubMedID 19965927

  View details for PubMedCentralID PMC2840861

• Adherence to Osteoporosis Medications After Patient and Physician Brief Education: Post Hoc Analysis of a Randomized Controlled Trial AMERICAN JOURNAL OF MANAGED CARE Shu, A. D., Stedman, M. R., Polinski, J. M., Jan, S. A., Patel, M., Truppo, C., Breiner, L., Chen, Y., Weiss, T. W., Solomon, D. H. 2009; 15 (7): 417-424

  Abstract

  To examine whether adherence to osteoporosis medications can be improved by educational interventions targeted at primary care physicians (PCPs) and patients.Post hoc analysis of data collected as part of a prospective randomized controlled trial to improve initiation of osteoporosis management such as bone mineral density testing or osteoporosis drug initiation.The trial was conducted among patients at risk for osteoporosis enrolled in Horizon Blue Cross Blue Shield of New Jersey. For a 3-month period, randomly selected PCPs and their patients received education about osteoporosis diagnosis and treatment. The PCPs received face-to-face education by trained pharmacists, while patients received letters and automated telephone calls. The control group received no education. We assessed medication adherence during 10 months following the start of the intervention using the medication possession ratio (MPR), the ratio of available medication to the total number of days studied.These analyses included 1867 patients (972 randomized to the intervention group and 875 to the control group) and their 436 PCPs. During 10 months following the intervention, the median MPRs were 74% (interquartile range [IQR], 19%-93%) for the intervention group and 73% (IQR, 0%-93%) for the control group (P = .18). The median times until medication discontinuation after the intervention were 85 days (IQR, 58-174 days) for the intervention group and 79 days (IQR, 31-158 days) for the control group.The educational intervention did not significantly improve medication compliance or persistence with osteoporosis drugs.

  View details for Web of Science ID 000268159100002

  View details for PubMedID 19589009

  View details for PubMedCentralID PMC2885859