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Kevin CJ Yuen,1 Lewis S Blevins,2 David R Clemmons,3 Mads Faurby,4 Andrew R Hoffman,5 Nicky Kelepouris,6 Janice M Kerr,7 Jens Magelund Tarp,4 Maria Fleseriu8 1Barrow Pituitary Center, Barrow Neurological Institute and St. Joseph’s Hospital and Medical Center, University of Arizona College of Medicine and Creighton School of Medicine, Phoenix, AZ, USA; 2Department of Neurosurgery, University of California, San Francisco, CA, USA; 3Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, NC, USA; 4Global Evidence, Pricing and Access, Novo Nordisk A/S, Søborg, Denmark; 5Department of Medicine, Stanford University, Stanford, CA, USA; 6Department of Medical Affairs BioPharm, CMR, Novo Nordisk Inc., Plainsboro, NJ, USA; 7Department of Endocrinology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA; 8Pituitary Center, Departments of Medicine and Neurological Surgery, Oregon Health and Science University, Portland, OR, USACorrespondence: Kevin CJ Yuen, Barrow Pituitary Center, Barrow Neurological Institute and St. Joseph’s Hospital and Medical Center, University of Arizona College of Medicine and Creighton School of Medicine, 475 N. 5th Street, Phoenix, AZ, 85004, USA, Tel +1 602 406-2748, Fax +1 602 406-2770, Email kevin.yuen@commonspirit.orgPurpose: Adult growth hormone deficiency (AGHD) is often underdiagnosed and undertreated, leading to costly comorbidities. Previously, we developed an algorithm to identify individuals in a commercially insured US population with high, moderate, or low likelihood of having AGHD. Here, we estimate and compare direct medical costs by likelihood level.Patients and Methods: Retrospective, observational analysis using the Truven Health MarketScan database to analyze direct medical costs relating to inpatient and outpatient claims, outpatient prescription claims, medication usage, clinical utilization records, and healthcare expenditures. Patients were categorized into groups based on

CONTEXT: Early initiation of growth hormone (GH) therapy is recommended for short children born small for gestational age (SGA); however, real-world data indicate that treatment is often delayed. OBJECTIVE: We aimed to assess the impact of patient age at GH therapy initiation on long-term growth outcomes and safety in short children born SGA. METHODS: Analysis of pooled data from NordiNet® International Outcome Study (NCT00960128; 469 European clinics) and the ANSWER Program (NCT01009905; 207 US clinics), two large, complementary observational studies. Patients received GH as prescribed by their treating physician. Enrolled patients born SGA were categorized into three groups based on their age at GH treatment initiation: 2 to <4 years, 4 to <6 years, and ≥6 years. Patient characteristics at birth and GH initiation, auxology, and safety data were evaluated. RESULTS: The effectiveness analysis (treatment-naïve and prepubertal patients at GH initiation) included 3318 patients: 10.7% aged 2 to <4 years at therapy initiation, 31.6% aged 4 to <6 years, and 57.7% aged ≥6 years. Following 8 years of therapy, the mean improvement in height standard deviation score from baseline was significantly greater in the 2 to <4 years group vs the 4 to <6 years (+2.5 vs +2.2; P = 0.0054) and ≥6 years groups (+2.5 vs +1.7; P < 0.0001). No unexpected safety events were reported. CONCLUSION: Early initiation of GH therapy in short children born SGA may be an important contributor to height optimization. The data are reassuring regarding the long-term safety of GH therapy in this population.

CONTEXT: Growth hormone (GH) treatment has a generally good safety profile; however, concerns about increased mortality risk in adulthood have been raised. OBJECTIVE: This work aims to assess the long-term safety of GH treatment in clinical practice. METHODS: Data were collected from 676 clinics participating in 2 multicenter longitudinal observational studies: the NordiNet International Outcome Study (2006-2016, Europe) and ANSWER Program (2002-2016, USA). Pediatric patients treated with GH were classified into 3 risk groups based on diagnosis. Intervention consisted of daily GH treatment, and main outcome measures included incidence rates (events/1000 patient-years) of adverse drug reactions (ADRs), serious adverse events (SAEs), and serious ADRs, and their relationship to GH dose. RESULTS: The combined studies comprised 37 702 patients (68.4% in low-risk, 27.5% in intermediate-risk, and 4.1% in high-risk groups) and 130 476 patient-years of exposure. The low-risk group included children born small for gestational age (SGA; 20.7%) and non-SGA children (eg, with GH deficiency; 79.3%). Average GH dose up to the first adverse event (AE) decreased with increasing risk category. Patients without AEs received higher average GH doses than patients with more than one AE across all groups. A significant inverse relationship with GH dose was shown for ADR and SAE incidence rates in the low-risk group (P = .003 and P = .001, respectively) and the non-SGA subgroup (both P = .002), and for SAEs in the intermediate- and high-risk groups (P = .002 and P = .05, respectively). CONCLUSIONS: We observed no indication of increased mortality risk nor AE incidence related to GH dose in any risk group. A short visual summary of our work is available (1).

Context: Growth hormone (GH) treatment has a generally good safety profile; however, concerns about increased mortality risk in adulthood have been raised. Objective: This work aims to assess the long-term safety of GH treatment in clinical practice. Methods: Data were collected from 676 clinics participating in 2 multicenter longitudinal observational studies: the NordiNet International Outcome Study (2006-2016, Europe) and ANSWER Program (2002-2016, USA). Pediatric patients treated with GH were classified into 3 risk groups based on diagnosis. Intervention consisted of daily GH treatment, and main outcome measures included incidence rates (events/1000 patient-years) of adverse drug reactions (ADRs), serious adverse events (SAEs), and serious ADRs, and their relationship to GH dose. Results: The combined studies comprised 37702 patients (68.4% in low-risk, 27.5% in intermediate-risk, and 4.1% in high-risk groups) and 130476 patient-years of exposure. The low-risk group included children born small for gestational age (SGA; 20.7%) and non-SGA children (eg, with GH deficiency; 79.3%). Average GH dose up to the first adverse event (AE) decreased with increasing risk category. Patients without AEs received higher average GH doses than patients with more than one AE across all groups. A significant inverse relationship with GH dose was shown for ADR and SAE incidence rates in the low-risk group (P=.003 and P=.001, respectively) and the non-SGA subgroup (both P=.002), and for SAEs in the intermediate-and high-risk groups (P=.002 and P=.05, respectively). Conclusions: We observed no indication of increased mortality risk nor AE incidence related to GH dose in any risk group. A short visual summary of our work is available (1).

Objective: To evaluate use of pegvisomant, a GH receptor antagonist, as monotherapy in ACROSTUDY, a global safety surveillance study set in 14 countries (373 sites).Methods: A descriptive analysis of safety, magnetic resonance imaging (MRI) reading and treatment outcomes in 710 subjects who received at least one pegvisomant dose as monotherapy during and up to 5 years follow-up in ACROSTUDY.Results: Subjects received 5.4 yr. (mean) of pegvisomant and were followed in ACROSTUDY 3.8 yr. (mean). A total of 1255 adverse events were reported in 345 subjects (48.6%). Serious adverse events were reported in 133 (18.7%) subjects including 22 deaths, none of which were attributed to pegvisomant use. Of 670 (94%) subjects with at least one liver function test reported in ACROSTUDY, 8 (1.2%) had reported increases in transaminases > 3X ULN. No liver failure was reported. Based on central MRI reading, 12 of 542 subjects (2.2%) had a confirmed increase or increase/decrease in tumor size. Injection-site reactions were reported in 2.3%. At 5 years of therapy, IGF-1 level was reported normal in 67.5% (mean dose 17.2 mg/day) and elevated in 29.9% (mean dose 19.8 mg/day). Subjects on 20 mg per day or more rose from 36% at 3 years to 41% at 5 years of therapy.Conclusions: ACROSTUDY data indicate that pegvisomant used as sole medical therapy is safe and effective medical treatment for acromegaly. The reported low incidence of pituitary tumor size increase and liver enzyme elevations are reassuring and support the positive benefit-risk of pegvisomant therapy.