Faculty Bibliography

Lonapegsomatropin (TransCon hGH) is an investigational once-weekly prodrug of somatropin for the treatment of GHD. Previous trials in treatment-naive (52-week heiGHt Trial) and treatment-experienced children (26-week fliGHt Trial) have reported the efficacy and safety of lonapegsomatropin. Subjects were eligible to enter the open-label extension enliGHten Trial, which continues to evaluate weekly lonapegsomatropin in pediatric GHD. In heiGHt, treatment-naive subjects received lonapegsomatropin (Group A; vial/syringe) or daily somatropin (Group B; pen device). In fliGHt, treatment-experienced subjects switched to lonapegsomatropin from daily somatropin (Group C; vial/syringe). Lonapegsomatropin was administered at a starting dose of 0.24 mg hGH/kg/wk. Upon entry into enliGHten, all subjects received lonapegsomatropin (vial/ syringe), and switched to TransCon hGH Auto-Injector pending regional availability. A total of 298 (of 303 eligible) subjects continued into enliGHten (A: n=103; B: n=55; C: n=140). The mean dose remained approximately 0.24 mg hGH/kg/wk for Group A/B at Week 104 and was 0.20 mg hGH/kg/wk for Group C at Week 78. Subjects starting heiGHt on daily somatropin who switched to lonapegsomatropin continued to approach their average parental height, with height standard deviation score (SDS) improving from -3.0 at baseline to -1.52 at Week 104. Subjects from the fliGHt Trial also continued to approach their average parental height, with height SDS improving from -1.42 at fliGHt baseline to -0.69 at Week 78. Observed Mean annualized height velocity (AHV) at Week 78 was 8.4 cm/year. heiGHt subjects starting lonapegsomatropin continued to approach their average parental height, with height SDS improving from -2.89 at baseline to -1.37 at Week 104. As of the data cut (01 June 2020), 5 subjects have met or exceeded their target height and 11 subjects have grown to within 2 cm of their target height. Mean (SD) average IGF-1 SDS remained stable and generally within the expected range for all groups (Week 104, A:0.95 [1.22], B:1.04 [1.25]; Week 78, C:1.81 [1.08]). Across all phase 3 trials, lonapegsomatropin produced a dose linear IGF-1 response. With lonapegsomatropin treatment, the adverse event (AE) profile remained consistent with what was observed in the parent trials, with no new safety signals, comparable tolerability, and a mean body mass index (BMI) SDS approaching zero. Across the broad population of the phase 3 program, subjects treated with lonapegsomatropin for up to 2 years continued to approach their average parental height, with a safety profile comparable to daily somatropin, including a similar AE profile, tolerability, and stable BMI

Growth hormone (GH) replacement therapy currently requires daily subcutaneous injections. Somapacitan is a long-acting GH-derivative in development for once-weekly use in children with GH deficiency (GHD). A phase 2, multinational, randomised, open-label, controlled trial (NCT02616562) investigated the efficacy and safety of somapacitan compared with daily GH (NorditropinR). GH-treatment-naive prepubertal children with GHD received 0.04 (n=16), 0.08 (n=15) or 0.16 mg/kg/week (n=14) somapacitan, or daily GH 0.034 mg/kg/day (0.24 mg/kg/week; n=14) for 1 year, followed by a 2-year safety extension with all patients on somapacitan (n=45) receiving 0.16 mg/kg/week, while daily GH dose was unaltered. Safety endpoints comprised frequency of adverse events (AEs). The 1-year and 2-year results have been reported previously. Here, we report the efficacy and safety of somapacitan after 3 years of treatment. At year 3, mean (SD) height velocity (HV) was 8.9 (1.7), 7.8 (1.5) and 8.4 (1.7) cm/year for 0.04/0.16 mg/kg/week, 0.08/0.16 mg/kg/ week and 0.16/0.16 mg/kg/week somapacitan, respectively, vs 7.6 (2.0) cm/year for daily GH. Change in mean (SD) height standard deviation score (SDS) from baseline to 3 years was 2.39 (1.00), 2.37 (0.97) and 2.67 (1.42) for somapacitan, respectively, vs 2.10 (0.85) for daily GH. The observed HV results for the somapacitan groups and daily GH arm in the third year, were similar. Change in insulin-like growth factor-I SDS from baseline to year 3 was 3.26 (1.04), 3.52 (1.43) and 3.66 (1.29) for somapacitan, respectively, vs 3.40 (1.58) for daily GH. Number of AEs (% of patients) was as follows: somapacitan 0.04/0.16 mg/kg/week, 72 (75.0%); 0.08/0.16 mg/kg/week, 126 (93.3%); 0.16/0.16 mg/kg/week, 120 (100%); and daily GH, 95 (100%). In all treatment groups, the rate of AEs per 100 patientyears of exposure was lower in the 2-year safety extension than the first year. The most common AEs across the pooled somapacitan groups were pyrexia (40% for somapacitan and 14% for daily GH), influenza (20% and 21%), nasopharyngitis (16% and 21%), vomiting (13% and 7%), constipation (11% and 0%), allergic rhinitis (11% and 21%), otitis media (11% and 7%), tonsillitis (11% and 0%) and gastroenteritis (11% and 14%). Most AEs were mild to moderate and unlikely to be treatment related. These 3-year data support the efficacy results observed in the first and second year of somapacitan treatment of GHD; no new safety signals were observed

Please state why this abstract is "late-breaking" Data was not available at normal abstract submission deadlineObjectives Once-weekly TransCon hGH demonstrated statistically greater annualized height velocity and ? height standard deviation score (SDS) at Week 52 compared to Genotropin and had a similar safety and tolerability profile in the phase 3 heiGHt Trial evaluating treatment-naive children with GHD. Here, we report outcomes for subjects from heiGHt who continued in the ongoing enliGHten long-term extension trial for 26 more weeks. Methods In heiGHt, treatment-naive, prepubertal subjects with GHD were randomized 2:1 to TransCon hGH 0.24 mg hGH/kg/week or an equivalent weekly dose of Genotropin; in enliGHten, all subjects received TransCon hGH. Two groups were analyzed: Group A (TransCon hGH in heiGHt and enliGHten) and Group B (Genotropin in heiGHt, TransCon hGH in enliGHten). Safety and growth outcomes were evaluated every ~13 weeks in both trials. IGF-1 was sampled on postdose Day 5 (+/-1 day) in enliGHten, representing the average IGF-1 over the week. A by-visit ANCOVA model was used to analyze numeric efficacy endpoints. Results All but one subject continued into enliGHten (A: N=103, B: N=55). The statistically significant treatment difference in ? height SDS (Group A vs B) at Week 52 (N=159; 1.10 vs 0.96, P=0.0149) was sustained through Week 78 (N=154; 1.39 vs 1.24, P=0.0436), demonstrating persistence of catch-up growth for both groups and maintenance of superior treatment effect for subjects treated with TransCon hGH in the first year of therapy. At Week 78, the least-squares mean (SE) average IGF-1 SDS (N=153) was 0.52 (0.15) for Group A and 0.59 (0.19) for Group B. Mean (SD) BMI SDS at Week 78 was 0.0 (0.8) and 0.1 (0.9) for Group A and B, respectively. Adverse events (AEs) were comparable between groups in heiGHt. During enliGHten, 48.7% (76/156) and 1.9% (3/156) of subjects experienced AEs and serious AEs, respectively; the AE profile was consistent with that observed in heiGHt. A low titer of anti-hGH binding antibodies were detected in <10% of subjects upon treatment with TransCon hGH in heiGHt and enliGHten; no neutralizing antibodies were detected. Lab parameters (HbA1c, cortisol, free thyroxine) were stable and generally remained within the normal range throughout the trials. Conclusions Results demonstrated maintenance of favorable treatment effect in subjects treated with TransCon hGH beyond the first year of therapy. TransCon hGH treatment through 78 weeks demonstrated an AE and immunogenicity profile comparable to daily hGH therapy

STATEMENT OF PROBLEM OR QUESTION (ONE SENTENCE): For patients who require frequent and intensive therapy services after hospitalization, delivering post-acute rehabilitation in patients' homes offers a potential alternative to care in skilled nursing facilities (SNF). OBJECTIVES OF PROGRAM/INTERVENTION (NO MORE THAN THREE OBJECTIVES): To deliver SNF-level post-acute rehabilitation and transitional care within the home. DESCRIPTION OF PROGRAM/INTERVENTION, INCLUDING ORGANIZATIONAL CONTEXT (E.G. INPATIENT VS. OUTPATIENT, PRACTICE OR COMMUNITY CHARACTERISTICS) : The Rehabilitation-at-Home (RaH) program was a 30-day bundle of postacute rehabilitation and transitional care delivered within the home from October 2015 to September 2017. The program included a multidisciplinary home-based team of providers, including physicians, physical, occupational and speech therapists, and social workers. Participants were eligible if they were 18 years or older, resided in Manhattan, NY, and qualified for SNF-based rehabilitation services. Patients were admitted from home, the Emergency Department, and inpatient observational, medical and surgical units. The 30-day bundle included an "active" phase of home- based medical and rehabilitation services followed by a "plus" phase of transitional care. MEASURES OF SUCCESS (DISCUSS QUALITATIVE AND/OR QUANTITATIVE METRICS WHICH WILL BE USED TO EVALUATE PROGRAM/INTERVENTION): We abstracted demographic data, characteristics of hospitalization or acute care, participant functional mobility, and characteristics of RaH treatment through chart review. Seven providers and investigators (6 physicians, 1 physical therapist) reviewed RaH notes from medical providers and therapists to identify functional mobility, goal achievement, and barriers to care and judge global functional improvement. To identify factors associated with greater functional improvement, we used multivariable logistic regression with the binary outcome of considerable vs. moderate/slight/no global functional improvement. FINDINGS TO DATE (IT IS NOT SUFFICIENT TO STATE FINDINGS WILL BE DISCUSSED): 237 patients participated in RaH over 264 episodes of care. Participants were predominantly over the age of 85 (57%; mean 84.2, SD 10.0 years) and of non-Hispanic white (70%) race and ethnicity. The majority were admitted after hospitalization (88.2%) for conditions representing 117 different diagnostic related groups. Average length of stay in RaH was 14.2 (SD 6.5) days with patients receiving 1.83 (SD 2.22) medical provider, 1.67 (SD 1.58) nursing, and 5.24 (SD 1.05) physical therapist visits weekly. The majority of patients fully or almost fully met their goals for bed mobility (65%), bed transfer (69%), chair transfer (67%), and ambulation (64%) with the majority achieving moderate or considerable (61%) global functional improvement. Achieving moderate or considerable global improvement was negatively associated with dementia diagnosis (OR 0.30, 95% CI 0.10-0.88) and positively associated with higher baseline ambulation (OR 4.74, 95% CI 1.95- 11.51). At 30 days, 87.3% of participants were living within the community. KEY LESSONS FOR DISSEMINATION (WHAT CAN OTHERS TAKE AWAY FOR IMPLEMENTATION TO THEIR PRACTICE OR COMMUNITY?): Delivering SNF-level post-acute rehabilitation care in patients' homes for a broad range of diagnoses was feasible, and most participants achieved moderate or considerable functional improvement. This approach may help older adults maintain living status in the community

INTRODUCTION/BACKGROUND:Almost 20 years after the first international guidelines on the diagnosis and treatment of GHD have been published, clinical practice varies significantly. The low accuracy of endocrine tests for GHD and the burden caused by ineffective treatment of individual patients were strong motives for national endocrine societies to set up national guidelines regarding how to diagnose GHD in childhood. This audit aims to review the current state and identify common changes, which may improve the diagnostic procedure. METHODS:A group of eight German pediatric endocrinologists contacted eight pediatric endocrinologists from Spain, France, Poland, the UK, the Netherlands, Denmark, Italy, and the US. Each colleague responded as a representative for the own country to a detailed questionnaire containing 22 open questions about national rules, guidelines, and practice with respect to GHD diagnostics and GH prescription. The results were presented and discussed in a workshop and then documented in this study which was reviewed by all participants. RESULTS:National guidelines are available in 7 of 9 countries. GH is prescribed by pediatric endocrinologists in most countries. Some countries have established boards that review and monitor prescriptions. Preferred GH stimulation tests and chosen cutoffs vary substantially. Overall, a trend to lowering the GH cutoff was identified. Priming is becoming more popular and now recommended in 5 out of 9 countries; however, with different protocols. The definition of pretest-conditions that qualify the patient to undergo GH testing varies substantially in content and strictness. The most frequently used clinical sign is low height velocity, but definition varies. Height, IGF-1, and bone age are additional parameters recommended in some countries. CONCLUSIONS:GHD diagnostics varies substantially in eight European countries and in the US. It seems appropriate to undertake further efforts to harmonize endocrine diagnostics in Europe and the US based on available scientific evidence.

The Growth Hormone Research Society (GRS) convened a Workshop in March 2019 to evaluate the diagnosis and therapy of short stature in children. Forty-six international experts participated at the invitation of GRS including clinicians, basic scientists, and representatives from regulatory agencies and the pharmaceutical industry. Following plenary presentations addressing the current diagnosis and therapy of short stature in children, breakout groups discussed questions produced in advance by the planning committee and reconvened to share the group reports. A writing team assembled one document that was subsequently discussed and revised by participants. Participants from regulatory agencies and pharmaceutical companies were not part of the writing process. Short stature is the most common reason for referral to the pediatric endocrinologist. History, physical examination, and auxology remain the most important methods for understanding the reasons for the short stature. While some long-standing topics of controversy continue to generate debate, including in whom, and how, to perform and interpret growth hormone stimulation tests, new research areas are changing the clinical landscape, such as the genetics of short stature, selection of patients for genetic testing, and interpretation of genetic tests in the clinical setting. What dose of growth hormone to start, how to adjust the dose, and how to identify and manage a suboptimal response are still topics to debate. Additional areas that are expected to transform the growth field include the development of long-acting growth hormone preparations and other new therapeutics and diagnostics that may increase adult height or aid in the diagnosis of growth hormone deficiency.

Short stature remains the most common reason for referral to a pediatric Endocrinologist and its management remains a challenge. One of the main controversies is the diagnosis of idiopathic short stature and the role of new technologies for genetic investigation of children with inadequate growth. Complexities in management of children with short stature includes selection of who should receive interventions such as recombinant human growth hormone, and how should this agent dose be adjusted during treatment. Should anthropometrical data be the primary determinant or should biochemical and genetic data be used to improve growth response and safety? Furthermore, what is considered a suboptimal response to growth hormone therapy and how should this be managed? Treatment of children with short stature remains a "hot" topic and more data is needed in several areas. These issues are reviewed in this paper.

Growth hormone (GH) is used to treat short stature and growth failure associated with growth disorders. Birth size and GH status variably modulate response to GH therapy. The aim of this study was to determine the effect of birth size on response to GH therapy, and to determine the impact of GH status in patients born small for gestational age (SGA) on response to GH therapy. Data from the prospective, non-interventional American Norditropin® Studies: Web-Enabled Research (ANSWER) Program were analyzed for several growth outcomes in response to GH therapy over 3 years. GH-naïve children from the ANSWER Program were included in this analysis: SGA with peak GH ≥10 ng/mL (20 mIU/l), SGA with peak GH <10 ng/mL (20 mIU/l), isolated growth hormone deficiency (IGHD) born SGA, IGHD not born SGA, and idiopathic short stature. For patients with IGHD, those who did not meet criteria for SGA at birth showed greater improvements in height SDS and BMI SDS than patients with IGHD who met criteria for SGA at birth. For patients born SGA, response to GH therapy varied with GH status. Therefore, unlike previous guidelines, we recommend that GH status be established in patients born SGA to optimize GH therapy.