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Abstract Context Growth hormone deficiency (GHD) in children is currently treated with daily injections of GH, which can be burdensome for patients and their parents/guardians. Somapacitan is a GH derivative in development for once-weekly treatment of GHD. Objective This work aimed to assess the efficacy and safety of somapacitan, and associated disease/treatment burden, after 4 years of treatment and 1 year after switching to somapacitan from daily GH. Methods This long-term safety extension of a multicenter, controlled phase 2 trial (NCT02616562) took place at 29 sites in 11 countries. Patients were prepubertal, GH-naive children with GHD. Fifty patients completed 4 years of treatment. Patients in the pooled group received somapacitan (0.04, 0.08, 0.16 mg/kg/week) for 1 year, followed by the highest dose (0.16 mg/kg/week) for 3 years. Patients in the switched group received daily GH 0.034 mg/kg/day for 3 years, then somapacitan 0.16 mg/kg/week for 1 year. Main outcome measures were height velocity (HV), change from baseline in HV SD score (SDS), change from baseline in height SDS, disease burden, and treatment burden for patients and parents/guardians. Results Changes from baseline in HV and HV SDS were similar and as expected in both groups. Observer-reported outcomes showed that patients and parents/guardians seem to have experienced a reduced treatment burden when switching from daily GH to somapacitan. Most parents/guardians (81.8%) strongly/very strongly preferred somapacitan over daily GH. Conclusions Somapacitan showed similar efficacy and safety in patients who continued somapacitan treatment and those who switched from daily GH to somapacitan. Once-weekly injections may lead to a reduced treatment burden relative to once-daily injections. A plain-language summary of this work is available.

Abstract Context Growth hormone (GH) replacement requires daily GH injections, which is burdensome for some adult patients with GH deficiency (AGHD). Objective To demonstrate efficacy and safety of somapacitan, a once-weekly reversible albumin-binding GH derivative, versus placebo in AGHD. Design Randomized, parallel-group, placebo-controlled (double-blind) and active-controlled (open-label) phase 3 trial, REAL 1 (NCT02229851). Setting Clinics in 17 countries. Patients Treatment-naïve patients with AGHD (n = 301 main study period, 272 extension period); 257 patients completed the trial. Interventions Patients were randomized 2:2:1 to once-weekly somapacitan, daily GH, or once-weekly placebo for 34 weeks (main period). During the 52-week extension period, patients continued treatment with somapacitan or daily GH. Main outcome measures Body composition measured using dual-energy x-ray absorptiometry (DXA). The primary endpoint was change in truncal fat percentage to week 34. Insulin-like growth factor 1 (IGF-I) standard deviation score (SDS) values were used to dose titrate. Results At 34 weeks, somapacitan significantly reduced truncal fat percentage (estimated difference: −1.53% [−2.68; −0.38]; P = 0.0090), demonstrating superiority compared with placebo, and it improved other body composition parameters (including visceral fat and lean body mass) and IGF-I SDS. At 86 weeks, improvements were maintained with both somapacitan and daily GH. Somapacitan was well tolerated, with similar adverse events (including injection-site reactions) compared with daily GH. Conclusions In AGHD patients, somapacitan administered once weekly demonstrated superiority over placebo, and the overall treatment effects and safety of somapacitan were in accordance with known effects and safety of GH replacement for up to 86 weeks of treatment. Somapacitan may provide an effective alternative to daily GH in AGHD. A short visual summary of our work is available (1).

Study Design and Objective Randomised, double-blind, crossover trial to confirm bioequivalence of somapacitan, a long-acting growth hormone (GH), in 5 mg/1.5 mL and 10 mg/1.5 mL strengths in equimolar doses. Methods Healthy participants were randomised (1:1:1) to subcutaneous somapacitan treatment in one dosing period with 5 mg/1.5 mL and two periods with 10 mg/1.5 mL. Eligibility criteria included age 18–45 years and body mass index 18.5–24.9 kg/m 2 . Exclusion criteria included history of GH deficiency, previous GH treatment, weight > 100.0 kg and participation in any clinical trial of an investigational medicinal product within 45 days or five times the half-life of the previous investigational product before screening. Area under the curve from time 0 until last quantifiable observation (AUC 0– t ), maximum serum concentration ( C max ), time to C max and terminal half-life of somapacitan and safety were assessed. Results In total, 33 participants were randomised. For AUC 0– t , estimated treatment ratio (ETR) (5 mg/1.5 mL versus 10 mg/1.5 mL) was 0.95 (90% confidence interval [CI] 0.89–1.01). Point estimate and 90% CIs were within the acceptance range (0.80–1.25). For C max , ETR was 0.77 (90% CI 0.68–0.89). Point estimate and 90% CIs were outside the acceptance range (0.80–1.25). Mean insulin-like growth factor-I (IGF-I) and IGF-I standard deviation score concentration–time curves for each strength were almost identical. No new safety issues were identified. Conclusions Bioequivalence criterion for somapacitan 5 mg/1.5 mL and 10 mg/1.5 mL was met for AUC 0– t but not for C max . The two strengths had equivalent IGF-I responses. Trial Registration ClinicalTrials.gov, NCT03905850 (3 April 2019). Plain Language Summary Somapacitan is a long-acting growth hormone used to treat people with growth hormone deficiency. Somapacitan is injected under the skin with an injection pen. The dose is based on a person’s body weight and how they respond to treatment. We compared two strengths of injection pen, containing either 5 or 10 mg of somapacitan per 1.5 mL. For both strengths, participants were given the same dose. We wanted to understand whether the body absorbs these different strengths into the bloodstream in the same way. We also measured levels of insulin-like growth factor-I (IGF-I), a hormone formed when growth hormone is present in the blood, to see the effect of different strengths of somapacitan on the body. In our study, 33 healthy adults received one round of injection using the somapacitan 5 mg pen and two rounds using the somapacitan 10 mg pen, all at least 3 weeks apart. We found no differences in the amount of somapacitan being absorbed into the bloodstream, nor how fast it was absorbed. The peak amount of somapacitan in the bloodstream was higher in people using the 10 mg pen. There were no differences in IGF-I levels following use of either injection pen. Overall, our results show both strengths of somapacitan lead to similar responses in the body. Having different strength options could allow doctors to adjust the dose of somapacitan more easily, depending on a patient’s response to treatment.

Introduction Somapacitan is a long-acting growth hormone (GH) derivative being developed for once-weekly dosing in patients with GH deficiency (GHD). Our objective was to evaluate the impact of kidney or hepatic impairment on somapacitan exposure in adults. Methods In two open-label, parallel-group, single-center, 6-week trials, eligible subjects (18–75 years of age, body mass index 18.5–34.9 kg/m 2 , GH-naïve, without GHD) were divided into five kidney (total n  = 44) or three hepatic ( n  = 34) function groups. Subjects with normal kidney/hepatic function were matched to those with kidney/hepatic impairment by age, sex, and body weight. Subjects received three subcutaneous somapacitan administrations (0.08 mg/kg) on days 1, 8, and 15. Blood samples were collected before each dose, at 28 time points throughout 2 weeks after the last dose, and at follow-up (3–4 weeks after the last dose). The primary endpoint was area under the somapacitan serum concentration–time curve up to 1 week after the last dose (AUC 0–168 h ), while secondary endpoints included AUC 0–168 h of insulin-like growth factor (IGF)-I. Results In the kidney impairment trial, somapacitan AUC 0–168 h was higher in groups with severe kidney impairment and requiring hemodialysis versus the normal kidney function group (estimated ratio and 90% confidence interval 1.75 [1.00–3.06] and 1.63 [1.01–2.61], respectively). AUC 0–168 h of IGF-I was increased in the moderate impairment group (1.35 [1.09–1.66]), severe impairment group (1.40 [1.10–1.78]), and requiring hemodialysis group (1.24 [1.01–1.52]), compared with the normal function group. In the hepatic impairment trial, somapacitan AUC 0–168 h was significantly higher in the moderate impairment group compared with the normal hepatic function group (4.69 [2.92–7.52]). IGF-I AUC 0–168 h was lower in both hepatic impairment groups (0.85 [0.67–1.08] for the mild impairment group and 0.75 [0.60–0.95] for the moderate impairment group) compared with the normal function group. No new safety or tolerability issues were observed. Conclusions In summary, somapacitan exposure increased with level of kidney/hepatic impairment. Clinically, this will be taken into account when treating adults with GHD with somapacitan, as doses should be individually titrated. Clinical Trial Registration NCT03186495 (kidney impairment trial, registered 12 June 2017); NCT03212131 (hepatic impairment trial, registered 30 June 2017). Plain Language Summary Somapacitan is a long-acting growth hormone molecule for patients with growth hormone deficiency. After its administration as a subcutaneous injection, the action of somapacitan can be affected by kidney or liver disease. Thus, we conducted two trials in which the pharmacokinetic and pharmacodynamic properties of somapacitan were compared between adult subjects with different degrees of worsened kidney or liver function and their healthy counterparts. We found that subjects with severely impaired kidney function and those requiring hemodialysis had a higher somapacitan exposure in blood serum compared with subjects with normal kidney function. The concentration of insulin-like growth factor (IGF)-I, an effector molecule of growth hormone, was also increased with decreased kidney function. In subjects with moderate hepatic function impairment, somapacitan exposure was also higher than those with normal hepatic function; however, the IGF-I concentrations were lower, both at baseline and after dosing with somapacitan. Our results indicate that patients with growth hormone deficiency and kidney or liver disease may need different doses of somapacitan than people with healthy kidneys and/or liver. However, this will be taken into account because somapacitan doses will be individually titrated for each patient with growth hormone deficiency.

Abstract Context Somapacitan is a long-acting growth hormone (GH) in development for once-weekly treatment of GH deficiency (GHD). Optimal monitoring of insulin-like growth factor-I (IGF-I) levels must account for weekly IGF-I fluctuations following somapacitan administration. Objective To develop and assess the reliability of linear models for predicting mean and peak IGF-I levels from samples taken on different days after dosing. Design A pharmacokinetic/pharmacodynamic model was used to simulate IGF-I data in adults and children following weekly somapacitan treatment of GHD. Setting and Patients 39 200 IGF-I profiles were simulated with reference to data from 26 adults and 23 children with GHD. Intervention(s) The simulated dose range was 0.02 to 0.12 mg/kg for adults and 0.02 to 0.16 mg/kg for children. Simulated data with >4 average standard deviation score were excluded. Main Outcome Measure(s) Linear models for predicting mean and peak IGF-I levels based on IGF-I samples from different days after somapacitan dose. Results Robust linear relationships were found between IGF-I sampled on any day after somapacitan dose and the weekly mean (R2 > 0.94) and peak (R2 > 0.84). Prediction uncertainties were generally low when predicting mean from samples taken on any day (residual standard deviation [RSD] ≤ 0.36) and peak from samples taken on day 1 to 4 (RSD ≤ 0.34). IGF-I monitoring on day 4 and day 2 after dose provided the most accurate estimate of IGF-I mean (RSD < 0.2) and peak (RSD < 0.1), respectively. Conclusions Linear models provided a simple and reliable tool to aid optimal monitoring of IGF-I by predicting mean and peak IGF-I levels based on an IGF-I sample following dosing of somapacitan. A short visual summary of our work is available (1).

Application of weather radar data in urban hydrological applications has evolved significantly during the past decade as an alternative to traditional rainfall observations with rain gauges. Advances in radar hardware, data processing, numerical models, and emerging fields within urban hydrology necessitate an updated review of the state of the art in such radar rainfall data and applications. Three key areas with significant advances over the past decade have been identified: (1) temporal and spatial resolution of rainfall data required for different types of hydrological applications, (2) rainfall estimation, radar data adjustment and data quality, and (3) nowcasting of radar rainfall and real-time applications. Based on these three fields of research, the paper provides recommendations based on an updated overview of shortcomings, gains, and novel developments in relation to urban hydrological applications. The paper also reviews how the focus in urban hydrology research has shifted over the last decade to fields such as climate change impacts, resilience of urban areas to hydrological extremes, and online prediction/warning systems. It is discussed how radar rainfall data can add value to the aforementioned emerging fields in current and future applications, but also to the analysis of integrated water systems.

Background Somapacitan, a long-acting growth hormone (GH) derivative, has been well-tolerated in children with GH deficiency (GHD) and adults (healthy and adult GHD), in phase I, single- and multiple-dose trials, respectively, and has pharmacokinetic and pharmacodynamic properties supporting a once-weekly dosing regimen. Objective In the absence of a multiple-dose phase I trial in children with GHD, the aim was to develop a pharmacokinetic/pharmacodynamic model to predict somapacitan exposure and insulin-like growth factor-I (IGF-I) response after once-weekly multiple doses in both children and adults with GHD. Methods Pharmacokinetic/pharmacodynamic models were developed from pharmacokinetic and IGF-I profiles in three phase I trials of somapacitan (doses: healthy adults, 0.01–0.32 mg/kg; adult with GHD, 0.02−0.12 mg/kg; children with GHD, 0.02–0.16 mg/kg) using non-linear mixed-effects modeling. Pharmacokinetics were described using a non-linear one-compartment model with dual first- and zero-order absorption through a transit compartment, with saturable elimination. IGF-I profiles were described using an indirect response pharmacokinetic/pharmacodynamic model, with sigmoidal-effect relationship. Results The non-linear pharmacokinetic and IGF-I data were well-described in order to confidently predict pharmacokinetic/pharmacodynamic profiles after multiple doses in adults and children with GHD. Body weight was found to be a significant covariate, predictive of the differences observed in the pharmacokinetics and pharmacodynamics between children and adults. Weekly dosing of somapacitan provided elevated IGF-I levels throughout the week, despite little or no accumulation of somapacitan, in both adults and children with GHD. Conclusion This analysis of somapacitan pharmacokinetic/pharmacodynamic data supports once-weekly dosing in adults and children with GHD. Trial Registration ClinicalTrials.gov identifier numbers NCT01514500, NCT01706783, NCT01973244.

Background and Objective Once-daily injectable recombinant human growth hormone (GH) formulations (e.g. Norditropin ® ; Novo Nordisk A/S) are used to treat GH deficiency in children and adults, with much of the therapeutic effect mediated via the insulin-like growth factor-I (IGF-I) response. Despite a long history of use, there are few data on the pharmacokinetics and pharmacodynamics (serum IGF-I response) of this therapy, or of potential differences in the relationship of GH pharmacokinetic/pharmacodynamic (PK/PD) effects between children and adults. This study aimed to characterise the GH pharmacokinetics and IGF-I profile following daily subcutaneous GH in adults and children with GH deficiency. Methods A model was developed based on a population PK/PD modelling meta-analysis of data from three phase I clinical trials (two using Norditropin ® as a comparator with somapacitan, and one as a comparator with a pegylated GH product). Sequential model building was performed, first developing a model that could describe GH pharmacokinetics. A PD model of IGF-I data was then developed using PK and PD data, and where all PK parameters were kept fixed to those estimated in the PK model. Results The model developed accurately describes and predicts GH pharmacokinetics and IGF-I response. Body weight was shown to have an important inversely correlated influence on GH exposure (and IGF-I standard deviation score), and this largely explained differences between adults and children. Conclusions The pharmacokinetics/pharmacodynamics developed here can inform expectations about the PD effects of different doses of GH in patients with GH deficiency of different body weights, regardless of their age. Clinical Trial Registration Pooled modelling analysis of data from ClinicalTrials.gov identifiers NCT01973244, NCT00936403 and NCT01706783. Dates of registration NCT01973244: 22 October, 2013; NCT00936403: 9 July, 2009; NCT01706783: 11 October, 2012.

Major histocompatibility complex class II (MHCII) molecules play an important role in cell-mediated immunity. They present specific peptides derived from endosomal proteins for recognition by T helper cells. The identification of peptides that bind to MHCII molecules is therefore of great importance for understanding the nature of immune responses and identifying T cell epitopes for the design of new vaccines and immunotherapies. Given the large number of MHC variants, and the costly experimental procedures needed to evaluate individual peptide–MHC interactions, computational predictions have become particularly attractive as first-line methods in epitope discovery. However, only a few so-called pan-specific prediction methods capable of predicting binding to any MHC molecule with known protein sequence are currently available, and all of them are limited to HLA-DR. Here, we present the first pan-specific method capable of predicting peptide binding to any HLA class II molecule with a defined protein sequence. The method employs a strategy common for HLA-DR, HLA-DP and HLA-DQ molecules to define the peptide-binding MHC environment in terms of a pseudo sequence. This strategy allows the inclusion of new molecules even from other species. The method was evaluated in several benchmarks and demonstrates a significant improvement over molecule-specific methods as well as the ability to predict peptide binding of previously uncharacterised MHCII molecules. To the best of our knowledge, the NetMHCIIpan - 3 . 0 method is the first pan-specific predictor covering all HLA class II molecules with known sequences including HLA-DR, HLA-DP, and HLA-DQ. The NetMHCpan - 3 . 0 method is available at http://www.cbs.dtu.dk/services/NetMHCIIpan-3.0 .