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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).

Treatment of persistent short stature in children born small for gestational age (SGA) requires daily growth hormone (GH) injections that can be burdensome for patients and caregivers. Once-weekly somapacitan is a long-acting GH currently in phase 3 development for replacement therapy in children with GH deficiency. We report the 26-week results of the first phase 2, multinational, randomized, open-label, controlled, dose-finding trial (NCT03878446) investigating the efficacy and safety of somapacitan as treatment for short stature in children born SGA compared with daily GH (Norditropin®, Novo Nordisk A/S). A total of 62 (35.5% female) GH-treatment-naïve, prepubertal children received 0.16, 0.20 or 0.24 mg/kg/week subcutaneous (s.c.) somapacitan, or 0.035 or 0.067 mg/kg/day s.c. daily GH for 26 weeks (main phase). All children are subsequently included in an extension to this trial. The primary outcome was annualized height velocity (HV). At week 26, the estimated mean HV was: 8.9, 11.0 and 11.3 cm/year for 0.16 mg/kg/week (n=12), 0.20 mg/kg/week (n=13) and 0.24 mg/kg/week (n=12) somapacitan, respectively, versus 10.3 and 11.9 cm/year for 0.035 mg/kg/day (n=12) and 0.067 mg/kg/day (n=13) daily GH, respectively. A dose-dependent response in the estimated mean HV was observed with both somapacitan and daily GH. The effect of somapacitan on HV was not statistically significantly different compared with daily GH. A similar pattern was observed for change from baseline in height standard deviation score (SDS) and change from baseline in HV SDS. Consistent dose-dependent increases were observed in insulin-like growth factor-I (IGF-I) SDS with both somapacitan and daily GH. Exposure-response modeling of somapacitan exposure versus HV and IGF-I SDS vs. HV indicated an exposure-dependent increase in HV for both these parameters. Somapacitan was well tolerated at all doses investigated, with no safety or local tolerability issues identified. There were no clinically relevant findings with respect to glucose metabolism, and no detection of anti-drug antibodies in any of the dose groups. In conclusion, all investigated doses of weekly somapacitan were efficacious and well tolerated throughout the study period. Based on the totality of data on improvements in height-based parameters combined with exposure-response analyses, a somapacitan dose of 0.24 mg/kg/week appears as the most efficacious dose, providing similar efficacy, safety and tolerability to daily GH 0.067 mg/kg/day after 26 weeks of treatment. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m., Monday, June 13, 2022 12:51 p.m. - 12:56 p.m.

Growth hormone (GH) replacement therapy usually requires daily subcutaneous (s.c.) injections that can be burdensome for patients and their caregivers. Somapacitan, a long-acting reversible albumin-binding GH derivative, is in development for once-weekly s.c. administration in children with GH deficiency (GHD). REAL4 is a randomised, multi-national, open labelled, and active-controlled parallel group phase 3 trial, comprising a 52-week main phase and three-year extension period (NCT03811535). Two-hundred GH-treatment-naïve, prepubertal children with GHD (74.5% male) were randomly assigned in a 2: 1 ratio to receive 0.16 mg/kg/week s.c. somapacitan (n=132) or daily s.c. GH (0.034 mg/kg/day Norditropin®; n=68). The 52-week main trial results are presented here. The primary endpoint was annualized height velocity (HV) after 52 weeks of treatment. At week 52, the estimated mean HV was 11.2 cm/year for somapacitan compared to 11.7 cm/year for daily GH. The estimated treatment difference was -0.5 [95% CI -1.1 to 0.2] cm/year, confirming non-inferiority (non-inferiority threshold: -1.8 cm/year). Secondary height-related endpoints supported the primary endpoint. Insulin-like growth factor-I standard deviation score (IGF-I SDS) showed consistent increases for both somapacitan and daily GH over the 52 weeks, with change differences from baseline not statistically significant between treatment groups. At week 52, mean IGF-I SDS levels were similar between somapacitan (+0.28) and daily GH (+0.10) and within normal range (-2 to +2). Somapacitan was well tolerated, with no safety or local tolerability issues identified. There were no clinically relevant findings with respect to changes in glucose metabolism, no neutralizing anti-somapacitan or anti-GH antibodies were detected, and a low number of patients reported injection-site reactions, with similar proportions for somapacitan (5.3%) and daily GH (5.9%). In both treatment groups, 1.5% of patients reported injection site pain. Adherence was high for both treatments. The mean and median adherence for somapacitan treatment were 95.8% and 100%, respectively. The mean and median adherence for the daily GH group were 88.3% and 96.9%, respectively. In conclusion, once-weekly somapacitan has a similar efficacy and safety profile as daily GH with similar mean IGF-I levels in treatment-naïve children with GHD. Presentation: Sunday, June 12, 2022 1:06 p.m. - 1:11 p.m., Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Objective The absorption, distribution and elimination of oral semaglutide, the first oral glucagon-like peptide-1 receptor agonist for treating type 2 diabetes, was investigated using a population pharmacokinetic model based on data from clinical pharmacology trials. Methods A previously developed, two-compartment pharmacokinetic model, based on subcutaneous and intravenous semaglutide, was extended to include data from six oral semaglutide trials conducted in either healthy volunteers or subjects with renal or hepatic impairment. Five trials employed multiple doses of oral semaglutide (5–10 mg) and one was a single-dose (10 mg) trial. In a separate analysis, the model was re-estimated using data from a trial in subjects with type 2 diabetes. Results The model accurately described concentration profiles across trials. Post-dose fasting time, co-ingestion of a large water volume, and body weight were the most important covariates affecting semaglutide exposure. Bioavailability was 0.8% when oral semaglutide was dosed using the recommended dosing conditions (30 min post-dose fasting time, administered with ≤ 120 mL of water), increasing with a longer post-dose fasting time and decreasing with higher water volume. Within-subject variability in bioavailability was 137%, which with once-daily dosing and a long half-life translates into 33% within-subject variability in steady-state exposure. There was no significant difference in oral bioavailability of semaglutide in healthy subjects and subjects with type 2 diabetes. Conclusions The updated model provided a general characterisation of semaglutide pharmacokinetics following oral, subcutaneous and intravenous administration in healthy subjects and subjects with type 2 diabetes. Within-individual variation of oral bioavailability was relatively high, but reduced considerably at steady state. ClinicalTrials.gov identifiers NCT01572753, NCT01619345, NCT02014259, NCT02016911, NCT02249871, NCT02172313, NCT02877355.

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.

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.

The development of new large molecule drug therapies along with the innovation of biologic-device combination products such as prefilled syringes, autoinjectors and pen injectors have significantly impacted the treatment of new diseases and has improved the process of administering parenteral medicines. To support the regulatory approval of a new biologic-device combination products or subsequent chemistry, manufacturing and control changes impacting a combination product, sponsor companies must thoroughly assess the potential impact to product quality, safety and efficacy. In this report, a risk-based process to determine the potential impact to product quality, safety, and efficacy as well as corresponding regulatory actions supporting a chemistry, manufacturing and control change is presented. The risk assessment includes the standardized assessment of a) chemistry, manufacturing and control risk factors, potential responses and appropriately weighted scoring; b) pharmacokinetic risk factors, potential responses and appropriately weighted scoring; and c) the use of a 2-dimensional risk grid to combine the chemistry, manufacturing and control risks and pharmacokinetic risks to provide a regulatory recommendation. Three case studies (two clinical case studies and a post-approval case study) are provided to demonstrate the assessment process and capabilities. Graphical Abstract

Disclosure: R.J. Kildemoes: Employee; Self; Novo Nordisk. Stock Owner; Self; Novo Nordisk. Y. Kamal Lyauk: Employee; Self; Novo Nordisk. J.C. Blair: Speaker; Self; Novo Nordisk, Pfizer, Inc., Ipsen. Other; Self; Novo Nordisk. B.S. Miller: Consulting Fee; Self; Novo Nordisk, Abbvie, Endo Pharmaceuticals, Ascendis Pharma, Bristol-Myers Squibb, Pfizer, Inc., EMD Serono, BioMarin Pharmaceutical, Tolmar. Research Investigator; Self; Alexion Pharmaceuticals, Inc., Abbvie, Aeterna Zentaris, Amicus, Lumos Pharma, Novo Nordisk, Lysogene, OPKO Health, Pfizer, Inc., Prevail Therapeutics, Sangamo Therapeutics. J. Mori: None. M. Højby Rasmussen: Employee; Self; Novo Nordisk. Stock Owner; Self; Novo Nordisk. P.F. Backeljauw: Consulting Fee; Self; Novo Nordisk, Novartis Pharmaceuticals, Ascendis Pharma, BioMarin Pharmaceutical, Tolmar Pharmaceuticals, Cavalry Biosciences, Ipsen. Research Investigator; Self; Novo Nordisk, Novartis Pharmaceuticals, Ipsen. Growth hormone (GH) replacement therapy improves overall health and adult height in children with GH deficiency (GHD). GH stimulates insulin-like growth factor-I (IGF-I) release, the biomarker commonly used for guiding GH dose adjustments to ensure optimal long-term safety and efficacy. This study aims to provide model-based insights into the dose-IGF-I responses of once-weekly somapacitan, a novel long-acting GH, compared to daily GH in pediatric patients with GHD. Pharmacokinetic/pharmacodynamic (PK/PD) modeling was used to characterize somapacitan dose-IGF-I response and to predict the response to change of dosing day and missed dosing of somapacitan. Analyses included dosing information and 1473 PK samples from 210 GHD patients treated with somapacitan across three trials: phase 1 (NCT01973244), phase 2 (NCT02616562; REAL3), and phase 3 (NCT03811535; REAL4), as well as 1381 IGF-I samples from 186 GHD patients treated with somapacitan from REAL3 and REAL4. A clear dose-response relationship was observed with increasing somapacitan exposure and increasing change from baseline IGF-I SDS. A linear model permitted the development of a tool to calculate the estimated average weekly IGF-I exposure from a single IGF-I sample obtained at any time within the somapacitan dosing interval at steady state. In practice, the use of this tool will require knowledge of the timing of the somapacitan injection relative to the timing of the IGF-I sample collection. IGF-I SDS simulations support flexible dosing day changes while maintaining a minimum of 4 days between doses. In this study, we present a practical guide that may inform clinicians about the expected weekly average IGF-I concentration in somapacitan-treated pediatric patients with GHD from a single sample taken on any chosen day during the weekly dosing interval. The ability to determine weekly average IGF-I enhances our understanding of somapacitan dosing and should support physicians in monitoring long-term safety and efficacy of this therapy. Furthermore, we provide insights on flexibility to change of dosing day and missed dosing of somapacitan. Presentation: Thursday, June 15, 2023