OPKO Health (Canada)

Abstract Background: Somatrogon, a long-acting recombinant human growth hormone, is being developed as a once weekly treatment for pediatric patients (pts) with GHD. A phase 2, 12 month study (NCT01592500) in pts with GHD showed that weekly somatrogon at 0.66 mg/kg/week had similar efficacy and safety to daily Genotropin. Pts who completed 12 months of treatment could be enrolled into an open-label extension (OLE). Aims: Evaluate the safety and efficacy of long-term exposure to somatrogon in pediatric pts with GHD who continued in the OLE for up to an additional 5 years. Methods: Methods for the main phase 2 study were published previously (Zelinska et al, 2017), in which 53 pts were randomized to 1 of 3 weekly somatrogon dose cohorts (0.25, 0.48, and 0.66 mg/kg/week) or the daily Genotropin cohort (0.24 mg/kg/week) for 12 months. After the main study (Periods I/II), 48 pts who consented to participate continued in the OLE, consisting of 3 periods: Period III=12 additional months at original somatrogon dose (Genotropin recipients randomized to 1 of the 3 somatrogon dose regimens); Period IV=subsequent years 2-4 with all pts receiving somatrogon at 0.66 mg/kg/week; Period V=ongoing, with pts transitioned from the vial to a pre-filled pen device at the same somatrogon dose (0.66 mg/kg/week). Data up to 1 year of Period V are reported. Results: Overall subject retention in different periods of this long-term study ranged from 87.5% to 97.7%. 39 pts (81.3%) reported at least one treatment-emergent adverse event (TEAE). Most TEAEs were mild or moderate in intensity and most were classified as unrelated to study treatment. 3 pts (6.3%) reported at least 1 serious adverse event (SAE); most SAEs were considered unrelated to study treatment, except for 1 instance of scoliosis. At the end of Period III, the mean annual height velocity (HV) was similar for the 0.25 and 0.48 mg/kg/week dose cohorts (7.73±1.89 and 7.54±1.28 cm/year, respectively) but was higher in the 0.66 mg/kg/week dose cohort (8.81±1.12 cm/year), consistent with the results of the main study. The HV at Periods IV and V showed sustained growth response. Height SDS showed consistent improvement and near normalization of height for age and gender after up to 6 years on somatrogon, irrespective of initial cohort assignment; height SDS at baseline of the main study was -3.98±1.22 and was well within the normal range at -0.69±0.87 at the end of Year 1 in Period V. IGF-1 SDS values remained above baseline and were maintained within the therapeutic target range with weekly somatrogon treatment at all time points in all OLE periods. Anti-drug antibodies (ADAs) were reported in 18 pts, of which 10 pts had ADAs in the main study. The presence of ADAs did not impact efficacy or safety. Conclusions: Somatrogon administered once weekly for up to 5 years after the main study was generally well tolerated and participants showed sustained improvement in annual HV, height SDS, and delta height SDS.

Abstract Objectives: Somatrogon (hGH-CTP) is a long acting recombinant human growth hormone, consisting of the amino acid sequence of hGH and three copies of the carboxy-terminal peptide (CTP) of human chorionic gonadotropin (hCG) being developed as a once weekly treatment for children with pGHD. This report summarizes data from the first year of the optional open-label extension (OLE) of the pivotal phase 3 global trial (ClinicalTrials. gov: NCT02968004), comparing the efficacy and safety of children switched from Genotropin (rhGH; somatropin) to somatrogon (Geno/Soma) and children maintained on somatrogon (Soma/Soma). Methods: During the main study, 224 children were randomized to receive either once weekly somatrogon (0.66 mg/kg, n=109) or once daily Genotropin (0.24 mg/kg/wk, n=115) for 12 months. Of these, 222 completed the 12-month main study, and 212 chose to enter the OLE study. By Sept 30, 2020, 161 children (including 76 Geno/Soma) had complete auxological data at month 12 of the OLE. Results: At the end of the main study, mean height velocity and gain in height SDS for the somatrogon cohort were 10.10 cm/year and 0.92; for the Genotropin cohort these were 9.78 cm/year and 0.87. Baseline values for the OLE (Soma/Soma group and Geno/Soma group, respectively): height SDS was -1.95 and -1.84, BMI was 17.03 and 15.48 kg/m2 while bone age was 6.54 and 6.40 years. At month 12 (of the OLE), the mean height velocity and the change in height SDS was 8.04 cm/year and 0.41 (Soma/Soma group) and 8.21 cm/year and 0.47 (Geno/Soma group); BMI was 18.07 and 17.49 kg/m2 and bone age was 8.48 and 8.41 years. IGF-1 SDS values were 1.15, and 1.28, while the IGFBP-3 SDS were 0.29 and 0.42, respectively. Dose reductions were required in 16.3% and 20.4% of patients due to IGF-1 SDS >2. Pubertal status changed from Tanner 1 (at OLE baseline) for 13.6% of Soma/Soma patients and 14.6% of Geno/Soma patients. Mean glucose, HbA1c, thyroid function (free T4 and TSH) and cholesterol (total, LDL and HDL) values remained similar to baseline in both groups across the 12 months OLE. The majority of adverse events in both cohorts were mild to moderate (Soma/Soma 94.2%, Geno/Soma 93.5%) and there were no clinically concerning safety observations. During the first 12 months of the OLE six patients discontinued in the Geno/Soma group due to AEs vs zero in the Soma/Soma group. Conclusions: Height velocities and change in height SDS in the OLE were similar between the Geno/Soma and Soma/Soma cohorts. The main phase of the global pivotal phase 3 trial demonstrated that somatrogon (hGH-CTP) given once weekly is non-inferior to Genotropin (hGH) while the OLE demonstrated that catch-up growth continued into the second year of treatment, with ‘switch’ from Genotropin to somatrogon non-inferior to somatrogon given for two years. Metabolic (glycemic, lipid and thyroid) parameters were similar between groups and not meaningfully different from the main study.

IGF-1 is often used as a biomarker to evaluate the efficacy and safety of hGH replacement therapy. Typically, the mean IGF-1 SDS level during the dosing interval, rather than the peak value, guides clinical decision-making: sustained mean values > +2 may require hGH dose modifications. With long-acting formulations (administered weekly), the IGF-1 evaluation paradigm needs to take into account when the sample was obtained relative to the last administered dose. Previous studies with OPKO’s once weekly Somatrogon (hGH-CTP), demonstrated that IGF-1 SDS peaked ~ 48 hours post-dose and that values at ~ 96 hours best approximated the mean IGF-1 SDS throughout the dosing interval [1]. Data from the pivotal Phase 3 non-inferiority study comparing treatment with Somatrogon to Genotropin allowed further evaluation of the IGF-1 SDS analysis paradigm.Enrolled subjects were randomized to receive treatment with either once weekly Somatrogon (0.66 mg/kg; N=109) or once daily Genotropin (0.034 mg/kg; N=115). IGF1 was sampled ~ five times during 52 weeks of treatment with Somatrogon, providing a total of 557 samples obtained after the first dose of Somatrogon. IGF-1 SDS values were calculated using Bidlingmaier’s equations [2].Analysis of IGF-I SDS data from the Phase 3 study showed that the previously-developed model, with adjustments to two parameters (baseline IGF-1, EC50) and adapted to fit IGF-1 values in the absence of Somatrogon concentration data, fit the IGF-1 data for Somatrogon with minimal bias. This allowed prediction of IGF-1 SDS values at timepoints throughout the dosing interval as well as calculation of the mean value during a dosing interval. Of the samples obtained between 48–72 hours post-dose (representing peak IGF-1 SDS), approximately 17% had an IGF1 SDS > +2. At 96 hours (corresponding to mean IFG-1 SDS), fewer than 2% of modeled values were > +2. Mean IGF-1 SDS over the dosing interval was between -1 and +1 for all subjects.These findings indicate that IGF-1 SDS values need to be interpreted in the context of when the sample was obtained relative to the last dose of Somatrogon. Our results indicate that samples obtained 96 hours post-dose best represent mean IGF-1 levels and that values obtained between 48–72 hours post-dose represent values closer to peak IGF-1 concentrations. In our Phase 3 study, of the 557 samples collected from 114 patients during the 12-month Somatrogon treatment period, fewer than 2% of the corresponding values at 96 hours postdose (estimated from a pharmacokinetic/pharmacodynamic model) had IGF-1 SDS levels > +2.1. Fisher DM, et al. Horm Res Paediatr 2017;87:324. 2. Bidlingmaier M, et al. J Clin Endocrinol Metab 2014;99:1712

Virtual reality (VR) has the potential to offer experiences which are engaging and rewarding. In VR, the focus is shifted from the person's efforts in producing a movement or completing a task to that of interaction with the virtual environment. We have found that participants place value and meaning on and enjoy the activities programmed. Virtual reality interventions have been shown to improve cognitive function and concentration through an individual's interaction with a pleasant activity. Importantly, the enjoyment experienced while working with VR may increase the level of participation. In addition to generating realistic situations for testing, intervention and collection of data, the provision of immediate and positive feedback through VR has been shown to increase self esteem and empowerment. We will report outcomes from several intervention and feasibility trials using a flat screen virtual reality system with survivors of traumatic brain injury, community living older adults and children with spastic cerebral palsy. Gross motor movements were elicited through various game-like VR applications without the need for head-mounted displays or other peripherals. The impact of VR exercise participation ranged from improvements in clinical measures of functional balance and mobility, time on task, as well as participant and care provider perceptions of enjoyment, independence and confidence. Although still preliminary, our data suggest that simple applications of virtual reality have significant impacts on physical and psychosocial variables. Possibilities for and benefits of home and community-based access to virtual reality based programs will be explored.