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ENDO 2020

Cures 2: Exogenous Approach - Cell (Beta) Replacement Therapy for T1D

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technical paper

Purpose: Treatment with denosumab (DMAB) decreases bone resorption and fracture risk. Following discontinuation, bone resorption increases, bone mass is lost and fractures have been reported. The aim of the study was to investigate if an infusion of zoledronic acid (ZOL) can prevent increases in bone turnover and bone loss in patients previously treated with DMAB and if the timing of the ZOL infusion is important. Methods: The study was a 2-year randomized, open label, interventional study in patients with osteopenia after DMAB treatment for an average of 4.6 years. ZOL was administrated 6 months (6M group, n=20) or 9 months (9M group, n=20) after the last DMAB injection or when bone turnover was increased (OBS group, n=20). Patients in the OBS and the 9M groups were monitored closely and if p-carboxy-terminal collagen crosslinks (CTX) increased > 1.26 ug/l (50% above the range for postmenopausal women and elderly men), if BMD decreased > 5% at the lumbar spine or total hip, or if a patient suffered a low energy vertebral or hip fracture, ZOL was administered. In the OBS group, ZOL was administered no later than month 6. The patients were monitored with DXA 6, 12 and 24 months after treatment. ZOL was re-administered if BMD decreased > 5% at the lumbar spine or total hip or if CTX increased above 1.26 ug/l. We report the outcome 12 months after the initial ZOL infusion. The study is ongoing. Results: A total of 60 postmenopausal women and men with a mean age of 67.7 (range 51-85) years were enrolled in the study. In the OBS group 1, 2, 6, 1 and 0 patients fulfilled the CTX or BMD criteria for treatment 1, 2, 3, 4 and 5 months after baseline. The remaining 10 patients were treated at month 6. In the 9M group 2 patients fulfilled the CTX criteria for ZOL treatment at month 2. A total of 10, 5 and 5 patients in the 6M, 9M and OBS groups, respectively were re-retreated. In the 6M group CTX decreased initially, but increased rapidly thereafter, and 6 months after ZOL, CTX was 0.60±0.08 g/L (mean±SEM). CTX increased rapidly in the 9M and OBS Groups before ZOL, was suppressed by ZOL but increased again thereafter; CTX was 0.47±0.05 μg/L and 0.47±0.05 μg/L 6 months after ZOL in the 9M and the OBS groups, respectively. Mean CTX was within the premenopausal reference range 12 months after ZOL in all 3 groups. From study baseline to twelve months after ZOL BMD at the lumbar spine had decreased by 4.8±0.7%, 4.1±1.1%, and 4.7±1.2% in the 6M, 9M and OBS groups, respectively (p≤0.002 for all without differences between groups) and at the total hip by 2.6±0.5%, 3.2±0.8%, and 3.6±0.8% in the 6M, 9M and OBS groups, respectively (p≤0.001 for all without differences between groups). The decline in BMD was more pronounced in the months before ZOL in the 9M and OBS groups whereas the decline was steadier in the 6M group. Conclusion: Treatment with ZOL irrespective of the timing did not fully prevent loss of BMD in patients with osteopenia.

Treatment with Zoledronic Acid Subsequent to Denosumab Cannot Fully Prevent Bone Loss

Background: The Phase 3 fliGHt Trial evaluated children with growth hormone deficiency (GHD) of a broad range of baseline demographics and treatment durations who switched from daily growth hormone (hGH; somatropin) therapy to once-weekly TransCon hGH. TransCon hGH is an investigational long-acting prodrug consisting of 3 components: hGH, an inert carrier that protects it, and a linker that temporarily binds the two. When injected into the body, at physiologic pH and temperature, unmodified hGH is gradually released in a predictable manner.Methods: All subjects initiated open-label once-weekly TransCon hGH 0.24 mg hGH/kg/week irrespective of prior daily hGH dose. Subjects 3 to 17 years old must have been treated with daily hGH for 13 to 130 weeks; subjects 6 months to 3 years old may have been treatment-naïve or treated with daily hGH for ≤130 weeks. The primary objective was to assess safety and tolerability over this 26-week trial. Efficacy measures included annualized height velocity (AHV), height standard deviation score (SDS), and insulin-like growth factor 1 (IGF-1) SDS.Results: Of the 146 enrolled subjects, 98.6% completed the trial. Mean age at baseline was 10.6 years (range: 1, 17). The majority (97.9%) were treatment-experienced with a prior daily hGH mean dose of 0.29 mg/kg/week (range: 0.13, 0.49); 3 subjects were treatment-naïve and <3 years old. Just over half the subjects (56.8%) experienced a treatment-emergent adverse event (TEAE), with only 4.1% of subjects experiencing a TEAE considered related to study drug. No TEAE led to discontinuation of study drug. The type and frequency of TEAEs reported were similar to the published adverse event profile of daily hGH therapies. Mean hemoglobin A1c remained 5.2% at baseline and Week 26. No neutralizing antibodies were detected; low-titer anti-hGH binding antibodies were detected in 2.8% of subjects. Growth outcomes were as expected for this treatment-experienced heterogenous population, with a least-squares mean (LSM) AHV of 8.7 cm/year (95% CI: 8.2, 9.2) at Week 26 and LSM height SDS change from baseline to Week 26 of +0.25 (95% CI: 0.21, 0.29). In the age-defined subgroups, mean observed AHV at Week 26 ranged from 8.2 to 16.2 cm/year and mean observed height SDS change from baseline to Week 26 ranged from +0.23 to +0.96. Of note, the linear relationship between average IGF-1 SDS and TransCon hGH doses demonstrated in previous treatment-naïve trials was preserved in this population of treatment-experienced children who had dose titrations.Conclusions: TransCon hGH treatment outcomes, including AHV and height SDS, were as expected across a diversity of ages, disease characteristics, and treatment experiences, reflective of a real-world setting. Dose titrations of TransCon hGH demonstrated a predictable IGF-1 response. Switching to TransCon hGH resulted in a similar adverse event profile to daily hGH therapy.

Phase 3 FliGHt Trial: Experience of Switching from Daily Growth Hormone Therapy to Once-Weekly TransCon HGH in Children with Growth Hormone Deficiency

Background: Somatrogon (hGH-CTP) is a long acting recombinant human growth hormone (rhGH; somatropin) in development for once weekly treatment of children with growth hormone deficiency (GHD). Somatrogon contains the amino acid sequence of hGH and three copies of the carboxy-terminal peptide (CTP) derived from human chorionic gonadotropin. A 12 month phase 2 trial of once weekly Somatrogon vs daily Genotropin in children with GHD demonstrated that 0.66 mg/kg/wk of Somatrogon had a similar benefit - risk profile as 0.24 mg/kg/wk of Genotropin. The open label extension of this phase 2 study has generated an additional 5 years of longitudinal efficacy and safety data with this dose. This report summarizes top line results from a pivotal phase 3 global trial (ClinicalTrials.gov: NCT02968004) designed to investigate the non-inferiority of once weekly Somatrogon hGH-CTP compared to daily hGH after 12 months in treatment-naive prepubertal children with GHD. Methods: The Phase 3 trial enrolled 224 subjects who were randomized in a 1:1 ratio to receive either once weekly Somatrogon hGH-CTP (0.66 mg/kg) or once daily Genotropin (0.24 mg/kg/wk) for 12 months. Randomization was stratified by geographic region, peak GH level and age. The primary endpoint of the study was height velocity (HV) at month 12; secondary endpoints included HV at month 6, change in height SDS at month 6 and 12, IGF-1 and IGF-I SDS, immunogenicity, and safety. Results: At baseline, the mean (SD) age and height SDS of the somatrogon (N=109, 75.2% male) and Genotropin (N=115, 68.7% male) groups were 7.83 (2.66) and -2.94 (1.29) and 7.61 (2.37) and -2.78 (1.27), respectively. One subject in each group discontinued during the 12 month study, and 95% of the completers continued into an open-label extension study. At month 12, mean HV was 10.12 cm/yr in the Somatrogon group and 9.78 cm/yr in the Genotropin group, with the treatment difference of 0.33 cm/year favoring Somatrogon. The lower bound of the two-sided 95% confidence interval of the treatment difference was -0.39, which was higher than the pre-established non-inferiority margin and demonstrated non-inferiority of once weekly somatrogon vs daily Genotropin therapy. Height velocity at month 6 (10.60 cm/yr vs 10.04 cm/yr), change in height SDS at months 6 (0.54 vs 0.48) and 12 (0.92 vs 0.87) were likewise numerically higher in the Somatrogon-treated cohort. The majority of adverse events were mild to moderate in severity (somatrogon: 78.9%, Genotropin: 79.1%) and, overall, weekly somatrogon was generally well-tolerated and comparable to daily Genotropin. Conclusion: Top-line results from the pivotal phase 3 trial demonstrate that Somatrogon (hGH-CTP) given once weekly by sc injection is non-inferior to Genotropin (hGH) given once daily and that once weekly somatrogon administration was generally well-tolerated in patients with pGHD.

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Cures 2: Exogenous Approach - Cell (Beta) Replacement Therapy for T1D

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