Faculty Bibliography

Introduction Although there are some recommendations in the literature on the assessments that should be performed in children on recombinant human growth hormone (rhGH) therapy, the level of consensus on these measurements is not clear. The objective of the current study was to identify the minimum dataset (MDS) that could be measured in a routine clinical setting across the world, aiming to minimise burden on clinicians and improve quality of data collection. Methods This study was undertaken by the GH Scientific Study Group (SSG) in GloBE-Reg, a new project that has developed a common registry platform that can support long-term safety and effectiveness studies of drugs. Twelve clinical experts from 7 international endocrine organisations identified by the GloBE-Reg Steering Committee, 2 patient representatives and representatives from 2 pharmaceutical companies with previous GH registry expertise collaborated to develop this recommendation. A comprehensive list of data fields routinely collected by each of the clinical and industry experts for children with GHD was compiled. Each member was asked to determine the: (1) Importance of the data field and (2) Ease of data collection. Data fields that achieved 70% consensus in terms of importance qualified for the MDS, provided <50% deemed the item difficult to collect. Results A total of 246 items were compiled and 27 removed due to redundancies, with 219 items subjected to the grading system. Of the 219 items, 111 achieved at least 70% consensus as important data to collect when monitoring children with GH deficiency (GHD) on rhGH treatment. Sixty-nine of the 219 items were deemed easy to collect. Combining the criteria of importance and ease of data collection, 63 met the criteria for the MDS. Several anomalies to the MDS rule were identified and highlighted for discussion, including whether the patients were involved in current or previous clinical trials, need for HbA1c monitoring, other past medical history, and adherence, enabling formulation of the final MDS recommendation of 43 items; 20 to be completed once, 14 every 6 months and 9 every 12 months. Conclusion In summary, this exercise performed through the GloBE-Reg initiative provides a recommendation of the minimum dataset requirement, collected through real-world data, for the monitoring of safety and effectiveness of rhGH in children with GHD, both for the current daily preparations and the newer long-acting growth hormone.

Taliglucerase alfa is an enzyme replacement therapy approved for Gaucher disease. We assessed the duration/compliance/safety of such home infusions in commercial use in four countries where home infusion programs are available. The treatment duration/compliance study included 173 patients (Israel, 58; US, 61; Brazil, 48; Australia, 6) who received ≥1 taliglucerase alfa home infusion through 6/2021. The median age at home therapy initiation was 38 (range, 2-87) years; 58% were females. The median treatment duration (at home) was 2.7 (range, 0.04-9.0) years. The annual compliance rate was stable (≥95%) throughout the study period. A search of the Pfizer global safety database (through 6/2021), identified 19 adverse events (AEs) as related to "definite home use" and 14 to "possible home use" of taliglucerase alfa; 42.4% of these AEs were serious; none were fatal. Twelve serious AEs in five separate case reports were considered treatment related: one case of chest discomfort/pain and hypertension and one case of erythema associated with a toe blister, for which causality could not be excluded; pain in extremity; projectile vomiting and chills, alongside excessive eye blinking; and an infusion-related AE (pruritus). In conclusion, this real-life global study demonstrated that taliglucerase alfa home infusions are safe with high compliance rates.

CONTEXT/BACKGROUND:KIGS is a large, international database (1987-2012) of children treated with recombinant human growth hormone (rhGH) in real-world settings. OBJECTIVE:To evaluate the safety and efficacy of rhGH from the full KIGS cohort. DESIGN, PATIENTS, SETTING, AND INTERVENTION/UNASSIGNED:Data were collected by investigators from children with growth disorders treated with rhGH (Genotropin® [somatropin]; Pfizer, NY). Safety was evaluated in all treated patients, and efficacy in those treated for ≥1 year. A subgroup included patients treated for ≥5 years (≥2 years prepubertal) who had reached near-adult height (NAH). MAIN OUTCOMES/RESULTS:Adverse events (AEs), serious AEs (SAEs), and height growth. RESULTS:The full KIGS cohort (N = 83,803 [58% male]) was treated for idiopathic GH deficiency (IGHD; 46.9%), organic GHD (10.0%), small for gestational age (SGA; 9.5%), Turner syndrome (TS; 9.2%), idiopathic short stature (ISS; 8.2%), and others (16.2%). Median rhGH treatment duration was 2.7 years and observation 3.1 years. SAEs occurred in 3.7% of patients and death in 0.4%. The most common SAEs were recurrence of craniopharyngioma (n = 151), neoplasm (n = 99), and cancer (n = 91); and scoliosis (n = 91). Median first-year delta height-SDS (Prader) in prepubertal patients was 0.66 (IGHD), 0.55 (ISS), 0.58 (TS), 0.71 (SGA). Median gains in NAH-SDS were 1.79 (IGHD), 1.37 (ISS), and 1.34 (SGA) for boys, and 2.07 (IGHD), 1.62 (ISS), 1.07 (TS), and 1.57 (SGA) for girls. CONCLUSION/CONCLUSIONS:Data from KIGS, the largest and longest running international database of rhGH-treated children, show that rhGH is safe and increases short-term height gain and adult height across GHD and non-GHD conditions.

Objectives: Somatrogon is a long-acting recombinant human growth hormone (GH) approved by the EMA as a once weekly treatment for children with pediatric GH deficiency (GHD). (Table Presented) A global phase 3 study compared the efficacy and safety of onceweekly somatrogon with once-daily Genotropin in pediatric subjects with GHD. The objective of this subgroup analysis was to evaluate the efficacy and safety of once-weekly somatrogon vs once-daily Genotropin in the subset of Asian subjects.
Method(s): This open-label phase 3 study enrolled 224 subjects who were randomized 1:1 to receive either once-weekly somatrogon (0.66 mg/kg/week) or once-daily Genotropin (0.24 mg/kg/ week) 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 months 6 and 12, IGF-1, IGF-I SDS, and bone maturation. This subgroup analysis focused on 45 Asian subjects from Australia, Great Britain, India, New Zealand, South Korea, Spain, Taiwan and the United States of America.
Result(s): Within this subgroup of Asian subjects, both treatment groups (somatrogon:n=24; Genotropin:n=21) had similar demographic and baseline characteristics. The least squares mean HV at month 12 was 10.94 cm/year in the somatrogon group and 9.56 cm/year in the Genotropin group with missing data imputed; the treatment difference of 1.38 cm/year favored somatrogon. The lower bound of the two-sided 95% confidence interval of the treatment difference (somatrogon-Genotropin) was -0.14 for this subgroup, similar to that for the overall study population (-0.24), for which the efficacy of once-weekly somatrogon was demonstrated to be non-inferior to once-daily Genotropin. The observed HV at month 6 was higher in the somatrogon group than in the Genotropin group (11.23 vs 8.31 cm/year). The somatrogon group also showed greater improvement in height SDS and IGF-1 SDS from baseline at months 6 and 12, compared with the Genotropin group. Both treatment groups had a similar proportion of subjects with adverse events (somatrogon: 83.3%; Genotropin: 76.2%) and serious adverse events were recorded for one and two subjects in the somatrogon and Genotropin groups, respectively.
Conclusion(s): The efficacy and safety results from this analysis of Asian subjects in the global study are consistent with those from the overall study population, in which non-inferiority of onceweekly somatrogon to once-daily Genotropin was demonstrated. Clinicaltrials.gov:NCT02968004

Background: Paediatric growth hormone deficiency (pGHD) is treated with daily somatropin (recombinant human growth hormone) injections. High rates of discontinuation and poor adherence to treatment, which are associated with worse growth outcomes, have been documented previously, for example in the US and EU. Discontinuation of somatropin has not yet been evaluated using real-world data in Japan.
Objective(s): To describe discontinuation of, and persistence to, daily somatropin treatment among children with pGHD in Japan.
Method(s): This was a retrospective cohort study of children (>=3 and <16 years old) who were prescribed somatropin, using two Japan-based databases, Japan Medical Data Center (JMDC) and Medical Data Vision (MDV). Children were required to have >=1 prescription for somatropin (first prescription = index date) within each study period (1st January 2002 to 30th June 2021 for JMDC and 1st January 2009 to 31st October 2021 for MDV) and >=1 GHD diagnosis code without a somatropin prescription during the 6-months pre-index. Children were required to be continuously enrolled in the database >=6 months preceding and >=3 months following index date. Children were followed for up to 48 months post-index. Early persistence was defined as proportion of children with >1 refill of somatropin subsequent to the initial prescription. Discontinuation was defined as the first observation of a gap in therapy (using >60 and >90-day gap thresholds) between successive somatropin prescription fill dates. Persistence was defined as continuous refills of somatropin with no gaps in therapy. Time to discontinuation/non-persistence was evaluated using Kaplan Meier methods, and Cox proportional hazards models identified predictors of time to discontinuation.
Result(s): Among the children included in this study (JMDC N=452, MDV N=573), most were male (JMDC 64.8%, MDV 60.0%). Mean age (standard deviation) was 8.8 years (3.6) in JMDC and 7.5 years (3.6) in MDV. Early persistence was high across both cohorts (JMDC 91.2%, MDV 83.4%). Using the more conservative 90-day gap definition for discontinuation, a sizable proportion of children discontinued over the follow-up period: JMDC 19% at 12 months, 35% at 48 months, and MDV 33% at 12 months, 54% at 48 months. No meaningful predictors of discontinuation were identified.
Conclusion(s): Despite high early persistence with somatropin, many children with pGHD in Japan were increasingly non-persistent over time: at 48 months post-index, one-third to onehalf of children discontinued therapy. These results suggest a need for new strategies to support medication use over time among children with pGHD in Japan

Objectives: Somatrogon, a long-acting recombinant human growth hormone (GH) consisting of the amino acid sequence of human GH (hGH) and three copies of the carboxy-terminal peptide (CTP) of human chorionic gonadotropin, is approved by the EMA for treatment of children with GH deficiency (GHD). In this phase 3 study, children with GHD received either somatrogon or Genotropin. The impact of testing positive for anti-drug antibodies to somatrogon (ADA+) on the efficacy and safety of somatrogon was evaluated.
Method(s): In the 12-month main study, subjects were randomized to once-weekly somatrogon (0.66 mg/kg/week) or once-daily Genotropin (0.24 mg/kg/week). After the main study, subjects could enroll in an open label extension (OLE), where all subjects received somatrogon (0.66 mg/kg/week). Samples to assess ADAs were collected quarterly during the main study and every 6 months during the OLE. Using electrochemiluminescence assays, samples were initially assessed for anti-somatrogon ADAs; ADA+ samples were further assessed for anti-hGH and anti-CTP ADAs. Neutralizing ADAs (NAb) to somatrogon and hGH were identified in assays measuring inhibition of somatrogon/hGH-stimulated cell proliferation. Subjects with >=1 ADA+ result were compared with subjects with no ADA+ samples (ADA-).
Result(s): By Month 12, 84/109 (77.1%) somatrogon-treated subjects had >=1 ADA+ result; most were anti-hGH+. Two of the 84 subjects tested NAb+ for somatrogon. At OLE Month 12, of the 212 subjects (108 subjects had received Genotropin in the main study), 114 (53.8%) had >=1 ADA+ result; most ADA samples were anti-hGH. No additional subjects tested NAb+ for somatrogon while 3 subjects tested NAb+ for hGH. ADA status had no effect on growth parameters (Table). Being ADA+ was associated with numerically higher mean IGF-1 SDS values and greater changes from baseline but there was considerable overlap between ADA+ and ADA- subjects (Table). The presence of ADAs to somatrogon did not affect the incidence of treatment-emergent adverse events (AEs), serious AEs, or AEs of special interest; there was no association between the incidence of AEs and ADA titer.
Conclusion(s): ADA+ did not affect the efficacy or safety of somatrogon

Objectives: Somatrogon is a long-acting recombinant human growth hormone (GH) approved by the EMA as a once weekly treatment for children with GH deficiency (GHD). The peak stimulated GH cut-off value for diagnostic criteria for GHD varies according to country-specific guidelines. The objective of this subgroup analysis of the pivotal phase 3 somatrogon study was to evaluate the primary and secondary efficacy endpoints for subjects with a peak GH value <6.7 ng/ml.
Method(s): This phase 3 study enrolled 224 subjects, randomized 1:1 to receive either once-weekly somatrogon (0.66mg/kg/ week) or once-daily Genotropin (0.24mg/kg/week) for 12 months. Randomization was stratified by geographic region, peak GH level, and age. The study's primary endpoint 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, IGF-1 SDS, and bone maturation. This subgroup analysis focused on 135 subjects with a peak GH value <6.7 ng/mL (67 subjects received somatrogon and 68 received Genotropin).
Result(s): In this subgroup, the least squares (LS) mean HV at month 12 was 10.11 cm/year and 9.77 cm/year in somatrogon- and Genotropin-treated subjects, respectively, with the treatment difference of 0.34 cm/year favoring somatrogon. This was similar to the overall study population (peak GH value <10 ng/ml), whose LS mean HV at month 12 was 10.10 cm/year and 9.78 cm/year for somatrogon- and Genotropin-treated subjects, respectively, with a treatment difference of 0.33 favoring somatrogon. The efficacy of once-weekly somatrogon was statistically demonstrated to be non-inferior to once-daily Genotropin in the overall study population. In this subgroup, mean changes in height SDS at months 6 (0.57 vs 0.50) and 12 (0.96 vs 0.91) were numerically higher in somatrogon-treated subjects. Stratification by age (3 to 7 years, >7 years), gender, and region showed most values for HV and change in height SDS at months 6 and 12 were higher for the somatrogon group compared with the Genotropin group. The increase in IGF-1 SDS from baseline to month 12 was higher in the somatrogon group (+2.84) versus the Genotropin group (+1.06). Mean bone maturation observed at 12 months was similar between both groups (both 0.69).
Conclusion(s): The findings from this analysis of subjects with a peak GH value <6.7 ng/mL are consistent with those from the overall study population, in which non-inferiority of once-weekly somatrogon to once-daily Genotropin was statistically demonstrated

CONTEXT/BACKGROUND:Somatrogon is a long-acting recombinant human growth hormone (rhGH) in development for once-weekly treatment of children with growth hormone deficiency (GHD). OBJECTIVE:Compare the efficacy and safety of once-weekly somatrogon with once-daily somatropin in prepubertal children with GHD. DESIGN/METHODS:12-month, open-label, randomized, active-controlled, parallel-group, phase 3 study. INTERVENTION/METHODS:Subjects were randomized 1:1 to receive once-weekly somatrogon (0.66 mg/kg/week) or once-daily somatropin (0.24 mg/kg/week) for 12 months. PATIENTS OR OTHER PARTICIPANTS/METHODS:228 prepubertal children (boys aged 3-11 years, girls aged 3-10 years) with GHD, impaired height and height velocity (HV), and no prior rhGH treatment were randomized and 224 received ≥1 dose of study treatment (somatrogon: 109; somatropin: 115). MAIN OUTCOME MEASURES/METHODS:The primary endpoint was annualized HV at month 12. RESULTS:HV at month 12 was 10.10 cm/year for somatrogon-treated subjects and 9.78 cm/year for somatropin-treated subjects, with a treatment difference (somatrogon-somatropin) of 0.33 (95% CI: -0.24, 0.89). The lower bound of the two-sided 95% confidence interval was higher than the prespecified non-inferiority margin (-1.8 cm/year), demonstrating non-inferiority of once-weekly somatrogon vs daily somatropin. HV at month 6 and change in height SDS at months 6 and 12 were similar between both treatment groups. Both treatments were well tolerated, with a similar percentage of subjects experiencing mild to moderate treatment-emergent adverse events in both groups (somatrogon:78.9%, somatropin:79.1%). CONCLUSIONS:The efficacy of once-weekly somatrogon was non-inferior to once-daily somatropin, with similar safety and tolerability profiles.

CONTEXT/BACKGROUND:Data on long-term safety of growth hormone (GH) replacement in adults with GH deficiency (GHD) are needed. OBJECTIVE:To evaluate the safety of GH in the full KIMS (Pfizer International Metabolic Database) cohort. DESIGN, PATIENTS, SETTING, AND INTERVENTION/UNASSIGNED:The worldwide, observational KIMS study included adults and adolescents with confirmed GHD. Patients were treated with GH (Genotropin ® [somatropin]; Pfizer, NY) and followed through routine clinical practice. MAIN OUTCOME MEASURES/METHODS:Adverse events (AEs) and clinical characteristics (e.g., lipid profile, glucose) were collected. RESULTS:15,809 GH-treated patients were analyzed (mean follow up of 5.3 years). AEs were reported in 51.2% of patients (treatment-related in 18.8%). Crude AE rate was higher in patients who were older, had GHD due to pituitary/hypothalamic tumors, or adult-onset GHD. AE rate analysis adjusted for age, gender, etiology, and follow-up time showed no correlation with GH dose. 606 deaths (3.8%) were reported (146 by neoplasms, 71 by cardiac/vascular disorders, 48 by cerebrovascular disorders). Overall de novo cancer incidence was comparable to that in the general population (standard incidence ratio 0.92; 95% CI 0.83-1.01). De novo cancer risk was significantly lower in patients with idiopathic/congenital GHD (0.64; 0.43-0.91), but similar in those with pituitary/hypothalamic tumors or other etiologies versus the general population. Neither adult-onset nor childhood-onset GHD was associated with increased de novo cancer risks. Neutral effects were observed in lipids/fasting blood glucose levels. CONCLUSIONS:These final KIMS cohort data support the safety of long-term GH replacement in adults with GHD as prescribed in routine clinical practice.