Objective To report the final long-term safety and efficacy analyses of patients with acromegaly treated with pegvisomant from the ACROSTUDY. Design Global (15 countries), multicentre, ...non-interventional study (2004–2017). Methods The complete ACROSTUDY cohort comprised patients with acromegaly, who were being treated with pegvisomant (PEGV) prior to the study or at enrolment. The main endpoints were long-term safety (comorbidities, adverse events (AEs), pituitary tumour volumes, liver tests) and efficacy (IGF1 changes). Results Patients (n = 2221) were treated with PEGV for a median of 9.3 years (range, 0–20.8 years) and followed up for a median of 7.4 years (range, 0–13.9 years). Before PEGV, 96.3% had received other acromegaly treatments (surgery/radiotherapy/medications). Before PEGV treatment, 87.2% of patients reported comorbidities. During ACROSTUDY, 5567 AEs were reported in 56.5% of patients and of these 613 were considered treatment-related (in 16.5% of patients) and led to drug withdrawal in 1.3%. Pituitary imaging showed a tumour size increase in 7.1% of patients; the majority (71.1%) reported no changes. Abnormal AST or ALT liver tests occurred in 3.2% of patients. IGF1 normalization rate improved over time, increasing from 11.4% at PEGV start to 53.7% at year 1, and reaching 75.4% at year 10 with the use of ≥30 mg PEGV/day in an increasing proportion of patients. Conclusion This comprehensive review of the complete cohort in ACROSTUDY confirmed the overall favourable benefit-to-risk profile and high efficacy of PEGV as mono- and combination therapy in patients with an aggressive course/uncontrolled/active acromegaly requiring long-term medical therapy for control.
The Kabi/Pfizer International Growth Database (KIGS) is a large, international database (1987-2012) of children treated with recombinant human growth hormone (rhGH) in real-world settings.
This work ...aimed to evaluate the safety and efficacy of rhGH from the full KIGS cohort.
Data were collected by investigators from children with growth disorders treated with rhGH (Genotropin somatropin; Pfizer). Safety was evaluated in all treated patients, and efficacy in those treated for 1 year or more. A subgroup included patients treated for 5 years or more (≥ 2 years prepubertal) who had reached near-adult height (NAH). Main outcomes included adverse events (AEs), serious AEs (SAEs), and height growth.
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-SD score (SDS) (Prader) in prepubertal patients was 0.66 (IGHD), 0.55 (ISS), 0.58 (TS), and 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.
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.
Data on long-term safety of growth hormone (GH) replacement in adults with GH deficiency (GHD) are needed.
To evaluate the safety of GH in the full KIMS (Pfizer International Metabolic Database) ...cohort.
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.
Adverse events (AEs) and clinical characteristics (e.g., lipid profile, glucose) were collected.
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.
These final KIMS cohort data support the safety of long-term GH replacement in adults with GHD as prescribed in routine clinical practice.
Somatrogon is a long-acting recombinant human growth hormone (rhGH) in development for once-weekly treatment of children with growth hormone deficiency (GHD).
We aimed to compare the efficacy and ...safety of once-weekly somatrogon with once-daily somatropin in prepubertal children with GHD.
In this 12-month, open-label, randomized, active-controlled, parallel-group, phase 3 study, participants 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. A total of 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). The primary endpoint was annualized HV at month 12.
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 2-sided 95% CI was higher than the prespecified noninferiority margin (-1.8 cm/year), demonstrating noninferiority of once-weekly somatrogon vs daily somatropin. HV at month 6 and change in height standard deviation score 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%).
The efficacy of once-weekly somatrogon was noninferior to once-daily somatropin, with similar safety and tolerability profiles. (ClinicalTrials.gov no. NCT02968004).
Abstract
Context
Individual patients vary in their response to growth hormone (GH). No large-scale genome-wide studies have looked for genetic predictors of GH responsiveness.
Objective
To identify ...genetic variants associated with GH responsiveness.
Design
Genome-wide association study (GWAS).
Setting
Cohorts from multiple academic centers and a clinical trial.
Patients
A total of 614 individuals from 5 short stature cohorts receiving GH: 297 with idiopathic short stature, 276 with isolated GH deficiency, and 65 born small for gestational age.
Intervention
Association of more than 2 million variants was tested.
Main Outcome Measures
Primary analysis: individual single nucleotide polymorphism (SNP) association with first-year change in height standard deviation scores. Secondary analyses: SNP associations in clinical subgroups adjusted for clinical variables; association of polygenic score calculated from 697 genome-wide significant height SNPs with GH responsiveness.
Results
No common variant associations reached genome-wide significance in the primary analysis. The strongest suggestive signals were found near the B4GALT4 and TBCE genes. After meta-analysis including replication data, signals at several loci reached or retained genome-wide significance in secondary analyses, including variants near ST3GAL6. There was no significant association with variants previously reported to be associated with GH response nor with a polygenic predicted height score.
Conclusions
We performed the largest GWAS of GH responsiveness to date. We identified 2 loci with a suggestive effect on GH responsiveness in our primary analysis and several genome-wide significant associations in secondary analyses that require further replication. Our results are consistent with a polygenic component to GH responsiveness, likely distinct from the genetic regulators of adult height.
To evaluate adherence to, and discontinuation of, somatropin treatment over 4 years in a US population-based study of children with pediatric growth hormone deficiency (pGHD).
A retrospective cohort ...analysis of commercially insured patients ≥3 and <16 years, diagnosed with pGHD, newly treated with somatropin was conducted using Optum De-identified Clinformatics Data Mart. Index date was defined as the first prescription for somatropin between 01 July 2002 and 30 September 2019. Five non-exclusive patient cohorts were identified (>3, 12, 24, 36, and 48 months of post-index continuous enrollment). Suboptimal adherence was defined as medication possession ratio <80%. Discontinuation was defined as the date at which a gap of >60 days between somatropin fills first occurred. Cox proportional hazards regression was used to evaluate time to discontinuation.
In the 12-month cohort (n = 3091), mean age was 11.3 ± 2.9 years, 75.9% were male, 70.9% white, 9.4% Hispanic, 3.6% Asian, and 3.1% black. The proportion with suboptimal adherence at months 12 and 48 was 19.6% and 35.9%, respectively. Discontinuation occurred in 42.2% of patients. The rate of discontinuation (HR 95% CI) was higher for age ≥10 (1.74 1.53-1.98), females (1.35 1.21-1.50), black and Hispanic race/ethnicity (1.50 1.18-1.90 and 1.27 1.09-1.49 compared to White) and obesity (1.69 1.19-2.40).
Suboptimal adherence increases with treatment duration, and risk of discontinuation is associated with age, female gender, black or Hispanic race/ethnicity, and obesity. Strategies that facilitate adherence among children at risk of discontinuation may improve clinical outcomes.
Limited real-world data from routine clinical care are available on the safety and effectiveness of treatment with taliglucerase alfa in patients with Gaucher disease (GD).
Taliglucerase Alfa ...Surveillance (TALIAS), a multinational prospective Drug Registry of patients with GD, was established to evaluate the long-term safety (primary objective) and effectiveness (secondary objective) of taliglucerase alfa. We present an interim analysis of the data from the Drug Registry collected over the 5-year period from September 2013 to January 2019.
A total of 106 patients with GD (15.1% children aged < 18 years; 53.8% females) treated with taliglucerase alfa have been enrolled in the Drug Registry, as of January 7, 2019. The median duration of follow-up was 795 days with quartiles (Q1, Q3) of 567 and 994 days. Fifty-three patients (50.0%) were from Israel, 28 (26.4%) were from the United States, and 25 (23.6%) were from Albania. At the time of enrollment, most patients (87.7%) had received prior enzyme replacement therapy (ERT). Thirty-nine of the 106 patients had treatment-emergent adverse events (AEs). Twelve of the 106 patients experienced serious AEs; two patients experienced four treatment-related serious AEs. Four patients died, although none of the deaths was considered to be related to taliglucerase alfa treatment by the treating physicians. Nine patients discontinued from the study, including the four who died. At baseline, patients with prior ERT had a higher mean hemoglobin concentration and platelet counts than treatment-naïve patients, likely reflecting the therapeutic effects of prior treatments. During follow-up, the hemoglobin concentration and platelet counts increased in the treatment-naïve patients and remained relatively constant or increased slightly in patients with prior ERT. Spleen and liver volumes decreased in treatment-naïve patients.
The interim data showed no new or emergent safety signals. The overall interim data are consistent with the clinical program experience and known safety and effectiveness profile of taliglucerase alfa.
Abstract Somatrogon‐ghla is a long‐acting, recombinant human growth hormone approved for the treatment of pediatric patients with growth hormone deficiency. Forty‐nine healthy, adult males were ...enrolled in a randomized, crossover study to compare somatrogon exposure after subcutaneous doses administered using a frozen vial presentation or a prefilled, multiple dose pen. Somatrogon, insulin‐like growth factor‐I, and IGF‐1 binding protein‐3 concentrations were collected for up to 240 hours post dose to assess pharmacokinetic and pharmacodynamic responses. There was a 2‐week washout between administration of the doses. Seven participants did not complete the study due to withdrawal of consent (n = 2) or loss to follow‐up. Two treatment‐emergent adverse events, headaches, were judged by the investigator as possibly related to study drug administration. Both were mild. Injection site reactions were observed in 6/48 participants after administration with the pen and 12/46 after administration using the vial. Drug and biomarker concentrations were assessed using validated assays and noncompartmental methods were used to determine pharmacokinetic and pharmacodynamic parameters. Bioequivalence was demonstrated for somatrogon area under the concentration‐time curve, but not for the peak somatrogon concentration, where the lower limit of the 90% confidence interval for the ratio of pen/vial was 74.2%, which is less than the lower limit, 80.0%, dictated by bioequivalence criteria. The IGF‐1 responses were largely within bioequivalence limits. It was concluded that the 2 formulations are comparable.
Somatrogon is a long-acting recombinant human growth hormone used to treat patients with paediatric growth hormone deficiency (pGHD). This global phase 3 study compared the efficacy and safety of ...once-weekly somatrogon with once-daily somatropin in children with GHD.
Prepubertal patients were randomized 1:1 to once-weekly somatrogon (0.66 mg/kg/week) or once-daily somatropin (0.24 mg/kg/week) for 12 months. The primary endpoint was height velocity (HV) at month 12; secondary endpoints included HV at month 6 and change in height standard deviation score (SDS) at months 6 and 12 and insulin-like growth factor 1 (IGF-1) SDS.
This
subgroup analysis focused specifically on Asian children (somatrogon: n=24 and mean age=7.76 years; somatropin: n=21 and mean age=8.10 years) across eight countries. Mean HV at month 12 was 10.95 cm/year (somatrogon) and 9.58 cm/year (somatropin); the treatment difference of 1.38 cm/year favoured somatrogon. The lower bound of the two-sided 95 % CI of the treatment difference (somatrogon-somatropin) was -0.20, similar to the overall study population (-0.24). Compared with the somatropin group, the somatrogon group had numerically higher HV at month 6 (8.31 vs. 11.23 cm/year); a similar trend was observed for height SDS and IGF-1 SDS at months 6 and 12. Safety and tolerability were similar between treatment groups; adverse events occurred in 83 % of somatrogon-treated children and 76 % of somatropin-treated children.
This subgroup analysis demonstrated that somatrogon efficacy and safety in Asian children were consistent with the overall study population, where once-weekly somatrogon was non-inferior to once-daily somatropin. Clinicaltrials.gov: NCT02968004.
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