Pegvisomant monotherapy is effective and safe in treatment of acromegaly. However, some clinicians combine pegvisomant with somatostatin analogues (SSA) or dopamine agonist (DA). In this analysis of ACROSTUDY, a long-term non-interventional study, the use of combination regimens was evaluated. Based on their baseline treatment, 2043 patients were retrospectively categorized as: long-acting SSA combined with pegvisomant, ‘Combo SSA’ 768 patients (38%); DA combined with pegvisomant, ‘Combo DA’ 123 (6%); pegvisomant monotherapy, ‘Peg mono’ 1128 (55%). Treatment patterns changed over the 10-year period, with recent patients more likely to receive any combination (20% in 2003 vs 54% in 2012). Combo SSA use varied widely among countries from 22% to 78%. Exposure periods of the three treatment modalities were defined from pegvisomant start until the last visit in ACROSTUDY; patients could switch treatment categories. At year 4, IGF-I was normal in 62% of Combo SSA, 63% of Combo DA and 65% of Peg mono groups. Pegvisomant was initiated as daily injections in 94% of patients in the Peg mono group, 66% of Combo SSA and 91% of Combo DA patients. During 6169 years of treatment exposure, 3424 adverse events (AEs) were reported in 946 (51%) patients, of which 617 (18%) were serious and 401 (12%) were considered treatment related. The reported incidence of serious AEs and treatment-related non-serious AEs were similar among the three treatment modalities. This analysis describes real-world clinical care and shows favorable efficacy and safety for Peg mono and combinations. Novel findings include an increased use of combination therapy over time and variability in treatment modalities between countries.
Christian J Strasburger, Anders Mattsson, Patrick Wilton, Ferah Aydin, Judith Hey-Hadavi and Beverly M K Biller
Charlotte Höybye, Oskar Ragnarsson, Peter J Jönsson, Maria Koltowska-Häggström, Peter Trainer, Ulla Feldt-Rasmussen and Beverly M K Biller
Patients in remission from Cushing's disease (CD) have many clinical features that are difficult to distinguish from those of concomitant GH deficiency (GHD). In this study, we evaluated the features of GHD in a large cohort of controlled CD patients, and assessed the effect of GH treatment.
Design and methods
Data were obtained from KIMS, the Pfizer International Metabolic Database. A retrospective cross-sectional comparison of background characteristics in unmatched cohorts of patients with CD (n=684, 74% women) and nonfunctioning pituitary adenoma (NFPA; n=2990, 39% women) was conducted. In addition, a longitudinal evaluation of 3 years of GH replacement in a subset of patients with controlled CD (n=322) and NFPA (n=748) matched for age and gender was performed.
The cross-sectional study showed a significant delay in GHD diagnosis in the CD group, who had a higher prevalence of hypertension, fractures, and diabetes mellitus. In the longitudinal, matched study, the CD group had a better metabolic profile but a poorer quality of life (QoL) at baseline, which was assessed with the disease-specific questionnaire QoL-assessment of GHD in adults. After 3 years of GH treatment (mean dose at 3 years 0.39 mg/day in CD and 0.37 mg/day in NFPA), total and low-density lipoprotein cholesterol decreased, while glucose and HbAlc increased. Improvement in QoL was observed, which was greater in the CD group (−6 CD group versus −5 NFPA group, P<0.01).
In untreated GHD, co-morbidities, including impairment of QoL, were more prevalent in controlled CD. Overall, both the groups responded similarly to GH replacement, suggesting that patients with GHD due to CD benefit from GH to the same extent as those with GHD due to NFPA.
Oskar Ragnarsson, Charlotte Höybye, Peter J Jönsson, Ulla Feldt-Rasmussen, Gudmundur Johannsson, Beverly M K Biller and Maria Kołtowska-Häggström
Cushing's disease (CD) and non-functioning pituitary adenoma (NFPA) are rare in paediatric patients. The aim of this study was to describe long-term consequences in adults with GH deficiency (GHD) treated for CD or NFPA during childhood.
Design, patients and methods
This was a retrospective analysis of data from KIMS (Pfizer International Metabolic Database). Background characteristics, anthropometry and comorbidity were studied in 47 patients diagnosed with childhood-onset (CO)-CD and 62 patients with CO-NFPA. Data from 100 ACTH-sufficient patients with CO-idiopathic hypopituitarism (CO-Idio) were used for comparison. Cardiovascular risk profile was analysed at baseline and at 1 year on GH treatment in a subgroup of patients (17 CO-CD, 24 CO-NFPA and 55 CO-Idio) not receiving GH treatment at study entry.
The median age at diagnosis of pituitary tumour was 14.0 years (range 10–17) in patients with CO-CD and 13.7 years (range 8–17) in CO-NFPA. In addition to GHD, 41% of patients with CO-CD had three or four other pituitary hormone deficiencies compared with 78% of patients with CO-NFPA (P<0.001). Eighty-nine per cent of patients with CO-CD had height SDS lower than 0 compared with 61% of patients with CO-NFPA (P=0.002). Hypertension was more common in CO-CD compared with CO-Idio (23 vs 9%, P=0.018). At 1 year on GH treatment, total- and low-density lipoprotein-cholesterol decreased significantly in CO-CD but not in CO-NFPA.
Adult patients with GHD following treatment for paediatric CD and NFPA have long-term adverse consequences. Despite more severe hypopituitarism in CO-NFPA, patients with CO-CD have more frequently compromised final stature.
Nicholas A Tritos, Philippe Chanson, Camilo Jimenez, Donna King, Peter J Jönsson, Anne Klibanski and Beverly M K Biller
To examine the effectiveness and safety of primary pegvisomant monotherapy.
Retrospective analysis of data extracted from ACROSTUDY (global observational outcomes study of patients with acromegaly treated with pegvisomant).
The earliest time to insulin-like growth factor 1 (IGF-1) normalization on pegvisomant monotherapy was determined. Both the proportion of patients who achieved IGF-1 normalization and the time to IGF-1 normalization on pegvisomant monotherapy were assessed.
Eligible patients included 28 subjects on primary medical therapy (PT) and 176 controls on adjunctive pegvisomant therapy treated postoperatively, including 43 who were naïve to medical therapy (NMT) and 133 who were previously treated medically and were washed out (WASH). IGF-1 normalization occurred in 76.9% (PT), 85.2% (NMT) and 78.3% (WASH) patients (P = NS). Median times to IGF-1 normalization were 0.5 year (PT), 0.7 year (NMT) and 0.6 year (WASH), P = NS. On survival analysis, the fraction of patients controlled on pegvisomant monotherapy was not different between groups. Higher baseline IGF-1 levels, obtained at study entry, predicted a lower likelihood of IGF-1 normalization on monotherapy (P = 0.012). Safety data include low prevalence of skin rashes, injection site reactions and reversible transaminase elevations. There was one patient (NMT) with a verified increase in tumor size.
Pegvisomant monotherapy, administered either as primary medical therapy or as adjunctive therapy according to local practice, led to IGF-1 normalization in >75% of patients. Pegvisomant monotherapy had a favorable safety profile, consistent with previous observations. Prospective data are needed to further evaluate the role of primary pegvisomant monotherapy in acromegaly.
Nicholas A Tritos, Amir H Hamrahian, Donna King, Susan L Greenspan, David M Cook, Peter J Jönsson, Michael P Wajnrajch, Maria Koltowska-Häggstrom and Beverly M K Biller
Childhood-onset GH deficiency (COGHD) is associated with low bone mineral density (BMD). Adults with persistent COGHD may be at risk for insufficient bone accrual or bone loss during adulthood. The purpose of this study was to identify BMD predictors and to characterize the effects of GH replacement on BMD in COGHD adults with persistent GHD.
Retrospective analysis of the KIMS database.
Variables predicting standardized BMD (sBMD) were identified. The effect of GH replacement (3 years) on BMD was examined.
Three hundred and fourteen COGHD adults (148 women, 166 men; 62 non-naïve, 178 semi-naïve, and 74 true naïve, depending on length and timing of previous GH replacement), who had BMD measured in lumbar spine (LS) and femoral neck (FN) at study entry.
In semi-naïve subjects, a longer gap in GH replacement between childhood and adulthood was predictive of lower sBMD in the FN (r=−0.18, P=0.038). TSH deficiency predicted lower sBMD in the LS (r=−0.16, P=0.052). In true naïve patients, a longer gap between onset of pituitary disease and study entry (r=−0.35, P=0.012), and female gender (r=−0.27, P=0.043) independently predicted lower sBMD in the FN. There were no differences in BMD increases between non-naïve, semi-naïve, and true naïve subjects on GH replacement.
In semi-naïve subjects a longer interval off GH replacement was associated with lower sBMD in the FN. Among true naïve patients, a longer gap between the onset of pituitary disease and GH replacement, and female gender predicted lower sBMD in the FN.
Ulla Feldt-Rasmussen, Georg Brabant, Dominique Maiter, Björn Jonsson, Andy Toogood, Maria Koltowska-Haggstrom, Aase Krogh Rasmussen, Michael Buchfelder, Bernhard Saller and Beverly M K Biller
We studied whether the severity of GH deficiency (GHD) defined as i) GH-peak on stimulation tests (insulin tolerance test (ITT), arginine, and glucagon), ii) number of additional pituitary deficits, or iii) baseline IGF1 SDS could impact the response to GH treatment. We further explored whether iv) IGF1 SDS after 24 months of GH replacement or v) ΔIGF1 SDS from baseline to 24 months was related to the phenotypic response to GH treatment.
Design, patients, and measurements
The patient cohort (n=1752; 50% women) was obtained from KIMS (Pfizer International Metabolic Database). The patients were divided into three groups of approximately equal size (tertiles) according to the stimulated GH-peak values and baseline IGF1 SDS and were studied at baseline, 12, and 24 months of GH therapy.
Lower baseline IGF1 SDS predicted better response in weight, BMI, total cholesterol, and triglycerides, while IGF1 SDS after 24 months was associated with reduction in waist/hip ratio, total cholesterol, and improved quality of life (QoL). Age-correlated negatively with the response in body weight, BMI, waist, IGF1 SDS, and total and LDL-cholesterol.
Response in weight and BMI was greater in men than in women, whereas women showed greater improvement in QoL than men. Patients with more severe GHD as assessed by lower GH-peaks and more pituitary hormone deficiencies had a greater increase in IGF1 SDS. The increase in IGF1 SDS was associated with a reduction in waist/hip ratio and an increase in weight, BMI, and triglycerides. There was no correlation with other lipids, blood pressure, or glucose.
Our findings indicate that baseline and 24 months, IGF1 and its degree of increase during GH replacement were more important than stimulated peak GH to predict the phenotypic response.
Paula P B Silva, Fatemeh G Amlashi, Elaine W Yu, Karen J Pulaski-Liebert, Anu V Gerweck, Pouneh K Fazeli, Elizabeth Lawson, Lisa B Nachtigall, Beverly M K Biller, Karen K Miller, Anne Klibanski, Mary Bouxsein and Nicholas A Tritos
Both acromegaly and adult growth hormone deficiency (GHD) are associated with increased fracture risk. Sufficient data are lacking regarding cortical bone microarchitecture and bone strength, as assessed by microfinite element analysis (µFEA).
To elucidate both cortical and trabecular bone microarchitecture and estimated bone strength in men with active acromegaly or GHD compared to healthy controls.
Design and subjects
Cross-sectional study at a clinical research center, including 48 men (16 with acromegaly, 16 with GHD and 16 healthy controls).
Areal bone mineral density (aBMD), cortical and trabecular bone microarchitecture and estimated bone strength (µFEA) at the radius and tibia.
aBMD was not different between the 3 groups at any skeletal site. At the radius, patients with acromegaly had greater cortical area (P < 0.0001), cortical thickness (P = 0.0038), cortical pore volume (P < 0.0001) and cortical porosity (P = 0.0008), but lower trabecular bone density (P = 0.0010) compared to controls. At the tibia, patients with acromegaly had lower trabecular bone density (P = 0.0082), but no differences in cortical bone microstructure. Compressive strength and failure load did not significantly differ between groups. These findings persisted after excluding patients with hypogonadism. Bone microarchitecture was not deficient in patients with GHD.
Both cortical and trabecular microarchitecture are altered in men with acromegaly. Our data indicate that GH excess is associated with distinct effects in cortical vs trabecular bone compartments. Our observations also affirm the limitations of aBMD testing in the evaluation of patients with acromegaly.
Michael Buchfelder, Aart-Jan van der Lely, Beverly M K Biller, Susan M Webb, Thierry Brue, Christian J Strasburger, Ezio Ghigo, Cecilia Camacho-Hubner, Kaijie Pan, Joanne Lavenberg, Peter Jönsson and Juliana H Hey-Hadavi
ACROSTUDY is an international, non-interventional study of acromegaly patients treated with pegvisomant (PEGV), a growth hormone receptor antagonist and has been conducted since 2004 in 15 countries to study the long-term safety and efficacy of PEGV. This report comprises the second interim analysis of 2090 patients as of May 12, 2016.
Descriptive analyses of safety, pituitary imaging and outcomes on PEGV treatment up to 12 years were performed.
Prior to starting PEGV, 96% of patients had reported surgery, radiation, medical therapy or any combinations of those. At start of PEGV, 89% of patients had IGFI levels above the upper limit of normal (ULN). The percentage of patients with normal IGFI levels increased from 53% at year 1 to 73% at year 10, and the average daily dose of PEGV increased from 12.8 mg (year 1) to 18.9 mg (year 10). A total of 4832 adverse events (AEs) were reported in 1137 patients (54.4%), of which 570 were considered treatment related in 337 patients (16.1%). Serious AEs were reported in 22% of patients, of which 2.3% were considered treatment related. Locally reported MRIs showed most patients (72.2%) had no change in tumor size relative to the prior scan; 16.8% had a decrease, 6.8% an increase and 4.3% both. In patients with normal liver tests at PEGV start, an ALT or AST elevation of >3× ULN at any time point during their follow-up was reported in 3%.
This second interim analysis confirms that long-term use of PEGV is an effective and safe treatment in patients with acromegaly.
John Newell-Price, Rosario Pivonello, Antoine Tabarin, Maria Fleseriu, Przemysław Witek, Mônica R Gadelha, Stephan Petersenn, Libuse Tauchmanova, Shoba Ravichandran, Pritam Gupta, André Lacroix and Beverly M K Biller
Monitoring of patients with Cushing’s disease on cortisol-lowering drugs is usually performed with urinary free cortisol (UFC). Late-night salivary cortisol (LNSC) has an established role in screening for hypercortisolism and can help to detect the loss of cortisol circadian rhythm. Less evidence exists regarding the usefulness of LNSC in monitoring pharmacological response in Cushing’s disease.
Exploratory analysis evaluating LNSC during a Phase III study of long-acting pasireotide in Cushing’s disease (clinicaltrials.gov: NCT01374906).
Mean LNSC (mLNSC) was calculated from two samples, collected on the same days as the first two of three 24-h urine samples (used to calculate mean UFC [mUFC]). Clinical signs of hypercortisolism were evaluated over time.
At baseline, 137 patients had evaluable mLNSC measurements; 91.2% had mLNSC exceeding the upper limit of normal (ULN; 3.2 nmol/L). Of patients with evaluable assessments at month 12 (n = 92), 17.4% had both mLNSC ≤ULN and mUFC ≤ULN; 22.8% had mLNSC ≤ULN, and 45.7% had mUFC ≤ULN. There was high variability in LNSC (intra-patient coefficient of variation (CV): 49.4%) and UFC (intra-patient CV: 39.2%). mLNSC levels decreased over 12 months of treatment and paralleled changes in mUFC. Moderate correlation was seen between mLNSC and mUFC (Spearman’s correlation: ρ = 0.50 [all time points pooled]). Greater improvements in systolic/diastolic blood pressure and weight were seen in patients with both mLNSC ≤ULN and mUFC ≤ULN.
mUFC and mLNSC are complementary measurements for monitoring treatment response in Cushing’s disease, with better clinical outcomes seen for patients in whom both mUFC and mLNSC are controlled.
Christian J Strasburger, Peter Vanuga, Juraj Payer, Marija Pfeifer, Vera Popovic, László Bajnok, Miklós Góth, Veˇra Olšovská, L‘udmila Trejbalová, Janos Vadasz, Eyal Fima, Ronit Koren, Leanne Amitzi, Martin Bidlingmaier, Oren Hershkovitz, Gili Hart and Beverly M K Biller
Growth hormone (GH) replacement therapy currently requires daily injections, which may cause distress and low compliance. C-terminal peptide (CTP)-modified growth hormone (MOD-4023) is being developed as a once-weekly dosing regimen in patients with GH deficiency (GHD). This study’s objective is to evaluate the safety, pharmacokinetics (PK), pharmacodynamics (PD) and efficacy of MOD-4023 administered once-weekly in GHD adults.
54 adults with GHD currently treated with daily GH were normalized and randomized into 4 weekly dosing cohorts of MOD-4023 at 18.5%, 37%, 55.5% or 123.4% of individual cumulative weekly molar hGH dose. The study included 2 stages: Stage A assessed the effectiveness and PK/PD profiles of the 4 dosing regimens of MOD-4023. Stage B was an extension period of once-weekly MOD-4023 administration (61.7% molar hGH content) to collect further safety data and confirm the results from Stage A.
Dose-dependent response was observed for both PK and PD data of weekly MOD-4023 treatment. Insulin-like growth factor I (IGF-I) SDS levels were maintained within normal range. The 18.5% cohort was discontinued due to low efficacy. MOD-4023 was well tolerated and exhibited favorable safety profile in all dose cohorts. The reported adverse events were consistent with known GH-related side effects.
Once-weekly MOD-4023 administration in GHD adults was found to be clinically effective while maintaining a favorable safety profile and may obviate the need for daily injections. Weekly GH injections may improve compliance and overall outcome. The promising results achieved in this Phase 2 study led to a pivotal Phase 3 trial, which is currently ongoing.