ARTICLES Long-term treatment of acromegaly with pegvisomant, a growth hormone receptor antagonist Aart Jan van der Lely, R Kent Hutson, Peter J Trainer, G Michael Besser, Ariel L Barkan, Laurence Katznelson, Anne Klibanski, Vivien Herman-Bonert, Shlomo Melmed, Mary Lee Vance, Pamela U Freda, Paul M Stewart, Keith E Friend, David R Clemmons, Gudmundur Johannsson, Stavros Stavrou, David M Cook, Lawrence S Phillips, Christian J Strasburger, Suzanne Hacker, Kenneth A Zib, Robert J Davis, John A Scarlett, Michael O Thorner Summary significantly decreased (p<0·05). Two patients experienced progressive growth of their pituitary tumours, and two Background Pegvisomant is a new growth hormone receptor other patients had increased alanine and asparate antagonist that improves symptoms and normalises insulin- aminotransferase concentrations requiring withdrawal from like growth factor-1 (IGF-1) in a high proportion of patients treatment. Mean pituitary tumour volume in 131 patients with acromegaly treated for up to 12 weeks. We assessed followed for a mean of 11·46 months (0·70) decreased by the effects of pegvisomant in 160 patients with acromegaly 0·033 cm3 (0·057; p=0·353). treated for an average of 425 days. Interpretation Pegvisomant is an effective medical treatment Methods Treatment efficacy was assessed by measuring for acromegaly. changes in tumour volume by magnetic resonance imaging, and serum growth hormone and IGF-1 concentrations in 152 Lancet 2001; 358: 1754–59 patients who received pegvisomant by daily subcutaneous See Commentary 1743 injection for up to 18 months. The safety analysis included 160 patients some of whom received weekly injections and Introduction are excluded from the efficacy analysis. Current treatments for acromegaly, which is usually caused by an adenoma of the pituitary, attempt to control Findings Mean serum IGF-1 concentrations fell by at least the disease by reducing growth hormone secretion from 50%: 467 ␮g/L (SE 24), 526 ␮g/L (29), and 523 ␮g/L (40) the tumour either by surgery, radiotherapy, or in patients treated for 6, 12 and 18 months, respectively medication. Unfortunately, when strict biochemical (p<0·001), whereas growth hormone increased by 12·5 ␮g/L criteria are applied, surgery cures only 60% of patients (2·1), 12·5 ␮g/L (3·0), and 14·2 ␮g/L (5·7) (p<0·001). Of overall, and less than half of patients with the patients treated for 12 months or more, 87 of 90 (97%) macroadenomas, which represent most cases seen.1,2 achieved a normal serum IGF-1 concentration. In patients The role of radiotherapy remains limited owing to withdrawn from pegvisomant (n=45), serum growth hormone slow onset of effect, ineffectiveness in normalising concentrations were 8·0 ␮g/L (2·5) at baseline, rose to 15·2 IGF-1 concentrations, and a high occurence of ␮g/L (2·4) on drug, and fell back within 30 days of panhypopituitarism.3–5 Current medical therapy is also withdrawal to 8·3 ␮g/L (2·7). Antibodies to growth hormone less effective than desired. Dopamine agonists rarely were detected in 27 (16·9%) of patients, but no tachyphylaxis normalise growth hormone and IGF-1, and have side- was seen. Serum insulin and glucose concentrations were effects that limit long-term tolerability and compliance.6,7 Somatostatin analogues, such as octreotide or lanreotide, bind to somatostatin receptors present on the Erasmus Medical Centre Rotterdam, 40 Dr Molewaterplein, 3015 tumour, and inhibit growth hormone secretion. GD Rotterdam, Netherlands (A J van der Lely MD); University of However, IGF-1 is normalised in only about 65% of Tennessee, Knoxville, TN, USA (R K Hutson MD); Christie Hospital, patients.8–11 Manchester, UK (P J Trainer MD); St Bartholomew’s Hospital, Pegvisomant (B2036–PEG; Sensus Drug Development London, UK (G M Besser MD); University of Michigan Medical Corporation, Austin, TX, USA) is a new, genetically- Center, Ann Arbor, MI, USA (A L Barkan MD); Massachusetts engineered analogue of human growth hormone which General Hospital, Boston, MD, USA (L Katznelson MD, functions as a highly selective growth hormone receptor A Klibanski MD); Cedars-Sinai Medical Center, Los Angeles, CA, antagonist.12,13 In a 12 week, placebo-controlled study,14 USA (V Herman-Bonert MD; S Melmed MD); University of Virginia clinical symptoms were significantly improved and Health Sciences Center, Charlottesville, VA, USA (M L Vance MD, serum IGF-1 concentrations normalised in 89% of M O Thorner FRCP); Columbia College of Physicians and Surgeons, acromegalic patients treated with pegvisomant. However, New York, NY, USA (P U Freda MD); Queen Elizabeth Hospital, Birmingham, UK (P M Stewart MD); University of Texas serum growth hormone concentrations also increased M D Anderson Cancer Center, Houston, TX, USA (K E Friend MD); substantially in compensation, raising the questions of University of North Carolina School of Medicine, Chapel Hill, NC, whether additional increases in serum growth hormone USA (D R Clemmons MD); Såhlgrenska University Hospital, concentrations might occur if treatment was prolonged, Goteborg, Sweden (G Johansson MD); New York University Medical whether a sustained increase in serum growth hormone Center, New York, NY, USA (S Stavrou MD); Oregon Health Sciences might overcome the receptor-blocking action of the drug University, Portland, OR, USA (D M Cook MD); Emory University (ie, induce tachyphylaxis), or whether the increase in School of Medicine, Atlanta, GA, USA (L S Phillips MD); Klinikum growth hormone might be accompanied by growth of Innenstadt, Ludwig-Maximilians-Universität, Munich, Germany the pituitary tumour.15 The long-term efficacy of (C J Strasburger MD); StatWorks Inc, Chapel Hill, NC, USA pegvisomant is also thought to be compromised by the (S Hackett MS); and Sensus Drug Development Corporation, Austin, development of antibodies to growth hormone or to TX, USA (K A Zib BS, R J Davis PharmD, J A Scarlett MD) pegvisomant. We report here the results of an analysis of Correspondence to: Dr Aart Jan van der Lely the long-term safety and efficacy of pegvisomant in 160 (e-mail: [email protected]) patients with acromegaly treated for up to 18 months. 1754 THE LANCET • Vol 358 • November 24, 2001 For personal use. Only reproduce with permission from The Lancet Publishing Group. ARTICLES Patients and methods in the initial study protocol. Age-adjusted normal limits Patients for IGF-1 were used. Antibodies to growth hormone were We screened patients with acromegaly, aged 18 years or measured at about monthly intervals throughout older, at the participating clinics. At the first screening treatment in all patients. Because pegvisomant interfered visit treatment with somatostatin analogues and dopamine with the assay, the measurement of pegvisomant agonists was discontinued in the patients receiving these antibodies was made in samples obtained after drugs. A second screening visit took place a minimum of 2 pegvisomant treatment had been discontinued for a weeks after discontinuation of somatostatin analogues and month. 5 weeks after discontinuation of dopamine agonists. Serum IGF-1 was measured by a competitive binding Patients were eligible for enrolment if their serum IGF-1 radioimmunoassay (Nichols Institute Diagnostics, San concentration at that visit was at least 1·3 times the upper Juan Capistrano, CA, USA). Serum growth hormone was limit of the age-adjusted normal range, according to local measured using antiserum saturated with B2036 (the laboratory values. The study protocols were approved by protein component of pegvisomant) to eliminate cross- the human research committee at each site, and all reactions with pegvisomant. The sensitivity of the assay patients gave written informed consent before was 0·5 ␮g/L, with an inter-assay coefficient of variation confirmation of eligibility. of 16% (Endocrine Sciences, Calabasas Hills, California, USA). Antibodies to growth hormone were measured by Methods radioimmunoassay (Endocrine Sciences). Antibodies to Patients received pegvisomant as a once daily pegvisomant were assessed in a semi-quantitative subcutaneous injection according to one of two clinical screening assay by use of radiolabelled pegvisomant and a protocols (SEN-3613A and SEN-3614/15). 38 patients polyethylene glycol precipitation system. The assays for initially received weekly dosing (protocol SEN-3611/13) serum IGF-1, growth hormone and antibodies to growth before being switched to daily dosing (protocol SEN- hormone and and pegvisomant were done by a single 3613A). Only their daily dosing data are included in the laboratory (Endocrine Sciences). Serum pegvisomant efficacy analysis. Patients participating in protocol SEN- concentrations were measured by a specific 3614/15 received only daily dosing. radioimmunoassay (Phoenix International Life Sciences, Daily dosing in both protocols began at 10 mg per day Saint-Laurent, Quebec, Canada). All other clinical and was titrated up or down as necessary in 5 mg per day laboratory samples were analysed with standard increments until the patient’s serum IGF-1 concentration commercial assays. was normal or a maximum dose of 40 mg per day was reached. In SEN-3613A, the minimum dose titration Statistical analysis interval was 2 weeks after the last dosing change. In SEN- The assumption of the normality of the IGF-1, growth 3614/15, the dose adjustment was permitted no sooner hormone, insulin, glucose and glycated haemoglobin data than 8 weeks after the last dosing change. The 12 week, was investigated by use of a Shapiro-Wilks test, in which placebo-controlled data for patients who initially received the null hypothesis that the data represented a random pegvisomant in protocol SEN-3614/15 have been sample from the normal distribution was rejected. previously reported. 14 Therefore, the Wilcoxon’s signed rank test, which is a All data from patients with acromegaly exposed to non-parametric analogue to the paired-difference t test, pegvisomant in the clinical development programme were was used for assessing the statistical significance of the included in the safety analysis.