Treatment of Acromegaly with the Growth Hormone–Receptor Antagonist Pegvisomant
Peter J. Trainer, M.D., William M. Drake, M.B., Laurence Katznelson, M.D., Pamela U. Freda, M.D., Vivien Herman-Bonert, M.D., A.J. van der Lely, M.D., Eleni V. Dimaraki, M.D., Paul M. Stewart, M.D., Keith E. Friend, M.D., Mary Lee Vance, M.D., G. Michael Besser, M.D., D.Sc., and John A. Scarlett, M.D.
Background Patients with acromegaly are treated with surgery,radiation therapy, and drugs to reduce hypersecretion of growthhormone, but the treatments may be ineffective and have adverseeffects. Pegvisomant is a genetically engineered growth hormone–receptorantagonist that blocks the action of growth hormone.
Methods We conducted a 12-week, randomized, double-blind studyof three different daily doses of pegvisomant (10 mg, 15 mg,and 20 mg) and placebo, given subcutaneously, in 112 patientswith acromegaly.
Results The mean (±SD) serum concentration of insulin-likegrowth factor I (IGF-I) decreased from base line by 4.0±16.8percent in the placebo group, 26.7± 27.9 percent in thegroup that received 10 mg of pegvisomant per day, 50.1±26.7percent in the group that received 15 mg of pegvisomant perday, and 62.5±21.3 percent in the group that received20 mg of pegvisomant per day (P<0.001 for the comparisonof each pegvisomant group with placebo), and the concentrationsbecame normal in 10 percent, 54 percent, 81 percent, and 89percent of patients, respectively (P<0.001 for each comparisonwith placebo). Among patients treated with 15 mg or 20 mg ofpegvisomant per day, there were significant decreases in ringsize, soft-tissue swelling, the degree of excessive perspiration,and fatigue. The score for total symptoms and signs of acromegalydecreased significantly in all groups receiving pegvisomant(P0.05). The incidence of adverse effects was similar in allgroups.
Conclusions On the basis of these preliminary results, treatmentof patients who have acromegaly with a growth hormone–receptorantagonist results in a reduction in serum IGF-I concentrationsand in clinical improvement.
Acromegaly is a chronic debilitating disorder resulting fromexcessive secretion of growth hormone and a resulting increasein the production of insulin-like growth factor I (IGF-I). Itis usually caused by somatotroph adenomas of the pituitary gland.The goal of treatment is to reverse the effects of the hypersecretionof growth hormone and normalize production of IGF-I. Effectivetreatment ameliorates the symptoms and signs of the diseaseand lowers the mortality rate.
The current treatments for acromegaly are surgical removal ofthe adenoma, radiation therapy, and drug treatment. Among patientstreated surgically, only 60 percent of patients overall andless than half of those with large tumors (the majority of patients)can be classified as cured according to strict biochemical criteria.1,2,3,4These low rates are presumably due to incomplete surgical resection.Radiation therapy is characterized by delayed effect, poor efficacy,and a high incidence of panhypopituitarism.5,6 Dopamine-agonistdrugs, such as bromocriptine and cabergoline, are effectivein only a minority of patients, and their adverse effects limittolerability and compliance.7,8,9 Somatostatin agonists, suchas octreotide, inhibit the secretion of growth hormone, butthe secretion of growth hormone and the production of IGF-Iare reduced to normal in only about 50 percent of patients.10,11,12,13,14These agonists also inhibit the secretion of insulin, glucagon,and several gastrointestinal hormones and can cause cholelithiasis.15
Pegvisomant is a genetically engineered analogue of human growthhormone that functions as a growth hormone–receptor antagonist.16,17We conducted a 12-week study of the efficacy and tolerabilityof pegvisomant in patients with acromegaly.
Methods
Patients
The diagnosis of acromegaly was established on the basis ofsymptoms and signs at presentation, evidence of a pituitaryadenoma on computed tomography or magnetic resonance imagingof the pituitary fossa, and high serum concentrations of IGF-I.Of the 112 patients enrolled in the study, 93 had undergonepituitary surgery, of whom 57 had also been treated with conventionalradiation therapy. Six patients had undergone irradiation withoutsurgery, nine had received only drug therapy, and four had receivedno therapy. Patients who had received a long-acting somatostatinanalogue within 12 weeks before enrollment were not eligiblefor the study.
Protocol
The study protocol was approved by the human-research committeeat each study site, and all patients gave written informed consentbefore eligibility was confirmed. At the first screening visit,therapy with somatostatin analogues and dopamine agonists wasdiscontinued in the patients receiving such treatment. The secondscreening visit took place a minimum of two weeks after thediscontinuation of somatostatin-analogue therapy and five weeksafter the discontinuation of dopamine-agonist therapy. Patientswere eligible for enrollment if their serum IGF-I concentrationat the second screening visit was at least 1.3 times the upperlimit of the age-adjusted normal range, according to local laboratoryvalues.
Clinical and laboratory assessments were conducted at the twoscreening visits, at the base-line visit, and 2, 4, 8, and 12weeks after the initiation of treatment. The assessments consistedof a history taking and physical examination; completion ofa questionnaire designed to evaluate five symptoms and signsof acromegaly (soft-tissue swelling, arthralgia, headache, excessiveperspiration, and fatigue), with scores ranging from 0 (no symptoms)to 8 (severe, incapacitating symptoms); measurement of serumgrowth hormone while the patient was fasting; measurement ofserum IGF-I, free IGF-I, IGF-binding protein 3 (IGFBP-3), andthe acid-labile subunit of IGFBP-3; and routine laboratory tests(measurement of hematologic values and serum chemistry valuesand urinalysis with microscopical evaluation). In addition,the ring size of the fourth digit of the right hand (or thefifth, if the fourth was too large) was measured with the useof 58 standardized European jeweler's rings (Jewel Toolcraft,Birmingham, United Kingdom), ranging in diameter from 12.5 mmto 25 mm. Magnetic resonance imaging of the pituitary and electrocardiographywere performed and serum samples were obtained for assay foranti–growth hormone antibodies before the base-line visitand at the end of the study. Pituitary-tumor volumes were calculatedfrom the magnetic resonance images18 by a single evaluator whowas unaware of the patients' treatment assignments. Adverseeffects were recorded at each visit.
Treatment
The patients were stratified according to the serum IGF-I concentrationat the second screening visit (values 1.3 to 2.0 times the upperlimit of the age-adjusted normal range vs. values >2.0 timesthe upper limit). The patients were then randomly assigned atthe base-line visit to receive either pegvisomant (at a dailydose of 10 mg, 15 mg, or 20 mg) or a placebo. In order to decreasethe amount of time needed to achieve steady-state serum pegvisomantconcentrations, patients assigned to pegvisomant treatment receivedan 80-mg loading dose of the drug at the base-line visit, andthe patients assigned to placebo received a loading dose ofplacebo.
Pegvisomant was prepared as a lyophilized powder containing10 mg, 15 mg, or 20 mg of pegvisomant, 1.36 mg of glycine, 36mg of mannitol, 1.04 mg of dibasic, anhydrous sodium phosphate,and 0.36 mg of monobasic sodium phosphate monohydrate. The placebocontained the same ingredients except for pegvisomant. Pegvisomantand placebo were reconstituted with 1 ml of water for injectionand were self-administered as once-daily subcutaneous injectionsfor 12 weeks. The study was double-blinded, and only the statisticianpreparing the randomization schedule was aware of treatmentassignments.
Serum Assays
Serum IGF-I was measured by radioimmunoassay (Nichols InstituteDiagnostics, San Juan Capistrano, Calif.), and serum free IGF-Iby a two-site immunoradiometric assay (Diagnostic Systems Laboratory,Webster, Tex.). Serum IGFBP-3 was measured by radioimmunoassay(Endocrine Sciences, Calabasas Hills, Calif.) and the serumacid-labile subunit of IGFBP-3 by sandwich enzyme-linked immunosorbentassay (Diagnostic Systems Laboratory). Serum growth hormonewas measured by radioimmunoassay (Endocrine Sciences), whichwas modified to avoid cross-reactivity with pegvisomant. Anti–growthhormone antibodies were measured by radioimmunoassay (EndocrineSciences).
Statistical Analysis
Continuous variables, including the primary efficacy end point(the percentage change in the serum IGF-I concentration frombase line), other biochemical-efficacy variables (serum concentrationsof free IGF-I, IGFBP-3, and the acid-labile subunit of IGFBP-3),and ring size were compared with the use of analysis of variance,with study sites pooled according to geographic area. An expandedstatistical model incorporating a term for the interaction betweentreatment and center as well as covariates (e.g., base-lineserum IGF-I and growth hormone concentrations, IGF-I valuesat study entry, sex, and base-line body weight) was used inthe analysis of the primary efficacy variable.
We compared the frequency of normal serum IGF-I concentrationsin the treatment groups at any time after base line and at 12weeks, using a logistic-regression model with the independentvariables of treatment, pooled study site, and base-line serumIGF-I concentration. At the other scheduled visits (at two,four, and eight weeks), we used a Cochran–Mantel–Haenszeltest, with the data stratified according to pooled study site.Symptoms and signs were categorized as worse, unchanged, orimproved, and the results in the treatment groups were comparedwith the use of the extended Cochran–Mantel–Haenszeltest, with adjustment for pooled study site. All P values aretwo-sided.
Results
The base-line characteristics of the patients in the treatmentgroups were similar (Table 1). A total of 112 patients (63 menand 49 women) were enrolled and received study medication. Themean (±SD) age was 48±14 years, and the mean durationof acromegaly was 8±8 years.
Table 1. Base-Line Characteristics of Patients with Acromegaly.
Four patients withdrew from the study. One patient in the placebogroup withdrew because of persistent headache (in this case,the outcome was classified as lack of efficacy). Another patientin the placebo group was withdrawn from the study after fivedays of treatment, after a review of his magnetic resonanceimage revealed a large pituitary adenoma displacing and compressingthe optic chiasm. This patient had undergone no assessmentsof efficacy, and therefore his base-line data were not includedin the efficacy analysis but were included in the safety analysis.A patient assigned to 15 mg of pegvisomant withdrew after oneweek of treatment because of persistent headaches (classifiedas lack of efficacy), and another patient in this group waswithdrawn from the study at nine weeks because of high serumaminotransferase concentrations (described below).
Efficacy
Serum IGF-I concentrations decreased in all three pegvisomantgroups, whereas the concentrations did not change appreciablyin the placebo group (Table 2 and Figure 1). No interactionsof treatment with study site were detected. There was a dose-dependentincrease in the frequency of normal serum IGF-I concentrationsin the three pegvisomant groups (Table 2). Two of the threepatients in the group receiving 20 mg of pegvisomant in whomthe serum IGF-I concentration did not fall to normal had substantialdecreases, from 1032 to 420 ng per milliliter in one patient(age-adjusted upper limit of normal, 360) and from 761 to 420ng per milliliter in the other (age-adjusted upper limit ofnormal, 290). There were also dose-dependent reductions in serumconcentrations of free IGF-I, IGFBP-3, and the acid-labile subunitof IGFBP-3 in the three pegvisomant groups (Figure 1).
Figure 1. Serum Concentrations of Insulin-like Growth Factor I (IGF-I), Free IGF-I, IGF-Binding Protein 3 (IGFBP-3), and the Acid-Labile Subunit of IGFBP-3 in Patients with Acromegaly.
For all four measures, the values at all visits after base line (week 0) were significantly lower (P0.05) in the three pegvisomant groups than in the placebo group. T bars indicate means ±SE.
The mean scores for individual symptoms and signs and the meantotal score increased slightly in the placebo group and decreasedin all the pegvisomant groups (Table 3), with significant decreasesin the scores for soft-tissue swelling, excessive perspiration,and fatigue and in the total score. The mean ring size at baseline corresponded to a size "X" standard European jeweler'sring. The mean (±SD) ring size at 12 weeks had decreasedby 0.1±2.3 size in the placebo group, by 0.8±1.6size in the group receiving 10 mg of pegvisomant (P=0.16 forthe comparison with placebo), by 1.9±2.0 sizes in thegroup receiving 15 mg (P=0.001), and by 2.5±3.3 sizesin the group receiving 20 mg (P<0.001).
Table 3. Changes in Scores for Symptoms and Signs of Acromegaly.
Serum Growth Hormone Concentrations, Anti–Growth Hormone Antibodies, and Tumor Volume
Serum growth hormone concentrations increased and then plateauedin the pegvisomant groups in a dose-dependent fashion that coincidedwith the magnitude and timing of the reduction in serum IGF-Iconcentrations (data not shown). The serum growth hormone concentrationsat 12 weeks in the patients treated with 15 mg or 20 mg of pegvisomantper day were significantly higher than those of the patientsin the placebo group (Table 2). Serum anti–growth hormoneantibodies in titers ranging from 1:4 to 1:64 were detectedin five patients treated with 10 mg of pegvisomant per day,one patient treated with 15 mg, and two patients treated with20 mg. No patient had a significant change in tumor volume duringthe study, nor did the mean tumor volume change significantlymore in any pegvisomant group than in the placebo group (Table 2).
Safety
Pegvisomant was well tolerated. The incidence of reported adverseeffects was similar in all four study groups (Table 4). Injection-sitereactions were reported by two patients receiving 10 mg of pegvisomantper day, one patient receiving 15 mg, and three patients receiving20 mg and were characterized as mild, erythematous, self-limitedreactions that did not require treatment. The only serious adverseeffect was in a patient treated with 15 mg of pegvisomant whowas withdrawn from the study because he had a serum alanineaminotransferase concentration of 904 U per liter (normal range,0 to 47) and a serum aspartate aminotransferase concentrationof 389 U per liter (normal range, 0 to 37) after eight weeksof treatment. The patient had mild fatigue, his serum bilirubinand alkaline phosphatase concentrations did not rise, viralserologic tests were negative, and ultrasonography of the liverwas normal.
Table 4. Adverse Effects That Occurred in at Least 10 Percent of Patients.
The abnormal serum enzyme values returned to normal within eightweeks after the discontinuation of the study drug but rose againafter a four-week rechallenge with 10 mg of pegvisomant perday. This rechallenge was approved by the human-research committee,and the patient gave written informed consent. The values returnedto normal once more after discontinuation of the drug. Withthe exception of the values for this patient, the mean serumalanine aminotransferase and aspartate aminotransferase concentrationsdid not increase significantly in any group during the study.No other patient had more than small, clinically unimportantchanges in any laboratory test.
Discussion
The action of growth hormone is initiated by dimerization ofthe extracellular domain of the growth hormone receptor by asingle growth hormone molecule.19 Pegvisomant is an analogueof human growth hormone, with nine mutations that increase itsaffinity for one of the binding sites on the receptor and abolishbinding to a second site, thereby preventing functionally correctdimerization of the receptor.17 Because it is pegylated (polyethyleneglycol polymers are covalently bound to the protein), it hasa long biologic half-life, and the likelihood of antibody formationis low.20,21,22,23 Pegvisomant is a highly selective ligandfor the growth hormone receptor, and it does not cross-reactwith other receptors, including the prolactin receptor.24 Incontrast to the mechanism of action of dopamine-agonist drugs7,8,9and somatostatin analogues, agents that inhibit growth hormonesecretion,10,11,12,13,25,26 the efficacy of pegvisomant is independentof any characteristics of the somatotroph tumor. Instead, pegvisomantblocks the ability of growth hormone to stimulate productionof IGF-I, the main mediator of the somatotrophic actions ofgrowth hormone.
In this 12-week, double-blind, placebo-controlled study, pegvisomantsignificantly ameliorated both the clinical and the biochemicalmanifestations of acromegaly. The onset of action of pegvisomantwas rapid, with 75 percent or more of the maximal reductionin serum IGF-I concentrations occurring within 2 weeks afterthe initiation of therapy, and was sustained during the 12-weekcourse of treatment. The contribution of the loading dose tothis rapid onset of action is not known.
Pegvisomant was well tolerated; the incidence of adverse effectswas similar in the placebo group and all three pegvisomant groups.Despite the possibility that pegvisomant treatment might leadto further increases in growth hormone secretion, and even totumor growth, the increase in serum growth hormone concentrationswas small, was not progressive, and was not associated withany evidence of tumor growth. Very low titers of anti–growthhormone antibodies were detected in the serum of only 8 of the80 patients who were treated with pegvisomant. However, becauseof the relatively short duration of this study, as well as theoccurrence of high serum aminotransferase concentrations inone patient, we suggest caution in the interpretation of thedata on safety.
Longer treatment of more patients will be required before anyconclusions can be drawn regarding the safety of the drug, includingits effects on tumor size and hepatic function. However, giventhe efficacy and minimal adverse effects identified in thisstudy, pegvisomant has the potential to become a useful medicaltreatment for acromegaly.
Supported by a grant from Sensus Drug Development.
Drs. Thorner and Clemmons have served as consultants to SensusDrug Development, and Drs. Trainer, Freda, van der Lely, Vance,Besser, Barkan, and Rose have received travel support, honorariums,or both from Sensus.
We are indebted to Jane Evanson, M.D. (Royal London Hospital,London), for assessing changes in tumor volume; to JonathanR. Smith, Ph.D. (Quintiles, Research Triangle Park, N.C.), forcontributing to the development of the statistical-analysisplan; to Mark Stene, Ph.D. (Endocrine Sciences, Calabasas Hills,Calif.), for the development of growth hormone assays; to RolfGunnarsson, M.D., Ph.D. (Sensus Drug Development, Stockholm),for his invaluable participation in discussions regarding theprotocol design, the conduct of the study, and the analysisof the results; and to the clinical coordinators at the studysites, without whom the trial could not have been conducted.
Source Information
From the Christie and South Manchester University Hospitals, Manchester, United Kingdom (P.J.T.); St. Bartholomew's Hospital, London (W.M.D., G.M.B.); Massachusetts General Hospital, Boston (L.K.); Columbia College of Physicians and Surgeons, New York (P.U.F.); Cedars–Sinai Medical Center, Los Angeles (V.H.-B.); Academic Hospital Dijkzigt, Rotterdam, the Netherlands (A.J.L.); the University of Michigan Medical Center, Ann Arbor (E.V.D.); the University of Birmingham, Birmingham, United Kingdom (P.M.S.); the University of Texas M.D. Anderson Cancer Center, Houston (K.E.F.); the University of Virginia Health Sciences Center, Charlottesville (M.L.V.); and Sensus Drug Development, Austin, Tex. (J.A.S.). Other authors were Michael O. Thorner, M.B., D.Sc., University of Virginia Health Sciences Center, Charlottesville; Craig Parkinson, M.B., the Christie and South Manchester University Hospitals, Manchester, United Kingdom; Anne Klibanski, M.D., Massachusetts General Hospital, Boston; Jeffrey S. Powell, M.D., Columbia College of Physicians and Surgeons, New York; Ariel L. Barkan, M.D., University of Michigan Medical Center, Ann Arbor; Michael C. Sheppard, M.D., Ph.D., University of Birmingham, Birmingham, United Kingdom; Mario Maldonado, M.D., University of Texas M.D. Anderson Cancer Center, Houston; D. Roderick Rose, M.D., and David R. Clemmons, M.D., University of North Carolina School of Medicine, Chapel Hill; Gudmundur Johannsson, M.D., Ph.D., and Bengt-Åke Bengtsson, M.D., Sahlgrenska University Hospital, Göteborg, Sweden; Stavros Stavrou, M.D., and David L. Kleinberg, M.D., New York University Medical Center, New York; David M. Cook, M.D., Oregon Health Sciences University, Portland; Lawrence S. Phillips, M.D., Emory University School of Medicine, Atlanta; Martin Bidlingmaier, M.D., and Christian J. Strasburger, M.D., Klinikam Innenstadt, Ludwig-Maximilians-Universität, Munich, Germany; Suzanne Hackett, M.S., and Kenneth Zib, B.S., StatWorks, Chapel Hill, N.C.; and William F. Bennett, Ph.D., and Robert J. Davis, Pharm.D., Sensus Drug Development, Austin, Tex.
Address reprint requests to Dr. Scarlett at Sensus Drug Development, 98 San Jacinto Blvd., Suite 430, Austin, TX 78701, or at chip{at}sensuscorp.com.
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0.05). The incidence of adverse effects was similar in all groups. 
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