Long-term Experience of Pegvisomant Therapy as a Treatment for Acromegaly
Abstract and Introduction
Aims To evaluate the long-term efficacy and safety of pegvisomant as a treatment for acromegaly.
Design Retrospective analysis of clinical and trial data from all patients treated with pegvisomant since 1997 at two centres with common protocols.
Results Fifty-seven patients (age range 27–78 years) have been treated with pegvisomant since 1997 for up to 91 months (median 18 months). Before commencing pegvisomant, patients had an IGF-I above the upper limit of normal (ULN) of the age-related reference range (median 1·8 × ULN, range 1·2–4·1). Ninety-five per cent normalized IGF-I using a median dose of 15 mg daily (range 10 mg alternate day to 60 mg daily) with no influence of gender on dose requirement. Five patients had combination therapy with either somatostatin analogues (SSA) or cabergoline. Two patients initially controlled on 10 mg and 20 mg required dose increases (to 20 mg + 40 mg) over 24 months to reduce IGF-I. Twenty-seven patients stopped pegvisomant. Reasons included side-effects [abnormal liver function tests (LFTs)] and patient choice. Two patients developed elevated liver transaminases, which normalized on stopping pegvisomant. Patients had 6–12-monthly pituitary magnetic resonance imaging (MRI) scans. One patient had significant tumour size increase.
Conclusion This long-term experience in 57 patients indicates pegvisomant to be effective, safe and well-tolerated. Raised transaminases occurred within the first month of therapy in two patients, and tumour growth was seen in one patient (tumour was growing prior to pegvisomant). In two patients increasing doses of pegvisomant were required to keep IGF-I within the target range.
Successful treatment of acromegaly with reduction of serum IGF-I and GH levels to within appropriate reference ranges normalizes mortality and reduces morbidity. The main treatment strategy is transsphenoidal surgery followed by radiotherapy and/or medical therapy if surgery is not curative. Pegvisomant is a GH receptor antagonist licensed for the treatment of acromegaly, the use of which in Europe is restricted to patients with active disease despite surgery and/or radiotherapy and somatostatin analogues (SSA).
The short-term effects of pegvisomant were defined in an initial 12-week, double-blind, placebo-controlled study, in which 89% of patients receiving 20 mg daily achieved a serum IGF-I level within the age-adjusted reference range. This efficacy was confirmed by a multicentre dose titration open-label extension study in 160 patients treated for up to 18 months, in which 97% patients achieved control at doses up to a maximum of 40 mg daily. More recently, data collated from the German Acrostudy database during 2 years of treatment with pegvisomant in a clinical practice setting have shown lower rates of control, with 64% of patients achieving a serum IGF-I within the reference range at 6 months and 74% at 24 months; this is the longest treatment period reported to date.
Smaller studies of selected patients have illustrated the ability of pegvisomant to control IGF-I levels in patients refractory to dopamine agonists (DA) and/or SSA. In these studies IGF-I control was achieved with pegvisomant treatment despite resistance to SSA or DA therapy.
Pegvisomant has been used successfully in combination with SSA and it has been demonstrated that the abnormalities of insulin sensitivity, lipids and bone turnover associated with active acromegaly resolve with pegvisomant treatment.
As with any drug with a novel mode of action, there is a need for long-term safety data. The fall in IGF-I induced by pegvisomant is accompanied by an increase in GH secretion from the pituitary, raising concern that this could reflect or induce growth of the underlying pituitary tumour. Reports of early experience with pegvisomant included details of a significant increase in tumour size in two patients out of 167, although one of these patients had a tumour that was considered to be growing prior to initiation of the treatment. The German Acrostudy database has documented tumour growth in 3% of patients taking the medication for up to 2 years, although again some of these tumours were considered to be growing prior to pegvisomant therapy.
Abnormal liver function, specifically raised liver transaminases, has been described with pegvisomant. The mechanism of the liver function disturbance is not understood but available evidence suggests it resolves on discontinuation of the drug.
To address the long-term efficacy and safety of pegvisomant in the clinical setting we retrospectively analysed data from all patients treated with pegvisomant over the past 10 years using common protocols at two UK centres.