Use of Pegvisomant in acromegaly. An Italian Society of Endocrinology guideline

Acromegaly management is a significant challenge for endocrinologists. The Acromegaly Consensus Group developed several statements on the management of acromegaly and specifically on its medical treatment [1‐3]. Acromegaly is a quite rare condition generally caused by a growth hormone (GH)-secreting pituitary adenoma [4]. Delayed diagnosis leads to prevalent presentation of the disease at the stage of macroadenoma (two-thirds of patients) and frequent persistence of active disease after surgery which remains in many patients the primary treatment option [5]. However, active acromegaly is potentially a life threatening condition due its severe systemic complications [6, 7] Therefore, elevated GH and insulin-like growth factor (IGF)-1 levels need to be strictly controlled after failure of surgery with medical or radiation treatments [8]. Furthermore, criteria for disease control may not be fulfilled in a considerable proportion of patients undergoing medical treatment with somatostatin receptor ligands (SRLs) after unsuccessful surgery [9, 10]. Accordingly, some acromegaly patients require the administration of GH antagonist Pegvisomant [11]. Pegvisomant has been introduced in clinical practice more than a decade ago as a medical therapy of acromegaly. However, specific guidelines for Pegvisomant use in acromegaly are lacking. Therefore, the Italian Society of Endocrinology constituted a task force with the objective of assessing the published literature and the clinical experience with Pegvisomant. This group involved endocrinologists recognized experts in the field of acromegaly management and their understanding of the data reported so far worldwide as well as their recommendations for Pegvisomant use in clinical practice are presented here. Biochemical and clinical results of Pegvisomant, indications, treatment modalities, combination therapies, safety and regulatory and cost/efficacy issues were evaluated. Evidences were graded with GRADE system [1‐3, 12, 13] based on the quality of evidence as very low quality (VLQ; expert opinion with one or a small number of small uncontrolled studies in support), low quality (LQ; large series of small uncontrolled studies), moderate quality (MQ; one or a small number of large uncontrolled studies or meta-analyses), or high quality (HQ; controlled studies or large series of large uncontrolled studies with sufficiently long follow-up). Recommendations were defined discretionary (DR) if based on VLQ-LQ evidence, or strong (SR) if supported by MQ-HQ evidence.

Pegvisomant is a drug designed to block the GH receptor (GHR) and, therefore, GH action. The discovery of this GHR antagonist was made possible by the elucidation of the structure–function relationship of GH and its receptor [11, 14]. Growth hormone is a 22 kDa polypeptide with 191 amino acids, two disulphide bonds and four alpha helices synthesized in the anterior pituitary and central to regulation of growth and differentiation. It has many other biological actions including enhancement of protein synthesis, lipolysis and hyperglycemic effects. Although GH may have direct effects on peripheral tissues most of its growth promoting effects are mediated by IGF-1 [15‐17]. Growth hormone has two distinct domains (sites one and two) that interact with preformed GHR dimer on plasma membrane triggering conformational changes required for signaling [18]. The affinity of GH binding site one for GHR is high whereas the affinity of site two is lower. After initial high affinity binding at site one, subsequent binding at site two produces functional receptor dimerization. After the GH/GHR interaction, a series of intracellular signaling systems is mobilized, resulting in the activation or inactivation of genes responsible for GH action [19].

Pegvisomant is a GH analog with a single-aminoacid substitution at position 120 that generates the antagonist. Additional changes include amino acid substitutions within binding site 1 and a further modification by the addition of polyethylene glycol moieties [20]. The GHR antagonist acts by failing to induce proper or functional GHR dimerization. The pegylated [polyethylene glycol (PEG)] counterpart Pegvisomant is generated by the conjugation of GHR antagonist with four or five moieties of PEG 5000; PEG molecule addition increases the size of the antagonist and its serum half life from ~30 min to more than 100 h, by reducing renal clearance and intravascular proteolysis, and reduces immunogenicity of the molecule [21]. Like GH, the GHR antagonist has a relatively small size (22 kDa), and is normally cleared via the kidneys and/or GHR internalization [22].

Circulating GH values are not useful as biochemical marker of Pegvisomant effects in acromegaly both because endogenous GH secretion may increase during treatment due to negative feedback and, particularly, due to cross-reactivity of GH with Pegvisomant in most GH assays [21] (HQ). Therefore, GH should not be measured in monitoring Pegvisomant treatment (SR). Normalization of IGF-1 levels represents the main end point of Pegvisomant treatment (HQ) [23, 24] although sudden and remarkable GH increase during Pegvisomant therapy could be a marker of tumor re-growth [25] (VLQ). Many studies reported IGF-1 normalization or marked reduction in acromegaly patients treated with Pegvisomant [26] (HQ). In addition, improvement in quality of life was suggested even adding Pegvisomant in patients already effectively controlled by SRLs [27] (VLQ). However, reported effectiveness of Pegvisomant varied widely depending on the type of study (clinical trial vs. observational) as it happens with other medical therapies in acromegaly [3] (MQ). Indeed, serum IGF-1 levels normalized in more than 90 % of patients particularly in initial clinical trials [28‐32], while the control rate was lower in studies performed in the clinical setting and based on the retrospective analysis of disease-specific databases [33‐39] (Table 1). Inadequate dose titration, poor compliance to daily injections, suboptimal selection of patients and technical problems related to IGF-1 assay could justify a lower than expected efficacy in “real life” conditions (VLQ), since the existence of a true “biochemical resistance” to Pegvisomant, as observed with SRLs [40], has not been clearly documented yet (VLQ). Effectiveness of Pegvisomant may be inversely correlated to baseline IGF-1 levels and starting dose should be higher and dose titration more rapid in patients with a worse endocrine profile (VLQ) [26, 41]. Better efficacy of Pegvisomant was associated with male gender, leanness, lower baseline GH and/or IGF-1 levels, previous irradiation, and related to treatment duration and appropriate dose titration (LQ) [37, 38, 41]. The role of d3GHR polymorphism, which could modify receptor sensitivity to GH [42], in response to Pegvisomant is still controversial (VLQ) [43‐45]. Availability of validated assays is crucial for monitoring appropriately effectiveness of treatment and dose titration (SR). For this reason, IGF-1 values should be measured with the same method over time in each patient (SR). At present, considerable differences exist among available assays, due to lack of standardization, use of different types of antibodies and interference of binding proteins (MQ) [46]. Moreover, specific age-related normative intervals are rarely obtained, as recommended by available general guidelines [10], in local populations by centralized laboratories (LQ). Finally, given the within-individual biological variation of IGF-1 assays caution should be also used in interpreting values close to reference limits even if obtained with the same method [47, 48] (DR).

Treatment with Pegvisomant improves clinical syndrome of acromegaly in a high percentage of patients (HQ), positively impacts glucose metabolism (MQ), quality of life (MQ) and cardiovascular and skeletal complications (MQ) [49] (Table 2).

Pegvisomant is traditionally indicated for treatment of acromegaly patients with inadequate response to pituitary adenomectomy or radiation therapy, or for those intolerant or resistant to SRLs (HQ). However, a clear-cut definition of resistance to SRLs is missing (VLQ) [74]. In fact, during SRL therapy biochemical control is defined as random basal GH lower than 1 mcg/liter and IGF-1 levels below the upper limit of normal range for age (MQ) [3]. Using these strict criteria [10] normalization of biochemical activity in unselected patients with acromegaly after long-term (>6–12 months) treatment with maximal SRL doses occurs approximately in 25–50 % of cases [3, 75‐77] (MQ). Non-responders to SRL therapy (minimal effect on GH and IGF-I levels and on tumor shrinkage) should be switched to Pegvisomant (SR). In partial responders to SRLs, Pegvisomant monotherapy or combination therapy with Pegvisomant and SRL should be considered (DR). Tumor shrinkage quite frequently (around 50 % of treated patients) occurs during therapy with SRLs often but not necessarily together with biochemical normalization [78‐80] (MQ). Interestingly, in patients with acromegaly and McCune Albright syndrome surgery and even radiation therapy often can not be performed [81] and SRLs have very low chances to be effective [81] (LQ). In these patients, Pegvisomant can be considered as primary treatment (DR). Moreover, primary post-surgical medical treatment with Pegvisomant should be considered in patients already proven to be resistant to SRLs as those who underwent a sufficiently long (>3–6 months) trial of pre-surgical SRL treatment which demonstrated to be ineffective in controlling GH and IGF-1 (unless a > 75 % surgical debulking is achieved [82]) (DR). Primary post-surgical Pegvisomant treatment can be considered in patients after irradiation in whom elevated IGF-1 levels may persist for long time but likelihood of tumor regrowth is modest [1] (DR) and in patients with poorly controlled diabetes mellitus in whom SRLs may potentially worsen glucose metabolism [51‐54] (DR).

Pegvisomant is administered by subcutaneous injections. Ten, 15, and 20 mg per vial are available dosages. Initially, treatment regimens contemplated a 40–80 mg loading dose. In clinical practice this procedure has not proven to be useful and has been abandoned (LQ) [23]. Daily administration is the most effective because it achieves higher serum Pegvisomant concentrations with a lower dose of drug (MQ) [29, 83]. The target of therapy is to achieve serum IGF-I in the middle of age-related reference range (MQ) [11]. Starting dose is usually 10 mg/day and maximum maintenance dose which currently can be administered based on regulatory indications is 30 mg daily (LQ) [84]. For patients who require a dose >20 mg daily, Pegvisomant treatment is more inconvenient due to daily multiple injections (VLQ) [85]. After treatment start, serum IGF-I levels fall within 2 weeks and then reach a plateau after 4 weeks (HQ) [29]. Consequently, it is suggested to measure IGF-I 4 to 6 weeks after beginning treatment and after every change of dose until biochemical control is reached (DR). Once serum IGF-I levels are normalized, they should be monitored every 3–6 months [38] since Pegvisomant dose may require up- or down-titration in the same individual during treatment (DR) [3].