Abstract
Context
Although combination therapy of acromegaly with long-acting somatostatin analogs (LA-SSAs) and pegvisomant (PEGV) normalizes insulin-like growth factor-1 (IGF1) levels in the majority of patients, it requires long-term adherence. Switching from combination therapy to monotherapy with weekly PEGV could improve patients’ comfort, but the efficacy is unknown.
Objective
To assess the efficacy of switching to PEGV monotherapy in patients well controlled on combination therapy of LA-SSAs and PEGV.
Design
Single-center, open-label observational pilot study. LA-SSA therapy was discontinued at baseline and all patients were switched to PEGV monotherapy for 12 months. If IGF1 levels exceeded 1.0 times upper limit of normal (ULN), PEGV dose was increased by 20 mg weekly.
Subjects and methods
The study included 15 subjects (eight males), with a median age of 58 years (range 35 – 80) on combination therapy of high-dose LA-SSAs and weekly PEGV for >6 months, and IGF1 levels within the normal range. Treatment efficacy was assessed by measuring serum IGF1 levels.
Results
After 12 months of weekly PEGV monotherapy, serum IGF1 levels of 73% of the subjects remained controlled. In one patient, LA-SSA had to be restarted due to recurrence of headache. IGF1 levels increased from a baseline level of 0.62 × ULN (range 0.30 – 0.84) to 0.83 × ULN (0.30 – 1.75) after 12 months, while the median weekly PEGV dose increased from 60 (30 – 80) mg to 80 (50 – 120) mg.
Conclusion
Our results suggest that switching from combination therapy of LA-SSAs and PEGV to PEGV monotherapy can be a viable treatment option for acromegaly patients without compromising efficacy.
Introduction
Acromegaly is a rare disease characterized by somatic overgrowth and endocrine dysfunction due to excessive secretion of growth hormone (GH) and subsequent elevation of insulin-like growth factor-1 (IGF1) levels. In more than 90% of patients, it is caused by a benign growth hormone-secreting pituitary adenoma (1). In acromegaly patients, the main causes of death are due to cardiovascular and respiratory diseases (2, 3). Normalization of GH and IGF1 levels will result in normal mortality rates, reduced morbidity, and a reduction in symptoms (3).
The GH receptor antagonist pegvisomant (PEGV) is the medical treatment that has the highest reported efficacy (4). PEGV can be administered with or without long-acting somatostatin analogs (LA-SSAs) (5, 6). Administration of PEGV alone at a mean weekly dose of 130 mg can normalize IGF1 levels in over 90% of patients (7). If LA-SSAs and PEGV are used together, a similar efficacy of over 90% is achieved. However, a considerably lower mean weekly dose of 77 – 80 mg PEGV is required; this may result in a more cost-effective treatment.
Both LA-SSAs and PEGV are administered, respectively, as i.m. and s.c. injections. LA-SSAs are injected every 4 weeks, while PEGV can be injected either as a daily or as a weekly injection. While most studies on efficacy have been based on clinical trials that evaluated the daily injection (7, 8), only one study has assessed the weekly injection. Higham et al. (9) reported a normalization of IGF1 in 71% of acromegaly patients (n = 7) treated with weekly PEGV monotherapy.
Switching from combined therapy of LA-SSAs and PEGV to PEGV monotherapy in pateints can reduce the total number of injections, and therefore improve patient adherence. In addition, PEGV monotherapy allows for easier dose adaptation.
In this pilot study, we assessed the effect of switching from combination therapy to weekly PEGV monotherapy. The main outcome parameters were the proportion of patients with normalized IGF1 levels after 12 months follow-up with weekly PEGV monotherapy.
Subjects and methods
Patients
In 2009, a prospective observational study enrolled 15 subjects (8 males) with acromegaly from a single center, who were treated with a combination of LA-SSAs (13 lanreotide autogel, 2 octreotide LAR) and PEGV (Table 1). These patients received a combination therapy because their serum IGF1 levels exceeded the normal range or because their acromegaly symptoms persisted during high dose of LA-SSA monotherapy (5). Inclusion criteria for this study were a stable LA-SSA dose, the use of PEGV as a weekly injection, and biochemical remission for over 6 months before enrolment, defined by an IGF1 within the normal range for sex and age of < 1.0 upper limit of normal (ULN) (8). The cause of acromegaly needed to be a GH-secreting pituitary adenoma and the allowed dose of weekly PEGV was ≤ 80 mg. The median age of the study group was 58 (range 35 – 80) years. Three patients had undergone surgery of the pituitary adenoma in the past, while six patients had undergone with both surgery and radiotherapy. Radiotherapy was administered at least 5 years before study entry. Six patients had only received medical treatment. Three patients had diabetes and were on oral medication, while one diabetes patient also used insulin treatment. All patients gave their written informed consent, and the study was approved by our local institutional review board.
Baseline characteristics of all subjects (n = 15).
| Characteristics | n (%) |
| Demographics | |
| Sex, female | 8 (53.3) |
| Age, median (range) | 58 (35 – 80) |
| Diabetes mellitus type II | 3 (20) |
| Previous treatments | |
| Transsphenoidal surgery | 3 (20) |
| Transsphenoidal surgery and radiotherapy | 6 (40) |
| Primary medical therapy | 6 (40) |
| Weekly PEGV dose (mg; median (range)) | 60 (9.3 – 33.4) |
| Serum assessments, median (range) | |
| IGF1 (nmol/L) | 15.7 (9.3 – 33.4) |
| IGF1 × ULN | 0.62 of ULN (0.30 – 0.84) |
| GH (μg/L) | 3.03 (0.19 – 15.95) |
| Glucose (mmol/L) | 5.4 (3.4 – 20) |
| HbA1c (mmol/L) | 6.1 (5.1 – 9.2) |
| Long-acting somatostatin analogs | |
| Lanreotide autogel | 13 (87) |
| Octreotide LAR | 2 (13) |
One patient had to be restarted with LA-SSAs during the study period due to a recurrence of symptoms and therefore did not want to continue with the PEGV alone. This patient was reported as uncontrolled and was censored from the results after withdrawal, but was counted as treatment failure.
Study
At the start of the study, LA-SSAs were discontinued for 12 months and only PEGV was continued. Every 6 weeks, patients visited our out-patient clinic to measure IGF1, hemoglobin A1c (HbA1c), glucose, insulin, cholesterol, free fatty acids, and triglycerides levels. During the visits, data on symptoms and safety assessments were collected and the dose of PEGV was adjusted if necessary. IGF1 levels were measured by immunometric assays (Diagnostic Products Corp., Los Angeles, CA, USA) and were interpreted according to the sex-dependent and age-dependent ranges (10). GH and serum PEGV levels were measured at the start of the trial, after 6 months, and after 12 months. As endogenous GH was in the presence of PEGV, GH levels were measured using a specific assay free of interference of the drug (11). When IGF1 levels exceeded the normal range, the PEGV dose was further increased by 20 mg/week. This was continued until the IGF1 levels were within the normal range for sex and age and PEGV dose was not changed. Doses were divided into two equal portions per week when PEGV exceeded 80 mg. Efficacy of PEGV monotherapy was assessed 12 months after discontinuation of the combination therapy. Safety assessment included measurement of serum alkaline phosphatase, γ-glutamyltranspeptidase, alanine aminotransferase, aspartate aminotransaminase, lactate dehydrogenase, and total bilirubin. A pituitary MRI was performed before study entry and after the study.
Statistical analysis
Prism version 5.00 for windows (GraphPad Software) was used for the statistical analyses of the data. Although the nature of the study was mainly descriptive, pertinent data were analyzed using Wilcoxon’s signed-rank test. Statistical significance was defined by P < 0.05 (two-tailed). Data were expressed as median ± (range), unless specified otherwise.
Results
Efficacy of combination therapy vs PEGV monotherapy
Fifteen patients were enrolled in this study. At baseline, the IGF1 levels of all patients were controlled with a median IGF1 level of 62% of the ULN (range 30 – 84%) (Fig. 1). At 6 months, IGF1 levels started to increase to 100% of the ULN (range 43 – 220%). The slow increase of IGF1 started 12 weeks after cessation of the LA-SSA. At baseline, patients were using PEGV at a median dose of 60 mg (range 30 – 80 mg). After 12 months, median IGF1 levels increased to 83% (30 – 175%) of the ULN (P < 0.05; Fig. 1). The median PEGV dose had been increased to 80 mg (50 – 120 mg; P < 0.05). IGF1 remained controlled in 11 of 15 subjects (73%) after 12 months of weekly PEGV monotherapy.
IGF1 levels at baseline and after 12 months of pegvisomant therapy. IGF1 levels expressed as times upper limit of normal, at baseline (n=15) and after 12 months (n=14). One patient restarted somatostatin analogs due to recurrence of symptoms.
Citation: European Journal of Endocrinology 174, 5; 10.1530/EJE-15-1150
IGF1 levels at baseline and after 12 months of pegvisomant therapy. IGF1 levels expressed as times upper limit of normal, at baseline (n=15) and after 12 months (n=14). One patient restarted somatostatin analogs due to recurrence of symptoms.
Citation: European Journal of Endocrinology 174, 5; 10.1530/EJE-15-1150
IGF1 levels at baseline and after 12 months of pegvisomant therapy. IGF1 levels expressed as times upper limit of normal, at baseline (n=15) and after 12 months (n=14). One patient restarted somatostatin analogs due to recurrence of symptoms.
Citation: European Journal of Endocrinology 174, 5; 10.1530/EJE-15-1150
At the start of the study, median serum PEGV levels were 3.00 mg/L (0.25 – 19.44). After an initial decrease in serum PEGV levels 2.23 (0.44 – 12.10) at 6 months, PEGV levels increased to 4.36 mg/L (range 1.12 – 21.28) at 12 months. Between 6 and 12 months, the serum PEGV levels were significantly higher (P = 0.01), but no difference was found between baseline and 6 or 12 months.
We compared PEGV levels between the subjects in whom IGF1 levels were elevated and those who had levels that remained within the normal range after 12 months. We observed that after 12 months, acromegaly patients with an elevated IGF1 tended to have lower PEGV levels, this was 3.85 mg/L (1.30 – 4.39 mg/L) in noncontrolled patients compared with 5.54 mg/L (1.12 – 21.28 mg/L) in controlled patients (P = 0.25). Weekly PEGV doses and increases in doses were not different between controlled and noncontrolled patients: the baseline median PEGV dose was 60 (30–80 mg) in controlled vs 60 (40–80 mg) in noncontrolled patients. After 12 months, the respective median PEGV dose increased to 80 (50–120 mg) in controlled vs 100 (80 – 120 mg) in noncontrolled patients. The median increase in PEGV dose was + 10 (0 – 60 mg) in those who were controlled after 12 months, while this was + 40 (20 – 40 mg) for those who were noncontrolled.
Five subjects did not require changes in PEGV dosing, because their IGF1 level remained within the age-adjusted normal limits. All five subjects had received combination therapy longer period (5.88 (2.26 – 6.01) years) than the other 10 subjects (2.52 (1.48 – 6.39) years).
Over time, the GH levels tended to increase during PEGV monotherapy. At baseline, we measured 2.99 μg/L (range 0.19 – 15.95 μg/L) compared with 3.22 μg/L (0.12 – 79.14 μg/L) at 6 months, and 6.36 μg/L (range 0.180 – 31.45 μg/L) at 12 months. The GH levels at baseline and 6 and 12 months were significantly different (P < 0.05), except for baseline vs 12 months (P = 0.055).
Safety assessment
No significant safety issues were observed during PEGV monotherapy. After 12 months, glycosylated HbA1c decreased significantly from 6.0% (5.1 – 9.2%) to 5.9% (5.0 – 9.1%; P = 0.02). The patients with diabetes had no alterations to their anti-diabetic medication during the study.No significant elevation of liver enzymes was observed and the MRI of pituitary did not show any change in tumor size. One patient who withdrew from the study had severe headaches, which was resolved after reinitiating LA-SSAs.
Discussion
In this study, we followed 15 acromegaly patients who were previously biochemically controlled with LA-SSAs and weekly PEGV. These patients had been switched to combination therapy because their IGF1 levels could not be controlled by LA-SSA monotherapy. In this study, we discontinued LA-SSAs and continued with weekly PEGV monotherapy. At baseline, 100% of the subjects had IGF1 levels within the normal limits during combination therapy. After 12 months follow-up, 73% remained controlled.
The efficacy of 73% is in the same range as the efficacy of 68% reported by the ACROSTUDY group. However, we achieved this proportion of IGF1 normalization at a median PEGV dose of 80 mg/week after 12 months, whereas the ACROSTUDY group reported this at a median PEGV dose of 17.2 mg/day after 5 years, which corresponds to approximately 120 mg/week (12). The subjects enrolled in our study used relatively low doses of PEGV and had used the combination with LA-SSAs for at least 1.5 years. As this may have had an impact on our results, these results cannot be extrapolated to all patients using combination therapy.
The slow and gradual increase in serum IGF1 levels that we observed 16 weeks after discontinuation of LA-SSAs is in line with the expected washout time of the LA-SSAs and the carryover effect of the LA-SSAs of about 15 – 20 weeks (5, 13, 14). During 12-month follow-up, 5 of 15 patients did not need any dose adaptation. Although IGF1 levels also increased in these patients, they remained within the age-adjusted normal range. Combination therapy in these five patients lasted for longer period, than for the other patients in the study. A longer period of treatment with LA-SSA might result in prolonged ‘suppression’ of GH, which may improve the efficacy of PEGV, a competitive inhibitor of the GH receptor (4). In the total population, single measurements of GH tended to increase at 6 and 12 months during the study. However, subjects in whom IGF1 remained within the normal range tended to have lower GH levels than those with elevated IGF1 levels.
Subjects in whom IGF1 levels increased after the discontinuation of the LA-SSAs tended to have lower PEGV serum levels, despite treatment with similar doses of PEGV. One would expect that PEGV levels would decrease after discontinuation of LA-SSAs, because LA-SSAs increase the PEGV serum levels by approximately 20% compared with an identical dose of PEGV alone (6, 11). This observation explains the difference in PEGV levels between controlled and uncontrolled patients at 6 months, but not the difference in PEGV levels at 12 months. A potential explanation is that uncontrolled patients do not increase in PEGV serum levels as much as controlled patients when the weekly dose of PEGV is increased. The large difference in serum PEGV levels between subjects has been reported previously (15). Possibly due to the small sample size of our study, however, we found no association between PEGV dose and previously reported characteristics such as adiposity and body weight.
One patient who was discussed in the safety analysis was withdrawn from the study because she suffered from severe headaches, even though serum IGF1 level was controlled (98% of ULN). After recommencing LA-SSA cotreatment, the headache disappeared. The pituitary MRI scan showed no explanation for the headache. In this specific case, we suspect that there was a causal relationship between discontinuation of LA-SSA and headache. As expected, HbA1c levels decreased significantly in these patients in our study. However, the change was very small, and therefore of dubious clinical relevance.
This was a pilot study on monotherapy with weekly PEGV to assess whether ceasing LA-SSAs is a viable option in a selection of our patients on combination therapy. A drawback of this pilot study is the small sample size. Nevertheless, our results suggest that a significant number of acromegaly patients on low-dose PEGV in combination with LA-SSAs can temporarily stop their LA-SSA treatment for at least a year. These treatment interruptions may improve patient adherence to the medication and reduce the economic burden of long-term use of expensive medications.
We conclude that discontinuing LA-SSAs and continuing with PEGV may be an interesting alternative for a selected group of patients that are well controlled with a combination of LA-SSAs and relatively low doses of PEGV. It is possible to maintain biochemical control up to 12 months in a substantial number of patients without raising the dose of PEGV. In patients who have previously been treated for an extended time with LA-SSAs, there is no need for adjust therapy even after 12 months. It seems sensible to determine the usability of structured interruptions in medical therapy in patients with acromegaly in a larger study.
Declaration of interest
A J van der Lely is consultant for Novartis Pharma, Pfizer International and received grants from Novartis Pharma, Ipsen Pharma International, and Pfizer International. S N received research grant from Ipsen and Pfizer. J O L J is a consultant for Pfizer and Novartis and has received lecture fees and unrestricted research grants from Novartis, Pfizer, and IPSEN. The other authors have nothing to disclose.
Funding
This research did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sector.
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