Profile of pegvisomant in the management of acromegaly: an evidence based review of its place in therapy

Figures & data

Table 1 Summary of main pegvisomant studies: efficacy and safety

Author/year	Follow-up	N	Type of study	Previous treatments			PEG treatment	IGF-I normalization		PEG doses (mg/d)	Adverse events
				Surgery	RDT	Medical SSA DA	PEG M% PEG + SSA%	Any time during study	At the end of study	All/controlled/uncontrolled cases	Skin reaction	Liver dysfunction	Tumor Growth
Trainer et al 2000^Citation18	12 w	81	CT	83%	56%		100% 0%	89%	82%	20 mg/d	7.5%	1.25%	0%
Van der Lely et al 2001^Citation21	425 d	160	CT	84%	59%	SSA 73% DA 48%	100% 0%	92%–97%		18–19.6/NA/NA mg/d	1 1.25%	1.25%	1.25%
Schreiber et al 2007^Citation30	23.8 m	229	OBS	90.4%	43.2%	SSA 94.3%	100% 0%		70.9%–76.3%	18.2/NA/NA mg/d	7.4%	5.2%	3.1%
Trainer 2009^Citation25	1.66 y	792	OBS	79.2%	32.8%		63% 23%		62%	NA/106 mg w/113 mg w	1.13%	3.7%	5.3%
Higham et al 2009^Citation32	18 m	57	CS	74%	86%	SSA/DA 100%	89.4% 5.3%	88%		NA/15/NA mg/d	NA	5.2%	1.75%
Buchfelder et al 2009^Citation24	118 w	371	OBS	89.4%	42%	SSA/DA 89.1 %	80% 16%		58,4%–71.3%	ΝΑ/17.5/22.5 mg/d	3.2%	5.3%	2.4%
Marazuela et al 2009^Citation31	22.7 m	44	CS	95.4%	61%	SSA 100% DA 57%	100% 0%		84%	17/NA/NA mg/d	4.5%	6.8%	6.8%
Van der Lely et al 2012^Citation26	3.7 y	1,288	OBS	74%	28.1%	SSA/DA 87.8%	63,4% 36.6%		63.2%	ΝΑ/18/20 mg/d	2.2%	2.5%	3.2%
Grottoli et al 2014^Citation83	4.3 y	341	OBS				41,9% 50.4%		60.9%	NA/18.1/22.3 mg/d	0.29%	8.4%	8.8%
Freda et al 2014^Citation25	5.4 y	710	OBS	81.4%	31.4%	SSA/DA 86.9%	100% 0%		67.5%	NA/17.2/19.8 mg/d	2.3%	1.2%	2.2%
Neggers et al 2014^Citation34	4.9 y	141	CS	41.1%	11.6%	SSA 100%	0% 100%	97.3%		80 mg/w	2.8%	13.5%	0.9%

Abbreviations: PEG, pegvisomant; CT, clinical trial; OBS, observational study; CS, clinical setting; d, days; m, months; w, weeks; y, years; RDT, radiotherapy; SSA, somatostatin analogs; DA, dopamine agonist; PEG M, PEG monotherapy; NA, not available.

Table 2 Possible causes of lower than expected efficacy of PEG in clinical studies compared to the results observed in pivotal studies

1. Failure of dose titration 2. Failure in patients’ compliance 3. Methodological issues regarding IGF-I assays 4. Problems with increasing dose above 20 mg/day with the currently available formulations or because of economic issues 5. Different criteria used to assess IGF-I normalization between pre-clinical (lowest IGF-I criteria: even a single normal IGF-I during the follow-up was classified as IGF-I normalization) and observational studies (latest IGF-I criteria: normal IGF-I level on a cross-sectional manner at a predefined time or at the last follow-up) 6. Temporary loss of IGF-control requiring a dosage adjustment (occurring in 34%–48% of patients)^30,33 7. Some of the uncontrolled cases in observational studies probably represent transient changes of IGF-I levels due to dose adjustments, IGF-I assays’ variations or alternatively mild elevations of IGF-I (ie, IGF-I > 1 × ULN and < 1.3×ULN) for which the corresponding physician does not deem it necessary to adjust PEG dosage

Abbreviations: PEG, pegvisomant; ULN, upper limit of normal.

Table 3 Determinants of pegvisomant dosage

Determinant	Effect	Reference
GH level/IGF-I level	Direct correlation with PEG required dose	56
Sex	Higher GH and GHBP levels with lower IGF-I level in women. Requiring a weight-corrected PEG dose 4.7 mg/day higher than in men	31,54–56
Radiotherapy	Irradiated patients require 3.3 mg/day less PEG dose	31,56
Weight	PEG dose required increases with body weight	56
Diabetes mellitus (type 2)	Higher insulin level, higher expression of hepatic GHR, higher required PEG dose	56
SSA co-treatment	Lower insulin level, lower expression of hepatic GHR, lower required PEG dose	48,58
d3-GHR	More severe disease and lower rate of IGF-I normalization after surgery and SSA therapy	62
	d3-GHR patients required lower PEG doses and fewer months to normalize IGF-I	63,64
	d3-GHR not related to PEG dose	65
IGF-I (cyto-adenosine	IGF-I 194 bp allele (20 CA repeats): more resistant to therapies	66
(CA) repeats in IGF-I gene)	IGF-I (CA repeats) no influence on outcome	67

Abbreviations: GH, growth hormone; SSA, somatostatin analogs; GHR, growth hormone receptor; PEG, pegvisomant; GHBP, growth hormone binding protein.

Table 4 Tumor changes evaluation and mechanisms of tumor growth

Evaluation of changes in tumor size requires: 1) standardized MRI protocol; 2) a skilled neuroradiology team and; 3) the review of all previous radiological studies. Forty to fifty percent of suspected tumor growths are not confirmed after this careful evaluation.^26,68
Mechanism of tumor growth	Frequency	Comments
1) Withdrawal of previous SSA treatment	~30%	Can produce, during the first year, a rebound to the original tumor size without further tumor progression^68,84
2) Tumor increasing in size before the initiation of PEG treatment^68,69	~30%	Only possible to detect by reviewing all previous radiological studies
3) Tumor progression first documented after the start of PEG	~30%	True tumor progressions during PEG treatment

Abbreviations: PEG, pegvisomant; MRI, magnetic resonance imaging; SSA, somatostatin analogs.

Table 5 Changes in tumor size during ACROSTUDY, local versus central MRI readings

ACROSTUDY: Pituitary MRI local evaluation (N=936 with mean follow-up 3.7 years)
No change in tumor size	78.8%
Changed tumor size	21.2%	Decrease	12.6%
		Increase	7.2%
		Both increase and decrease	1.4%
MRI central re-evaluation in a subset of 128 cases: 121 of them with changes in tumor size reported on local evaluation
No change in tumor size	32%
Changed tumor size	53.1%	Decrease	29.7%
		Increase	17.9%
		Both increase and decrease	5.4%
Insufficient data for diagnosis	14.8%
Central re-evaluation of pituitary MRI only confirmed 53.1% of tumor changes locally reported

Central re-evaluation of pituitary MRI only confirmed 53.1% of tumor changes locally reported

Abbreviation: MRI, magnetic resonance imaging.

Figure 1 Follow-up magnetic resonance images showing changes in tumor size during different treatment regimes in a patient with acromegaly.

Notes: (A) 1997: diagnosis of acromegaly. The patient underwent surgery and achieved normalization of GH/IGF-I levels, and postoperative MRI revealed no tumor remnant. (B) 2001: biochemical and clinical recurrence of GH hypersecretion, without visible tumor on MRI. (C) 2004: after 3 years on maximum doses of SSA therapy combined with cabergoline, immediately prior to initiating PEG. (D) 2005: tumor growth (red arrow) after 15 months on PEG monotherapy, in which IGF-I levels were normalized. (E) 2006: after a second and unsuccessful surgery, coexisting with moderate GH hypersecretion. (F) 2008: after 18 months on treatment with maximum SSA doses with suboptimal control a new tumor growth (red arrow) was evidenced. The patient was then treated with pituitary irradiation.
Abbreviations: GH, growth hormone; MRI, magnetic resonance imaging; SSA, somatostatin analogs; PEG, pegvisomant.

Table 6 Economic cost of drugs for acromegaly in Spain in 2014

Mean PEG doses	Annual costs (€)		Total annual
	Pegvisomant therapy	SSA therapy	cost(€)
PEG monotherapy (dose requirements)^Citation29
Controlled patients (17,2 mg/d)	45,964	–	45,964
Uncontrolled patients (19.8 mg/d)	52,912	–	52,912
Combined SSA + PEG (dose requirements)^Citation34
–80 mg PEG/week and 30 mg/28 d octreotide LAR	30,457	12,775	43,232
–80 mg PEG/week and 120 mg/28 d lanreotide autogel	30,457	16,164	46,620

Note: The average cost has been calculated based on the mean dose of PEG and SSA described in large series of treatment with PEG monotherapy and combination therapy by the use of PEG and SSA.

Abbreviations: PEG, pegvisomant; SSA, somatostatin analogs; d, day; LAR, long acting repeatable.

Figure 2 Pegvisomant (PEG) place in the algorithm of treatment of persistent acromegaly after surgery.

Abbreviations: CAB, cabergoline; GH, growth hormone; SSA, somatostatin analogs; DM, diabetes mellitus; US, United States.

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