SPECIAL FEATURE

Clinical Review

A Critical Analysis of Clinically Available Analog Formulations for Therapy of

Robert D. Murray and Shlomo Melmed

Department of Endocrinology (R.D.M.), Leeds Teaching Hospitals National Health Service Trust, Leeds LS9 7TF, ; and

Department of Medicine (S.M.), Cedars Sinai Medical Center, University of California Los Angeles School of Medicine, Los Angeles, Downloaded from https://academic.oup.com/jcem/article/93/8/2957/2598353 by guest on 24 September 2021 California 90048

Context: Short and long-acting somatostatin (SRIF) analogs are approved for clinical use in acro- megaly. Recent analysis of the relative efficacy of LAR and lanreotide SR on the GH-IGF-I axis in acromegaly favored octreotide LAR in the secondary treatment of patients not preselected by SRIF responsiveness. A novel aqueous formulation of lanreotide, lanreotide Autogel (ATG), has recently been approved and is the predominant (and only in the United States) formulation of lanreotide used clinically.

Objective: We performed a critical review of SRIF analog treatment to establish the relative efficacy of three clinically available SRIF analog preparations, octreotide LAR, lanreotide SR, and lanreotide ATG (Somatuline depot in the United States) in control of the GH-IGF-I axis in acromegaly.

Data Sources: Data were drawn from MEDLINE and the bibliography of analyses of long-acting SRIF analogs.

Data Collection: We reviewed the largest studies of sc octreotide, octreotide LAR, and lanreotide SR, all that included biochemical end-point data for lanreotide ATG, and studies that directly compared the efficacy of octreotide LAR and lanreotide SR.

Data Synthesis: Caveats considered included differences in baseline GH and IGF-I values, patient selection, and interassay and intraassay variability, confounding the analysis. Studies comparing patients treated contiguously with lanreotide SR and octreotide LAR are fraught with method- ological problems, however, are suggestive of marginally greater efficacy in control of the GH-IGF-I axis for octreotide LAR. Lanreotide ATG shows noninferiority to lanreotide SR. Five small studies directly comparing octreotide LAR and lanreotide ATG suggest no significant differences between these preparations in control of biochemical end-points.

Conclusion: Lanreotide ATG and octreotide LAR are equivalent in the control of symptoms and biochemical markers in patients with acromegaly. (J Clin Endocrinol Metab 93: 2957–2968, 2008)

cromegaly is a rare disease resulting from a benign pituitary cular, cerebrovascular, and respiratory disease (2–4). The most A somatotrophinoma in over 95% of cases (1), and is char- robust determinant of excess mortality is the circulating GH level acterized clinically by excessive skeletal growth, soft tissue en- (2, 5), though some studies have suggested that IGF-I levels may largement, disability, and shortened life expectancy. Estimates of contribute to adverse mortality outcomes (6, 7). Successful man- the excess mortality from epidemiological studies suggest an ap- agement requires aggressive reduction of GH levels to less than proximate 2-fold relative risk ascribed primarily to cardiovas-

0021-972X/08/$15.00/0 Abbreviations: ATG, Autogel; SRIF, somatostatin; SSTR, specific receptor subtype. Printed in U.S.A. Copyright © 2008 by The Endocrine Society doi: 10.1210/jc.2008-0027 Received January 4, 2008. Accepted May 2, 2008. First Published Online May 13, 2008

J Clin Endocrinol Metab, August 2008, 93(8):2957–2968 jcem.endojournals.org 2957 2958 Murray and Melmed SRIF Analogs J Clin Endocrinol Metab, August 2008, 93(8):2957–2968

2.5 ␮g/liter (5 mU/liter) to achieve mortality rates equivalent to tively. Collectively, these studies suggested that biochemical con- the normal population (2, 5). trol of acromegaly with clinical improvement could be achieved Therapeutic modalities available to achieve this target include in 50–60% of patients using thrice daily sc octreotide (Table 1). surgery, radiotherapy, and medical therapy. Surgery by a skilled neurosurgeon remains the mainstay of management, especially for small tumors. However, biochemical control is achieved in Long-Acting SRIF Analogs less than 50% of patients with macroadenomas, but greater than 80% of microadenomas (1). Control of GH and IGF-I levels after Octreotide requires sc administration three times per day to radiotherapy occurs over a period of many years and frequently maintain GH suppression, and biochemical “escape” was fre- takes more than a decade. Therefore, medical therapy plays a quently observed at the end of the dosing interval impacting on crucial role in a large proportion of patients with acromegaly overall biochemical control. In an effort to increase the dosing who fail to be cured by surgery, or during the interim while the interval and provide more sustained control of GH levels, two Downloaded from https://academic.oup.com/jcem/article/93/8/2957/2598353 by guest on 24 September 2021 effects of radiotherapy are realized. Somatostatin (SRIF) analogs long-acting depot formulations of SRIF analogs, octreotide LAR introduced in the mid-1980s have become the mainstay of med- and lanreotide SR, were developed. Both peptide molecules are ical management (1, 8). SRIF analogs have been used with suc- comprised of eight amino acids with a disulfide bridge, and are cess as primary therapy in which operative intervention is un- formulated as microspheres of biodegradable polymer contain- likely to be curative or is associated with an unacceptable risk of ing the active peptide. Octreotide LAR 10–30 mg is injected im morbidity and mortality (1, 9, 10). every 4 wk and lanreotide SR 30 mg im every 7–14 d. Efficacy of In this review we have confined comparisons of efficacy of both these preparations in the treatment of acromegaly has been long-acting SRIF analogs in patients with acromegaly to the bio- shown in a large number of studies (27–34). Most studies ex- chemical control of disease. Relative tumor shrinkage is an im- amining the efficacy of long-acting SRIF analogs have studied portant determinant of which SRIF analog is used clinically, patients after surgery and/or radiotherapy, however, more re- however, there are currently no data from studies randomizing cently, have included a subset of patients who have been treated patients to different analogs and using tumor shrinkage as a as primary therapy. Current evidence supports a similar rate of primary end-point. Switch studies are of limited value because GH and IGF-I normalization in patients treated as primary or tumor shrinkage is greatest when SRIF analogs are used as pri- secondary therapy (9, 30). Due to difficulties differentiating be- mary therapy and during the first 3-months treatment. tween primary and secondary treatment in most studies, this review will not differentiate between these subgroups. Baldelli et al. (27) and Verhelst et al. (28) studied the efficacy SRIF and Octreotide of lanreotide SR in 118 and 66 patients with acromegaly, re- spectively (Table 1). In both studies patients were switched from SRIF is widely distributed within multiple organ systems, and sc octreotide to lanreotide SR, and the dose of the latter opti- plays an important role in regulating release and other mized on the basis of the biochemistry. Overall, lanreotide SR physiological functions (11). The two most biologically active was found to be more efficacious in controlling GH and IGF-I SRIF isoforms comprise 14 or 28 amino acids. SRIF action is levels than sc octreotide, with 44–77% of patients achieving mediated through five specific receptor subtypes (SSTRs) (1–5) biochemical targets. The largest two studies of octreotide LAR differentially expressed in a tissue-specific pattern, thereby con- enrolled 151 and 110 patients with active acromegaly (29, 30) ferring functional and therapeutic specificity of ligand action (Table 1). In the first of these studies, Lancranjan and Atkinson (12). Somatotrophs preferentially express SSTR2 and SSTR5 (1999) (29) commenced patients on octreotide LAR after 4-wk (13–15), and respond predominantly to SSTR2-binding analogs individualized sc octreotide, whereas in the second study, pa- (16, 17). SSTRs interact with each other (18), indicating complex tients were naive to SRIF analogs (30). Biochemical targets of GH pituitary cell responsiveness to receptor ligands (19). SRIF ana- less than 2.5 ␮g/liter and a normalized IGF-I were achieved in logs also act at the periphery to inhibit GH action (20). Both 63–75% of patients. However, of note is that the overall per- octreotide and lanreotide exhibit similar affinities for SSTR2 and centage of patients controlled by lanreotide SR and octreotide SSTR5 in vitro, and apparent differences in clinical efficacy LAR was not unduly different from that observed in previous discussed in this review, therefore, likely relate to differences studies strictly optimizing the dose of sc octreotide. in pharmacodynamics and of the various A direct comparison of the percentages of patients achieving formulations. GH and IGF-I targets at the end of these four relatively large Recognition that SRIF is the primary physiological negative studies suggests that octreotide LAR exhibits greater efficacy regulator of pituitary GH release led to investigation of a ther- than lanreotide SR. However, in the Lancranjan and Atkinson apeutic role for SRIF in managing acromegaly. Although SRIF (29) study, all patients were selected on the basis of a significant inhibited GH release from somatotrophinomas (21, 22), clinical known prior response to sc octreotide. Therefore, it is likely that usefulness was limited due to a half-life of 2–3 min. This thera- this cohort would have responded well to any clinically available peutic limitation was eased by the development of the SRIF an- long-acting SRIF analog. This interpretation is supported by ex- alog, octreotide, first used in clinical trials in 1984 (23, 24). Two amining the proportion of patients with suppression of GH less of the largest studies using this peptide were published in the than 2.5 ␮g/liter when receiving sc octreotide. This proportion early 1990s (25, 26), and included 189 and 115 patients, respec- was 65.8% in the Lancranjan and Atkinson (29) study in com- J Clin Endocrinol Metab, August 2008, 93(8):2957–2968 jcem.endojournals.org 2959

TABLE 1. Summary of the largest studies in the medical literature examining efficacy of sc octreotide, octreotide LAR, and lanreotide SR

SRIF analog No. Study design Results Side effects Study weaknesses Vance and sc OCT 189 Treated 6 d-231 wk (median Mean GH decreased in 94%; GI or local injection site Open study. Variable Harris, 1991 24.2 wk); sc OCT 100- IGF-I decreased in 92%; S/E in 37%; Glu treatment duration. (26) 1500 (median 300) ␮g/d; GH Ͻ5 ␮g/liter in 45%; tolerance reduced in Variable dose 13 on sc infusions; dose IGF-I normalized (Ͻ2 U/ml) 48% escalation (biochemical escalation based on clinical in 46%. Tumor size vs. clinical). Nonage- and biochemical response decreased Ͼ20% in 44% related reference range for IGF-I. No data on how many pts achieved GH Ͻ2.5 ␮g/ Downloaded from https://academic.oup.com/jcem/article/93/8/2957/2598353 by guest on 24 September 2021 liter Ezzat et al., sc OCT 115 Initial 4-wk randomized to sc During first phase 26% with GI S/E in 88%, but Dose fixed and not 1992 (25) OCT tds or placebo; 4-wk GH Ͼ5 ␮g/liter achieved persisted in only 10% titrated to optimize WO, then randomized to GH Ͻ2 ␮g/liter, and 58% at 6 months biochemical response; 6-month sc OCT 100 or with an elevated IGF-I Non age-related 250 mg tds achieved a normal value on reference range for OCT IGF-I During 6-month treatment; 21 and 16% on 250 and 100 ␮g tds achieved GH Ͻ2 ␮g/liter, and 68 and 55% normalized IGF-I levels, respectively; 19 and 37% on high and low dose showed tumor size reduction (Ͼ1-mm diameter) Baldelli et al., LAN SR 118 Patients on sc OCT titrated to sc OCT resulted in GH Ͻ2.5 GI S/E in 69 and 47% Open design; sc OCT 2000 (27) maximum dose of 600 ␮g/liter and a normalized on initiation sc OCT dose limited to 600 ␮g/d, WO 4–8 wk, then IGF-I in 34 and 47% of and LAN SR, ␮g/d; LAN SR dose LAN SR 30 mg 2 wkly for patients, respectively. At respectively; 42% titrated up to a 3 months. Dose frequency 24-month LAN SR, GH and injection site maximum of 30 mg increased to every 10 d if IGF-I levels were controlled discomfort with LAN every 10 d GH Ͼ2.5 ␮g/liter after in 77 and 63%, SR 3-month LAN SR. Total respectively. Significant duration LAN SR 24 tumor shrinkage (Ͼ20% months volume) in 22% primary therapy pts Verhelst et al., LAN SR 66 Patients treated LAN SR 30 In patients previously treated GI S/E in 62% on initial Open design. Prior 2000 (28) mg every 14 d. Dose with sc OCT, 35% wk after LAN SR. Pain treatment with sc OCT frequency increased to achieved a normal IGF-I at injection site in not in a study setting every 10 d if IGF-I not level. After 12-month LAN 27% and may not have controlled at 3 months, SR, 45 and 44% achieved been optimized and to every 7 days if IGF-I aGHϽ2.5␮g/liter and still elevated at 6 months; normal IGF-I. Tumor 55 patients previously shrinkage Ͼ25% volume treated with sc OCT for a in 36% at 12 months mean of 31.7 months Lancranjan and OCT LAR 151 European multicenter study. GH Ͻ2.5 ␮g/liter in 65.8% S/E in 72.8%. Only Open design. Patients Atkinson, Individualized sc OCT for 4 on sc OCT and 70% on 15.9% related to selected on this basis 1999 (29) wk and achieved GH Ͻ10 OCT LAR. IGF-I values were OCT LAR. Majority GI of known ␮g/liter. Thereafter treated normal in 63% on sc OCT and transient. responsiveness to OCT. with OCT LAR 20 mg 4 and 66% on OCT LAR Injection site pain/ Unclear if sc OCT wkly for 3 months. At 3 erythema in 11–12% optimized months if GH Ͻ1 ␮g/liter, dose reduced to 10 mg, and if GH Ͼ5 ␮g/liter, dose increased to 30 mg 4 wkly. Study duration 48 wk Cozzi et al., OCT LAR 110 OCT LAR initiated at 20 mg 4 At study completion 72 and Transient GI symptoms Open design. Only pts 2003 (30) wkly and dose adjusted to 75% achieved GH Ͻ2.5 in 8%. Injection site with a 20% or greater achieve GH Ͻ2.5 ␮g/liter ␮g/liter and normal IGF-I, pain in 4.5% decrease in GH and/or and normalized IGF-I. respectively. Tumor volume IGF-I after 6 months Mean duration of follow- reduction Ͼ25% in 46% continued in the study up 30 months pts overall, and 77% of primary therapy group

GI, Gastrointestinal; Glu, glucose; LAN SR, lanreotide microparticle; OCT, octreotide; pts, patients; S/E, side effects; tds, three times daily; wkly, weekly; WO, washout. 2960 Murray and Melmed SRIF Analogs J Clin Endocrinol Metab, August 2008, 93(8):2957–2968 parison with 34% in the Baldelli et al. (27) study, despite similar derived from just a single study (39). It is on the basis of these two treatment protocols when receiving sc octreotide. In the Cozzi et studies alone, when compared with the more robust lanreotide al. (30) study, patients who did not achieve a 20% or greater SR data, that octreotide LAR was reported to be more efficacious reduction in GH and/or IGF-I were actively excluded from the in “unselected” patients (35). study. This exclusion criterion led to a self-fulfilling hypothesis There are however a number of studies that have directly such that the final result of the study reflects only enrolled pa- compared the efficacy of lanreotide SR with octreotide LAR tients proven to respond to treatment. Given these biases it is (Table 2) (39, 44–46, 48). Four of these studies were small, pertinent to note that the aforementioned two studies (29, 30) containing only five to 15 patients (44–46, 48). Three of these comprised over 50% of the SRIF responsive patients (n ϭ 486) four studies switched patients stabilized on lanreotide SR for at that were analyzed in a recent metaanalysis (35) comparing ef- least 6 months to octreotide LAR (44–46), and the forth com- ficacy of octreotide LAR with lanreotide SR. Therefore, it is pared biochemical control between a group of patients on lan- likely that these two studies significantly influenced the outcome reotide SR with those on octreotide LAR (48). Two studies Downloaded from https://academic.oup.com/jcem/article/93/8/2957/2598353 by guest on 24 September 2021 of that analysis (35). showed octreotide LAR to result in significantly greater control of GH and IGF-I levels compared with lanreotide SR (45, 46), whereas the further two studies showed no significant difference Lanreotide SR and Octreotide LAR between treatments (44, 48). However, in the latter two studies, GH and IGF-I levels were moderately lower when the patients There has been controversy over the relative efficacy of the two were receiving octreotide LAR. clinically available long-acting SRIF analogs, lanreotide SR and The aforementioned studies are limited by small numbers octreotide LAR, in the management of acromegaly. Most avail- and, therefore, statistical power to show differences between able data comparing lanreotide SR and octreotide LAR relate to treatments. Chanson et al. (39) studied 125 patients initially secondary treatment after surgery or radiotherapy. A recent treated with at least three injections of lanreotide SR 30 mg every analysis contained too few published studies of primary therapy 10–14 d. Thereafter, patients were randomized in a 3:1 ratio to using these agents to allow valid comparisons to be made (35). octreotide LAR 20 mg four weekly (n ϭ 98) or to continue their Furthermore, a large proportion of studies include both primary current lanreotide SR schedule (n ϭ 27). After 3 months on the and secondary treatment without stratification of the cohort be- latter regimens, those who remained on lanreotide SR were fore analysis. Considering biochemical efficacy, the outcome of switched to octreotide LAR 20 mg every 4 wk, and in those who this metaanalysis suggested octreotide LAR to have greater ef- were randomized to octreotide LAR 20 mg every 4 wk, the dose ficacy in achieving both GH (54 vs. 48%) and IGF-I (63 vs. 42%) was individualized to achieve GH levels less than 2.5 ␮g/liter normalization compared with lanreotide SR in “unselected” pa- (39). In those patients who remained on lanreotide SR for a tients (35). There was no significant difference in achievement of further 3 months, there was no significant change in GH or IGF-I targets for GH and IGF-I in patients selected on the basis of prior levels. A normal IGF-I was achieved in 52% of patients. In the 3 sensitivity to SRIF analogs. Furthermore, there was no signifi- months after switching from lanreotide SR to octreotide LAR 20 cant difference in absolute GH (4.1 vs. 5.3 ␮g/liter) or IGF-I (330 mg four weekly, a significant decrease in GH (3.7 Ϯ 0.5 vs. 2.6 Ϯ vs. 432 ng/ml) values between “unselected” patients on oct- 0.4 ␮g/liter) and IGF-I (436 Ϯ 23 vs. 360 Ϯ 23 ng/ml) was ob- reotide and lanreotide SR, respectively. Although not significant, both values were notably lower in the octreotide LAR treated served, with 65% achieving a normal IGF-I. In the subgroup that group (35). underwent titration of the octreotide LAR dose for a further 3 There are a number of methodological difficulties inherent to months, IGF-I levels were normalized in 56% (39). metaanalyses of such complex conditions as acromegaly and The cumulative data from these studies suggest that oct- involving measurement of biochemical variables. One of the reotide LAR is modestly more efficacious than lanreotide SR in most significant confounding variables is the lack of standard- the biochemical control of acromegaly (Table 2). There are two ization of GH and IGF-I assays, making comparison of absolute major caveats in the interpretation of these data. First, lanreotide values between studies almost impossible. Furthermore, defini- SR was the initial therapy in all studies, and there is evidence tion of achievement of biochemical targets is dependent on a derived from some of the largest studies of SRIF analogs to sug- robust reference range to establish normative values, which was gest that control of acromegaly may improve with long-term a concern in earlier studies (9, 25, 26, 36). If we put aside the therapy in the absence of dosage change (30, 39). This was ex- challenges with the assays, a review of the studies included in the emplified in the Chanson et al. (39) study, in which patients who metaanalysis reveals the study populations to be heterogeneous simply continued lanreotide SR for a further 3 months without in terms of initial patient entry criteria. Pretreatment GH and dose change showed a decrease in GH and IGF-I levels. Second, IGF-I values impact significantly on the achievement of control many of the aforementioned studies switched patients on lan- with SRIF analogs (10, 26, 30, 37, 38). Although the metaanaly- reotide SR under routine clinical care to octreotide LAR under sis (35) examined 12 studies of secondary octreotide LAR ther- study conditions and compared efficacy. It is unclear from these apy (10, 29, 30, 39–47), after stratification for those who were studies whether the frequency of lanreotide SR dosing had been and were not preselected on the basis of SRIF responsiveness, the optimized before the change in therapy. Despite these caveats the latter cohort included patients from only two studies (39, 46). In consistent findings of the aforementioned studies, on balance, fact, 92% of patients included in the “unselected” cohort were lend support to the conclusion that octreotide LAR exhibits lnEdcio ea,Ags 08 93(8):2957–2968 2008, August Metab, Endocrinol Clin J

TABLE 2. Summary of biochemical end-points of studies comparing efficacy of octreotide LAR and lanreotide SR

Baseline Normal IGF-I SRIF Baseline GH IGF-I Final GH Final IGF-I GH <2.5 Normal IGF-I GH <2.5 Mean dose analog No. (␮g/liter) (ng/ml) (␮g/liter) (ng/ml) ␮g/liter (n) (n) ␮g/liter (mg/4 wk) Study design Turner et al., SR 9 14.0 Ϯ 8.3a 49.0 Ϯ 24.5b 4.5 Ϯ 1.6c 24.7 Ϯ 4.4b 7d 5 103 Ϯ 15.8 Open, on SR for up 1999 (46) to 12 months, SR to LAR, 1–5 LAR 10 3.1 Ϯ 1.1c 21.9 Ϯ 3.9b 8d 7 24.0 Ϯ 5.2 months WO, SR and LAR titrated Cozzi et al., SR 12 46.1 Ϯ 14.6 959 Ϯ 94 7.2 Ϯ 1.5 460 Ϯ 61 1 4 1 98.3 Ϯ 29.8 Open, SR to LAR, no 1999 (45) WO, SR and LAR LAR 12 5.1 Ϯ 1.1 374 Ϯ 60 4 5 2 23.3 Ϯ 8.9 titrated Kendall-Taylor SR 5 6.4 Ϯ 1.7 48.4 Ϯ 11.2b 2.6 Ϯ 0.8 26.0 Ϯ 4.5b 4 5 4 Open, SR to LAR, et al., 2000 2ϩ months WO, (44) LAR 5 8.7 Ϯ 0.3 47.4 Ϯ 15.5b 2.3 Ϯ 0.6 26.7 Ϯ 6.4b 4 5 4 22.0 Ϯ 4.5 SR and LAR titrated Chanson et SR 116 3.7 Ϯ 0.5 57 Ϯ 3b 58/107 53/111 75.6 Ϯ 15.0 Open, SR to LAR20, al., 2000 no WO, LAR later (39) LAR 107 2.6 Ϯ 0.4 47 Ϯ 3b 73 70 20 Ϯ 0 titrated (data not shown) Ronchi et al., SR 15 10.4 Ϯ 10.0 90 Ϯ 37b 3.0 Ϯ 2.0 56 Ϯ 19b 5 Open, 2003 (48) nonrandomized comparison study, LAR 12 8.8 Ϯ 5.0 92 Ϯ 37b 2.7 Ϯ 1.7 45 Ϯ 22b 5 primary end-point Glu metabolism LAN SR 70/133 (52.6%) 72/152 (47.4%) OCT LAR 89/134 (66.4%) 92/146 (63.0%)

Glu, Glucose; LAR, octreotide LAR; SR, lanreotide microparticle; SR to LAR, initial treatment with lanreotide microparticle followed by octreotide LAR; WO, washout. a Data for nine, and in mU/liter. b Data in nmol/liter. jcem.endojournals.org c Data in mU/liter. d Number of patients with GH Ͻ 5 mU/liter.

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greater efficacy compared with lanreotide SR in controlling ex- Lanreotide SR and Lanreotide ATG cess GH and IGF-I secretion characteristic of acromegaly. In contrast to the data included in the recent metaanalysis com- paring the efficacy of lanreotide SR and octreotide LAR (35), the predominant formulation of lanreotide currently used in clinical Lanreotide Autogel (ATG) practice is lanreotide ATG. Few data concerning this preparation were available when the metaanalysis was performed. Initial Acknowledgment of the limitations of lanreotide SR led to the studies of efficacy of lanreotide ATG compared relative efficacy development of a more prolonged acting formulation of lan- with lanreotide SR with the aim of testing the noninferiority of reotide, lanreotide ATG (Somatuline depot; Tercica, Brisbane, the new formulation (Table 3). CA). Lanreotide ATG is a novel formulation of lanreotide ace- The initial multicenter study enrolled 144 patients who re-

tate within a supersaturated aqueous solution. The combination ceived lanreotide SR for at least 3 months (50), and switched Downloaded from https://academic.oup.com/jcem/article/93/8/2957/2598353 by guest on 24 September 2021 of hydrophobic and hydrophilic residues, together with the di- their therapy to an equivalent monthly dose of lanreotide ATG. sulfide bridge, leads to self-association of lanreotide molecules After 3 months the dose of lanreotide was titrated to control GH when mixed with water and the formation of a homogeneous and IGF-I levels (51). GH, IGF-I, and lanreotide levels after semisolid gel. This preparation is formulated as a prefilled sy- 3-month lanreotide ATG were not significantly different from ringe containing 60, 90, or 120 mg lanreotide, and is adminis- those on lanreotide SR (Table 3) (50). Titration of the lanreotide tered as a deep sc injection every 4 wk. ATG dosage according to the biochemistry led to an increment Pharmacokinetic and population pharmacodynamic data for in dose in approximately 50% of the patients (51). When efficacy lanreotide ATG (49–52) show mean minimum steady-state lan- was assessed after completion of 12-month titrated lanreotide Ͻ Ͻ reotide levels to display a dose-dependent proportional increase ATG, GH (P 0.001) and IGF-I (P 0.01) levels were lower, (49, 52). Levels of lanreotide after injection of lanreotide ATG and lanreotide levels higher than observed on the fixed dose of ␮ reach similar values to lanreotide SR after three to four injec- lanreotide ATG or lanreotide SR. GH values less than 2.5 g/liter tions, and in the long-term result in slightly higher steady-state and an age-normalized IGF-I were achieved in 68 and 50% of levels (49, 52). Four injections are required to achieve 90% of the patients with titrated lanreotide ATG, compared with 49 and Ͻ Ͼ long-term steady-state level. A mean serum concentration of 44% on lanreotide SR (P 0.0001 and P 0.05, respectively). 1.13 ng/ml is required to achieve GH values less than 2.5 ␮g/liter, Data concerning the long-term follow-up of patients main- tained on lanreotide ATG for a further 2–3 yr after inclusion in however, the IC50 is highly variable between patients (49). The the initial multicenter and extension studies are reported for co- overall model is comparable to that observed with octreotide horts enrolled at two centers (57, 58) (Table 3). These studies had LAR, which shows similar pharmodynamic properties, high in- limited power however, and collectively showed lanreotide ATG terpatient variability, and incomplete GH suppression (53). to be equally effective in controlling GH levels but to result in In an intention to treat analysis of a 48-wk study of the effi- lower IGF-I levels and a greater number of patients achieving a cacy of titrated lanreotide ATG, GH (Ͻ2.5 ␮g/liter) and nor- normal IGF-I compared with lanreotide SR. malized IGF-I levels were achieved in 85 and 43%, symptoms In a multicenter study, 97 patients stabilized on lanreotide SR were controlled, and the formulation was well tolerated (54). In for a mean duration of 3.1 Ϯ 0.3 yr were changed to an equiv- 21 patients stabilized on lanreotide ATG, nine showed good alent dose of lanreotide ATG 120 mg at a variable dose frequency control, and 12 suboptimal GH and IGF-I values. Seven of the for three to five injections (59). Assessment performed one dos- nine controlled patients had the dose frequency extended from ing interval after the final dose of lanreotide ATG showed a four to six weekly while maintaining GH and IGF-I targets, re- higher proportion of patients achieving a GH less than 2.5 ␮g/ sulting in an annual cost savings of around $50,000 (55). In the liter (44 vs. 54%; P ϭ 0.052), but no change in the proportion 12 patients with suboptimal control despite lanreotide ATG achieving IGF-I levels considered as normal (55 vs. 56%). doses of 120 mg every 4 wk, an increase in frequency to every 3 The available data show noninferiority of lanreotide ATG wk, with the exception of one individual, failed to significantly compared with lanreotide SR in terms of efficacy quantified both improve disease control. This study highlights that, similar to biochemically and clinically (Table 3). The data suggest lan- previous studies using octreotide LAR (31), the dose interval can reotide ATG to have greater efficacy in the control of GH and be extended in patients in whom biochemical control is obtained IGF-I levels, however, the aforementioned studies are plagued by without loss of efficacy. In a further study, patients were given similar design faults to those previously described when com- the option of continuing to receive their injections from health paring octreotide LAR and lanreotide SR, namely: 1) lanreotide care professionals or receiving their injections at home, either by SR was administered before lanreotide ATG in all studies, and self-administration or their partner (56). Local injection tolera- biochemical improvements frequently occur with time as a result bility was good for both groups, and safety profiles were similar. of previous radiotherapy and long-term SRIF analog therapy; 2) Patients/partners administered lanreotide ATG with no detri- it is unclear whether the dose of lanreotide SR had been opti- mental effect on efficacy (56). When taken together, these two mized in patients enrolled in the studies; 3) where lanreotide studies suggest that the lanreotide ATG formulation may provide levels were available, these were higher when being treated with a subset of patients the greatly improved convenience of home lanreotide ATG and reflected the improvement in GH and IGF-I injection and at a dosing frequency of 6 wk or longer. values, suggesting that improved efficacy may be a dose effect; lnEdcio ea,Ags 08 93(8):2957–2968 2008, August Metab, Endocrinol Clin J

TABLE 3. Summary of biochemical end-points of studies comparing efficacy of lanreotide SR and lanreotide ATG

Baseline Baseline Normal IGF-I SRIF GH IGF-I Final GH Final IGF-I GH < 2.5 GH < 2.5 Mean dose analog No. (␮g/liter) (ng/ml) (mg/liter) (ng/ml) ␮g/liter (n) Normal IGF-I (n) ␮g/liter (mg/4 wk) Study design Caron et al., 2002 SR 107 646 Ϯ 27 2.8 Ϯ 0.2 323 Ϯ 16 51 48 35 81.7 Ϯ 22.6 144 pts enrolled, 107 (50) completed study. Open. On SR Ͼ3 months. SR to ATG. No WO. Equivalent ATG 107 2.9 Ϯ 0.2 317 Ϯ 15 60 51 42 81.7 Ϯ 22.6 monthly dosing. No titration of ATG. ATG ϫ3 doses Caron et al., 2004 SR 123 2.8 Ϯ 0.2 332 Ϯ 15 61 55 40 79.3 Ϯ 22.8 130 enrolled. 1 yr extension (51) study of Caron et al., 2002 (50), ATG dose ATG 123 2.4 Ϯ 0.2 287 Ϯ 12 83 62 52 93.2 Ϯ 27.6 titrated. Dose increased in 53%. LAN levels higher on ATG c/i SR Gutt et al., 2005 SR 11 1.3 (0.4–4.9) 1.2 (0.6–2.9) 3 92.7 Ϯ 21.0 Open, SR to ATG, no WO, (58) ATG titrated, 4 yr follow- ATG 11 1.3 (0.7–4.6) 0.98 (0.3–2.3) 6 109 Ϯ 20.2 up on ATG, subgroup of (50, 51) Caron et al., 2006 SR 14 33.4 Ϯ 13.5 572 Ϯ 52 2.7 Ϯ 0.7 312 Ϯ 34 8 5 5 79.3 Ϯ 14.9 2-yr extension study of (57) Caron et al., 2002 (50, ATG 14 2.7 Ϯ 0.5 260 Ϯ 26 7 8 5 98.6 Ϯ 27.4 51), subgroup analysis. ATG dose titrated Lucas and Astorga, SR 93 4.3 Ϯ 0.5 336 Ϯ 24 (F) 43 51 33 74.4 Ϯ 20.2 97 pts enrolled. On SR 2006 (59) 423 Ϯ 30 (M) ϫ3.1 Ϯ 0.1 yr. Open, SR to ATG120. No WO. ATG 93 3.8 Ϯ 0.5 314 Ϯ 23 (F) 50 52 37 74.4 Ϯ 20.2 equivalent monthly 414 Ϯ 32 (M) dosing. No titration of ATG

LAN SR 102/337 (30.3%) 107/348 (30.7%) 73/337(21.7%) jcem.endojournals.org LAN ATG 117/337 (34.7%) 117/348 (33.6%) 84/337(24.9%)

ATG, Lanreotide ATG; F, female; LAN, lanreotide; M, male; pts, patients; SR, lanreotide microparticle; SR to ATG, initial treatment with lanreotide SR followed by lanreotide ATG; WO, washout.

2963 Downloaded from https://academic.oup.com/jcem/article/93/8/2957/2598353 by guest on 24 September 2021 September 24 on guest by https://academic.oup.com/jcem/article/93/8/2957/2598353 from Downloaded 2964 Murray and Melmed SRIF Analogs J Clin Endocrinol Metab, August 2008, 93(8):2957–2968 and 4) lanreotide ATG was given after lanreotide SR in all stud- the dose was increased and in two reduced. IGF-I values after ies, and, thus, improvements may, in part, reflect improvements three further injections of lanreotide ATG were lower (P ϭ 0.03), in biochemical control as a result of radiotherapy or prolonged and a higher percentage achieved normal IGF-I levels (60 vs. medical therapy. Intuitively it can be concluded that by main- 80%; P Ͻ 0.01) (62). In the fourth of the four switch studies (63), taining higher and more constant steady-state lanreotide levels, 23 acromegalic patients stabilized on octreotide LAR for 6–18 lanreotide ATG results in improved control of excessive GH and months were switched to lanreotide ATG 120 mg six weekly for IGF-I secretion in patients with acromegaly while improving four injections after a 3-month washout period. Thereafter, the convenience for the patient and clinician. frequency of lanreotide 120 mg injection was dependent on GH and IGF-I levels for a further two to three doses. GH and IGF-I values while on octreotide LAR were not significantly different Octreotide LAR and Lanreotide ATG from those after either the fixed dose or after titration of lan-

reotide ATG (63). GH levels less than 2.5 ␮g/liter and normal Downloaded from https://academic.oup.com/jcem/article/93/8/2957/2598353 by guest on 24 September 2021 Five relatively small studies have compared the efficacy of lan- IGF-I values were achieved in 43 and 35% of patients, respec- reotide ATG (Somatuline depot) to that of octreotide LAR in tively, when on octreotide LAR, and 60 and 41% after titration patients with acromegaly (60–64) (Table 4). In the first of these of lanreotide ATG. studies, seven patients with active acromegaly receiving oct- The final study compared octreotide LAR and lanreotide reotide LAR 20–30 mg monthly for a mean of 2.8 yr were com- ATG in a randomized cross-over design in 10 patients previously menced on lanreotide ATG after a washout period (60). Patients stabilized on octreotide LAR (64). The duration of each treat- were randomized to receive lanreotide ATG 60, 90, or 120 mg, ment arm was 6 months. Individual octreotide LAR doses re- and thereafter the dose titrated to achieve a GH less than 1.9 mained unchanged from those before enrollment in the study, mg/liter (5 mU/liter) and an age-normalized IGF-I level. Twenty- whereas lanreotide ATG doses were 60, 90, or 120 mg for pa- four hour GH profiles on the two treatments were remarkably tients who were receiving octreotide LAR at 10, 20, and 30 mg, similar, with no differences noted in secretory characteristics respectively. Six patients, respectively, achieved target GH levels when examined by deconvolution analysis (60). Pulsatile (114 Ϯ of less than 0.96 ␮g/liter on both treatment arms, however, the 30 vs. 130 Ϯ 35 ␮g/liter⅐24 h) and total (209 Ϯ 64 vs. 233 Ϯ 77 absolute change in GH levels was significantly greater on oct- ␮g/liter⅐24 h) GH levels were not different between the octreotide reotide LAR (Ϫ0.65 vs. Ϫ0.58 ␮g/liter) (64). Five and six pa- and lanreotide ATG treatment arms. Six weeks after withdrawal tients achieved normal IGF-I levels while receiving octreotide of either analog, GH and IGF-I levels showed no treatment- LAR and lanreotide ATG, respectively. After the study six pa- related differences (60). tients chose to continue on octreotide LAR and four on lan- In a second study, 25 patients with active acromegaly on a reotide ATG. stable dose of octreotide LAR (20 mg, n ϭ 13; 30 mg, n ϭ 11; and All five studies comparing lanreotide ATG with octreotide are 40 mg, n ϭ 1) for at least 6 months were switched to lanreotide relatively small, though collectively show noninferiority of lan- ATG 90 mg monthly for three injections, after which the dose reotide ATG compared with octreotide LAR (Table 3). Of note was titrated to achieve a GH less than 2.5 ␮g/liter and an age- is that three of these five studies assessed the efficacy of lanreotide normalized IGF-I level (60 mg, n ϭ 3; 90 mg, n ϭ 4; and 120 mg, ATG after only three injections after either initiation of therapy n ϭ 18) (61). After 24-wk treatment with lanreotide ATG, the or dose change and, thus, before steady-state levels had been mean serum GH and IGF-I concentrations remained unchanged obtained. Secondary end-points of these studies suggest that lan- when compared with baseline values under octreotide LAR. GH reotide ATG leads to fewer technical problems with injections values less than 2.5 ␮g/liter were observed in 64% on octreotide and possibly a lower incidence of local injection site reactions, LAR and 48% with lanreotide ATG (nonsignificant), with 52% though this is not borne out in all studies (64). achieving a normal IGF-I in both treatment arms (61). There was a significant reduction in acromegalic symptom score over the duration of the study, and local side effects were observed less Discussion frequently with lanreotide ATG. Technical problems with injec- tions of lanreotide were not observed, compared with 60 of 150 Medical therapy using SRIF analogs has continued to evolve octreotide LAR injections, primarily attributable to viscosity of since the initial studies examining effects of SRIF on GH secre- the injection material (61). tion. The introduction of the long-acting SRIF analog, oct- In a similar study, 12 patients receiving octreotide LAR 20 mg reotide, in 1984 as a thrice daily parenteral therapy established for at least 4 months and who had achieved GH values of less an undeniably important role for these analogs in the manage- than 10 ␮g/liter were changed to lanreotide ATG 90 mg for four ment of acromegaly. Sustained release microparticle formula- injections, and thereafter the dose titrated to achieve a GH level tions of two SRIF analogs, lanreotide SR and octreotide LAR, less than 2 ␮g/liter (Ͻ5 mU/liter) (62). Two patients withdrew became available for use in the early to mid-1990s, greatly im- before the end of the study. GH and IGF-I after the initial three proving convenience for the patient while allowing stable steady- lanreotide 90 mg injections were not significantly different from state levels of these drugs to be maintained. Both preparations those reported while on octreotide LAR 20 mg (62). Adjustment require im injection with a dosing frequency of 28 d for oct- of the lanreotide ATG dose on the basis of GH levels was un- reotide LAR and 7–14 d for lanreotide SR. The former prepa- dertaken before administration of the fifth dose; in three patients ration has been associated with needle viscosity during admin- lnEdcio ea,Ags 08 93(8):2957–2968 2008, August Metab, Endocrinol Clin J

TABLE 4. Summary of biochemical end-points of studies comparing efficacy of octreotide LAR and lanreotide ATG

Baseline Normal IGF-I SRIF Baseline GH IGF-I Final GH Final IGF-I GH <2.5 Normal IGF-I GH <2.5 Mean dose analog No. (␮g/liter) (ng/ml) (mg/liter) (ng/ml) ␮g/liter (n) (n) ␮g/liter (mg/4 wk) Study design Alexopoulou et al., OCT 25 30.2 Ϯ 25.2a 917 Ϯ 431b 2.4 Ϯ 1.8 337 Ϯ 201 16 13 9 25.2 Ϯ 5.9 Open, OCT to LAN, no 2004 (61) LAN 25 2.9 Ϯ 2.4 332 Ϯ 193 12 13 8 108 Ϯ 21.2 WO, LAN titrated Ashwell et al., OCT 10 8.0 Ϯ 3.7c 485 Ϯ 105 3.0 Ϯ 1.7c 212 Ϯ 70 9d 66d 20 Ϯ 0.0 Open, GH Ͻ10 ␮g/liter 2004 (62) on OCT20, OCT to LAN 10 3.3 Ϯ 1.6c 154 Ϯ 61 9d 88d 93.0 Ϯ 22.1 LAN, no WO, LAN titrated van Thiel et al., OCT 7 59.5 Ϯ 32.7e 3.0 Ϯ 0.8 40 Ϯ 4f 433d 24.3 Ϯ 5.3 Open. Pts OCT 2004 (60) responsive. OCT to LAN 7 5.3 Ϯ 2.7 55 Ϯ 8f 333d 111 Ϯ 22.7 LAN. WO ϫ 10 wk. LAN titrated Andries et al., OCT 10 1.7 Ϯ 2.0 266 Ϯ 104 0.9 Ϯ 0.8 265 Ϯ 133 10 5 5 Open, randomized cross- 2008 (64) over, no WO, on optimal OCT at LAN 10 0.9 Ϯ 0.7 271 Ϯ 136 1.4 Ϯ 1.6 261 Ϯ 155 7 6 5 baseline, “equivalent” LAN dose Ronchi et al., 2007 OCT 23 15.2 Ϯ 17.4 519 Ϯ 275 4.0 Ϯ 2.5 333 Ϯ 177 10 8 4 23.9 Ϯ 6.6 Open, OCT to LAN120, 3 (63) months WO, LAN LAN 22 9.9 Ϯ 11.3 544 Ϯ 312 3.8 Ϯ 5.7 356 Ϯ 187 13 9 7 96.4 Ϯ 27.4 titrated OCT LAR 49/75 (65.3%) 35/75 (46.7%) 27/75 (36.0%) LAN ATG 44/74 (59.5%) 39/74 (52.7%) 31/74 (41.9%)

LAR LAN, Lanreotide ATG; OCT, octreotide; OCT to LAN, initial treatment with octreotide LAR followed by lanreotide ATG; pts, patients; WO, washout. a Data available on 25. b Data available on 19. c Data in mU/liter. d GH target less than 5.0 mU/liter. e Data available on six in nmol/liter. jcem.endojournals.org f Data in nmol/liter.

2965 Downloaded from https://academic.oup.com/jcem/article/93/8/2957/2598353 by guest on 24 September 2021 September 24 on guest by https://academic.oup.com/jcem/article/93/8/2957/2598353 from Downloaded 2966 Murray and Melmed SRIF Analogs J Clin Endocrinol Metab, August 2008, 93(8):2957–2968 istration, though these are infrequent in Endocrine Units using Therefore, the use of currently available formulations in clin- this preparation regularly. A recent development has been the ical practice will be determined by a pragmatic approach based introduction of a supersaturated aqueous formulation (lan- on individual preference by the patient and clinician. The use of reotide ATG) in a prefilled syringe that requires deep sc admin- these generally safe long-acting analogs at six to eight weekly istration every 28 d. dosing intervals, combined with the possibility of self/partner The relative efficacy of the three clinically available SRIF an- administration, is a potential advantage in a subset of patients. alogs has been debated. Overall, octreotide LAR has been sug- gested to exhibit greater efficacy in achieving GH and IGF-I targets compared with lanreotide SR; however, this was ob- served only in patients treated after surgery and/or radiotherapy Acknowledgments and who had not been preselected on the basis of responsiveness Address all correspondence and requests for reprints to: Dr. Shlomo to SRIF analogs. Furthermore, there was no difference in abso- Melmed, Academic Affairs, Room 2015, Cedars Sinai Medical Cen- Downloaded from https://academic.oup.com/jcem/article/93/8/2957/2598353 by guest on 24 September 2021 lute GH and IGF-I values achieved in these individuals. A critical ter, 8700 Beverly Boulevard, Los Angeles, California 90048. E-mail: review of studies directly comparing these two preparations (Ta- [email protected]. ble 2) indicates that octreotide LAR is moderately more effica- Disclosure Statement: R.D.M. receives research support from Novo cious in controlling the GH - IGF-I axis in acromegaly; however, Nordisk and Ipsen, and lecture fees from Novo Nordisk. S.M. receives research support from Novartis and Biomeasures, and lecture fees from a number of biases favoring octreotide LAR have unwittingly Tercica. been introduced to these comparative studies. Biases and limi- tations of these studies include small patient number and, there- fore, limited statistical power, failure to randomize the treatment order of the analogs being compared, incomplete individualiza- References tion and optimization of the dose of each analog, and an as- 1. Melmed S 2006 Medical progress: acromegaly. N Engl J Med 355:2558–2573 sumption that dosing should be limited to the manufacturer’s 2. Bates AS, Van’t Hoff W, Jones JM, Clayton RN 1993 An audit of outcome of recommended regimen. treatment in acromegaly. Q J Med 86:293–299 Lanreotide ATG has advantages over lanreotide SR in the 3. Colao A, Ferone D, Marzullo P, Lombardi G 2004 Systemic complications of acromegaly: epidemiology, pathogenesis, and management. Endocr Rev 25: ease of administration, reduced dosing frequency, and mainte- 102–152 nance of more stable steady-state lanreotide levels. Few data 4. Holdaway IM, Rajasoorya RC, Gamble GD 2004 Factors influencing mor- concerning this formulation were included in the metaanalysis tality in acromegaly. J Clin Endocrinol Metab 89:667–674 5. Orme SM, McNally RJ, Cartwright RA, Belchetz PE 1998 Mortality and (35), and separate evaluation of this formulation was not per- cancer incidence in acromegaly: a retrospective cohort study. United Kingdom formed. Current data suggest that lanreotide ATG, similar to Acromegaly Study Group. J Clin Endocrinol Metab 83:2730–2734 octreotide LAR, may be marginally more efficacious in control- 6. Ayuk J, Clayton RN, Holder G, Sheppard MC, Stewart PM, Bates AS 2004 and pituitary radiotherapy, but not serum -like ling GH and IGF-I levels in patients with acromegaly compared growth factor-I concentrations, predict excess mortality in patients with ac- with lanreotide SR (Table 3). The studies performed are of sim- romegaly. 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