Review Article | Published:

New therapeutic agents for acromegaly

Nature Reviews Endocrinology volume 12, pages 9098 (2016) | Download Citation

Abstract

The currently available somatostatin receptor ligands (SRLs) and growth hormone (GH) antagonists are used to control levels of GH and insulin-like growth factor 1 (IGF-1) in patients with acromegaly. However, these therapies are limited by wide variations in efficacy, associated adverse effects and the need for frequent injections. A phase III trial of oral octreotide capsules demonstrated that this treatment can safely sustain suppressed levels of GH and IGF-1 and reduce the severity of symptoms in patients with acromegaly previously controlled by injectable SRL therapy, with the added benefit of no injection-site reactions. Phase I and phase II trials of the pan-selective SRL DG3173, the liquid crystal octreotide depot CAM2029 and an antisense oligonucleotide directed against the GH receptor have shown that these agents can be used to achieve biochemical suppression in acromegaly and have favourable safety profiles. This Review outlines the need for new therapeutic agents for patients with acromegaly, reviews clinical trial data of investigational agents and considers how these therapies might best be integrated into clinical practice.

Key points

  • Available medical therapies for acromegaly are limited by moderate and variable efficacy, the need for life-long monthly intramuscular and/or deep subcutaneous depot, or thrice-daily subcutaneous injections, as well as adverse effects

  • DG3173, an injectable somatostatin receptor ligand (SRL) in development, selectively suppresses secretion of growth hormone and seems to have negligible inhibitory effects on insulin secretion, which suggests it has a favourable hyperglycaemic adverse effect profile

  • The investigational agent CAM2029 slowly releases octreotide from a liquid crystal matrix and is administered subcutaneously via thin, prefilled syringes, which facilitates ease of use and delivery

  • Oral octreotide capsules (which are not yet approved) maintain biochemical control and improve symptoms in most patients who respond to injectable SRL therapy; they have a safety profile similar to that of injectable octreotide (except for injection-site reactions)

  • ATL1103, an antisense oligonucleotide in development, reduces serum levels of insulin-like growth factor 1 by blocking synthesis of growth hormone receptor, but might require frequent injections to maintain efficacy

  • Further investigation into new formulations of currently approved molecules, as well as those in clinical development, should optimize outcomes of medical therapy in patients with acromegaly

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    The relative roles of growth hormone and IGF-1 in controlling insulin sensitivity. J. Clin. Invest. 113, 25–27 (2004).

  2. 2.

    & The changing face of acromegaly — advances in diagnosis and treatment. Nat. Rev. Endocrinol. 8, 605–611 (2012).

  3. 3.

    Medical progress: acromegaly. N. Engl. J. Med. 355, 2558–2573 (2006).

  4. 4.

    , , & Systemic complications of acromegaly: epidemiology, pathogenesis, and management. Endocr. Rev. 25, 102–152 (2004).

  5. 5.

    , , & Pituitary tumor registry: a novel clinical resource. J. Clin. Endocrinol. Metab. 85, 168–174 (2000).

  6. 6.

    & Diagnosis of acromegaly: state of the art. Expert Opin. Med. Diagn. 7, 443–453 (2013).

  7. 7.

    et al. Mortality in patients with pituitary disease. Endocr. Rev. 31, 301–342 (2010).

  8. 8.

    et al. A paradigm shift in the monitoring of patients with acromegaly: last available growth hormone may overestimate risk. J. Clin. Endocrinol. Metab. 99, 478–485 (2014).

  9. 9.

    et al. Growth hormone and pituitary radiotherapy, but not serum insulin-like growth factor-I concentrations, predict excess mortality in patients with acromegaly. J. Clin. Endocrinol. Metab. 89, 1613–1617 (2004).

  10. 10.

    , & Factors influencing mortality in acromegaly. J. Clin. Endocrinol. Metab. 89, 667–674 (2004).

  11. 11.

    et al. Endoscopic transsphenoidal surgery for acromegaly: remission using modern criteria, complications, and predictors of outcome. J. Clin. Endocrinol. Metab. 96, 2732–2740 (2011).

  12. 12.

    et al. Expert consensus document: a consensus on the medical treatment of acromegaly. Nat. Rev. Endocrinol. 10, 243–248 (2014).

  13. 13.

    et al. Acromegaly: an Endocrine Society Clinical Practice Guideline. J. Clin. Endocrinol. Metab. 99, 3933–3951 (2014).

  14. 14.

    , , & Comparative effectiveness review of treatment options for pituitary microadenomas in acromegaly. J. Neurosurg. 117, 522–538 (2012).

  15. 15.

    , & Medical therapy in acromegaly. Nat. Rev. Endocrinol. 7, 291–300 (2011).

  16. 16.

    , , , & Acromegaly clinical trial methodology impact on reported biochemical efficacy rates of somatostatin receptor ligand treatments: a meta-analysis. J. Clin. Endocrinol. Metab. 99, 1825–1833 (2014).

  17. 17.

    et al. Tumor shrinkage with lanreotide autogel 120 mg as primary therapy in acromegaly: results of a prospective multicenter clinical trial. J. Clin. Endocrinol. Metab. 99, 1282–1290 (2014).

  18. 18.

    et al. Meta-analysis on the effects of octreotide on tumor mass in acromegaly. PLoS ONE 7, e36411 (2012).

  19. 19.

    , , & Octreotide. N. Engl. J. Med. 334, 246–254 (1996).

  20. 20.

    et al. Twelve months of treatment with octreotide-LAR reduces joint thickness in acromegaly. Eur. J. Endocrinol. 148, 31–38 (2003).

  21. 21.

    Somatostatin analogs in acromegaly. J. Clin. Endocrinol. Metab. 87, 3013–3018 (2002).

  22. 22.

    , , , & Clinical, quality of life, and economic value of acromegaly disease control. Pituitary 14, 284–294 (2011).

  23. 23.

    , , & Octreotide for acromegaly treatment: a reappraisal. Expert Opin. Pharmacother. 14, 2433–2447 (2013).

  24. 24.

    & Pharmacological treatment of acromegaly: its place in the overall therapeutic approach. J. Neurooncol. 117, 415–420 (2014).

  25. 25.

    , , & Long-term safety and efficacy of depot long-acting somatostatin analogs for the treatment of acromegaly. J. Clin. Endocrinol. Metab. 87, 4142–4146 (2002).

  26. 26.

    , & A meta-analysis of the effect of lowering serum levels of GH and IGF-I on mortality in acromegaly. Eur. J. Endocrinol. 159, 89–95 (2008).

  27. 27.

    et al. Successful mortality reduction and control of comorbidities in patients with acromegaly followed at a highly specialized multidisciplinary clinic. J. Clin. Endocrinol. Metab. 99, 4438–4446 (2014).

  28. 28.

    Pituitary gland: mortality in acromegaly reduced with multimodal therapy. Nat. Rev. Endocrinol. 10, 708–710 (2014).

  29. 29.

    et al. Pasireotide versus octreotide in acromegaly: a head-to-head superiority study. J. Clin. Endocrinol. Metab. 99, 791–799 (2014).

  30. 30.

    et al. Pasireotide versus continued treatment with octreotide or lanreotide in patients with inadequately controlled acromegaly (PAOLA): a randomised, Phase 3 trial. Lancet Diabetes Endocrinol. 2, 875–884 (2014).

  31. 31.

    et al. Hyperglycemia associated with pasireotide: results from a mechanistic study in healthy volunteers. J. Clin. Endocrinol. Metab. 98, 3446–3453 (2013).

  32. 32.

    The role of pasireotide in the treatment of acromegaly. Lancet Diabetes Endocrinol. 2, 855–856 (2014).

  33. 33.

    et al. Novel long-acting somatostatin analog with endocrine selectivity: potent suppression of growth hormone but not of insulin. Endocrinology 142, 477–486 (2001).

  34. 34.

    , , & Randomized study demonstrating that octreotide fluid crystal provides sustained octreotide bioavailability and similar IGF1 suppression to octreotide LAR (sandostatin LAR) in healthy volunteers. [abstract OR17-6], Presented at the Endocrine Society's 96th Annual Meeting and Exposition (2014).

  35. 35.

    et al. DG3173 (somatoprim), a unique somatostatin receptor subtypes 2-, 4- and 5-selective analogue, effectively reduces GH secretion in human GH-secreting pituitary adenomas even in octreotide non-responsive tumours. Eur. J. Endocrinol. 166, 223–234 (2012).

  36. 36.

    US National Library of Medicine. The effect of subcutaneous infusions of 3 doses of DG3173 on growth hormone levels in untreated acromegalics. ClinicalTrials.gov , (2015).

  37. 37.

    et al. Oral octreotide absorption in human subjects: comparable pharmacokinetics to parenteral octreotide and effective growth hormone suppression. J. Clin. Endocrinol. Metab. 97, 2362–2369 (2012).

  38. 38.

    et al. A novel suspension formulation enhances intestinal absorption of macromolecules via transient and reversible transport mechanisms. Pharm. Res. 31, 2010–2021 (2014).

  39. 39.

    et al. Safety and efficacy of oral octreotide in acromegaly: results of a multicenter Phase III trial. J. Clin. Endocrinol. Metab. 100, 1699–1708 (2015).

  40. 40.

    , , , & Determinants of oral octreotide capsules efficacy in acromegaly. [abstract OR 09-3], Presented at the 17th International Congress of Endocrinology and The Endocrine Society's 97th Annual Meeting and Exposition (2015).

  41. 41.

    et al. Treatment of acromegaly with the growth hormone-receptor antagonist pegvisomant. N. Engl. J. Med. 342, 1171–1177 (2000).

  42. 42.

    et al. Long-term safety of pegvisomant in patients with acromegaly: comprehensive review of 1288 subjects in ACROSTUDY. J. Clin. Endocrinol. Metab. 97, 1589–1597 (2012).

  43. 43.

    et al. Long-term treatment with pegvisomant as monotherapy in patients with acromegaly: experience from acrostudy. Endocr. Pract. 21, 1–32 (2014).

  44. 44.

    & Antisense oligonucleotides: basic concepts and mechanisms. Mol. Cancer Ther. 1, 347–355 (2002).

  45. 45.

    et al. A GH receptor antisense oligonucleotide inhibits hepatic GH receptor expression, IGF-I production and body weight gain in normal mice. J. Endocrinol. 189, 147–154 (2006).

  46. 46.

    et al. A Phase 2 study of antisense oligonucleotide therapy directed at the GH receptor demonstrates lowering of serum IGF-I in patients with acromegaly. [abstract OR09-1], Presented at the Endocrine Society's 97th Annual Meeting and Exposition (2015).

  47. 47.

    Acromegaly pathogenesis and treatment. J. Clin. Invest. 119, 3189–3202 (2009).

  48. 48.

    & Acromegaly. Orphanet J. Rare Dis. 3, 17 (2008).

  49. 49.

    & Pathophysiology of the neuroregulation of growth hormone secretion in experimental animals and the human. Endocr. Rev. 19, 717–797 (1998).

  50. 50.

    et al. Growth hormone-releasing hormone as an agonist of the ghrelin receptor GHS-R1a. Proc. Natl Acad. Sci. USA 105, 20452–20457 (2008).

  51. 51.

    et al. Central and peripheral actions of somatostatin on the growth hormone–IGF-I axis. J. Clin. Invest. 114, 349–356 (2004).

  52. 52.

    , , & Pituitary-independent effect of octreotide on IGF-I generation. Eur. J. Endocrinol. 160, 543–548 (2009).

  53. 53.

    , , , & Differential effects of octreotide and pasireotide on somatostatin receptor internalization and trafficking in vitro. J. Clin. Endocrinol. Metab. 94, 654–661 (2009).

  54. 54.

    & Genetic basis of endocrine disease: pituitary tumor pathogenesis. J. Clin. Endocrinol. Metab. 82, 1675–1681 (1997).

  55. 55.

    Treatment of acromegaly in the era of personalized and predictive medicine. Clin. Endocrinol. (Oxf.) 83, 3–14 (2015).

  56. 56.

    & A critical analysis of clinically available somatostatin analog formulations for therapy of acromegaly. J. Clin. Endocrinol. Metab. 93, 2957–2968 (2008).

  57. 57.

    et al. A structural and functional acromegaly classification. J. Clin. Endocrinol. Metab. 100, 122–131 (2015).

  58. 58.

    et al. Quantitative analysis of somatostatin receptor subtypes (1–5) gene expression levels in somatotropinomas and correlation to in vivo hormonal and tumor volume responses to treatment with octreotide LAR. Eur. J. Endocrinol. 158, 295–303 (2008).

  59. 59.

    et al. Partial surgical removal of growth hormone-secreting pituitary tumors enhances the response to somatostatin analogs in acromegaly. J. Clin. Endocrinol. Metab. 91, 85–92 (2006).

  60. 60.

    , , , & The implication of somatotroph adenoma phenotype to somatostatin analog responsiveness in acromegaly. J. Clin. Endocrinol. Metab. 90, 6290–6295 (2005).

  61. 61.

    , , , & Growth hormone granulation pattern and somatostatin receptor subtype 2A correlate with postoperative somatostatin receptor ligand response in acromegaly: a large single center experience. Pituitary 16, 490–498 (2013).

  62. 62.

    et al. Magnetic resonance imaging as a predictor of response to somatostatin analogs in acromegaly after surgical failure. J. Clin. Endocrinol. Metab. 95, 4973–4978 (2010).

  63. 63.

    , , , & Acromegaly: the disease, its impact on patients, and managing the burden of long-term treatment. Int. J. Gen. Med. 6, 31–38 (2013).

  64. 64.

    et al. Efficacy and tolerability of lanreotide Autogel therapy in acromegalic patients previously treated with octreotide LAR. Eur. J. Endocrinol. 151, 317–324 (2004).

  65. 65.

    , , , & Lanreotide extended-release aqueous-gel formulation, injected by patient, partner or healthcare provider in patients with acromegaly in the United States: 1-year data from the SODA registry. Pituitary 17, 13–21 (2014).

  66. 66.

    & Lipoatrophy induced by subcutaneous administration of octreotide in the treatment of acromegaly. Exp. Clin. Endocrinol. Diabetes 113, 340–343 (2005).

  67. 67.

    & Recognizing the evidence and changing practice on injection sites. Br. J. Nurs. 19, 1170–1174 (2010).

  68. 68.

    , , & PTR-3173 (somatoprim), a novel somatostatin analog with affinity for somatostatin receptors 2, 4 and 5 is a potent inhibitor of human GH secretion. J. Endocrinol. Invest. 27, 721–727 (2004).

  69. 69.

    Aspireo reports data in further Phase 1b study: somatoprim demonstrates superior side effect profile over octreotide. Aspireo Pharmaceuticals , (2014).

  70. 70.

    et al. Sandostatin LAR®: pharmacokinetics, pharmacodynamics, efficacy, and tolerability in acromegalic patients. Metabolism 44, 18–26 (1995).

  71. 71.

    , , & Lyotropic liquid crystalline phases formed from glycerate surfactants as sustained release drug delivery systems. Int. J. Pharm. 309, 218–226 (2006).

  72. 72.

    et al. Sustained-release delivery of octreotide from biodegradable polymeric microspheres. AAPS PharmSciTech 12, 1293–1301 (2011).

  73. 73.

    & Emerging drugs for acromegaly. Expert Opin. Emerg. Drugs 19, 79–97 (2014).

  74. 74.

    US National Library of Medicine. Phase II study of subcutaneous injection depot of octreotide in patients with acromegaly and neuroendocrine tumours (NETs). ClinicalTrials.gov , (2015).

  75. 75.

    et al. Intestinal absorption of the octapeptide SMS 201-995 visualized by fluorescence derivatization. Gastroenterology 100, 1544–1552 (1991).

  76. 76.

    , , , & Enteral absorption of octreotide. Br. J. Pharmacol. 105, 783–786 (1992).

  77. 77.

    & Molecular-weight-dependent pharmacokinetics of fluorescein-labeled dextrans in rats. J. Pharm. Sci. 81, 908–912 (1992).

  78. 78.

    & Impenetrable barriers or entry portals? The role of cell–cell adhesion during infection. J. Cell Biol. 195, 349–358 (2011).

  79. 79.

    , , & Intestinal epithelial responses to enteric pathogens: effects on the tight junction barrier, ion transport, and inflammation. Gut 52, 439–451 (2003).

  80. 80.

    , , , & Intestinal epithelial barrier function in liver cirrhosis: an extensive review of the literature. Liver Int. 33, 1457–1469 (2013).

  81. 81.

    Intestinal mucosal barrier function in health and disease. Nat. Rev. Immunol. 9, 799–809 (2009).

  82. 82.

    et al. Comparison of octreotide acetate LAR and lanreotide SR in patients with acromegaly. Clin. Endocrinol. (Oxf.) 53, 577–586 (2000).

  83. 83.

    Clinical efficacy and safety results for dose escalation of somatostatin receptor ligands in patients with acromegaly: a literature review. Pituitary 14, 184–193 (2011).

  84. 84.

    et al. Patient reported outcomes survey in acromegaly patients treated with parenteral somatostatin analogues. [abstract THR-484], Presented at the Endocrine Society's 97th Annual Meeting and Exposition (2015).

  85. 85.

    et al. Lipodystrophy in patients with acromegaly receiving pegvisomant. J. Clin. Endocrinol. Metab. 93, 3515–3518 (2008).

  86. 86.

    et al. Long-term efficacy and safety of combined treatment of somatostatin analogs and pegvisomant in acromegaly. J. Clin. Endocrinol. Metab. 92, 4598–4601 (2007).

  87. 87.

    et al. Long-term efficacy and safety of pegvisomant in combination with long-acting somatostatin analogs in acromegaly. J. Clin. Endocrinol. Metab. 99, 3644–3652 (2014).

  88. 88.

    , , , & A randomized, controlled, multicentre trial comparing pegvisomant alone with combination therapy of pegvisomant and long-acting octreotide in patients with acromegaly. Clin. Endocrinol. (Oxf.) 71, 549–557 (2009).

  89. 89.

    ATL1103 successfully progresses towards Phase II clinical trial. Antisense.com , (2011).

Download references

Acknowledgements

The author is grateful to S. Berman for skilled assistance in manuscript preparation.

Author information

Affiliations

  1. Pituitary Center, Department of Medicine, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Room 2015, Los Angeles, California 90048, USA.

    • Shlomo Melmed

Authors

  1. Search for Shlomo Melmed in:

Competing interests

S.M. serves as a scientific consultant for Chiasma and Isis Pharmaceuticals, as an educational consultant for Novartis and has received research grants from Ipsen and Pfizer.

Corresponding author

Correspondence to Shlomo Melmed.

About this article

Publication history

Published

DOI

https://doi.org/10.1038/nrendo.2015.196

Further reading