Drugs

, Volume 73, Issue 6, pp 563–574 | Cite as

Pasireotide: A Review of Its Use in Cushing’s Disease

Adis Drug Evaluation

Abstract

Pasireotide (Signifor®) is a new subcutaneous somatostatin analogue that acts via somatostatin receptors to inhibit the secretion of corticotropin from the pituitary adenoma in patients with Cushing’s disease. Pasireotide has a receptor binding profile that is distinct from that of other somatostatin analogues, binding with high affinity to somatostatin receptor subtype 5, which is strongly over expressed in corticotroph adenoma cells. Pasireotide is the first pituitary-directed agent to be approved for use in Cushing’s disease. In a phase III clinical trial in patients with Cushing’s disease, twice-daily pasireotide 600 or 900 μg for 6 months led to normalization of urinary free cortisol (UFC) levels in up to a quarter of all patients (primary endpoint) and significantly reduced mean UFC levels. The reduction in UFC levels is rapid (within one to two months) and sustained (up to 24 months). Most patients who do not have an early response to pasireotide do not respond at a later time point. Decreases in UFC levels achieved during pasireotide treatment are accompanied by decreases in serum and salivary cortisol levels, as well as improvements in clinical signs and symptoms, including body weight, blood pressure and health-related quality-of-life. Pasireotide has a generally similar tolerability profile to that of other somatostatin analogues, but is associated with a relatively high incidence of hyperglycaemia, requiring the addition or intensification of glucose-lowering medication in a substantial proportion of patients. Thus, pasireotide, together with on-going patient monitoring, provides a promising new option for the medical management of Cushing’s disease.

Notes

Disclosure

The preparation of this review was not supported by any external funding. During the peer review process, the manufacturer of the agent under review was offered an opportunity to comment on this article. Changes resulting from comments received were made by the author on the basis of scientific and editorial merit.

References

  1. 1.
    Biller BM, Grossman AB, Stewart PM, et al. Treatment of adrenocorticotropin-dependent Cushing’s syndrome: a consensus statement. J Clin Endocrinol Metab. 2008;93(7):2454–62.PubMedCrossRefGoogle Scholar
  2. 2.
    Feelders RA, Pulgar SJ, Kempel A, et al. The burden of Cushing’s disease: clinical and health-related quality of life aspects. Eur J Endocrinol. 2012;167(3):311–26.PubMedCrossRefGoogle Scholar
  3. 3.
    Lindholm J, Juul S, Jorgensen JO, et al. Incidence and late prognosis of Cushing’s syndrome: a population-based study. J Clin Endocrinol Metab. 2001;86(1):117–23.PubMedCrossRefGoogle Scholar
  4. 4.
    Reznik Y, Bertherat J, Borson-Chazot F, et al. Management of hyperglycaemia in Cushing’s disease: expert’s proposals on the use of pasireotide. Diabetes Metab. 2013;39(1):34–41.PubMedCrossRefGoogle Scholar
  5. 5.
    Etxabe J, Vazquez JA. Morbidity and mortality in Cushing’s disease: an epidemiological approach. Clin Endocrinol (Oxf). 1994;40(4):479–84.CrossRefGoogle Scholar
  6. 6.
    Patil CG, Prevedello DM, Lad SP, et al. Late recurrences of Cushing’s disease after initial successful transsphenoidal surgery. J Clin Endocrinol Metab. 2008;93(2):358–62.PubMedCrossRefGoogle Scholar
  7. 7.
    Arnaldi G, Boscaro M. New treatment guidelines on Cushing’s disease. F1000 Med Rep. 2009. doi: 10.3410/M1-64.
  8. 8.
    Hofland LJ, van der Hoek J, Feelders R, et al. The multi-ligand somatostatin analogue SOM230 inhibits ACTH secretion by cultured human corticotroph adenomas via somatostatin receptor type 5. Eur J Endocrinol. 2005;152(4):645–54.PubMedCrossRefGoogle Scholar
  9. 9.
    Lacroix A, Pivonello R. Medical treatment of Cushing’s disease with pasireotide. Eur Endocrinol. 2012;8(2):99–104.Google Scholar
  10. 10.
    European Medicines Agency. Signifor solution for injection: summary of product characteristics. 2012. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002052/WC500128056.pdf. Accessed 9 Jan 2013.
  11. 11.
    Novartis Pharmaceuticals Corporation. Signifor: full prescribing information. 2012. http://www.pharma.us.novartis.com/product/pi/pdf/signifor.pdf. Accessed 12 Jan 2013.
  12. 12.
    Batista DL, Zhang X, Gejman R, et al. The effects of SOM230 on cell proliferation and adrenocorticotropin secretion in human corticotroph pituitary adenomas. J Clin Endocrinol Metab. 2006;91(11):4482–8.PubMedCrossRefGoogle Scholar
  13. 13.
    Beglinger C, Hu K, Wang Y, et al. Multiple once-daily subcutaneous doses of pasireotide were well tolerated in healthy male volunteers: a randomized, double-blind, placebo-controlled, cross-over, phase I study. Endocrine. 2012;42(2):366–74.PubMedCrossRefGoogle Scholar
  14. 14.
    Golor G, Hu K, Ruffin M, et al. A first-in-man study to evaluate the safety, tolerability, and pharmacokinetics of pasireotide (SOM230), a multireceptor-targeted somatostatin analog, in healthy volunteers. Drug Des Devel Ther. 2012;6:71–9.PubMedCrossRefGoogle Scholar
  15. 15.
    Shenouda M, Maldonado M, Wang Y, et al. An open-label dose-escalation study of once-daily and twice-daily pasireotide in healthy volunteers: safety, tolerability, and effects on glucose, insulin, and glucagon levels. Am J Ther. 2012. doi: 10.1097/MJT.0b013e31824c3eb4.
  16. 16.
    Henry RR, Mudaliar S, Wetli-Hermosillo K, et al. Mechanism and management of hyperglycaemia associated with pasireotide: results from studies in healthy volunteers [abstract no. P260]. European Congress of Endocrinology; 30 Apr 4–May 2011; Rotterdam.Google Scholar
  17. 17.
    Feelders RA, de Bruin C, Pereira AM, et al. Pasireotide alone or with cabergoline and ketoconazole in Cushing’s disease. N Engl J Med. 2010;362(19):1846–8.PubMedCrossRefGoogle Scholar
  18. 18.
    van der Pas R, de Bruin C, Leebeek FWG, et al. The hypercoagulable state in Cushing’s disease is associated with increased levels of procoagulant factors and impaired fibrinolysis, but is not reversible after short-term biochemical remission induced by medical therapy. J Clin Endocrinol Metab. 2012;97(4):1303–10.PubMedCrossRefGoogle Scholar
  19. 19.
    Horsmans Y, Hu K, Ruffin M, et al. Effect of hepatic impairment on the pharmacokinetics of pasireotide (SOM230): results from a multicenter phase I study. J Clin Pharmacol. 2012;52(4):552–8.PubMedCrossRefGoogle Scholar
  20. 20.
    Boscaro M, Ludlam WH, Atkinson B, et al. Treatment of pituitary-dependent Cushing’s disease with the multireceptor ligand somatostatin analog pasireotide (SOM230): a multicenter, phase II trial. J Clin Endocrinol Metab. 2009;94(1):115–22.PubMedCrossRefGoogle Scholar
  21. 21.
    Boscaro M, Zhang Y, Sen K, et al. Long-term treatment of Cushing’s disease with pasireotide (SOM230): results from a Phase II extension study [abstract no. P640]. European Congress of Endocrinology, Prague, 24–28 Apr 2010.Google Scholar
  22. 22.
    Colao A, Petersenn S, Newell-Price J, et al. A 12-month phase 3 study of pasireotide in Cushing’s disease. N Engl J Med. 2012;366(10):914–24.PubMedCrossRefGoogle Scholar
  23. 23.
    Bertherat J, Schopohl J, Ludlam WH, et al. Long-term pasireotide use leads to significant and sustained improvements in the signs and symptoms of Cushing disease: 24-month results from a randomized phase III study [abstract]. In: 94th Annual Meeting and Expo of the Endocrine Society, Houston, 23–26 Jun 2012.Google Scholar
  24. 24.
    Lacroix A, Ludlam W, Mantero F, et al. Initial response to pasireotide treatment is predictive of 12-month response: results of a large, randomized, double-blind, phase III study in patients with Cushing disease [abstract]. In: 94th Annual Meeting and Expo of the Endocrine Society, Houston, 23–26 Jun 2012.Google Scholar
  25. 25.
    Schopohl J, Bertherat J, Ludlam W, et al. Long-term pasireotide use leads to improvements in the biochemical parameters of Cushing’s disease: 24-month results from a randomized phase III study [abstract no. P1410]. In: 15th International Congress of Endocrinology and 14th European Congress of Endocrinology, Florence, 5–9 May 2012.Google Scholar
  26. 26.
    Pivonello R, Petersenn S, Newell-Price J, et al. Pasireotide treatment in Cushing disease is associated with significant improvements in hypertension: 12-month results from a large phase III study [abstract]. In: 94th Annual Meeting and Expo of the Endocrine Society, Houston, 23–26 Jun 2012.Google Scholar
  27. 27.
    Gadelha M, Badia X, Zgliczynski W, et al. Pasireotide treatment is associated with clinically meaningful improvements in health-related quality of life in Cushing disease: results from a large, randomized, double-blind, phase III trial [abstract]. In: 94th Annual Meeting and Expo of the Endocrine Society, Houston, 23–26 Jun 2012.Google Scholar
  28. 28.
    Bertherat J, Ludlam WH, Pivonello R, et al. Pasireotide as a long-term treatment for patients with Cushing disease: 24-month safety results from a randomized phase III study [abstract]. In: 94th Annual Meeting and Expo of the Endocrine Society, Houston, 23–26 Jun 2012.Google Scholar
  29. 29.
    Fleseriu M, Petersenn S. Medical management of Cushing’s disease: what is the future? Pituitary. 2012;15(3):330–41.PubMedCrossRefGoogle Scholar
  30. 30.
    Trementino L, Cardinaletti M, Concettoni C, et al. Long-term efficacy of pasireotide in a patients with Cushing’s disease and diabetes: results in the short term are not always predictive of long-term response [abstract no. P108]. J Clin Endokrinol Stoffw. 2012;5(Special Issue 3).Google Scholar
  31. 31.
    Libe R, Groussin L, Bertherat J. Pasireotide in Cushing’s disease [letter]. N Engl J Med. 2012;366(22):2134.PubMedCrossRefGoogle Scholar
  32. 32.
    Ning G, Wang W, Maldonado M, et al. Long-term efficacy and safety of pasireotide in Cushing’s disease: a 36-month case report [abstract no. P353]. In: 15th International Congress of Endocrinology and 14th European Congress of Endocrinology, Florence, 5–9 May 2012.Google Scholar
  33. 33.
    Feelders RA, Hofland LJ. Medical treatment of Cushing’s disease. J Clin Endocrinol Metab. 2013;98(2):425–38.PubMedCrossRefGoogle Scholar
  34. 34.
    Ligueros-Saylan M, Zhang Y, Newell-Price J, et al. Evaluation of the efficacy and safety of pasireotide LAR in patients with mild-to-moderate Cushing’s disease: a randomized, double-blind, multicentre, phase III study design [abstract no. P1542.1]. In: 15th International Congress of Endocrinology and 14th European Congress of Endocrinology, Florence, 5–9 May 2012.Google Scholar

Copyright information

© Springer International Publishing Switzerland 2013

Authors and Affiliations

  1. 1.AdisAucklandNew Zealand

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