Long-term Medical Treatment of Cushing’s Disease with Pasireotide: A Review of Current Evidence and Clinical Experience

 

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Abstract

Cushing’s disease is a rare condition of chronic hypercortisolism caused by an adrenocorticotropic hormone-secreting pituitary adenoma and associated with debilitating complications and excess mortality. Transsphenoidal adenomectomy is generally first-line treatment but is contraindicated in some patients and associated with significant post-surgical recurrence. While there are few data to support long-term use of most pharmacologic treatments, pasireotide (a multireceptor-targeted somatostatin analog) recently demonstrated sustained benefit in a 12-month, multicenter, Phase III trial and in 2 long-term extension studies. The Phase III trial (N=162) demonstrated reductions in urinary free cortisol in most patients, with durable treatment effect over 12 months. Biochemical improvement was generally paralleled by reductions in Cushing’s-related signs and symptoms and enhanced health-related quality of life. Long-term treatment was evaluated in 58 patients who entered a planned 12-month extension phase. Reductions in urinary free cortisol remained stable throughout the extension, with further improvements noted in clinical signs and symptoms. Similar results were reported in the smaller Phase II extension (N=18; median treatment duration, 9.7 months; range, 2 months–4.8 years). Case reports have recently emerged demonstrating sustained disease control for upto 7 years in some patients. Safety considerations for long-term medical treatment with pasireotide are generally similar to those for other somatostatin analogs, except for the incidence and severity of hyperglycemia. Most patients experience new or worsening hyperglycemia with pasireotide treatment. Expert recommendations for treatment of pasireotide-associated hyperglycemia have recently been published and new studies are planned to elucidate the optimal treatment approach for pasireotide-associated hyperglycemia.

• References

• 1 Broder M, Neary M, Chang E et al. Incidence of Cushing’s Disease in the United States. Endocr Rev 2013;34:MON-91. Presented at ENDO 95^th Annual Meeting, June 17, 2013, in San Francisco, CA, USA
  PubMedGoogle Scholar
• 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: 311-326
  Google Scholar
• 3 Biller BM, Grossman AB, Stewart PM et al. Treatment of adrenocorticotropin-dependent Cushing’s syndrome: a consensus statement. J Clin Endocrinol Metab 2008; 93: 2454-2462
  CrossrefPubMedGoogle Scholar
• 4 Kim JH, Shin CS, Paek SH et al. Recurrence of Cushing’s disease after primary transsphenoidal surgery in a university hospital in Korea. Endocr J 2012; 59: 881-888
  CrossrefPubMedGoogle Scholar
• 5 European Medicines Authority. European Medicines Agency recommends suspension of marketing authorisations for oral ketoconazole. 2013 Available at http://www.ema.europa.eu/docs/en_GB/document_library/Press_release/2013/07/WC500146613.pdf Accessed December 18, 2013
  PubMedGoogle Scholar
• 6 FDA Drug Safety Communications. FDA limits usage of Nizoral (ketoconazole) oral tablets due to potentially fatal liver injury and risk of drug interactions and adrenal gland problems. 2013 Available at: http://www.fda.gov/downloads/Drugs/DrugSafety/UCM362444.pdf Accessed December 18, 2013
  PubMedGoogle Scholar
• 7 Korlym™ (mifepristone) full prescribing information. Corcept Therapeutics. Menlo Park, CA. Available at http://www.korlym.com/docs/KorlymPrescribingInformation.pdf Accessed December 18, 2013
  PubMed
• 8 Fleseriu M, Biller BM, Findling JW et al. SEISMIC Study Investigators. Mifepristone, a glucocorticoid receptor antagonist, produces clinical and metabolic benefits in patients with Cushing’s syndrome. J Clin Endocrinol Metab 2009; 97: 2039-2049
  PubMedGoogle Scholar
• 9 Illouz F, Dubois-Ginouves S, Laboureau S et al. Use of cabergoline in persisting Cushing’s disease. Annales d’Endocrinologie 2006; 67: 353-356
  PubMedGoogle Scholar
• 10 Godbout A, Manavela M, Danilowicz K et al. Cabergoline monotherapy in the long-term treatment of Cushing’s disease. Eur J Endocrinol 2010; 163: 709-716
  CrossrefPubMedGoogle Scholar
• 11 Pivonello R, De Martino MC, Cappabianca P et al. Lamberts SW, Colao A. The medical treatment of Cushing’s disease: effectiveness of chronic treatment with the dopamine agonist cabergoline in patients unsuccessfully treated by surgery. J Clin Endocrinol Metab 2009; 94: 223-230
  CrossrefPubMedGoogle Scholar
• 12 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: 115-122
  CrossrefPubMedGoogle Scholar
• 13 Boscaro M, Bertherat J, Findling J et al. Extended treatment of Cushing’s disease with pasireotide: results from a 2-year, Phase II study. Pituitary 2013; Aug 14. [Epub ahead of print] DOI: 10.1007/s11102-013-0503-3.
  PubMedGoogle Scholar
• 14 Colao A, Petersenn S, Newell-Price J et al. Pasireotide B2305 Study Group . A 12-Month Phase 3 study of pasireotide in Cushing’s disease. N Engl J Med 2012; 366: 914-924
  CrossrefPubMedGoogle Scholar
• 15 Schopohl J, Bertherat J, Ludlam WH et al. on behalf of the Pasireotide B2305 Study Group. Long-term pasireotide use leads to improvements in the biochemical parameters of Cushing’s disease: 24-month results from a randomized Phase III study. Abs P1410. Presented at the joint 15th International Congress of Endocrinology and the 14^th European Congress of Endocrinology (ICE/ECE), Florence, Italy, 5–9 May 2012
  PubMedGoogle Scholar
• 16 MacKenzie Feder J, Bourdeau I, Vallette S et al. Pasireotide monotherapy in Cushing’s disease: a single-centre experience with 5-year extension of Phase III trial. Pituitary 2013; Nov 28. [Epub ahead of print] DOI: 10.1007/s11102-013-0539-4.
  PubMedGoogle Scholar
• 17 Libé R, Groussin L, Bertherat J. Pasireotide in Cushing’s Disease. N Engl J Med 2012; 366: 2134-2135
  CrossrefPubMedGoogle Scholar
• 18 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: 1846-1848
  CrossrefPubMedGoogle Scholar
• 19 van der Pas R, de Bruin C, Pereira AM et al. Cortisol diurnal rhythm and quality of life after successful medical treatment of Cushing’s disease. Pituitary 2013; 16: 536-544
  CrossrefPubMedGoogle Scholar
• 20 Signifor ® (pasireotide) full prescribing information . Novartis Pharmaceuticals Corporation. Basel; Switzerland: Available at http://www.pharma.us.novartis.com/product/pi/pdf/signifor.pdf Accessed December 18, 2013
  Google Scholar
• 21 Paserchia LA, Hewett J, Woosley RL. Effects of ketoconazole on QTc [abstr]. Clin Pharmacol Ther 1994; 55: 146
  PubMedGoogle Scholar
• 22 Bertherat J, Ludlam WH, Pivonello R et al. on behalf of the Pasireotide B2305 Study Group . Long-Term Use of Pasireotide in Cushing’s Disease: 24-Month Safety Results from a Randomized Phase III Study. Abs P1405. Presented at the joint 15^th International Congress of Endocrinology and the 14th European Congress of Endocrinology (ICE/ECE), Florence, Italy, 5–9 May 2012
  PubMedGoogle Scholar
• 23 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; Jun 16. [Epub ahead of print] DOI: 10.1097/MJT.0b013e31824c3eb4.
  PubMedGoogle Scholar
• 24 Henry RR, Mudaliar S, Hermosillo Reséndiz K et al. Mechanism and Management of Hyperglycemia Associated with Pasireotide: Results from Studies in Healthy Volunteers. Abs. P260. Presented at the 13^th European Congress of Endocrinology (ECE), Rotterdam, The Netherlands, 30 April – 4 May 2011
  PubMedGoogle Scholar
• 25 Chisholm C, Greenberg GR. Somatostatin-28 regulates GLP-1 secretion via somatostatin receptor subtype 5 in rat intestinal cultures. Am J Physiol Endocrinol Metab 2002; 283: E311-E317
  CrossrefPubMedGoogle Scholar
• 26 Hansen L, Hartmann B, Bisgaard T et al. Somatostatin restrains the secretion of glucagon-like peptide-1 and -2 from isolated perfused porcine ileum. Am J Physiol Endocrinol Metab 2000; 278: E1010-E1018
  PubMedGoogle Scholar
• 27 Schmid HA, Brueggen J. Effects of somatostatin analogs on glucose homeostasis in rats. Journal of Endocrinology 2012; 212: 49-60
  CrossrefPubMedGoogle Scholar
• 28 Colao A, De Block C, Gaztambide MS et al. Managing hyperglycemia in patients with Cushing’s disease treated with pasieotide: medical expert recommendations. Pituitary 2013; 7. Apr 7 [Epub ahead of print] DOI: 10.1007/s11102-013-0483-3.
  PubMedGoogle Scholar
• 29 Shah P, Mudaliar S.. Pioglitazone: side effect and safety profile. Expert Opin Drug Saf 2010; 9: 347-354
  CrossrefPubMedGoogle Scholar
• 30 Truong HL, Nellesen D, Ludlam WH et al. Budget impact of pasireotide for the treatment of Cushing’s disease, a rare endocrine disorder associated with considerable comorbidities. J Med Econ 2014; 17: 288-295
  CrossrefPubMedGoogle Scholar
• 31 ClinicalTrials.gov. Efficacy and Safety of Pasireotide Administered Monthly in Patients With Cushing’s Disease. NCT01374906. Available at http://www.clinicaltrials.gov/ct2/show/NCT01374906 Accessed December 18, 2013
  PubMed