PMID-22397653 – Pasireotide Phase III Cushing Disease
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):914-924.
Quick Reference
| Property | Value |
|---|---|
| PMID | 22397653 |
| DOI | 10.1056/NEJMoa1105743 |
| Year | 2012 |
| Journal | New England Journal of Medicine |
| Study Type | RCT |
| Evidence Level | I |
| Sample | 162 adults with Cushing's disease |
| Peptide(s) Studied | Pasireotide |
Key Findings
- At 6 months, urinary free cortisol (UFC) normalized in 26.3% of the 600 mcg group and 14.6% of the 900 mcg group
- Median UFC decreased by 47.9% in the 600 mcg group from baseline
- Significant improvements in clinical signs: blood pressure, weight, BMI, LDL cholesterol, and clinical features of hypercortisolism
- Tumor volume decreased by a mean of -9.1% at 12 months
- Hyperglycemia was the most significant adverse event: 73% of patients developed hyperglycemia-related AEs; new-onset diabetes occurred in some patients — this is a class effect related to SSTR5-mediated suppression of insulin secretion
- This was the largest prospective interventional trial in Cushing's disease to date
Study Design
Multicenter, randomized, double-blind, Phase III trial (B2305, NCT00434148). Patients with persistent or recurrent Cushing's disease, or de novo patients not candidates for surgery, were randomized 1:1 to subcutaneous pasireotide 600 mcg or 900 mcg twice daily for 12 months. Primary endpoint: normalization of 24-hour UFC at 6 months without dose uptitration.
Limitations
- No placebo arm (ethical considerations in Cushing's disease)
- Two active dose arms but no comparator drug
- High rate of hyperglycemia limits clinical utility in patients with impaired glucose metabolism
- Stringent primary endpoint (UFC normalization without uptitration) may underestimate clinical benefit
- Short follow-up for a chronic disease
Clinical Relevance
This pivotal NEJM trial led to FDA approval of pasireotide (Signifor) for Cushing's disease in 2012, making it the first pituitary-directed medical therapy specifically approved for this indication. The SSTR5 selectivity of pasireotide provides a mechanistic rationale for its efficacy in corticotroph adenomas that poorly respond to SSTR2-selective agents (octreotide, lanreotide). However, the significant hyperglycemia risk requires careful glucose monitoring and often concomitant antidiabetic therapy.
Related
#research #RCT #pasireotide #evidence-level-I