Date: 2012-03-07
Type of information:
phase: 3
Announcement: results
publication in The New England Journal of Medicine (NEJM) of the article of A.Colao et al: A 12-Month Phase III Study of Pasireotide in Cushing's Disease. N Engl J Med 2012; 366:914-924. March 8, 2012.
Company: Novartis (Switzerland)
Product: Signifor® (pasireotide)
Action
mechanism: Pasireotide, an investigational multireceptor targeting somatostatin analog (SSA), binds with high affinity to four of the five somatostatin receptor subtypes (sst 1, 2, 3 and 5).
Disease: Cushing's disease
Therapeutic area: Rare diseases
Country:
Trial
details: PASPORT-CUSHINGS (PASireotide clinical trial PORTfolio - CUSHING'S disease) is a prospective randomized, double-blind, Phase III study conducted at 68 sites in 18 countries.
The study evaluated the efficacy and safety of pasireotide in 162 adult patients with persistent or recurrent Cushing's disease and UFC levels greater than 1.5 times the upper limit of normal (ULN), as well as in patients with newly diagnosed Cushing's disease who are not candidates for surgery.
Patients with primarily moderate to severe hypercortisolism were randomized to receive pasireotide sc injection in doses of 900µg (n=80) or 600µg (n=82) twice daily. The primary endpoint was the proportion of patients who achieved normalization of UFC after six months without dose up-titration relative to randomized dose. The primary endpoint was met in patients treated with 900µg sc twice daily.
Secondary endpoints included safety, proportion of patients with UFC <= ULN at months 3, 6 and 12 regardless of dose titration, proportion of patients with partial UFC control (defined as UFC > ULN and >=50% reduction from baseline); changes from baseline in plasma adrenocorticotropic hormone (ACTH), UFC, serum and salivary cortisol over time and changes from baseline in clinical signs, symptoms and health-related quality of life.
Latest
news: Novartis has announced that a study published in The New England Journal of Medicine (NEJM) found that the investigational drug Signifor® (SOM230, pasireotide), normalized cortisol levels and showed clinical benefit in patients with Cushing's disease. This study, which was first presented at the 14th Congress of the European Neuroendocrine Association in September 2010, is the first Phase III trial to demonstrate the efficacy of a medical therapy for Cushing's disease.
In the study, patients were randomized to receive pasireotide subcutaneous (sc) injection in doses of 900µg or 600µg twice daily. For the 900µg group, the study met the primary endpoint of normalizing urinary-free cortisol (UFC) levels, the key measure of biochemical control of the disease. UFC levels were normalized in 26.3% and 14.6% of patients with Cushing's disease randomized to receive pasireotide 900µg and 600µg twice daily, respectively, at six months of treatment. After 12 months of treatment, results confirmed the durability of the effect.
Study results also showed that cortisol levels decreased quickly in the majority of patients, with a median decrease of approximately 50% by month two, and remained stable in both groups through the end of the study. On average, as UFC levels were reduced, clinical manifestations of Cushing's disease improved including reduction of blood pressure, total cholesterol, weight and body mass index.
The trial, which represents the largest randomized study to evaluate a medical therapy in patients with Cushing's disease, is the basis for regulatory submissions for pasireotide under way worldwide for the treatment of this condition. In January, pasireotide received a positive CHMP opinion for the treatment of Cushing's disease, and if approved in the EU the brand name will be Signifor®.
After six months, the primary efficacy responder rate was 26.3% (95% confidence interval [CI], 16.6 to 35.9) and 14.6% (95% CI, 7.0 to 22.3), respectively, for the 900µg and 600µg groups. Based on pre-specified criteria (lower bound of 95% CI >15%), the 900µg group met the primary endpoint and the 600µg group did not meet the primary endpoint. After 12 months, the proportion of responders regardless of dose up-titration was 25.0% and 13.4%, respectively, for the 900µg and 600µg groups. The median reduction in UFC after six months was 47.9% for both groups. The median reduction in UFC after 12 months was 62.4% (900µg) and 67.6% (600µg). In patients with full or partial control of UFC levels at months 1 or 2, 71.4% remained on treatment until month 12 compared with 24.6% of those uncontrolled at months 1 and 2.
As may be expected with a treatment that lowers cortisol levels in Cushing's disease, 13 patients experienced adverse events associated with cortisol levels below the normal range. This was managed by dose reduction without loss of efficacy. There were no deaths during pasireotide treatment. Forty patients reported serious AEs (SAE); 19 were drug-related, including nine patients with a glucose related SAE (n=5 diabetes mellitus; n=4 hyperglycemia).
