Regulatory Decision Summary for Signifor LAR

The effect of Signifor LAR in Cushings disease patients was mainly evaluated in one pivotal phase 3 randomized, double-blind, multicenter clinical trial (Study G2304), with other supportive data from phase 1-3 studies using the short-acting pasireotide subcutaneous (s.c) and the long-acting LAR intramuscular (i.m) formulations (which provided the basis for Health Canadas previous approval of Signifor and Signifor LAR for the treatments of Cushings disease and acromegaly, respectively). The pivotal Study G2304 was conducted to evaluate the efficacy and safety of two dose regimens of Signifor LAR over a twelve month treatment period in Cushings disease patients with persistent or recurrent disease, or de novo patients who were not considered candidates for pituitary surgery.

The study enrolled 150 patients with a screening mean urinary free cortisol (mUFC) level of between 1.5 and 5 times the upper limit of normal (≥1.5 and ≤5x ULN), who were randomized in a 1:1 ratio to receive a starting dose of either 10 mg (N = 74) or 30 mg (N = 76) intramuscular Signifor LAR once every 28 days (q28d).Randomization was stratified by values of screening mUFC (1.5 to <2x ULN versus 2 to 5x ULN, respectively). After four months of treatment, patients who had a mUFC ≤1.5x ULN continued on the blinded starting dose to which they were randomized. Patients with a mUFC >1.5x ULN had their doses increased in a blinded manner from 10 mg to 30 mg, or from 30 mg to 40 mg, provided there were no tolerability concerns. Additional dose increases (up to a maximum of 40 mg) were allowed at months 7 and 9 (by one dose level if the mUFC was >1x ULN). Dose reduction by one dose level for tolerability was allowed in a blinded fashion during the first seven months, with a minimum dose level of 5 mg. After the first seven months, blinded down-titration of more than one dose level was allowed at any month.

The primary efficacy endpoint was the proportion of patients in each dose arm who were mUFC responders (24-hour mUFC ≤ULN) after seven months of treatment, regardless of dose up-titration status at month 4. The key secondary endpoint was the proportion of patients in each dose arm who were mUFC responders after seven months of treatment and who did not up-titrate the dose prior to month 7.

The study met its primary and key secondary efficacy objectives for both dose groups. Patients were considered responders if they remained on treatment until at least month 7 and achieved a month 7 mUFC ≤1x ULN, regardless of up-titration at month 4. At month 7, mUFC response was achieved in 39.2% (95% CI: 28.0, 51.2) and 40.8% (95% CI: 29.7, 52.7) of patients randomized to pasireotide LAR at starting doses of 10 mg and 30 mg once q28d, respectively, regardless of up titration at month 4. The response rates were higher in the lower mUFC stratum (mUFC ≥1.5x ULN to ≤2x ULN) than in the higher mUFC stratum (mUFC >2x ULN to ≤5x ULN). At month 4, 31 out of 74 (41.9%) patients and 28 out of 76 (36.8%) patients were up-titrated in the pasireotide LAR 10 mg and 30 mg arms, respectively. When all patients who up-titrated prior to month 7 were counted as non-responders, month 7 mUFC response was observed in 25.7% (95% CI: 16.2, 37.2) and 31.6% (95% CI: 21.4, 43.3) of patients randomized to pasireotide LAR at starting doses of 10 mg and 30 mg once q28d, respectively.

Safety data from Study G2304 demonstrated that Signifor LAR was overall well-tolerated, and its observed adverse drug reaction (ADR) profile was largely consistent with its known pharmacological actions and its established safety profile in acromegaly patients or the established safety profile of the Signifor s.c. formulation in Cushings disease patients. No new safety signals were identified.

Two on-treatment deaths were reported (both in the 30 mg dose group), but none were suspected to be related to the study drug. Serious ADRs were reported in 12 (8%) patients; the most common (incidence >1% in all patients) were cholelithiasis (3 [2%]) and blood cortisol decreased (2 [1.3%]). Adverse events leading to study discontinuation were reported in 19 (12.7%) patients; the most common (incidence >1%) were diabetes mellitus, hyperglycemia, cholelithiasis, and increased alanine aminotransferase. The most commonly reported ADRs were hyperglycemia, diarrhea, cholelithiasis, and diabetes mellitus. The frequency and severity of ADRs tended to be higher in the group starting at the higher dose of 30 mg, but this was not consistent for all ADRs. The most common ADRs requiring dose adjustment (down-titration) or temporary interruption were reported in 38 (25%) patients; the most common (incidence ≥2%) were adrenal insufficiency, diabetes mellitus, hyperglycemia, Addison disease, and decreased blood cortisol.

The observed beneficial effect of Signifor LAR on the hypercortisolism in Cushings disease translated into clinically relevant improvements in the signs and symptoms of the disease. Taking into account the severity of the disease, these effects outweigh the unfavorable effects of the drug including hyperglycemia, cholelithiasis, and hepatic adverse effects, which are considered to be manageable.

All safety concerns and uncertainties were adequately addressed in the Canadian product monograph and the benefit-harm-uncertainty profile is considered acceptable.