Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Also known as Pasireotide (SOM230), Signifor, SOM230
Pasireotide · 14 trials · 13 indications
The primary objective of this study was to compare the percentage of patients achieving biochemical control (defined as mean GH levels \<2.5 µg/L and normalization of sex- and age- adjusted IGF-1) at 24 weeks with pasireotide LAR 40 mg and pasireotide LAR 60 mg separately versus continued treatment with octreotide LAR 30 mg or lanreotide autogel (ATG) 120 mg. The primary efficacy variable is the proportion of patients with a reduction of mean GH levels to \< 2.5 µg/L and normalization of sex- and age-adjusted IGF-1 at 24 weeks.
Percentage of patients who received clinical benefit in symptom (diarrhea and/or flushing) improvement as: Diarrhea (D)+Flushing (F): Patients with a daily mean number (#) of at least four bowel movements and a total of five or more flushing episodes. Clinical Benefit Response Criteria (CBRC): \<4 daily mean bowel movements AND at least 20% reduction from Baseline in the daily mean # of bowel movements AND any reduction in the total # of flushing episodes compared with Baseline. (D) Patients with a daily mean # of at least four bowel movements and a total # of \<5 flushing episodes. (CBRC) \<4 daily mean bowel movements AND at least a 20% reduction from Baseline in the daily mean # of bowel movements. (F) Patients with a total # of at least 14 flushing episodes and a daily mean # of \<4 bowel movements (CBRC) At least a 30% reduction from Baseline in the total # of flushing episodes.
Percentage of participants with a reduction of mean GH levels to \<2.5μg/L (based on a 5-point 2-hour profile) and normalization of sex- and age-adjusted IGF-1. Post surgery = patients with prior surgery but no previous medical treatment for acromegaly De novo = patients with de novo disease who refused pituitary surgery or for whom pituitary surgery was contraindicated.
A responder in the primary efficacy analysis was a patient with a mUFC≤ULN at Month 6 and whose dose was not increased prior to Month 6.
Response rate is defined as percentage of patients with no glucose values \< 60 mg/dL at 90,120, 150 and 180 min during the Oral Glucose Tolerance Test (OGTT) at the end of s.c. dose escalation phase
A participant was a responder to a dose level if the mean GH level after dosing (t30, t60, t90, and t120) was below/equal to 2.5 microgram/litre (μg/L), and if the mean of IGF-1 of the two pre-dose values (t-30, t-1) was within normal limits for age-sex matched controls. If three or more of t30, t60, t90, or t120 were missing, mean GH was considered missing. If either t-30 or t-1 was missing, mean IGF-1 was considered missing. Pasireotide incident dose classes were defined by total daily doses ranges (\<1200 μg/d, 1200 to \<1500 μg/d, ≥ 1500 μg/d).
A participant was considered a responder if the mean UFC from the two 24-hour urine samples collected at Month 6 was within normal limits. The normal range for UFC is 55 to 276 nmol/day.
24-hour urine samples were collected to obtain mean UFC measurements. A negative mean change from baseline indicates improvement.
Complete Symptom Control: an average of ≤ 3 bowel movements per day for at least 15 consecutive days, with no more than 3 episodes on any given day, and no episodes of flushing over the time interval being studied. Partial Symptom Control: an average of \< 4 bowel movements per day for at least 15 consecutive days, with no more than 6 episodes per given day, and an average of fewer than 2 daily flushing episodes over the same given time interval. Treatment failure: Failure to obtain partial or complete treatment success over a consecutive 15-day period at a constant dose level.
The primary outcome is the number of hypoglycemic events occurring.
DLT is defined as an adverse event or abnormal laboratory value assessed as unrelated to disease progression, intercurrent illness, or concomitant medications as defined per study prototol. These will be evaluated according to the CTCAE v4.03.
Progression is defined as a PSA-increase of at least 25% and an absolute increase of at least 2 ng/ml from a nadir value, confirmed by a second value four weeks later.
Description: Cmax, AUCinf, AUClast, CL/F, CLR, glucose, insulin, glucagon
in patients with acromegaly and in patients with carcinoid disease
| Arm | Type | Description |
|---|---|---|
| Pasireotide LAR 40 mg | EXPERIMENTAL | Supplied in blinded fashion as 20 and 40 mg powder in vials and 2 mL vehicle in ampoule (for reconstitution) |
| Pasireotide LAR 60 mg | EXPERIMENTAL | Supplied in blinded fashion as 20 and 40 mg powder in vials and 2 mL vehicle in ampoule (for reconstitution) |
| Control arm (octreotide or lanreotide) | ACTIVE_COMPARATOR | If a patient is randomized to the open label arm the investigator will either: * be instructed to contact a Novartis delegate to initiate shipment of either octreotide LAR 30 mg or lanreotide ATG 120 mg from a Novartis or designee depot to the site, or * continue to dispense either octreotide LAR 30 mg or lanreotide ATG 120 mg available at the institution to the patient if permitted by local regulations. |
| Pasireotide LAR | ACTIVE_COMPARATOR | Patients assigned to pasireotide LAR will receive a 60 mg dose of pasireotide LAR i.m. depot injection once every 28 days (+/- 3 days) for 6 months at visits 2, 4, 5, 6, 7 and 8. A dose reduction to 40 mg is permitted if tolerability issues arise. In addition, after 24 hours of the first LAR injections the patients were permitted to use pasireotide s.c. formulation for breakthrough symptoms as needed. |
| Octreotide LAR | ACTIVE_COMPARATOR | Patients assigned to octreotide LAR will receive a 40mg dose of octreotide LAR i.m. depot injection once every 28 days (+/- 3 days) for 6 months at visits 2, 4, 5, 6, 7 and 8. A dose reduction to 30 mg is permitted if tolerability issues arise. Patients requiring a dose reduction are to return to the higher dose once the tolerability issue is resolved, if required for efficacy In addition, after 24 hours of the first LAR injections the patients were permitted to use octreotide s.c. formulation for breakthrough symptoms as needed. |
| Pasireotide 600 ug | EXPERIMENTAL | At randomization, participants received 600 ug subcutaneously (sc) twice daily (bid). Participants continued at this dose until month 6 if their month 3 mean urinary free cortisol (mUFC) was \<= 2 x the upper limit of normal (ULN) and the mUFC was below or equal to their baseline mUFC. Participants not meeting the mUFC criteria at month 3 were unblinded and required to increase their dose to 900ug bid on an open label basis. Participants had the option to continue in the extension phase as long as they did not meet any discontinuation criteria or until pasireotide was available commercially in their country. |
| Pasireotide 900 ug | EXPERIMENTAL | At randomization, participants received 900 ug subcutaneously (sc) twice daily (bid). Participants continued at this dose until month 6 if their month 3 mean urinary free cortisol (mUFC) was \<= 2 x the upper limit of normal (ULN) and the mUFC was below or equal to their baseline mUFC. Participants not meeting the mUFC criteria at month 3 were unblinded and required to increase their dose to 1200 ug bid on an open label basis. Participants had the option to continue in the extension phase as long as they did not meet any discontinuation criteria or until pasireotide was available commercially in their country. |
| SOM230 | EXPERIMENTAL | Subjects with dumping syndrome treated with pasireotide |
| Pasireotide s.c. Overall | EXPERIMENTAL | Participants received pasireotide as a daily subcutaneous (s.c) injection, every 12 hours at 9:00 AM and 9:00 PM at the dose at which the biochemical control was achieved (either 200, 400, or 600 microgram (μg)) for as long as the participant benefited from the treatment, and there were no safety or tolerability concerns (median duration of 22.7 months). |
| Pasireotide 600 μg BID SC or Ramp up Dose 900 μg BID SC | EXPERIMENTAL | Participants received pasireotide 600 micrograms (μg) twice daily (BID) subcutaneously (SC) to achieve or maintain urinary free cortisol (UFC) normalization. If UFC levels were increased at any time, participants received 900 μg BID SC, until no safety or tolerability concerns were observed as per investigators assessment. If the participant was unable to tolerate the 900 μg BID, dosing of 600 μg three times a day was given. |
| Sandostatin s.c. (Octreotide) | EXPERIMENTAL | - |
| Pasireotide (SOM230) | EXPERIMENTAL | - |
| Pasireotide | EXPERIMENTAL | - |
| SOM230 LAR | EXPERIMENTAL | - |
| Name | Type | Description |
|---|---|---|
| Pasireotide | DRUG | * Double-blind pasireotide LAR 40 mg i.m. injection once every 28 ± 2 days for 24 weeks or * Double-blind pasireotide LAR 60 mg i.m. injection once every 28 ± 2 days for 24 weeks |
| octreotide LAR 30mg | DRUG | In an open-label, active control arm, continue on the same treatment with octreotide LAR 30 mg every 28 ± 2 days as received for at least 6 months prior to randomization |
| lanreotide ATG 120mg | DRUG | In an open-label, active control arm, continue on the same treatment with lanreotide ATG 120 mg every 28 ± 2 days as received for at least 6 months prior to randomization |
| Octreotide | DRUG | Octreotide LAR 40mg i.m. depot injection - Patients may also receive octreotide 100 µg s.c. 3 times a day for symptom control as needed |
| SOM230 | DRUG | Pasireotide (SOM230) sc injection was provided as solution for injection in individual 1-point-cut 1 mL ampule, containing nominally 200 μg of pasireotide (as free base). Doses: 50, 100, 150 and 200 μg. Pasireotide im LAR depot injection was provided as micro particles powder in vials containing nominally 10, 20, 40 \& 60 mg of pasireotide (as free base) \& solvent for suspension for injection in ampules for the reconstitution of the LAR micro particles. Doses: 10, 20, 30, 40 or 60 mg |
| Pasireotide (SOM230), Octreotide (Sandostatin) | DRUG | - |
| Pasireotide (SOM230) | DRUG | Open label. Patients received starting dose of 300 µg of study drug subcutaneously (s.c.) twice (total of 600 µg ) daily for three days, which could be increased in 150 µg increments up to 900 µg twice daily (total 1800 µg daily) if control of symptoms was not achieved. Prior sponsor agreement was required for a higher dose. A dose of 2400 µg/day was the maximum allowed. Dose reductions of 300 µg/day were allowed at any time if unacceptable toxicity occurred. |
Inclusion Criteria: 1. Patients with written informed consent prior to any study related activity 2. Patients who had inadequately controlled acromegaly as defined by a mean GH concentration of a 5-point profile over a 2-hour period \> 2.5 µg/L and sex- and age-adjusted IGF-1 \> 1.3 x upper limit o...
Pasireotide is used to treat endocrine and neuroendocrine conditions including acromegaly, carcinoid tumor, Cushing disease, hepatic cirrhosis, hyperinsulinemic hypoglycemia, and symptomatic refractory resistant carcinoid disease. It is a small molecule somatostatin analog developed by Novartis AG and studied across these indications in controlled clinical trials.
Pasireotide targets somatostatin receptors SSTR2, SSTR3, SSTR1, and SSTR5, acting as an agonist at these receptors. This multi-receptor binding profile distinguishes it from agents that bind a narrower set of somatostatin receptor subtypes.
Pasireotide is developed by Novartis AG, which trades under the ticker NVS. Novartis is the sponsor of the clinical development program for pasireotide across its endocrine and neuroendocrine indications.
Pasireotide has been studied in Phase 3 clinical development, with Phase 3 trials completed in acromegaly and metastatic carcinoid disease. It is an investigational agent in the studies described here, and the program also includes completed Phase 1 pharmacokinetic and treatment plan studies.
Four completed pasireotide trials are referenced: NCT01137682 in inadequately controlled acromegaly, NCT00690430 in metastatic carcinoid disease, NCT00698464 evaluating pharmacokinetics in subjects with varying hepatic function, and NCT03103009, a treatment plan for hyperinsulinemic hypoglycemia after gastrointestinal tract surgery.
Pasireotide and octreotide are distinct drugs, though both are somatostatin analogs used in similar endocrine settings. Pasireotide is also known as SOM230. Two pasireotide Phase 3 trials, NCT01137682 and NCT00690430, used octreotide long acting release as a comparator arm.