Regulatory Decision Summary for Somatuline Autogel

Somatuline Autogel is a long-acting synthetic somatostatin analogue intended for the treatment of patients with carcinoid syndrome. The treatment with Somatuline Autogel 120 mg is to be administrated as monthly by deep subcutaneous injection. This drug was initially approved to treat acromegaly and its related symptoms, and subsequently to slow the progression of enteropancreatic neuroendocrine tumours (NETs).

Carcinoid syndrome is a rare disease that can cause flushing, diarrhea, and shortness of breath. The goals of therapy in these patients are to treat symptoms and reduce disease burden when possible. In NET patients with distant, unresectable metastatic disease, maintenance of quality of life through symptom control is an important goal in palliation, specifically given the indolent nature of disease progression.

The effect of Somatuline Autogel has been evaluated in one pivotal phase 3, 16-week, double-blind (DB), placebo-controlled study as well as in other supportive phase 2 and phase 3 studies, which served as the basis for the previous Health Canadas approval of Somatuline Autogel.

The pivotal Study 730 enrolled 115 patients with histopathologically-confirmed neuroendocrine tumours and a history of carcinoid syndrome (flushing and/or diarrhea). Patients were randomized 1:1 to receive Somatuline Autogel 120 mg (n = 59) or placebo (n = 56) by deep subcutaneous injection every 4 weeks. This study was designed to mimic the real life situation of patients with carcinoid syndrome as much as possible by allowing them to self-administer subcutaneous octreotide ≤600µg per day as rescue medication in addition to the study treatment, as needed, to control their symptoms. The use of short-acting octreotide and the severity and frequency of diarrhea and flushing symptoms were reported daily in electronic patient diaries.

The primary efficacy outcome measure was the percentage of days in which patients received at least one injection of rescue medication for symptom control during the 16-week double-blind phase. Average daily frequencies of diarrhea and flushing events were assessed secondarily. The study duration for efficacy was 52 weeks.

The study met its primary efficacy end point. Somatuline Autogel-treated patients had a statistically significant lower percentage of days of rescue medication use compared with placebo-treated patients (33.7% vs. 48.5% of days, respectively; p = 0.0165). The beneficial effect of Somatuline Autogel in reducing rescue medication use was evident regardless of baseline characteristics, including prior somatostatin analogue use, and global region. The average daily frequencies of diarrhea and flushing events in patients treated with Somatuline Autogel were numerically lower compared to patients treated with placebo, but were not statistically significantly different by hierarchical statistical testing.

Data from the pivotal study as well as from other different pooled safety data in patients with carcinoid syndrome and in patients with NETs showed that Somatuline Autogel was overall well tolerated and its adverse drug reactions profile observed was consistent with its known pharmacological actions and its established safety profile. No new safety signals have been identified after long-term clinical use or in the post marketing experience.

A total of 10 patients died during the pivotal study and none of these deaths were reported as related to Somatuline Autogel treatment. In the double-blind phase study, two patients (3.4%) in the Somatuline Autogel arm reported serious adverse events (SAEs), one of which (deafness permanent) was judged by the investigator to be related to study treatment. Other related-SAEs were reported in other studies, including one case of hyperglycemia and a few cases of glucose tolerance impaired events. Few treatment emergent adverse events led to study withdrawal due mainly to the underline disease progression. This product has a safety profile consistent with a somatostatin-analogue, with most common adverse events being diarrhoea, abdominal pain, nausea, constipation, flatulence, and vomiting. Headache, dizziness, and muscle spasms were reported more commonly with Somatuline Autogel than with placebo. In addition to these cases and due to somatostatins known effects on the gall balder, Somatuline Autogel was associated with cholethiasis in the safety database. This class of drugs is also known to lead mechanistically to dysglycemic events (either hyper and/or hypoglycemia), as somatostatin alters both insulin and glucagon secretion. These events were observed in the clinical safety database and are labelled in the Product Monograph.

Based on the pivotal design and its efficacy results, uncertainties existed regarding whether the use of Somatuline Autogel alone without the concomitant use of rescue medication can achieve improvement of symptoms associated with carcinoid syndrome. This uncertainty is reflected in the authorized indication "Somatuline Autogel is indicated for the treatment of adult patients with carcinoid syndrome; when used, Somatuline Autogel reduces the administration frequency of short-acting somatostatin analog rescue therapy".

The benefit harm/uncertainty/profile is considered acceptable for this new indication as described in the product monograph.