Regulatory Decision Summary for Xermelo
The Regulatory Decision Summary explains Health Canada’s decision for the product seeking market authorization. The Regulatory Decision Summary includes the purpose of the submission and the reason for the decision.
Type of submission:
What was the purpose of this submission?
This New Drug Submission (NDS) was filed in order to obtain marketing authorisation for Xermelo (telotristat ethyl) as an adjunctive therapy in the treatment of carcinoid syndrome diarrhea in patients inadequately controlled on somatostatin analogue therapy. The indication granted by Health Canada was:
Xermelo (telotristat ethyl) is indicated for the treatment of refractory carcinoid syndrome diarrhea, in combination with somatostatin analogue (SSA) therapy, in patients inadequately controlled by SSA therapy alone.
Why was the decision issued?
Carcinoid syndrome (CS) is a condition seen in patients with advanced neuroendocrine tumours, which originate most often in the intestines, pancreas or lungs, generally following metastasis to the liver. The syndrome is characterized by diarrhea, cutaneous flushing, wheezing, abdominal pain, and valvular heart disease. Diarrhea is often a prominent and debilitating feature of the condition. The manifestations of CS are considered to be due to excess circulating levels of several vasoactive compounds, particularly serotonin. Xermelo (telotristat) inhibits tryptophan hydroxylase, the rate-limiting enzyme controlling serotonin production, thereby decreasing circulating plasma serotonin levels. The therapeutic activity of Xermelo in CS is attributed to this effect.
Current first-line therapy for CS symptoms consists of treatment with a somatostatin analogue (SSA), either octreotide or lanreotide. Many patients experience improvement of symptoms, but over time, symptom control deteriorates for many patients. Currently, no treatment is approved specifically for CS patients with uncontrolled symptoms despite SSA therapy. An unmet medical need therefore exists for treatments to be used as an adjunct to SSA therapy, to control intractable carcinoid symptoms, particularly diarrhea.
The Xermelo clinical development programme demonstrated that telotristat therapy results in a clinically meaningful reduction in diarrhea frequency in a substantial proportion of carcinoid syndrome patients with persistent symptoms despite optimized SSA therapy. In a single Phase 3 pivotal trial, roughly one third of patients treated with telotristat showed a reduction of at least 2 bowel movements (BM) per day or a 30% reduction of daily BM frequency, compared to placebo. Open-label treatment for up to 48 weeks provided evidence of a sustained reduction in daily BM frequency.
With respect to safety, depression, severe constipation, and hepatic enzyme, increases have been observed with telotristat treatment. The long-term safety profile of Xermelo, extending up to 48 weeks, was consistent with the safety profile observed in the 12 week double-blind study period. Constipation and hepatic enzyme elevations are listed as Important Identified Risks, while depression is considered an Important Potential Risk in the Xermelo Risk Management Plan, and will be monitored through routine pharmacovigilance post-marketing.
Although the clinical development programme for Xermelo examined the safety and efficacy of a 500 mg dose three times daily, it did not demonstrate greater efficacy than the 250 mg dose, and depression, constipation, and hepatic enzyme increases were noted at a higher frequency at this higher dose; therefore, only the 250 mg dose was approved.
Overall, the benefit-risk profile of Xermelo is considered favourable as an adjunctive treatment for intractable diarrhea related to carcinoid syndrome in patients who are inadequately controlled on somatostatin analogue therapy.
Due to the possibility of brand name confusion, and consistent with measures in place in the United States, Xermelo will be distributed to patients through a restricted distribution system.
For more information on Health Canadas decision, please view the Summary Basis of Decision.
Approved; issued a Notice of Compliance in accordance with the Food and Drug Regulations.