Ipsen (Euronext: IPN; ADR: IPSEY) today announced that the Committee for Medicinal Products for Human Use (CHMP), the scientific committee of the European Medicines Agency (EMA), has adopted a positive opinion recommending the approval of Xermelo^® (telotristat ethyl) 250 mg three times a day (tid) for the treatment of carcinoid syndrome diarrhea in combination with somatostatin analogue (SSA) therapy in adults inadequately controlled by SSA therapy. The CHMP positive opinion will now be reviewed by the European Commission (EC), which has the authority to approve medicines for use in the 28 countries of the European Union, as well as Norway, Liechtenstein and Iceland.

David Meek, Chief Executive Officer of Ipsen, said: “The positive CHMP opinion for Xermelo^® is an important milestone towards providing innovative solutions along every step of the treatment pathway for neuroendocrine tumors. Xermelo^® is a novel treatment option and is the first oral tryptophan hydroxylase inhibitor, studied in combination with a somatostatin analog to demonstrate significant relief to patients and can contribute to an improved quality of life. We are very pleased to move closer to providing a new treatment option for European patients suffering from this debilitating condition.”

 “The medical community is very pleased to have Xermelo^® as a new therapeutic option for patients with carcinoid syndrome”, said Professor Juan Valle, University of Manchester and The Christie in Manchester, UK. He added “The positive safety and efficacy data of telotristat ethyl has meant that it has already been integrated in the majority of international guidelines including ENETS guidelines reflecting the high level of unmet need in this condition”.

 The detailed recommendations for the use of this product will be described in the Summary of Product Characteristics (SmPC), to be made available once the medication receives marketing authorization from the European Commission.

 

About the TELESTAR Phase 3 Pivotal Trial

The efficacy and safety of telotristat ethyl 250 mg taken tid were established in a 12-week double-blind, placebo-controlled, randomised, multicentre phase 3 trial. The study included a 36-week open-label extension period during which all patients were treated with a higher dose of telotristat ethyl. A total of 135 patients were recruited in 12 countries (AU, BE, CA, FR, DE, IL, IT, NL, ES, SE, UK, USA). The mean age was 64 years (range 37 to 88 years) and 52% were male. All patients had well-differentiated metastatic neuroendocrine tumours with documented history of carcinoid syndrome, and were treated with stable-dose SSAs for ≥ 3 months before enrolment. Patients had an average of four or more bowel movements (BM) per day: at baseline, mean daily BM frequency averaged over the baseline period were 5.2 and 6.1 counts/day in the placebo and telotristat ethyl 250 mg groups, respectively. The study included a 12-week double-blind treatment (DBT) period, in which patients initially received placebo (n=45) or telotristat ethyl 250 mg (n=45) or a higher dose (telotristat ethyl 500 mg; n=45) three times daily. During the study, patients were allowed to use rescue medication (short-acting SSA therapy) and anti-diarrheals for symptomatic relief but were required to be on stable-dose of long-acting SSA therapy for the duration of the DBT period.

The primary endpoint was the mean change from baseline in daily BM frequency averaged over the 12-week double blind period. Estimated difference in BM frequency per day versus placebo averaged over 12 weeks was -0.81 for telotristat ethyl 250mg (p<0.001).

A substantially greater proportion of patients on telotristat ethyl 250 mg tid achieved a durable response, defined as at least a 30 percent reduction in daily bowel movements over at least half the days of the 12-week DBT period: 44 percent on telotristat ethyl, as compared to 20 percent on placebo (p<0.040). When the full effect of telotristat ethyl is observed (during the last 6 weeks of the DBT period) the proportion of responders with at least 30% BM reduction was 51% (23/45) in the 250 mg group versus 22% (10/45) in the placebo group (post-hoc analysis).

Telotristat ethyl significantly reduced the percent change from baseline in urinary 5-hydroxyindole acetic acid (u-5HIAA) versus placebo at week 12 (p< 0.001).

 About the TELECAST Phase 3 Trial

The Phase 3 TELECAST study was designed similarly to TELESTAR study as a companion to this pivotal Phase 3 study to provide additional efficacy and safety information in patients with carcinoid syndrome.

A total of 76 patients were evaluated for efficacy. The mean age was 63 years (range 35 to 84 years) and 55% were male. All patients had a well-differentiated metastatic neuroendocrine tumour with carcinoid syndrome. Most patients (92.1%) had fewer than 4 BM per day and all except 9 were treated by SSA therapy.

The primary endpoints were the percent change from Baseline in u5-HIAA at Week 12 and incidence of treatment emergent adverse events (TEAEs). The mean u5-HIAA excretion at baseline was 69.1 mg/24hours in the telotristat ethyl 250 mg tid group (n=17) and 84.8 mg/24hours in the placebo group (n=22). The percent change from baseline in u5-HIAA excretion at week 12 was +97.7% in the placebo group versus -33.2% in the telotristat ethyl 250 mg tid group.

Notably, 40% of patients in the telotristat ethyl 250 mg tid treatment arm achieved a ≥30% reduction in BM frequency for at least 50% of the days in the double-blind treatment period, while there were no responders in the placebo arm (p=0.001).  

General safety information about Xermelo^®

In clinical trials, over 230 patients with carcinoid syndrome were treated with Xermelo^®. The placebo-controlled safety analyses were focused on the integrated data from the 12-week placebo-controlled double-blind periods from the two phase 3 randomized clinical trials. For this safety analysis, 71 patients received placebo and 70 patients received Xermelo^® 250 mg three times daily. The most commonly reported adverse reactions in patients treated with telotristat ethyl were abdominal pain (26%), gamma-glutamyl transferase increased (11%) and fatigue (10%). They were generally of mild or moderate intensity. The most frequently reported adverse reaction leading to discontinuation of telotristat ethyl was abdominal pain in 7.1% of patients (5/70).

About carcinoid syndrome (CS)

Well-differentiated neuroendocrine tumor (NET) is a relatively rare tumor type that arises from cells of the neuroendocrine system. Carcinoid syndrome (CS) occurs when well-differentiated NETs secrete large amounts of serotonin and other vasoactive products into the systemic circulation. Classically, symptoms associated with CS include cutaneous flushing, diarrhea, wheezing, abdominal pain, and in the long-term, valvular heart disease.

Somatostatin analogues (SSA) are the cornerstone of therapy for the relief of CS and tumor control. SSA inhibit the release of serotonin by NETs and have become first-line therapy for CS.

Due to the severe morbidity of CS and the lack of established treatment options, the population of patients with CS needing further control in addition to their SSA therapy is one with a high unmet medical need.

About Xermelo^® (telotristat ethyl)

Xermelo^® is a novel, orally administered, inhibitor of the enzyme tryptophan hydroxylase (TPH). Through inhibition of TPH, the rate-limiting step in the synthesis of serotonin, Xermelo^® was designed to reduce the production of serotonin within neuroendocrine tumors.

On 22 October 2014, Ipsen and Lexicon announced that they had entered into an exclusive licensing agreement for Ipsen to commercialize Xermelo^® (telotristat ethyl) in all territories excluding the United States and Japan, where Lexicon retains the rights.  On 28 February 2017, Lexicon received U.S. Food and Drug Administration (FDA) approval for Xermelo^® as a first and only orally administered therapy for the treatment of carcinoid syndrome diarrhea in combination with somatostatin analog (SSA) therapy in adults inadequately controlled by SSA therapy.