Products

Date: 2017-09-19

Type of information: Granting of a Market Authorisation in the EU

Product name: Xermelo® (telotristat etiprate - LX1032)

Compound: telotristat etiprate - (S)-ethyl2-amino-3-(4-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoate

Therapeutic area: Cancer - Oncology - Rare diseases

Action mechanism:

• enzyme inhibitor. Telotristat etiprate is an oral, small-molecule inhibitor of tryptophan hydroxylase (TPH) that reduces peripheral serotonin production without affecting brain serotonin levels.
• In October 2014, Ipsen and Lexicon announced that they had entered into an exclusive licensing agreement  for Ipsen to commercialize telotristat etiprate, excluding the US and Japan, with a focus on the symptomatic treatment of carcinoid syndrome inadequately controlled with SSAs. Lexicon retains sole rights to commercialize telotristat etiprate in the United States and Japan.
• Telotristat etiprate has received Fast Track and Orphan Drug designation from the FDA.

Company: Ipsen (France) Lexicon Pharmaceuticals (USA - TX)

Disease:

• carcinoid syndrome caused by neuroendocrine tumors
• carcinoid syndrome diarrhoea in combination with somatostatin analogue (SSA) therapy in adults inadequately controlled by SSA therapy

Latest news:

• • On September 19, 2017,  Ipsen announced that the European Commission has approved Xermelo® (telotristat ethyl) 250 mg three times a day for the treatment of carcinoid syndrome diarrhea in combination with somatostatin analogue (SSA) therapy in adults inadequately controlled by SSA therapy. This approval allows for the marketing of Xermelo® (telotristat ethyl) in the above indication in all 28 member states of the European Union, Norway and Iceland.
• • On July 20, 2017, the Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion, recommending the granting of a marketing authorisation for Xermelo® for the treatment of carcinoid syndrome diarrhoea in combination with a somatostatin analogue. The drug will be available as 250-mg film-coated tablets. The benefits with Xermelo® are its ability to decrease the number of bowel movements per day in patients whose carcinoid syndrome diarrhoea cannot be managed with somatostatin analogues alone. The most common side effects are abdominal pain, fatigue and increased gamma-glutamyl transferase (a liver enzyme).
• This positive opinion is based on the results of two randomized Phase 3 trials, TELESTAR and TELECAST. The efficacy and safety of telotristat ethyl 250 mg taken three times a day were established in the TELESTAR study. This 12-week double-blind, placebo-controlled, randomised, multicentre phase 3 trial also 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 a 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).
• • On February 28, 2017, the FDA approved Xermelo® (telotristat ethyl) tablets in combination with somatostatin analog (SSA) therapy for the treatment of adults with carcinoid syndrome diarrhea that SSA therapy alone has inadequately controlled. Xermelo®, in a regimen with SSA therapy, is approved in tablet form to be taken orally three times daily with food. Xermelo® inhibits the production of serotonin by carcinoid tumors and reduces the frequency of carcinoid syndrome diarrhea.
• The safety and efficacy of Xermelo were established in a 12-week, double-blind, placebo-controlled trial in 90 adult participants with well-differentiated metastatic neuroendocrine tumors and carcinoid syndrome diarrhea. These patients were having between four to 12 daily bowel movements despite the use of SSA at a stable dose for at least three months. Participants remained on their SSA treatment, and were randomized to add placebo or treatment with Xermelo® three times daily. Those receiving Xermelo® added on to their SSA treatment experienced a greater reduction in average bowel movement frequency than those on SSA and placebo. Specifically, 33 percent of participants randomized to add Xermelo® on to SSA experienced an average reduction of two bowel movements per day compared to 4 percent of patients randomized to add placebo on to SSA.
• The most common side effects of Xermelo® include nausea, headache, increased levels of the liver enzyme gamma-glutamyl transferase, depression, accumulation of fluid causing swelling (peripheral edema), flatulence, decreased appetite and fever. Xermelo® may cause constipation, and the risk of developing constipation may be increased in patients whose bowel movement frequency is less than four bowel movements per day. Patients treated with a higher than recommended dosage of Xermelo® developed severe constipation in clinical trials. One patient required hospitalization and two other patients developed complications of either intestinal perforation or intestinal obstruction. Patients should be monitored for severe constipation.
• • On July 18, 2016, Ipsen announced that the European Medicines Agency (EMA) has accepted the submission of filing for telotristat etiprate as an adjunct to somatostatin analogue therapy for the long-term treatment of carcinoid syndrome to improve symptom control in adult patients with metastatic neuroendocrine tumors. In addition to this European submission, Ipsen will pursue a worldwide regulatory plan for marketing authorization submissions in the territories where it operates. As such the Marketing Authorization Application was submitted to SwissMedic (the Swiss Regulatory Agency) on July 5th 2016.  Lexicon filed a New Drug Application in the United States on 30 March 2016 and was granted priority review on 31 May 2016 by the FDA.
• Regulatory submission is supported by the results of TELESTAR, a pivotal, placebo-controlled phase 3 clinical trial and TELECAST, the phase 3 companion study to TELESTAR. Results from TELESTAR demonstrated a statistically significant (p<0.001) reduction from baseline in the average number of daily bowel movements over the first 12-week study period in both treatment arms (250 mg tid and 500 mg tid) compared with placebo, thereby meeting the study’s primary endpoint. A statistically significant (p<0.001) reduction in urinary 5-hydroxyindoleacetic acid (the main metabolite of serotonin) was also observed at week 12 compared with placebo in both treatment arms.

Patents:

Submission of marketing authorization application USA : 2016-03-30

Submission of marketing authorization application UE: 2016-07-18

Withdrawal of marketing authorization application USA:

Withdrawal of marketing authorization application UE:

US authorization: 2017-02-28

UE authorization: 2017-09-19

Favourable opinion UE: 2017-07-20

Favourable opinion USA:

Orphan status USA: 2012-03-09

Orphan status UE: 2009-10-08

Pediatric exclusivit _USA:

Pediatric exclusivity UE:

OTC status:

Other news:

Is general: Yes