Summary Basis of Decision for Xermelo
Review decision
The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.
Product type:
Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Xermelo is located below.
Recent Activity for Xermelo
SBDs written for eligible drugs approved after September 1, 2012 will be updated to include post-authorization information. This information will be compiled in a Post-Authorization Activity Table (PAAT). The PAAT will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. PAATs will be updated regularly with post-authorization activity throughout the product's life cycle.
Post-Authorization Activity Table (PAAT) for Xermelo
Updated:
The following table describes post-authorization activity for Xermelo, a product which contains the medicinal ingredient telotristat ethyl (supplied as telotristat etiprate). For more information on the type of information found in PAATs, please refer to the Frequently Asked Questions: Summary Basis of Decision (SBD) Project: Phase II and to the list of abbreviations that are found in PAATs.
For additional information about the drug submission process, refer to the Management of Drug Submissions Guidance.
Drug Identification Number (DIN):
- DIN 02481553 - 250 mg telotristat ethyl (supplied as telotristat etiprate), tablet, oral
Post-Authorization Activity Table (PAAT)
| Activity/submission type, control number | Date submitted | Decision and date | Summary of activities |
|---|---|---|---|
| NC # 226139 | 2019-03-26 | Cancellation Letter Received2019-05-31 | Submission filed as a Level II (120 day) Notifiable Change to update the PM with new drug-drug interaction information. The sponsor cancelled the submission to refile with additional data. |
| Drug product (DIN 02481553) market notification | Not applicable | Date of first sale:2018-12-07 | The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations. |
| NDS # 208730 | 2017-11-01 | Issued NOC2018-10-12 | Notice of Compliance issued for New Drug Submission. |
Summary Basis of Decision (SBD) for Xermelo
Date SBD issued: 2019-01-25
The following information relates to the new drug submission for Xermelo.
Telotristat ethyl (supplied as telotristat etiprate)
250 mg, tablet, oral
Drug Identification Number (DIN):
- 02481553
Ipsen Biopharmaceuticals Canada Inc.
New Drug Submission Control Number: 208730
On October 12, 2018, Health Canada issued a Notice of Compliance to Ipsen Biopharmaceuticals Canada Inc. for the drug product Xermelo.
The market authorization was based on quality (chemistry and manufacturing), non-clinical (pharmacology and toxicology), and clinical (pharmacology, safety, and efficacy) information submitted. Based on Health Canada's review, the benefit-risk profile of Xermelo is favourable for the treatment of refractory carcinoid syndrome diarrhea, in combination with somatostatin analogue therapy, in patients inadequately controlled by somatostatin analogue therapy alone.
1 What was approved?
Xermelo is a first-in-class tryptophan hydroxylase inhibitor. It was authorized for the treatment of refractory carcinoid syndrome diarrhea, in combination with somatostatin analogue therapy, in patients inadequately controlled by somatostatin analogue therapy alone.
No data are available to Health Canada regarding the use of Xermelo in patients younger than 18 years of age. Consequently, an indication for pediatric use has not been authorized.
Evidence from clinical studies suggests that the use of Xermelo in the geriatric population (patients aged 65 years and over) is associated with no differences in safety or effectiveness in comparison to younger population, but greater sensitivity of some older individuals cannot be ruled out.
Xermelo is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container.
Xermelo was approved for use under the conditions stated in its Product Monograph taking into consideration the potential risks associated with the administration of this drug product.
Xermelo (250 mg, telotristat ethyl, supplied as telotristat etiprate) is presented as a tablet. In addition to the medicinal ingredient, the tablet contains croscarmellose sodium, hydroxypropylcellulose, anhydrous lactose, macrogol 3350, magnesium stearate, partially hydrolyzed polyvinyl alcohol, colloidal anhydrous silica, talc, and titanium dioxide.
Xermelo will be distributed through a restricted distribution network to specialists experienced in treating carcinoid syndrome, in order to mitigate the potential risk of a medication error due to brand name confusion between Xermelo and Xarelto (an anticoagulant drug).
For more information, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.
Additional information may be found in the Xermelo Product Monograph, approved by Health Canada and available through the Drug Product Database.
2 Why was Xermelo approved?
Health Canada considers that the benefit-risk profile of Xermelo is favourable for the treatment of refractory carcinoid syndrome diarrhea, in combination with somatostatin analogue therapy, in patients inadequately controlled by somatostatin analogue therapy alone.
Carcinoid syndrome develops in about 7-35% of patients with a neuroendocrine tumour. Neuroendocrine tumours, formerly known as carcinoid tumours, are rare tumours which arise from cells of the neuroendocrine system, primarily in the intestines, and less frequently in the pancreas, liver or other organs. These tumours are more common in individuals over 40 years of age, and reach the highest incidence in patients over the age of 65 years.
Carcinoid syndrome occurs when a well-differentiated neuroendocrine tumour secretes large amounts of vasoactive compounds, including serotonin, into the systemic circulation. 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.
It is estimated that there are 12,000 to 15,000 Canadians with neuroendocrine tumours, and more than 5,000 of them may suffer from carcinoid syndrome. Of these patients, approximately three quarters will develop carcinoid syndrome diarrhea.
Most patients with carcinoid syndrome are first treated with a somatostatin analogue (octreotide or lanreotide), which benefits many patients in terms of symptom relief. Unfortunately, tachyphylaxis (i.e., rapidly diminishing response to the drug) develops in 10-64% of patients, usually between three months and two years after initiation of somatostatin analogue treatment. When a patient's response to somatostatin analogue therapy wanes, the therapy is generally continued, while initiating additional symptomatic treatments. Optimization of somatostatin analogue treatment is usually achieved by adding doses of short-acting somatostatin analogue drugs for patients inadequately controlled on long-acting depot formulations. Other treatment options include surgical debulking of tumours, radiation, various liver-directed therapies, and chemotherapy, all aiming to reduce tumour mass.
Xermelo (telotristat ethyl) is a first-in-class tryptophan hydroxylase inhibitor. Since tryptophan hydroxylase is the rate-limiting enzyme for serotonin synthesis, its inhibition is expected to reduce the excess serotonin production generally seen in carcinoid syndrome, and thereby ameliorate the associated symptoms. Accordingly, Xermelo represents a complementary treatment to somatostatin analogue therapy.
Xermelo has been shown to be efficacious in reducing diarrhea frequency in a substantial proportion of carcinoid syndrome patients with persistent symptoms despite optimized somatostatin analogue therapy. The market authorization was primarily based on data from a single pivotal Phase III trial, Study LX-301 (TELESTAR). This was a 12-week, randomized, placebo-controlled, parallel-group, multicentre, double-blind trial. It involved 136 adult patients who had well-differentiated metastatic neuroendocrine tumours with carcinoid syndrome and were receiving somatostatin analogue therapy. There were 90 patients who received Xermelo 250 mg three times daily (TID) (number of patients [n] = 45) or telotristat ethyl 500 mg TID (n = 45), and 45 patients who received placebo. One patient randomized to telotristat ethyl 500 TID did not receive any study drug. Approximately one third of patients treated with Xermelo showed a reduction of at least 2 bowel movements per day or a 30% reduction of daily bowel movement frequency, compared to placebo. The pivotal trial also included a 36-week open-label extension during which all patients were treated with telotristat ethyl at 500 mg TID. Open-label treatment for up to 48 weeks provided evidence of a sustained reduction in daily bowel movement frequency. Supportive data were derived from another Phase III trial, Study LX-303 (TELECAST), which had a similar design to the pivotal study, and included 76 patients.
The identified potential safety issues associated with the use of Xermelo included depression, severe constipation, and hepatic enzyme increases. 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 (RMP). Their occurrence will be monitored through routine pharmacovigilance activities.
In the clinical development programme for Xermelo, the higher dose of 500 mg telotristat ethyl administered three times daily did not demonstrate greater efficacy than the 250 mg dose. Moreover, depression, constipation, and hepatic enzyme increases were noted at a higher frequency at this higher dose, compared to the 250 mg TID dose. Therefore, the sponsor requested approval only for the 250 mg dose of telotristat ethyl.
Patients who demonstrated a satisfactory efficacy response to Xermelo were shown to respond within the first months of treatment. Consequently, the Product Monograph advises reassessment of the need to continue treatment with Xermelo after 12 weeks of therapy. Discontinuation of treatment in patients who have not had a clinically relevant response to Xermelo will also limit the development of potential safety issues in these patients.
A Risk Management Plan (RMP) for Xermelo was submitted by Ipsen Biopharmaceuticals Canada Inc. to Health Canada. Following revisions, the RMP was considered to be acceptable. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will be put in place to minimize risks associated with the product.
The submitted inner and outer labels, package insert and Patient Medication Information section of the Xermelo Product Monograph meet the necessary regulatory labelling, plain language and design element requirements.
A Look-alike Sound-alike brand name assessment was performed and the proposed name Xermelo was accepted, considering that the drug will be distributed via a restricted distribution network.
Based on the non-clinical data and clinical studies, Xermelo has an acceptable safety profile for the target patient population. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Xermelo Product Monograph to address the identified safety concerns.
This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations. For more information, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.
3 What steps led to the approval of Xermelo?
Submission Milestones: Xermelo
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting: | 2015-01-20 |
| Submission filed: | 2017-11-01 |
| Screening | |
| Screening Acceptance Letter issued: | 2017-12-15 |
| Review | |
| Biopharmaceutics Evaluation complete: | 2018-07-26 |
| Review of Risk Management Plan complete: | 2018-08-24 |
| Quality Evaluation complete: | 2018-10-09 |
| Clinical Evaluation complete: | 2018-10-09 |
| Labelling Review complete, including Look-alike Sound-alike brand name assessment: | 2018-10-10 |
| Notice of Compliance issued by Director General, Therapeutic Products Directorate: | 2018-10-12 |
The Canadian regulatory decision on the quality, non-clinical and clinical review of Xermelo was based on a critical assessment of the data package submitted to Health Canada. The foreign reviews completed by the European Medicines Agency (EMA) and the United States Food and Drug Administration (FDA) were used as added references.
For additional information about the drug submission process, refer to the Management of Drug Submissions Guidance.
4 What follow-up measures will the company take?
Requirements for post-market commitments are outlined in the Food and Drugs Act and Regulations.
6 What other information is available about drugs?
Up to date information on drug products can be found at the following links:
- See MedEffect Canada for the latest advisories, warnings and recalls for marketed products.
- See the Notice of Compliance (NOC) Database for a listing of the authorization dates for all drugs that have been issued an NOC since 1994.
- See the Drug Product Database (DPD) for the most recent Product Monograph. The DPD contains product-specific information on drugs that have been approved for use in Canada.
- See the Notice of Compliance with Conditions (NOC/c)-related documents for the latest fact sheets and notices for products which were issued an NOC under the Notice of Compliance with Conditions (NOC/c) Guidance Document, if applicable. Clicking on a product name links to (as applicable) the Fact Sheet, Qualifying Notice, and Dear Health Care Professional Letter.
- See the Patent Register for patents associated with medicinal ingredients, if applicable.
- See the Register of Innovative Drugs for a list of drugs that are eligible for data protection under C.08.004.1 of the Food and Drug Regulations, if applicable.
7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical basis for decision
Clinical Pharmacology
The clinical pharmacological data support the use of Xermelo (telotristat ethyl, as telotristat etiprate) for its specified indication.
Both the prodrug (telotristat ethyl) and its active metabolite (telotristat) are inhibitors of L-tryptophan hydroxylases (TPH1 and TPH2, the rate limiting steps in serotonin biosynthesis). In vitro inhibitory potency of telotristat towards tryptophan hydroxylase is about 29 times higher than that of telotristat ethyl. Serotonin plays a critical role in regulating several major physiological processes, including secretion, motility, inflammation, and sensation of the gastrointestinal tract, and is over-secreted in patients with carcinoid syndrome. Serotonin is converted to 5-hydroxyindoleacetic acid (5-HIAA) which is excreted in the urine. Through inhibition of peripheral TPH1, Xermelo reduces the production of serotonin which can be measured by urinary 5-HIAA levels.
Pharmacokinetics
After oral administration, telotristat etiprate is rapidly hydrolyzed to telotristat ethyl and hippuric acid. Telotristat ethyl is further metabolized via carboxylesterases to its active and major metabolite telotristat prior to reaching the systemic circulation.
The pharmacokinetic properties of telotristat ethyl and its active metabolite have been characterized in healthy volunteers and patients with carcinoid syndrome.
Peak plasma concentration and exposure (the area under the concentration-time curve, AUC) of telotristat ethyl and telotristat appeared to be dose proportional following administration of a single dose of telotristat etiprate in the range of 100 mg to 1,000 mg. The apparent total volume of distribution for telotristat in patients with carcinoid syndrome was estimated at 348.7 L, suggesting tissue distribution. Both telotristat ethyl and telotristat were highly bound to plasma proteins (>99%). Telotristat ethyl and telotristat were predominantly eliminated in the feces (92.8%), with less than 0.4% being eliminated in the urine. In patients treated with telotristat ethyl (administered as telotristat etiprate) 250 mg three times daily, a slight accumulation of telotristat levels was observed with a median accumulation ratio based on AUC0-4h of 1.55, with a high inter-subject variability.
In a food-effect study, administration of a single dose of telotristat ethyl 500 mg (twice the recommended dose) with a high-fat meal resulted in higher exposure to both telotristat ethyl and telotristat compared with the fasted state. Therefore, Xermelo is recommended to be taken with food.
Special populations
Xermelo is not recommended in patients with severe renal impairment due to limited data. In addition, Xermelo is not recommended in patients with end-stage renal disease since it has not been studied in this patient population. In population pharmacokinetic analyses, creatinine clearance was found to have no significant effect on the pharmacokinetics of telotristat in patients with mild and moderate renal impairment. Hence, no dosage adjustment of Xermelo is required in these patient populations.
Xermelo is not recommended in patients with severe hepatic impairment (Child Pugh score C), since it has not been studied in this patient population. Based on tolerability, the recommended dose of Xermelo is 250 mg once daily in patients with moderate hepatic impairment (Child Pugh score B) and 250 mg twice daily in patients with mild hepatic impairment (Child Pugh score A).
Drug-Drug Interactions
A study examining the effect of short-acting octreotide (a somatostatin analogue) on the single-dose pharmacokinetics of telotristat ethyl in healthy volunteers showed a decrease of 86% and 81% in geometric mean maximum plasma concentration (Cmax) and AUC up to the last measurable concentration (AUC0-last) of telotristat ethyl, respectively. Also, the geometric mean Cmax and AUC0-last of telotristat were 79% and 68% lower, respectively. Accordingly, if treatment with short-acting octreotide is needed in combination with Xermelo, the short-acting octreotide must be administered at least 30 minutes after administration of Xermelo.
Co-administration of Xermelo with midazolam decreased the mean Cmax and AUC from time 0 extrapolated to infinity (AUC0-inf) of midazolam by 25% and 48%, respectively. Therefore, monitoring for suboptimal efficacy and, if necessary, increasing the dose of concomitant cytochrome P450 (CYP) 3A4 substrates (e.g., midazolam, everolimus, sunitinib, simvastatin, ethinyloestradiol, amlodipine, cyclosporine) are recommended in the Xermelo Product Monograph.
In vitro, telotristat ethyl treatment resulted in a concentration-dependent increase in CYP 2B6 messenger ribonucleic acid (mRNA) levels suggesting possible CYP 2B6 induction. Concomitant use of Xermelo may decrease the efficacy of drugs that are CYP 2B6 substrates (e.g., valproic acid, bupropion, sertraline) by decreasing their systemic exposure. Accordingly, monitoring for suboptimal efficacy of concomitant CYP 2B6 substrates is recommended in the Xermelo Product Monograph.
For further details, refer to the Xermelo Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Efficacy
The efficacy of Xermelo was established primarily on the basis of a single pivotal Phase III trial, Study LX-301. This was a 12-week, randomized, placebo-controlled, parallel-group, multicentre, double-blind trial. It enrolled 136 patients, including 90 patients who received either Xermelo 250 mg three times daily (TID) or telotristat ethyl 500 mg TID and 45 patients who received placebo. Patient characteristics reflected a typical adult patient population with well-established carcinoid syndrome. All patients had metastatic neuroendocrine tumours. The patients had a mean bowel movement (BM) frequency at baseline of 5.7 BM/day, despite optimized somatostatin analogue therapy and use of antidiarrheal agents. The duration of carcinoid syndrome symptoms was approximately five to six years prior to randomization. Most patients had elevated urinary levels of the serotonin metabolite 5-HIAA (u5-HIAA).
In the pivotal trial, Xermelo treatment resulted in a significant reduction from baseline in the number of BM/day averaged over the 12-week, double-blind study period, amounting to approximately 0.8 BM/day compared to placebo. The treatment differences compared to placebo were similar for both the 250 mg TID and 500 mg TID groups, and both treatment differences were statistically significantly different from placebo. Efficacy was seen early, and increased over time.
A supportive trial, Study LX-303, had a similar design to the pivotal trial and included 76 carcinoid syndrome patients but with less severe gastrointestinal symptoms, i.e., most patients (92.1%) had fewer than 4 BM/day, with a mean of 2.5 BM/day in the Xermelo 250 mg group. In Study LX-303, change in BM frequency was a secondary endpoint, while the primary endpoint was change in u5-HIAA levels. A significant decrease of approximately 0.5 BM/day from baseline was observed in both Xermelo dosage groups, compared to placebo. Thus, both Studies LX-301 and LX-303 demonstrated efficacy of Xermelo versus placebo in improving refractory carcinoid syndrome diarrhea.
A responder analysis was also conducted. Responders displayed a minimally clinically important treatment effect, defined as a reduction of ≥30% in BM/day for at least 50% of the study duration. In Study LX-301, the proportion of responders that met this criterion was 44.4% and 42.2% for the 250 mg TID and 500 mg TID groups, respectively, compared to 20.0% for placebo, with both differences reaching statistical significance as compared to placebo. In Study LX-303, the proportion of responders was 40.0% in both Xermelo treatment groups, compared to 0% in the placebo group, which was again significantly different from placebo for both dosage groups.
In Studies LX-301 and LX-303, which together enrolled 211 patients, the 140 Xermelo-treated patients displayed substantial reductions from baseline in mean urinary and plasma 5-HIAA, which were sustained over the 12-week double-blind treatment period.
Results of the open-label extension phases of Studies LX-301 and LX-303 support the durability of the effect of Xermelo on reductions in BM frequency, as well as 5-HIAA levels, for up to 48 weeks. It should be noted, however, that all patients in the open-label extension phases received telotristat ethyl 500 mg TID, higher than the approved 250 mg TID dose.
Overall, in Studies LX-301 and LX-303, both doses of telotristat ethyl demonstrated similar efficacy, with no subgroup of patients displaying greater benefit from the 500 mg dose compared to the 250 mg dose. In light of these findings and considering the safety concerns discussed in the Clinical Safety section, Health Canada granted market authorization for the Xermelo 250 mg TID dose.
Indication
The New Drug Submission for Xermelo was filed by the sponsor with the following indication:
- Xermelo (telotristat ethyl) is indicated 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 tumours.
To ensure safe and effective use of the product, Health Canada approved the following indication:
- Xermelo (telotristat ethyl) is indicated for the treatment of refractory carcinoid syndrome diarrhea, in combination with somatostatin analogue therapy, in patients inadequately controlled by somatostatin analogue therapy alone.
For more information, refer to the Xermelo Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Safety
The safety of Xermelo was evaluated in 239 patients with carcinoid syndrome, including a placebo-controlled safety dataset which comprised 211 patients enrolled in the 12-week Studies LX-301 and LX-303 (described in the Clinical Efficacy section). Of the 211 patients, 70 patients each received telotristat ethyl 250 mg TID and 500 mg TID. All patients who completed the two trials were able to continue in an open-label extension phase of the trials, in which all patients received telotristat ethyl 500 mg TID for up to 36 additional weeks. All but nine of the patients who originally received placebo participated in the open-label extension phase of the trials.
In the placebo-controlled trials, the most common adverse events considered drug-related in the Xermelo-treated patients were nausea and abdominal pain, particularly at the higher 500 mg TID dose. The incidences of nausea in the Xermelo 250 mg TID and the placebo groups were similar (12.9% and 12.7%, respectively), but nausea occurred in 22.9% of patients receiving telotristat ethyl 500 mg TID. Abdominal pain was reported in 24.3%, 25.7%, and 21.1% of patients in the Xermelo 250 mg TID, telotristat ethyl 500 mg TID, and placebo groups, respectively. Adverse events of constipation were reported in 5.7%, 7.1%, and 4.2% of patients in the Xermelo 250 mg TID, telotristat ethyl 500 mg TID, and placebo groups, respectively.
Due to the antiserotonergic effect of Xermelo, depression was predefined as an adverse event of special interest. Adverse events of depression were reported in 2.9%, 11.4 %, and 4.2% of patients in the Xermelo 250 mg TID, telotristat ethyl 500 mg TID, and placebo groups, respectively.
In light of the above, the risks of constipation and depression are appropriately addressed in the Warnings and Precautions section of the Xermelo Product Monograph. In addition, the Xermelo Risk Management Plan (RMP) lists constipation and fecaloma as important identified risks, and depression as an important potential risk associated with Xermelo treatment. Their occurrence will be monitored by routine pharmacovigilance activities.
Adverse events of elevations of serum alanine aminotransferase were reported in the placebo-controlled safety dataset in 2.9% of patients treated with Xermelo 250 mg TID, in 4.3% of patients treated with telotristat ethyl 500 mg TID, and in none of the placebo-treated patients. Adverse events of elevations of aspartate aminotransferase were reported in 1.4%, 2.9%, and 0% of patients in the Xermelo 250 mg TID, telotristat ethyl 500 mg TID, and placebo groups, respectively. Adverse events of gamma-glutamyl transferase elevations occurred in 7.1%, 7.1%, and in 0% of patients in the same groups, respectively. Alkaline phosphatase increases were only seen in 4.3% of patients of the telotristat ethyl 500 mg TID group, and an adverse event of elevated total bilirubin was reported in one patient receiving Xermelo 250 mg TID. No cases meeting Hy's Law criteria were reported by the sponsor.
Appropriate text has been included in the Warnings and Precautions section of the Xermelo Product Monograph describing elevations in hepatic transaminases associated with Xermelo treatment. Increased hepatic enzymes are listed as an important identified risk in the Xermelo RMP, and will be monitored through routine pharmacovigilance activities.
The safety profile of Xermelo in the long-term study period (up to 48 weeks) was comparable to that observed during the 12-week double-blind period of the studies.
Appropriate warnings and precautions are in place in the approved Xermelo Product Monograph to address the identified safety concerns.
For more information, refer to the Xermelo Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.2 Non-Clinical Basis for Decision
The non-clinical studies support the use of Xermelo (telotristat ethyl, as telotristat etiprate) for its specified indication.
The toxicity profile of telotristat etiprate was evaluated in mice, rats, rabbits and dogs. Telotristat etiprate is the hippurate salt form of telotristat ethyl, the free base form of the ethyl ester prodrug. There were no toxicologically significant findings associated with administration of telotristat etiprate that were considered a cause for concern to humans. The sponsor evaluated systemic exposure to telotristat ethyl and its active metabolite, telotristat. When compared with human exposure to the active metabolite, the calculated margin of exposure (animal-human) for each study was acceptable.
In a 26-week repeat-dose toxicity study in rats, telotristat etiprate was administered at 50, 200 and 500 mg/kg/day once daily. At 200 and 500 mg/kg/day, degeneration/necrosis in the non-glandular and/or glandular portions of the stomach and/or increased protein droplets in the glandular portions were observed. The relevance of the gastrointestinal findings to humans is not known. The no-observed-adverse-effect level (NOAEL) was considered to be 50 mg/kg/day, which is approximately 0.4 times the human exposure at the maximum recommended human dose (MRHD) of 750 mg/day for the active metabolite telotristat.
In a 39-week repeat-dose toxicity study in dogs, telotristat etiprate was administered at 75, 150 and 300 mg/kg/day once daily. Clinical signs were limited to an increase in the frequency of liquid feces at all doses. This was not considered an adverse finding. The NOAEL was considered to be 300 mg/kg/day, which is approximately 20 times the human exposure at the MRHD of 750 mg/day for the active metabolite telotristat.
Telotristat etiprate did not exhibit genotoxic potential in in vitro or in vivo genotoxicity tests. In addition, it did not exhibit carcinogenic potential in a 26-week carcinogenicity study conducted in transgenic (Tg.rasH2) mice. At the time of this submission, the sponsor had not evaluated the carcinogenic potential of telotristat etiprate in a two-year rat carcinogenicity study. The results of this study will be submitted at a later date, once the study has been completed. This approach was considered acceptable considering that telotristat did not exhibit genotoxic potential or carcinogenic potential in mice.
The reproductive and developmental toxicity profile of telotristat etiprate was evaluated in rats and rabbits. Treatment with telotristat etiprate was not associated with reproductive toxicity or teratogenicity. Developmental toxicity was observed in rats at 500 mg/kg/day (i.e., increased incidence of pup mortality from postnatal day 0 to postnatal day 4) and rabbits at 250 mg/kg/day (i.e., increased incidence of post-implantation loss in the presence of maternal toxicity) and 500 mg/kg/day (i.e., decreased fetal body weight in the presence of maternal toxicity).
The results of the non-clinical studies as well as the potential risks to humans have been included in the Xermelo Product Monograph. In view of the intended use of Xermelo, there are no pharmacological or toxicological issues within this submission which preclude authorization of the product.
For more information, refer to the Xermelo Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.3 Quality Basis for Decision
The Chemistry and Manufacturing information submitted for Xermelo has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes. Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review. Based on the stability data submitted, the drug product should be stored at room temperature (15ºC to 30ºC).
Proposed limits of drug-related impurities are considered adequately qualified, i.e., within International Council for Harmonisation limits and/or qualified from toxicological studies.
All sites involved in production are compliant with Good Manufacturing Practices.
All non-medicinal ingredients (described earlier) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations.
The excipient anhydrous lactose is of animal origin. Satisfactory information has been provided to establish that this excipient does not pose a risk of contamination with transmissible spongiform encephalopathy agents.