Regulatory Decision Summary for Ibsrela

Review decision

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.


Product type:

Drug

Medicinal ingredient(s):

tenapanor

Therapeutic area:

Drugs For Constipation

Type of submission:

New Drug Submission (New Active Substance)

Control number:

224850
What was the purpose of this submission?

 

This New Drug Submission (NDS) - New Active Substance (NAS) was filed by Knight Therapeutics Inc. to obtain market authorization for Ibsrela (tenapanor) for the treatment of irritable bowel syndrome with constipation (IBS-C) in adults.

 

Why was the decision issued?

 

Ibsrela (tenapanor) is a new class of drug with a novel mechanism of action. Tenapanor acts locally in the bowel by inhibiting the sodium-hydrogen exchanger 3, blocking sodium absorption in the gastrointestinal tract, and resulting in looser stools. Ibsrela is dose twice daily, immediately prior to the first meal of the day and immediately before dinner.

Knight Therapeutics Inc. has provided adequate efficacy and safety data to support the use of Ibsrela in the treatment of adults with irritable bowel syndrome with constipation (IBS-C). The primary efficacy data supporting this indication are derived from two pivotal studies in patients with IBS-C. The safety of Ibsrela is supported by data from these two pivotal studies and other studies in patients with IBS-C, as well as from studies in healthy subjects and studies conducted for a different indication in patients with chronic kidney disease.

The two pivotal studies were phase 3 randomised, double-blinded, placebo-controlled studies in adult patients diagnosed with IBS-C based on ROME III criteria. In these studies, patients were randomized 1:1 to receive Ibsrela 50 mg twice daily or placebo. The primary efficacy endpoint was the 6/12 week overall combined responder rate. In order to be meet the 6/12 overall combined responder endpoint, a patient was required to achieve at least a 30% reduction from baseline in mean abdominal pain score and an increase of at least one complete spontaneous bowel movement from baseline, both in the same week, for at least 6 of the first 12 weeks of treatment. Both studies met this primary endpoint, demonstrating a modest treatment benefit for Ibsrela. In the first study, 27% of patients in the Ibsrela group were overall combined responders compared to 19% in the placebo group; the difference [95% confidence interval (CI)] in response rates of 8% (2%, 15%) was statistically significant (p = 0.02). In the second study, 37% of patients in the Ibsrela group were overall combined responders compared to 24% in the placebo group; the difference in response rates of 13% (6%, 20%) was statistically significant (p<0.001).

In the safety analysis, the most commonly reported adverse event was diarrhea. In the pivotal studies, severe diarrhea was reported in 2.5% of Ibsrela-treated patients. In addition, diarrhea was reported at a higher frequency in patients with mild to moderate renal impairment than in patients with normal renal function in these studies. In the study in which patients with chronic kidney disease were treated with Ibsrela for an unrelated indication, drug-related adverse events of hyperkalemia requiring hospitalization and medical treatment were reported. However, no signal of hyperkalemia was found in the IBS-C pivotal studies in patients with mild to moderate renal impairment.

Safety and efficacy of Ibsrela have not been established in patients with renal or hepatic impairment, or in patients under 18 years of age. Patients with serum creatinine creatinine above 176 µmol/L, which includes all patients with severe renal impairment, and patients with hepatic impairment were excluded from the pivotal studies. Pharmacokinetic studies in subjects with renal impairment have not been conducted; and a pharmacokinetic study conducted in subjects with hepatic impairment was not available to Health Canada in the NDS. Studies in children have not been conducted.

Ibsrela is contraindicated in patients below 6 years of age. In young juvenile rats (less than 1 week old; approximate human age equivalent of less than 2 years of age), oral administration of tenapanor resulted in decreased body weight and mortality due to dehydration. Although there are no data available in older juvenile rats, given the deaths in younger rats and the lack of clinical safety and efficacy data in pediatric patients, the use of Ibsrela in patients 6 years to less than 18 years of age is not recommended.

A Risk Management Plan (RMP) for Ibsrela was submitted by Knight Therapeutics Inc. to Health Canada. Upon review, 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 put in place to minimise risks associated with the product.

Overall, Health Canada considered the benefit-harm-uncertainty of Ibsrela for the treatment of adult patients with IBS-C to be favourable.

 

Decision issued

Approved; issued a Notice of Compliance in accordance with the Food and Drug Regulations.