Regulatory Decision Summary for Trulance

Two pivotal Phase 3, randomized, double-blind, placebo-controlled studies were submitted in support of this New Drug Submission (NDS). Adult patients aged 18 to 85 years (inclusive) with irritable bowel syndrome with constipation (IBS-C), as defined by Rome III criteria, were included in the study population. The primary efficacy endpoint was an Overall Responder, defined as a patient who was a Weekly Responder (for both Abdominal Pain Intensity and Stool Frequency) for at least 6 of the 12 weeks of the study. An Abdominal Pain Intensity Weekly Responder was defined as a patient who experienced a decrease in the weekly average of worst abdominal pain in the past 24 hours score (measured daily) of at least 30 percent compared with the baseline weekly average. A Stool Frequency Weekly Responder was defined as a patient who experienced an increase of at least one CSBM per week from baseline.

The study objectives were met in both pivotal studies. In Study SP304203-04, the overall responder rate was significantly better in both 3 mg and 6 mg plecanatide treatments (30.2% and 29.5%, respectively) than placebo (17.8%; p-values: <0.001) for both plecanatide doses. The effect was apparent as early as week one. The key secondary efficacy endpoints were mostly supportive of the primary efficacy.

For the components of the primary efficacy endpoint, the number and percentage of abdominal pain responders for at least 6 of 12 week treatment weeks was statistically significantly higher in both treatment groups compared to placebo (31.6%, 41.3%; p=0.008 and 44.7%; p<0.001 for placebo, plecanatide 3 mg and plecanatide 6 mg, respectively). The number and percentage of stool frequency responders for at least 6 of 12 treatment weeks were also statistically significantly higher in both treatment groups compared to placebo (35.0%, 48.1% and 45% for placebo, plecanatide 3 mg; p<0.001 and plecanatide 6 mg; p=0.007, respectively). The treatment difference between plecanatide 3 mg and placebo was higher for the stool frequency component than that for the abdominal pain component.

In Study SP304203-05, the overall responder rate was significantly higher in both plecanatide 3 mg and 6 mg treatment groups (21.5% (p= 0009) and 24.0% (p<0.001), respectively) than placebo (14.2%). The response was evident as early as week 1. The key secondary efficacy endpoints were mostly supportive of the primary efficacy.

For the components of the primary efficacy endpoint, the number and percentage of abdominal pain responders for at least 6 of 12 week treatment weeks were significantly higher in both treatment groups compared to placebo (23.2%, 32.6% ; p<0.004 and 34.0%; p<0.001 for placebo, plecanatide 3 mg and plecanatide 6 mg, respectively). The number and percentage of stool frequency responders for at least 6 of 12 treatment weeks were also higher in plecanatide 3 mg treatment group compared to placebo (28.0%, 34.2% and 39.1% for placebo, plecanatide 3 mg; p=0.062 and plecanatide 6 mg; p=0.007, respectively. The treatment difference between plecanatide 3 mg and placebo was higher for the abdominal pain component than for the stool frequency component.

Overall, the data submitted in this NDS were supportive of the proposed indication for the 3 mg plecanatide. The sample size of subjects older than 65 years was too low to determine whether efficacy in this subpopulation differ from that in the target population.

In pooled data from pivotal studies, the most frequently reported preferred terms of Adverse Events (AEs) in the combined plecanatide group were diarrhea (4.7%), headache (1.6%), nausea (1.2%), urinary tract infection (1.1%), upper respiratory tract infection (1.0%), and abdominal pain (1.0%). Of these, diarrhea occurred more frequently in the combined plecanatide group than in the placebo group (4.7% versus 0.9%). The incidence of each event was either similar between treatment groups or greater in the 3 mg than in the 6 mg plecanatide group. The most frequently reported study-drug-related AEs in the combined plecanatide group were diarrhea and nausea. The incidence of these events was higher in the combined plecanatide group than in the placebo group (diarrhea: 3.7% versus 0.5% for combined plecanatide and placebo, respectively; nausea: 1.0% versus 0.5% for combined plecanatide and placebo, respectively), but was similar between the 3 mg and 6 mg plecanatide groups (3.9% and 3.6%, respectively, for diarrhea; 1.1% and 0.8%, respectively, for nausea). The incidence of severe diarrhea was higher in the combined plecanatide group than in the placebo group (0.6% versus 0.1%), and was also higher in the 3 mg plecanatide group than in the 6 mg plecanatide group (0.9% versus 0.4%). The risk of severe diarrhea is mitigated through labelling.

When Trulance was taken with food, there was a greater incidence of moderate and severe cramping compared to the fasted state. It is recommended that plecanatide should be taken without food in those subjects who developed abdominal cramping.

Studies in juvenile mice suggest that very young mice (<Postnatal Development (PND) 21) exhibit increased sensitivity to plecanatide compared with young adult or slightly older juvenile animals (≥PND 21). Mortality in juvenile mice was addressed in the relevant sections of Trulance product monograph. Trulance is contraindicated in patients less than 6 years of age due to the risk of serious dehydration based on the data from the juvenile toxicity studies in mice.

Overall, the benefit-risk is favorable for Trulance (3 mg dose) for the treatment of irritable bowel syndrome with constipation (IBS-C) in adults.