Synergy Pharmaceuticals has filed with the FDA its first new drug application (NDA) for plecanatide in chronic idiopathic constipation (CIC).

 “The submission of the plecanatide NDA for CIC marks a major milestone for Synergy as we move the product candidate another step closer to potential approval early next year,” said Gary S. Jacob, Ph.D., chairman and CEO of Synergy Pharmaceuticals.

The plecanatide NDA for CIC is supported by positive results from two phase III clinical trials which Synergy completed in 2015. If approved, Synergy plans to launch plecanatide with the CIC indication in the first quarter of 2017.

Each of the two randomized, double-blind, placebo-controlled pivotal phase III trials evaluated the efficacy and safety of two different plecanatide treatment doses (3mg and 6mg), taken as a tablet once-a-day, in adult patients with CIC. Both trials include a two-week pre-treatment baseline period, a 12-week treatment period, and a two-week post-treatment period.

The primary endpoint for both trials was the proportion of durable overall responders (%), which is currently the regulatory endpoint required for U.S. approval in CIC. The FDA has defined an overall responder as a patient who fulfills both ≥3 complete spontaneous bowel movements (CSBMs) per week plus an increase of ≥1 CSBM from baseline in the same week, for nine out of the 12 treatment weeks. In addition, the same patient must be a weekly responder for at least three of the last four treatment weeks in order to be considered a durable overall responder. Plecanatide has the potential to be the first drug approved for CIC using the more stringent regulatory requirement for durability of the overall response.

On June 17, 2015, Synergy announced positive top-line results from the first phase III clinical trial of plecanatide in 1,346 adult patients with CIC. Both plecanatide doses met the study’s primary endpoint and demonstrated statistical significance in the proportion of patients in the intention-to-treat population who were durable overall responders compared to placebo during the 12-week treatment period (21% in 3mg and 19.5% in 6mg dose groups compared to 10.2% in placebo; p<0.001 for both doses).

The most common adverse event was diarrhea, which only occurred in 5.9% of patients in 3mg and 5.5% of patients in 6mg dose groups compared to 1.3% of placebo-treated patients. Stool consistency was the key secondary endpoint reported with top-line analyses; both 3mg and 6mg plecanatide doses showed statistically significant improvement from baseline in Bristol Stool Form Scale (BSFS) scores compared to placebo (mean increase of 1.53 in 3mg and 1.52 in 6mg dose groups compared to a mean increase of 0.77 in placebo; p<0.001 for both doses). The observed improvements began at week 1, continued throughout the 12-week treatment period, and returned towards baseline with no indication of an exaggerated or rebound effect following discontinuation of treatment. 15 patients in the trial (1.1%) experienced serious adverse events but there was no imbalance across treatment groups in either incidences or individual serious adverse events. Overall, the rates of withdrawal from treatment because of an adverse event were low (5.1% in 3mg and 5% in 6mg dose groups compared to 1.3% in placebo) and discontinuations due to diarrhea were infrequent (2.7% in 3mg and 2.4% in 6mg dose groups compared to 0.4% in placebo). No clinically relevant abnormalities were observed in serum chemistries, hematology, urinalysis, ECG or vital signs measurements.

On July 30, 2015 Synergy announced positive top-line results from the second phase III clinical trial of plecanatide in 1,337 adult patients with CIC. Both plecanatide doses met the study’s primary endpoint and demonstrated statistical significance in the proportion of patients in the intention-to-treat population who were durable overall responders compared to placebo during the 12-week treatment period (20.1% in 3mg and 20% in 6mg dose groups compared to 12.8% in placebo; p=0.004 for both doses).The most common adverse event was diarrhea, which only occurred in 3.2% of patients in 3mg and 4.5% of patients in 6mg dose groups compared to 1.3% of placebo-treated patients. Both plecanatide doses showed statistically significant improvement from baseline in BSFS scores compared to placebo (mean increase of 1.49 in 3mg and 1.50 in 6mg dose groups compared to a mean increase of 0.87 in placebo; p<0.001 for both doses). The observed improvements began at Week 1, continued throughout the 12-week treatment period, and returned towards baseline with no indication of an exaggerated or rebound effect following discontinuation of treatment. Twenty patients in the trial (1.4%) experienced serious adverse events but there was no imbalance across treatment groups in either incidences or individual serious adverse events. Overall, the rates of withdrawal from treatment because of an adverse event were low (3.2% in 3mg and 3.8% in 6mg dose groups compared to 3% in placebo) and discontinuations due to diarrhea were infrequent (1.1% in 3mg and 1.1% in 6mg dose groups compared to 0.4% in placebo). No clinically relevant abnormalities were observed in serum chemistries, hematology, urinalysis, ECG or vital signs measurements.