Positive Phase III results for plecanatide as treatment for chronic idiopathic constipation- Synergy Pharmaceuticals

Synergy Pharmaceuticals has announced positive top-line results from the second of two pivotal phase III clinical trials evaluating the efficacy and safety of two different plecanatide treatment doses (3.0 mg and 6.0 mg), taken as a tablet once-a-day, in 1337 adult patients with chronic idiopathic constipation (CIC). Preliminary analysis of the data indicates that both plecanatide 3.0 mg and 6.0 mg 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 3.0 mg and 20.0% in 6.0 mg dose groups compared to 12.8% in placebo; p=0.004 for both doses). The durable overall responder endpoint is the current FDA endpoint required for US approval in CIC.

Importantly, plecanatide was safe and well tolerated at both doses; the most common adverse event was diarrhoea, which occurred in 3.2% of patients in 3.0 mg and 4.5% of patients in 6.0 mg dose groups compared to 1.3% of placebo-treated patients.

Stool consistency was the key secondary endpoint reported with top-line analyses; both 3.0 mg and 6.0 mg plecanatide doses showed statistically significant improvement from baseline in Bristol Stool Form Scale (BSFS) scores compared to placebo (mean increase of 1.49 in 3.0 mg and 1.50 in 6.0 mg 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.

20 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 3.0 mg and 3.8% in 6.0 mg dose groups compared to 3.0% in placebo) and discontinuations due to diarrhea were infrequent (1.1% in 3.0 mg and 1.1% in 6.0 mg dose groups compared to 0.4% in placebo).

Comment: Synergy will be competing with the first in the guanylate cyclase C (GC-C) agonist class – Allergan's Constella (linaclotide), also called Linzess, which was FDA approved in August 2012 as a once-daily treatment for IBS-C or CIC.

Comment: Barclays analysts pointed out that while the efficacy of Synergy's drug seems "marginally lower" than that of linaclotide, plecanatide recorded a diarrhoea rate of around 5%. Linaclotide is labeled with warnings that roughly 16% of patients experience the side effect, and Barclays believes that could differentiate the drugs if they ever go head to head. Average discontinuation rates due to adverse events were about 5% for plecanatide, while it was 8% for linaclotide.