Plecanatide may be safe, effective for chronic idiopathic constipation

ORLANDO – The investigational drug plecanatide appears to be safe and effective for patients with chronic idiopathic constipation, according to a 12-week randomized, double-blind, placebo-controlled trial.

Patients who received 3.0 mg of plecanatide daily had a statistically significant improvement in the number of complete spontaneous bowel movements (CSBMs), compared with the placebo group, reported Dr. Philip B. Miner, who is a consultant and researcher for the drug’s developer, Synergy Pharmaceuticals. He presented the abstract at the annual Digestive Disease Week.

Patients receiving 0.3 mg or 1.0 mg of plecanatide daily also achieved statistical significance in some of the other primary and secondary endpoints of the study, said Dr. Miner, president and medical director of the Oklahoma Foundation for Digestive Research. The reported diarrhea rate was roughly 10% at the highest dose.

But from the results so far, "I can’t tell if it’s any different compared to what we have available now," said Dr. Lauren B. Gerson, an assistant professor at Stanford (Calif.) University, who was not involved in the study. "It looks like it’ll probably be as efficacious, but you have to do a head-to-head trial to see if it’s any better. So it’s another drug we can use, but I’m not sure if it has additional benefits."

Plecanatide belongs to a new class of essentially nonsystemic oral drugs, guanylate cyclase C (GC-C) receptor agonists. The investigational drug mimics the natriuretic peptide uroguanylin, and induces intestinal fluid secretion into the lumen of the gastrointestinal tract.

Phase I and IIa trials have suggested that the drug will be useful in treating chronic idiopathic constipation (CIC) and irritable bowel syndrome with constipation (IBS-C), said Dr. Miner (Dig. Dis. Sci. 2013 April 27). The phase II trial, completed in December 2012, aimed to evaluate the safety, effectiveness, and dose-response profile of plecanatide in CIC patients.

The primary efficacy endpoint was the number of CSBMs per week. A weekly responder had more than three CSBMs per week and an increase of more than one CSBM from baseline.

Secondary endpoints included time to first spontaneous bowel movement (SBM) or CSBM; stool consistency, straining, and severity of constipation; Patient Assessment of Constipation Symptoms (PAC-SYM); and quality of life.

The 12-week study enrolled 951 patients with CIC, 946 of whom received the drug or placebo. The patients were randomized to four arms: 0.3 mg of plecanatide (237 patients), 1.0 mg (238), 3.0 mg (237), and placebo (234). The patients had fewer than three CSBMs per week, according to the modified Rome III CIC criteria. Patients were excluded if they had a Rome III IBS-C diagnosis; a previous major GI surgical history; or recognized causes of constipation, such as opioid use or hypothyroidism.

The majority of the patients were white women (85%), the mean patient age was 47 years, and the mean BMI was 27 kg/m².

The trial included a 5-week screening, a 2-week run-in, 12 weeks of treatment, and 2 weeks of post-treatment evaluation.

Of the 951 enrollees, 738 patients (77.3%) completed the treatment. The main reasons for withdrawal included adverse events (46 patients), administrative issues (95), and lack of efficacy (51), Dr. Miner reported.

Results showed that there were significantly more responders in the plecanatide groups in at least 9 of 12 weeks of the study. The greatest response was observed among patients on 3.0 mg of plecanatide (21.5%), compared with placebo (11.5%; P = .003). In the other two arms, 17.2% of the patients on 1.0 mg of plecanatide (P greater than .05), and 19% on 0.3 mg of plecanatide (P less than .05) were responders.

The durable responder rate – defined as responders in at least 9 of 12 weeks and in at least 3 of the last 4 weeks of treatment – was 19% for 3.0 mg of plecanatide, compared with 10.7% for placebo (P = .009).

The weekly responder rates for 3.0 mg of plecanatide were significantly superior to placebo from week 1 through 12, the results showed. More than half of patients had one or more CSBM weekly compared with baseline, over 12 weeks (52.3% of 3.0 mg vs. 36.8% of placebo, P less than .001).

Patients on 3.0 mg of plecanatide also achieved their first CSBM in nearly half the time of patients in the placebo group (54.7 hours vs. 124.5 hours for placebo, P less than .001). They also achieved their first SBM sooner (12.5 hours vs. 27.3 hours, P less than .001).

The median time to first SBM was 9.6 hours at 3.0 mg of plecanatide, compared with 25.1 hours for placebo (P less than .001).

The 3.0-mg plecanatide arm also showed significant improvements in secondary endpoints, including stool consistency and straining, compared with placebo (P less than .001). In addition, that arm had significant improvements in constipation-associated symptoms and quality of life relative to baseline (P less than .001), the results showed.

The cumulative days that rescue medication was used per month also significantly decreased among patients on 3.0 mg of plecanatide, compared with placebo (P less than .001).

Patients on 3.0 mg of plecanatide had the highest percentage of treatment-emergent adverse events (106 patients or 44.7%), compared with 1.0 mg of plecanatide (103 patients or 43.3%), 0.3 mg (99 or 31.8%), and placebo (96 or 40.7%).

The most common adverse event on the drug was diarrhea (9.7% on 3.0 mg of plecanatide vs. 1.3% on placebo). Seven patients (3%) on 3.0 mg of plecanatide withdrew due to diarrhea, compared with eight patients (3.4%) on 1.0 mg of plecanatide, two patients (0.8%) on 0.3 mg, and 1 patient (0.4%) in the placebo group.

Other adverse events included flatulence, abdominal pain, abdominal distention, nausea, nasopharyngitis, urinary tract infection, and headache. Serious adverse events, which were considered unrelated to the treatment, included noncardiac chest pain (1 patient on 0.3 mg of plecanatide), endometriosis (1 patient on 1.0 mg), and acute cholecystitis and hypoaesthesia with weakness (2 patients on 3.0 mg). Five patients in the placebo group experienced hypertension exacerbation, gastroenteritis, spontaneous abortion, atypical chest pain, and asthma exacerbation. Dr. Miner said he could not share the bloating data at the time of his presentation.

Dr. Gerson said that the ideal drug would "relieve constipation and other symptoms, but doesn’t have a lot of side effects. It’ll be nice to have a drug that is better tolerated than what’s available out there."

Synergy is preparing a clinical study report for submission to the Food and Drug Administration. It is presenting additional data in upcoming scientific meetings in 2013, according to a company news release.

The FDA approved linaclotide (Linzess) in August 2012 for treatment of CIC and IBS-C. Linaclotide, also a guanylate cyclase C agonist, is comarketed by Ironwood Pharmaceuticals and Forest Pharmaceuticals.

Dr. Miner is a consultant and has done research for Ventrus Biosciences and Synergy Pharmaceuticals. Dr. Gerson had no disclosures.

[email protected]

On Twitter @naseemsmiller

ORLANDO – The investigational drug plecanatide appears to be safe and effective for patients with chronic idiopathic constipation, according to a 12-week randomized, double-blind, placebo-controlled trial.

Patients who received 3.0 mg of plecanatide daily had a statistically significant improvement in the number of complete spontaneous bowel movements (CSBMs), compared with the placebo group, reported Dr. Philip B. Miner, who is a consultant and researcher for the drug’s developer, Synergy Pharmaceuticals. He presented the abstract at the annual Digestive Disease Week.

Patients receiving 0.3 mg or 1.0 mg of plecanatide daily also achieved statistical significance in some of the other primary and secondary endpoints of the study, said Dr. Miner, president and medical director of the Oklahoma Foundation for Digestive Research. The reported diarrhea rate was roughly 10% at the highest dose.

But from the results so far, "I can’t tell if it’s any different compared to what we have available now," said Dr. Lauren B. Gerson, an assistant professor at Stanford (Calif.) University, who was not involved in the study. "It looks like it’ll probably be as efficacious, but you have to do a head-to-head trial to see if it’s any better. So it’s another drug we can use, but I’m not sure if it has additional benefits."

Plecanatide belongs to a new class of essentially nonsystemic oral drugs, guanylate cyclase C (GC-C) receptor agonists. The investigational drug mimics the natriuretic peptide uroguanylin, and induces intestinal fluid secretion into the lumen of the gastrointestinal tract.

Phase I and IIa trials have suggested that the drug will be useful in treating chronic idiopathic constipation (CIC) and irritable bowel syndrome with constipation (IBS-C), said Dr. Miner (Dig. Dis. Sci. 2013 April 27). The phase II trial, completed in December 2012, aimed to evaluate the safety, effectiveness, and dose-response profile of plecanatide in CIC patients.

The primary efficacy endpoint was the number of CSBMs per week. A weekly responder had more than three CSBMs per week and an increase of more than one CSBM from baseline.

Secondary endpoints included time to first spontaneous bowel movement (SBM) or CSBM; stool consistency, straining, and severity of constipation; Patient Assessment of Constipation Symptoms (PAC-SYM); and quality of life.

The 12-week study enrolled 951 patients with CIC, 946 of whom received the drug or placebo. The patients were randomized to four arms: 0.3 mg of plecanatide (237 patients), 1.0 mg (238), 3.0 mg (237), and placebo (234). The patients had fewer than three CSBMs per week, according to the modified Rome III CIC criteria. Patients were excluded if they had a Rome III IBS-C diagnosis; a previous major GI surgical history; or recognized causes of constipation, such as opioid use or hypothyroidism.

The majority of the patients were white women (85%), the mean patient age was 47 years, and the mean BMI was 27 kg/m².

The trial included a 5-week screening, a 2-week run-in, 12 weeks of treatment, and 2 weeks of post-treatment evaluation.

Of the 951 enrollees, 738 patients (77.3%) completed the treatment. The main reasons for withdrawal included adverse events (46 patients), administrative issues (95), and lack of efficacy (51), Dr. Miner reported.

Results showed that there were significantly more responders in the plecanatide groups in at least 9 of 12 weeks of the study. The greatest response was observed among patients on 3.0 mg of plecanatide (21.5%), compared with placebo (11.5%; P = .003). In the other two arms, 17.2% of the patients on 1.0 mg of plecanatide (P greater than .05), and 19% on 0.3 mg of plecanatide (P less than .05) were responders.

The durable responder rate – defined as responders in at least 9 of 12 weeks and in at least 3 of the last 4 weeks of treatment – was 19% for 3.0 mg of plecanatide, compared with 10.7% for placebo (P = .009).

The weekly responder rates for 3.0 mg of plecanatide were significantly superior to placebo from week 1 through 12, the results showed. More than half of patients had one or more CSBM weekly compared with baseline, over 12 weeks (52.3% of 3.0 mg vs. 36.8% of placebo, P less than .001).

Patients on 3.0 mg of plecanatide also achieved their first CSBM in nearly half the time of patients in the placebo group (54.7 hours vs. 124.5 hours for placebo, P less than .001). They also achieved their first SBM sooner (12.5 hours vs. 27.3 hours, P less than .001).

The median time to first SBM was 9.6 hours at 3.0 mg of plecanatide, compared with 25.1 hours for placebo (P less than .001).

The 3.0-mg plecanatide arm also showed significant improvements in secondary endpoints, including stool consistency and straining, compared with placebo (P less than .001). In addition, that arm had significant improvements in constipation-associated symptoms and quality of life relative to baseline (P less than .001), the results showed.

The cumulative days that rescue medication was used per month also significantly decreased among patients on 3.0 mg of plecanatide, compared with placebo (P less than .001).

Patients on 3.0 mg of plecanatide had the highest percentage of treatment-emergent adverse events (106 patients or 44.7%), compared with 1.0 mg of plecanatide (103 patients or 43.3%), 0.3 mg (99 or 31.8%), and placebo (96 or 40.7%).

The most common adverse event on the drug was diarrhea (9.7% on 3.0 mg of plecanatide vs. 1.3% on placebo). Seven patients (3%) on 3.0 mg of plecanatide withdrew due to diarrhea, compared with eight patients (3.4%) on 1.0 mg of plecanatide, two patients (0.8%) on 0.3 mg, and 1 patient (0.4%) in the placebo group.

Other adverse events included flatulence, abdominal pain, abdominal distention, nausea, nasopharyngitis, urinary tract infection, and headache. Serious adverse events, which were considered unrelated to the treatment, included noncardiac chest pain (1 patient on 0.3 mg of plecanatide), endometriosis (1 patient on 1.0 mg), and acute cholecystitis and hypoaesthesia with weakness (2 patients on 3.0 mg). Five patients in the placebo group experienced hypertension exacerbation, gastroenteritis, spontaneous abortion, atypical chest pain, and asthma exacerbation. Dr. Miner said he could not share the bloating data at the time of his presentation.

Dr. Gerson said that the ideal drug would "relieve constipation and other symptoms, but doesn’t have a lot of side effects. It’ll be nice to have a drug that is better tolerated than what’s available out there."

Synergy is preparing a clinical study report for submission to the Food and Drug Administration. It is presenting additional data in upcoming scientific meetings in 2013, according to a company news release.

The FDA approved linaclotide (Linzess) in August 2012 for treatment of CIC and IBS-C. Linaclotide, also a guanylate cyclase C agonist, is comarketed by Ironwood Pharmaceuticals and Forest Pharmaceuticals.

Dr. Miner is a consultant and has done research for Ventrus Biosciences and Synergy Pharmaceuticals. Dr. Gerson had no disclosures.

[email protected]

On Twitter @naseemsmiller

ORLANDO – The investigational drug plecanatide appears to be safe and effective for patients with chronic idiopathic constipation, according to a 12-week randomized, double-blind, placebo-controlled trial.

Patients who received 3.0 mg of plecanatide daily had a statistically significant improvement in the number of complete spontaneous bowel movements (CSBMs), compared with the placebo group, reported Dr. Philip B. Miner, who is a consultant and researcher for the drug’s developer, Synergy Pharmaceuticals. He presented the abstract at the annual Digestive Disease Week.

Patients receiving 0.3 mg or 1.0 mg of plecanatide daily also achieved statistical significance in some of the other primary and secondary endpoints of the study, said Dr. Miner, president and medical director of the Oklahoma Foundation for Digestive Research. The reported diarrhea rate was roughly 10% at the highest dose.

But from the results so far, "I can’t tell if it’s any different compared to what we have available now," said Dr. Lauren B. Gerson, an assistant professor at Stanford (Calif.) University, who was not involved in the study. "It looks like it’ll probably be as efficacious, but you have to do a head-to-head trial to see if it’s any better. So it’s another drug we can use, but I’m not sure if it has additional benefits."

Plecanatide belongs to a new class of essentially nonsystemic oral drugs, guanylate cyclase C (GC-C) receptor agonists. The investigational drug mimics the natriuretic peptide uroguanylin, and induces intestinal fluid secretion into the lumen of the gastrointestinal tract.

Phase I and IIa trials have suggested that the drug will be useful in treating chronic idiopathic constipation (CIC) and irritable bowel syndrome with constipation (IBS-C), said Dr. Miner (Dig. Dis. Sci. 2013 April 27). The phase II trial, completed in December 2012, aimed to evaluate the safety, effectiveness, and dose-response profile of plecanatide in CIC patients.

The primary efficacy endpoint was the number of CSBMs per week. A weekly responder had more than three CSBMs per week and an increase of more than one CSBM from baseline.

Secondary endpoints included time to first spontaneous bowel movement (SBM) or CSBM; stool consistency, straining, and severity of constipation; Patient Assessment of Constipation Symptoms (PAC-SYM); and quality of life.

The 12-week study enrolled 951 patients with CIC, 946 of whom received the drug or placebo. The patients were randomized to four arms: 0.3 mg of plecanatide (237 patients), 1.0 mg (238), 3.0 mg (237), and placebo (234). The patients had fewer than three CSBMs per week, according to the modified Rome III CIC criteria. Patients were excluded if they had a Rome III IBS-C diagnosis; a previous major GI surgical history; or recognized causes of constipation, such as opioid use or hypothyroidism.

The majority of the patients were white women (85%), the mean patient age was 47 years, and the mean BMI was 27 kg/m².

The trial included a 5-week screening, a 2-week run-in, 12 weeks of treatment, and 2 weeks of post-treatment evaluation.

Of the 951 enrollees, 738 patients (77.3%) completed the treatment. The main reasons for withdrawal included adverse events (46 patients), administrative issues (95), and lack of efficacy (51), Dr. Miner reported.

Results showed that there were significantly more responders in the plecanatide groups in at least 9 of 12 weeks of the study. The greatest response was observed among patients on 3.0 mg of plecanatide (21.5%), compared with placebo (11.5%; P = .003). In the other two arms, 17.2% of the patients on 1.0 mg of plecanatide (P greater than .05), and 19% on 0.3 mg of plecanatide (P less than .05) were responders.

The durable responder rate – defined as responders in at least 9 of 12 weeks and in at least 3 of the last 4 weeks of treatment – was 19% for 3.0 mg of plecanatide, compared with 10.7% for placebo (P = .009).

The weekly responder rates for 3.0 mg of plecanatide were significantly superior to placebo from week 1 through 12, the results showed. More than half of patients had one or more CSBM weekly compared with baseline, over 12 weeks (52.3% of 3.0 mg vs. 36.8% of placebo, P less than .001).

Patients on 3.0 mg of plecanatide also achieved their first CSBM in nearly half the time of patients in the placebo group (54.7 hours vs. 124.5 hours for placebo, P less than .001). They also achieved their first SBM sooner (12.5 hours vs. 27.3 hours, P less than .001).

The median time to first SBM was 9.6 hours at 3.0 mg of plecanatide, compared with 25.1 hours for placebo (P less than .001).

The 3.0-mg plecanatide arm also showed significant improvements in secondary endpoints, including stool consistency and straining, compared with placebo (P less than .001). In addition, that arm had significant improvements in constipation-associated symptoms and quality of life relative to baseline (P less than .001), the results showed.

The cumulative days that rescue medication was used per month also significantly decreased among patients on 3.0 mg of plecanatide, compared with placebo (P less than .001).

Patients on 3.0 mg of plecanatide had the highest percentage of treatment-emergent adverse events (106 patients or 44.7%), compared with 1.0 mg of plecanatide (103 patients or 43.3%), 0.3 mg (99 or 31.8%), and placebo (96 or 40.7%).

The most common adverse event on the drug was diarrhea (9.7% on 3.0 mg of plecanatide vs. 1.3% on placebo). Seven patients (3%) on 3.0 mg of plecanatide withdrew due to diarrhea, compared with eight patients (3.4%) on 1.0 mg of plecanatide, two patients (0.8%) on 0.3 mg, and 1 patient (0.4%) in the placebo group.

Other adverse events included flatulence, abdominal pain, abdominal distention, nausea, nasopharyngitis, urinary tract infection, and headache. Serious adverse events, which were considered unrelated to the treatment, included noncardiac chest pain (1 patient on 0.3 mg of plecanatide), endometriosis (1 patient on 1.0 mg), and acute cholecystitis and hypoaesthesia with weakness (2 patients on 3.0 mg). Five patients in the placebo group experienced hypertension exacerbation, gastroenteritis, spontaneous abortion, atypical chest pain, and asthma exacerbation. Dr. Miner said he could not share the bloating data at the time of his presentation.

Dr. Gerson said that the ideal drug would "relieve constipation and other symptoms, but doesn’t have a lot of side effects. It’ll be nice to have a drug that is better tolerated than what’s available out there."

Synergy is preparing a clinical study report for submission to the Food and Drug Administration. It is presenting additional data in upcoming scientific meetings in 2013, according to a company news release.

The FDA approved linaclotide (Linzess) in August 2012 for treatment of CIC and IBS-C. Linaclotide, also a guanylate cyclase C agonist, is comarketed by Ironwood Pharmaceuticals and Forest Pharmaceuticals.

Dr. Miner is a consultant and has done research for Ventrus Biosciences and Synergy Pharmaceuticals. Dr. Gerson had no disclosures.

[email protected]

On Twitter @naseemsmiller