December 29, 2016
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Colonic release formulations of linaclotide show promise in IBS, other GI indications

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Two colonic release formulations of linaclotide showed improved abdominal pain relief in patients with irritable bowel syndrome, while one of them also showed improvement in bowel habits in a phase 2b trial, Ironwood and Allergan announced.

These results support further investigation of one formulation for IBS-C, and further investigation of the other formulation, which showed no effect on bowel function, in other GI indications associated with abdominal pain but not constipation, according to a pair of press releases.

Linzess (linaclotide; Ironwood, Allergan) is an immediate release formulation currently FDA-approved for IBS-C and chronic idiopathic constipation. It is a guanylate cyclase-C agonist that is thought to work by increasing intestinal fluid secretion and accelerating transit, and by reducing the activity of pain-sensing nerves.

Linaclotide colonic release-1 (CR1) is a new formulation designed for targeted delivery to the distal small intestine and colon, where most IBS-C-associated abdominal pain is thought to originate. Similarly, linaclotide colonic release-2 (CR2) is designed for targeted delivery to the colon.

To determine whether these two new formulations provide further reductions in activity of pain-sensing nerves in the distal small intestine and colon while maintaining an effect on fluid secretion, investigators performed a double blind, placebo controlled, dose ranging trial in which they randomly assigned 532 adults with IBS-C into one of eight treatment groups.

“With the linaclotide colonic release program, our intent was to dial up or down the two components of the linaclotide mechanism of action — the effect on pain-sensing nerves and the effect on fluid secretion — by varying where the drug is delivered,” Mark Currie, PhD, chief scientific officer and president of research and development at Ironwood, said in a press release. “These initial data support our hypothesis that delivery in the proximal ileum and colon could allow us to better isolate linaclotide’s ability to decrease the activity of pain-sensing nerves in the intestine.”

Patients who received 300 mcg of the CR1 formulation showed numerically greater improvements in abdominal pain compared with placebo and 290 mcg of the immediate release formulation of linaclotide: 38.8% of the 300 mcg CR1 group had at least a 30% reduction in abdominal pain plus an increase of at least one complete spontaneous bowel movement from baseline in the same week for at least half of the 12 weeks, compared with 21.2% of the placebo group and 31.8% of the 290 mcg immediate release group.

In addition, the 300 mcg CR1 group had a 56.2% improvement in abdominal pain relative to the placebo group, based on the average weekly change from baseline to week 12 on an 11-point scale, and also a 59.3% improvement in complete spontaneous bowel movements relative to placebo.

“CR1 300 mcg showed a numerically greater reduction in abdominal pain than IR 290 mcg each week beginning at week 5 and continuing for the remainder of the 12-week study, with a mean percent reduction from baseline at week 12 of 49.5% for CR1 300 mcg compared to 26.2% for placebo and 40.6% for IR 290 mcg,” according to a press release. “Additionally, patients treated with linaclotide CR1 300 mcg reported improvement in other abdominal and bowel symptoms commonly experienced by IBS-C patients, including abdominal discomfort and bloating.”

Diarrhea was the most common adverse event, occurring in 10.4% of the CR1 300 mcg group compared with 1.5% of the placebo group and 13.6% of the IR 290 mcg group. All were mild or moderate and resulted in discontinuation of treatment in 3%, 0% and 6.1% of the groups, respectively.

Conversely, the CR2 formulation and placebo showed comparable average weekly changes in Bristol Stool Form Scale scores and frequency of complete spontaneous bowel movements from baseline to week 12, suggesting no effect on bowel movement function with this formulation. However, CR2 at 30 mcg, 100 mcg and 300 mcg resulted in improved average weekly change in abdominal pain from baseline to week 12 compared with placebo, ranging from 33.8% to 36.6% improvements compared with 26.2% improvement with placebo.

Upper respiratory tract infection/nasopharyngitis was the most common adverse event in the CR2 group (3% vs. 4.5% in the placebo group). Diarrhea ranged from 0% to 3% in the CR2 groups vs. 1.5% for placebo.

“These findings support further investigation of CR2 in specific GI indications where patients experience abdominal pain but are not necessarily constipated, such as IBS-mixed, IBS with diarrhea, ulcerative colitis and diverticulitis,” according to the press release.

Brennan Spiegel, MD

Brennan Spiegel

“There is increasing research into the mechanisms underlying pain and other abdominal symptoms in GI disorders, including IBS, as well as research highlighting the hypersensitivity of pain-sensing nerves in the lower GI tract in many patients suffering from these conditions,” Brennan Spiegel, MD, director of Health Services Research at Cedars-Sinai Health System, said in the press release. “We currently have a limited number of treatment options for these patients, and a medicine that could address abdominal pain without impacting bowel function could represent a real advancement in care.”

The companies expect additional results from this trial to be presented at future scientific conferences and in peer reviewed publications, and plan to initiate phase 3 trials of CR1 for IBS-C in the second half of 2017, and also move CR2 into phase 2b trials for non-constipation subtypes of IBS.

They are also pursuing patents which they expect to provide coverage into the mid 2030s if approved, according to the press release.

“We believe the potentially enhanced clinical profile of linaclotide CR1 could support further growth of the Linzess franchise from $1 billion in U.S. net sales by 2020 to potentially greater than $2 billion in peak U.S. net sales,” Tom McCourt, chief commercial officer at Ironwood, said in the press release.

Disclosures: McCourt and Curry are employed by Ironwood, and Spiegel reports financial ties to Ironwood.