Ironwood and Allergan Report Topline Data Supporting Linaclotide

Ironwood and Allergan report topline phase IIb data supporting advancement of linaclotide colonic release-1 (CR1) in IBS-C.

Ironwood Pharmaceuticals, Inc. and Allergan plc announced positive topline data from a phase IIb clinical trial evaluating the investigational linaclotide colonic release-1 (CR1) formulation in adult patients with irritable bowel syndrome with constipation (IBS-C).

Topline data in this trial demonstrated numerically greater abdominal pain improvement with CR1 300 mcg compared to placebo and to the 290 mcg immediate release (IR) formulation of linaclotide. The companies intend to engage with the U.S. Food and Drug Administration (FDA) to discuss phase III development plans, with trials in adults with IBS-C expected to begin in the second half of 2017.

Linaclotide IR (Linzess) is currently FDA-approved and available for the treatment of adults with IBS-C or chronic idiopathic constipation (CIC). Linaclotide is thought to work in two ways, based on non-clinical studies: by decreasing the activity of pain-sensing nerves and by increasing fluid secretion into the intestine.

Linaclotide CR1 is designed to provide targeted delivery of linaclotide to the distal small intestine and colon, where the majority of the abdominal pain associated with IBS-C is believed to originate. This clinical trial was designed to evaluate whether CR1 could further decrease the activity of key pain-sensing nerves in the distal small intestine and colon while maintaining an effect on fluid secretion. Ironwood and Allergan also announced topline results from the same Phase IIb trial with a second formulation, linaclotide colonic release-2 (CR2), in a separate press release issued this week.

“Abdominal pain is usually the most difficult symptom to treat in patients with IBS-C. When that pain is not treated sufficiently, then that drives the patient back into my office again and again,” said Philip Schoenfeld, M.D., chief, gastroenterology section, John D. Dingell VA Medical Center and adjunct professor of medicine at the University of Michigan School of Medicine. “I’m encouraged by these initial data. This new formulation of linaclotide may produce additional relief of abdominal pain in patients with IBS-C.”

The double-blind, placebo-controlled, dose-ranging Phase IIb trial randomized 532 adult patients with IBS-C into one of eight possible treatment arms. The trial was exploratory in nature and comparisons to placebo were evaluated using nominal p-values. In the trial, CR1 300 mcg demonstrated improvement on the three prespecified key efficacy endpoints as follows:

6/12 APC+1 Responder: the percentage of patients to report at least a 30% reduction from baseline in abdominal pain and an increase of at least one complete spontaneous bowel movement (CSBM) from baseline, both in the same week for at least 6 out of 12 weeks, was 38.8% for CR1 300 mcg compared to 21.2% for placebo and 31.8% for IR 290 mcg.
Change from Baseline in Abdominal Pain: the average weekly change in abdominal pain from baseline to week 12 was -2.14 for CR1 300 mcg compared to -1.37 for placebo and -1.94 for IR 290 mcg, as measured on an 11-point scale. This translates to a 56.2% improvement in abdominal pain with CR1 300 mcg relative to placebo.
Change from Baseline in CSBM Frequency: the average weekly change in CSBM frequency from baseline to week 12 was 1.78 for CR1 300 mcg compared to 1.11 for placebo and 2.11 for IR 290 mcg. This translates to a 59.3% improvement in CSBM frequency with CR1 300 mcg relative to placebo.

In this trial, 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. 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.

The most common adverse event was diarrhea, which was reported in 10.4% of patients on CR1 300 mcg compared to 1.5% of patients on placebo and 13.6% of patients on IR 290 mcg. All diarrhea adverse events reported were mild or moderate in severity, with discontinuation resulting from diarrhea occurring in 3.0% of CR1 300 mcg patients compared to no placebo patients and 6.1% of IR 290 mcg patients.

Additional data from the Phase IIb trial are expected to be shared at upcoming scientific meetings and via peer-reviewed publications.

“Relief of abdominal pain is a key benefit motivating physicians to choose Linzess for patients suffering from IBS-C, and it is the primary driver of patient satisfaction,” said Tom McCourt, chief commercial officer of Ironwood. “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.”

“Linzess is the market-leading U.S. branded prescription medicine for adults with IBS-C or CIC and has been utilized by more than 1 million patients to date,” said Bill Meury, chief commercial officer of Allergan. “The CR1 formulation could provide an innovative brand to treat millions of additional suffering patients, extending the success of Linzess and demonstrating our continued commitment to improving GI care.”

Ironwood and Allergan are pursuing patent protection for CR1 and CR2 that, if issued, is expected to provide patent coverage into the mid-2030s.

(Source: Business Wire)