Positive progress for CIC in Phase 3
Ironwood’s linaclotide reaches primary endpoint in chronic idiopathic constipation trial
CAMBRIDGE, Mass.—Ironwood Pharmaceuticals Inc. is proving that good things can come in small packages—or small doses, as it were—with the announcement that its Phase 3 clinical trial of a 72 mcg dose of linaclotide in adults with chronic idiopathic constipation (CIC) met its primary endpoint. The U.S. Food and Drug Administration (FDA) has approved linaclotide, a guanylate cyclase-C agonist, as a 145 mcg capsule to be taken once daily by adults with CIC and as a 290 mcg capsule to be taken once daily by adults with irritable bowel syndrome with constipation (IBS-C).
“Linaclotide is the branded prescription market leader in the treatment of IBS-C and CIC, and we believe the availability of a 72 mcg dose could enhance its utility to physicians for use across the broad, heterogeneous CIC patient population, which encompasses some 35 million adult Americans,” Tom McCourt, chief commercial officer at Ironwood, commented in a press release. “With the successful completion of this trial, linaclotide has met all primary endpoints in all seven of its Phase 3 trials, spanning three doses and two indications. We are committed to continuing to innovate with this molecule, and we are developing multiple additional indications and formulations that, if approved, can address a broad spectrum of patient needs.”
This trial was a double-blind, placebo-controlled, multisite trial of 1,223 adult patients with CIC. The participants were randomized to receive either 72 mcg of linaclotide, 145 mcg of linaclotide or placebo once daily for 12 weeks. Top-line data for the trial showed that the 72 mcg dose of linaclotide resulted in statistically significant improvement compared to placebo on the 12-week complete spontaneous bowel movements (CSBM) overall responder endpoint, the primary endpoint for the trial. It also demonstrated statistically significant improvement compared to placebo on the durable CSBM overall responder endpoint, which is currently requested by the FDA for Phase 3 CIC trials. Both doses—72 mcg and 145 mcg—were generally well tolerated, with the most common adverse event being diarrhea. The majority of those cases were characterized as mild, and the rates of diarrhea and associated discontinuations were lower for the 72 mcg dose than the 145 mcg dose.
Based on this study and previous data, Ironwood and its partner, Allergan plc, plan to submit a supplemental new drug application to the FDA in the first half of 2016. Dr. Mark Currie, chief scientific officer and president of research and development at Ironwood, says the company and Allergan began working together in September 2007, when Ironwood and Forest Laboratories (now Allergan) signed a 50/50 collaboration to co-develop and co-promote linaclotide in the United States.
He remarks that with regard to the demand for CIC treatment options, “The market is large and the unmet need is great. While estimates vary, as many as 35 million adult Americans may suffer from CIC. Ironwood and Forest Pharmaceuticals—a former entity of Allergan—commissioned a web-based survey, and the results from that survey suggest that only 12 percent of adult CIC sufferers are medically diagnosed.”
And this is far from the only study of interest underway for linaclotide, according to Currie.
“Later this year, we expect data from our Phase 2 study evaluating linaclotide for the treatment of adults suffering from opioid-induced constipation,” he says. “In 2016, we plan to file, with our partner Astellas, an NDA for linaclotide for adult patients with IBS-C in Japan, an IDL for linaclotide for adult patients with IBS-C in China with our partner, AstraZeneca, and we anticipate Phase 2b data evaluating two linaclotide colonic release formulations in adults with IBS-C. Next year, we also plan to enroll our Phase 2b dose range finding studies of linaclotide for IBS-C in patients ages 7 to 17 and functional constipation in patients ages 6 to 17.”
Ironwood and Actavis market linaclotide as Linzess in the United States, while Almirall S.A. markets it as Constella in Europe. Ironwood has partnered with Astellas Pharma Inc. and AstraZeneca to develop and commercialize linaclotide in Japan and China, respectively.
Currie notes that things are also progressing well for Ironwood’s other pipeline candidates, pointing out that “Next year we also plan to initiate a dose-ranging Phase 2b study of IW-3718, our bile acid sequestrant, in patients with refractory GERD [gastroesophageal reflux disease], and we expect data from our Phase 2a study of IW-9179, evaluating this compound in patients with diabetic gastroparesis. Later this year, we plan to advance our clinical Phase 1 studies of IW-1973 and IW-1701, the first clinical compounds in our novel chemical series of pharmacologically distinct soluble guanylate cyclase stimulators, which we believe may have broad therapeutic potential. As you can see, this is an exciting time for us at Ironwood.”