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Irritable Bowel Syndrome (IBS)

August 18, 2014

Salix Pharmaceuticals reported results of a phase III study of rifaximin for the treatment of irritable bowel syndrome with diarrhea (IBS-D). The phase III, randomized, double-blind, placebo- controlled study evaluated repeat treatment with rifaximin 550mg TID (three times daily) for 14 days in subjects with IBS-D, who respond to an initial treatment course with rifaximin 550mg TID for 14 days. Results indicate a significantly greater proportion of rifaximin-treated subjects, compared to placebo-treated subjects, gained relief in both IBS-related abdominal pain and stool consistency during the PEP in the first repeat double-blind, placebo-controlled treatment phase, and continued to respond without recurrence through the end of week six following the second repeat double-blind, placebo-controlled treatment (p=0.0068). Results also indicate, compared to placebo-treated subjects, a significantly greater proportion of rifaximin-treated subjects gained relief in both IBS-related abdominal pain and stool consistency during the PEP in the first repeat double-blind, placebo- controlled treatment phase and continued to respond without recurrence through the end of week 12, independent of any additional treatment (p=0.0419).

May 5, 2014

Synergy Pharmaceuticals reported results of a phase IIb study of plecanatide in 424 patients with irritable bowel syndrome with constipation (IBS-C). The randomized, 12-week, double-blind, placebo-controlled, dose-ranging study evaluated the effects of 1mg, 3mg or 9mg plecanatide or placebo administered orally once daily to adults. During pre-treatment at baseline, patients are required to have at least three days in each week with pain scores = 3 on a zero to 10 scale. The plecanatide 3mg dose was selected for phase III based on achieving statistically significant improvement in the study’s primary endpoint and key secondary endpoints assessed in the topline analyses, which included change from baseline versus placebo over 12 weeks in: CSBM frequency (1.29 placebo v. 2.74, p=<0.001), worst abdominal pain intensity (-1.4 [-24.5%] placebo v.-2 [-33.9%], p=<0.05) and stool consistency (BSFS) (1.01 placebo v. 2.49, p=<0.001). Importantly, plecanatide 3mg dose also showed a statistically significant difference from placebo in the overall FDA responder endpoint (21% placebo v. 41.9%, p=<0.05). The treatment effects of plecanatide occurred within the first week. The company intends to initiate pivotal phase III trials in IBS-C patients in the second half of 2014.

February 17, 2014

Furiex Pharmaceuticals released results of phase III trials of eluxadoline for the treatment of diarrhea-predominant irritable bowel syndrome (IBS-d). The studies were randomized, double-blind, placebocontrolled studies in which patients received eluxadoline, 75mg twice-daily (BID), eluxadoline 100mg BID or placebo BID. A total of 2,428 subjects were enrolled across the two studies. The primary efficacy endpoint was a composite response evaluated over the initial 12 weeks of double-blind treatment for FDA evaluation. Response rates were compared based on patients who met the daily composite response criteria (improvement in pain and stool consistency) for at least 50% of the days from weeks 1 to 12 and weeks 1 to 26. Worst abdominal pain scores in the past 24 hours improved by 30% compared to baseline (average of week prior to randomization). The responder rates were 29.5% for eluxadoline 100mg, 28.9% for eluxadoline 75mg and 16.2% for placebo. Eluxadoline-treated patients demonstrated significantly higher rates of stool consistency response over weeks 1 to 12, namely 100mg=35.5%, 75mg=37.0% and placebo=20.9% (p =0.12). The company anticipates NDA submission by the end of the second quarter of 2014.

September 12, 2011

Furiex issued results from a phase II trial of MuDelta for diarrhea-predominant irritable bowel syndrome. This 12-week randomized, double-blind, placebo-controlled study enrolled 807 subjects who received twice daily (BID) treatment with either placebo or MuDelta at doses of 5, 25, 100 or 200 mg. The 5 mg dose group was dropped after a planned interim analysis, due to limited efficacy, while the other three doses were continued. The primary endpoint, a composite analysis of stool consistency and abdominal pain at week four compared with baseline symptoms, was met with statistical significance over placebo. The rates of treatment response were 12% for MuDelta at 25 mg BID (p≡0.041) and 13.8%; for Mu Delta 200 mg BID (P≡0.015) compared to 5.7% for placebo. Secondary endpoints were also reached at week 12, including relief of IBS-D symptoms and quality of life improvements. MuDelta was well-tolerated and had a favorable safety profile.

August 1, 2011

Lexicon Pharmaceuticals released results from a phase I trial of LX1033 for the treatment of diarrhea-predominant irritable bowel syndrome (IBS-d). This randomized, placebo-controlled trial enrolled 32 healthy subjects who received LX1033 at 250 mg, 500 mg, or 750 mg three times daily, 1,000 mg given twice daily, or placebo. The treatment duration was 14 days. Top-line results demonstrated that LX1033 was well tolerated at all doses and produced a statistically significant reduction in serotonin synthesis compared to placebo, as measured by both plasma (p<0.001) and urinary (p<0.01) 5-hydroxyindoleacetic acid (5-HIAA), a biomarker for serotonin synthesis.

November 8, 2010

Ironwood and Forest Laboratories reported positive results from a phase III trial of linaclotide for the treatment of irritable bowel syndrome with constipation (IBS-C). This U.S-based randomized, double-blind, placebo-controlled study, dubbed MCP-103-302, enrolled 805 subjects who received a once-daily dose of oral linaclotide 266 mcg or placebo for 26 weeks. The primary endpoints were assessed over the first 12 weeks of treatment an included two composite responder endpoints encompassing abdominal pain and complete spontaneous bowel movements (CSBMs), as well as two individual responder endpoints for abdominal pain and CSBMs. In order to be considered a responder, the endpoints had to be met for at least nine of the first 12 weeks of the treatment period (composite responder endpoint 1) and for at least six of the first 12 weeks (composite responder endpoint 2). A greater proportion of the linaclotide arm versus the placebo arm (12.7% vs. 3%; p<0.0001) had, in the same week, at least a 30 percent reduction in abdominal pain, at least three CSBMs, and an increase of one or more CSBMs. In the linaclotide arm, 18% of the subjects had at least three CSBMs and an increase of one or more CSBMs versus 5% in the placebo arm (p<0.0001). A greater proportion of the linaclotide arm compared to placebo arm (38.9% vs. 19.6%; p<0.0001) had at least a 30 percent reduction in abdominal pain. In addition, a greater proportion of the linaclotide arm compared to the placebo arm (33.7% vs. 13.9%; p<.0001) had, in the same week, at least a 30 percent reduction in abdominal pain and an increase of one or more CSBMs. The treatment was generally well tolerated and the most common adverse event was diarrhea.

September 20, 2010

Ironwood Pharmaceuticals and Forest Labs released positive results from a phase III trial of linaclotide for irritable bowel syndrome with constipation. This multicenter, randomized, double-blind, placebo-controlled trial (LIN-MD-31) enrolled 803 subjects who received either a 266 mcg once daily dose of linaclotide or placebo for a 12 week period. There were four primary efficacy endpoints: two composite responder endpoints encompassing abdominal pain and complete spontaneous bowel movements (CSBMs) and individual responder endpoints for abdominal pain and CSBMs. To be considered a responder, the first three endpoints had to be met for at least nine of the 12 weeks of the treatment, while the fourth had to be met for at least six of the 12 weeks. All four endpoints showed statistically significant improvement over placebo. In the linaclotide arm 12.1% of subjects had, in the same week, at least a 30 percent reduction in abdominal pain, at least three CSBMs, and an increase of one or more CSBMs versus 5.1% of the placebo arm (p≡0.0004). A greater proportion of the linaclotide arm compared to the placebo arm had, in the same week, at least three CSBMs and an increase of one or more CSBMs (19.5% versus 6.3%, p<0.0001). In the linaclotide arm 34.3% had at least a 30 percent reduction in abdominal pain versus 27.1% in the placebo arm (p≡0.0262). A greater proportion of linaclotide arm had, in the same week, at least a 30 percent reduction in abdominal pain and an increase of one or more CSBMs compared to placebo arm (33.6% versus 21%, p<0.0001) All secondary endpoints were also reached.

May 17, 2010

Salix released positive results from two phase III trials of Xifaxan for the treatment of non-constipation irritable bowel syndrome. These randomized, double-blind, placebo-controlled studies were dubbed TARGET-1 and TARGET-2 (Targeted, non-systemic; Antibiotic; Rifaximin; Gut-selective; Evaluation of; Treatment for non-C IBS). Each study enrolled 600 subjects across multiple sites in North America. The subjects received Xifaxan 550 mg or placebo three times daily for 14 days and were then followed for an additional ten weeks. The primary endpoint was defined as the percentage of patients who had adequate weekly relief of IBS symptoms for two or more weeks during the first four weeks following the two-week treatment period. The combined data show that 41% of subjects in the Xifaxan arm reached the primary endpoint versus 32% in the placebo arm (p≡0.0008). The key secondary endpoint, adequate relief of bloating, was reached by 40% of the Xifaxan arm versus 30% of the placebo arm (p≡0.0002).

November 23, 2009

Lexicon issued positive results from a phase II trial of LX1031 for the treatment of non-constipating irritable bowel syndrome (IBS). This four-week, randomized, double-blind, placebo-controlled study enrolled 155 subjects with either diarrhea-predominant IBS or mixed IBS. The subjects received one of two dose levels, a 250 mg or 1,000 mg dose, each administered four times daily. Top-line results showed that treatment with one gram of LX1031 four times daily produced a statistically significant improvement in global assessment of relief of IBS pain and discomfort over the four-week dosing period as compared to placebo (p≡0.0465). Improvements in global assessment parameters also corresponded with statistically significant improvements in stool consistency. LX1031 was well tolerated.

September 21, 2009

Salix issued positive results from two phase III trials of rifaximin for the treatment of non-constipation irritable bowel syndrome. These randomized, double-blind, placebo-controlled, multi-center studies were dubbed TARGET-1 and TARGET-2 (Targeted, non-systemic; Antibiotic; Rifaximin; Gut-selective; Evaluation of; Treatment for non-C IBS). Each study enrolled 600 subjects across the US and Canada. The subjects received rifaximin 550 mg dosed three times daily or placebo for 14 days. The primary endpoint was the proportion of subjects who achieved adequate relief of IBS symptoms for at least 2 weeks during the first 4 weeks of the 10-week follow-up phase. In each trial rifaximin demonstrated a statistically significant improvement for adequate relief of IBS symptoms as assessed over one month (weeks 3, 4, 5 and 6) following completion of a 14-day course of therapy. The key secondary endpoint of relief of IBS-related bloating also demonstrated statistical significance of rifaximin versus placebo in each trial.

October 13, 2008

Ironwood and Forest reported positive results from a phase IIb trial of linaclotide for the treatment of irritable bowel syndrome with constipation (IBS-C). This randomized, double-blind, placebo-controlled study enrolled 420 subjects. Following a no-drug washout period of 14-17 days the subjects received placebo or linaclotide once-daily in the morning at doses of 75 mcg, 150 mcg, 300 mcg or 600 mcg, for 12 weeks. The primary endpoint was the change in the overall mean weekly frequency of complete spontaneous bowel movements from the pre-treatment baseline through the 12-week treatment period. Statistical significance was reached for all linaclotide doses (2.5 to 3.6 versus 1.0; p = 0.0036 to <0.0001). In addition, abdominal pain was clinically and statistically significantly reduced in all linaclotide treatment groups compared to placebo (-0.7 to -0.9 change from baseline on a 5-point ordinal severity scale versus -0.5; p = 0.0239 to <0.0001). This improvement was more pronounced in the 26 percent of subjects with severe to very severe baseline abdominal pain (-0.8 to -1.3 versus -0.2; p = 0.0236 to <0.0001). Secondary endpoints, including spontaneous bowel movement frequency, stool consistency, straining, abdominal discomfort, bloating, IBS symptom severity, and global assessments were statistically significant for the 300 mcg and 600 mcg dose groups and for at least one of the two lower doses for each endpoint. Ironwood and Forest expect to have two phase III trials for IBS-C underway by January of 2009.

May 26, 2008

Salix reported positive results from a phase IIb trial of rifaximin for the treatment of diarrhea-associated irritable bowel syndrome (d-IBS). This multi-center, double-blind, placebo-controlled, randomized trial enrolled adult subjects who received rifaximin 550 mg twice daily or placebo for 14 days, followed by an additional 14 days of placebo in both groups and a 12-week follow-up phase. The co-primary endpoints were adequate relief of global IBS symptoms (SGA) and adequate relief of bloating (BL) compared to placebo. Both endpoints were reached, with a significant improvement over placebo in SGA (52% versus 44% respectively, P=0.03) and adequate relief of BL (46% versus 40%, P=0.04). Response was sustained up to 12 weeks after treatment was discontinued. Rifaximin improved both SGA and BL in equal to or greater than four weeks (p<0.05), during all four weeks (p=0.02), and at week three (p<0.02) and week four (p<0.02). At week four (end of treatment phase) subjects in the rifaximin arm achieved relief of SGA (53%) and BL (50%) compared to 43% and 42% of subjects in the placebo arm, respectively (p=0.01). At the end of the 12-week follow-up, rifaximin treatment resulted in an improvement in SGA versus placebo (62% versus 49%, respectively; p<0.05) and BL (59% versus 51%, respectively; p<0.05). Treatment was well tolerated with an adverse event profile comparable to placebo. Based on the results Salix plans to pursue FDA approval of rifaximin for this indication.

Tioga released positive results from a phase IIb trial of asimadoline for the treatment of irritable bowel syndrome (IBS). This randomized, double-blind, placebo-controlled, dose-ranging study enrolled 596 subjects with diarrhea-predominant IBS, constipation predominant IBS and alternating IBS. The subjects received asimadoline 0.15 mg, 0.5 mg or 1.0 mg tablets or placebo twice daily for 12 weeks. The primary endpoint was number of months a subject was a responder for adequate relief of pain. Secondary endpoints included adequate relief of IBS symptoms and straining. Benefit in subjects with D-IBS and A-IBS was observed while no benefit was observed in the C-IBS group. The subjects with D-IBS with at least moderate pain achieved a 27% improvement in the percent number of months with adequate relief of IBS pain compared to placebo (47% versus 20%, p=0.011) with the 0.5mg dose of asimadoline. A 25% increase in pain free days was seen with 0.5 mg asimadoline as compared with placebo (p=0.001). Statistically significant improvement in pain was seen by week three and persisted for the duration of treatment (p<0.05). Statistically significant improvements over placebo were seen at the 0.5 mg dose of asimadoline in the following secondary endpoints: urgency, adequate relief of IBS symptoms, stool frequency, bloating and daily pain. At the 1.0 mg dose of asimadoline statistically significant improvements were seen in the secondary endpoints of urgency, adequate relief of IBS symptoms, bloating and daily pain. The subjects with A-IBS with at least moderate pain achieved a 23% improvement in the percent number of months with adequate relief of IBS pain compared to placebo (50% versus 27%, p=0.022) with the 1.0 mg dose of asimadoline. Statistically significant benefit was also seen in the secondary endpoint of adequate relief of IBS symptoms at the 1.0 mg compared to placebo (57% versus 33%, p=0.032). Based on the results Tioga plans to continue with the development of asimadoline.

April 28, 2008

Alizyme released negative results from a phase III trial of renzapride for the treatment of constipation-predominant irritable bowel syndrome (IBS-C). This multicenter, randomized, double-blind, placebo-controlled, parallel-group trial enrolled one thousand eight hundred and twenty one subjects who received renzapride 4mg once a day, renzapride 2mg twice daily or placebo for twelve weeks. Of the enrolled subjects, one thousand seven hundred and ninety eight were evaluable for results. The primary endpoint, duration of relief of overall IBS symptom, reached statistical significance over placebo. The proportion of subjects who reported at least some improvement in their overall symptoms were about 60% in the two renzapride groups compared to about 55% in the placebo group each week, for a 5-6% average increase over the placebo group. In addition, limited effects were seen on the three key secondary endpoints, relief of abdominal pain, relief of bowel problems and relief of bloating. There were no safety and tolerability issues. Based on the results Alizyme has decided to discontinue clinical development of renzapride.

January 7, 2008

Dynogen reported positive results from a phase II trial of DDP-225 for the treatment of irritable bowel syndrome with diarrhea (IBS-d). This randomized, double-blind, placebo controlled trial enrolled eighty-seven women in the United States and Canada. The primary endpoint of adequate relief of pain and discomfort was achieved. The 1 mg dose of DDP225 administered once daily for eight weeks achieved a 71% response rate compared to a 25% response rate for placebo (p=0.009). Treatment was safe and well tolerated. Based on the results, Dynogen planned to initiate phase IIb trials in 2008.

May 28, 2007

Microbia reported positive results from a phase II trial of linaclotide for the treatment of irritable bowel syndrome with constipation (IBS-C). This double-blind, placebo-controlled trial enrolled 36 women who were evaluated in a five-day baseline and five-day treatment study. The primary endpoints were measurements of gastrointestinal transit and bowel function. When compared to placebo, the subjects who received linaclotide had a significant acceleration of ascending colon emptying and colonic transit at 48 hours post dose, as measured by scintigraphy. Stool consistency, stool frequency, straining and time to first bowel movement were also significantly improved when compared to placebo (p=< 0.05 for each). Based on the results Microbia plans to move forward with the development of linaclotide.

Sucampo issued positive results from two phase III trials of Amitzia for the treatment of irritable bowel syndrome with constipation (IBS-C). These double-blind, randomized, placebo- controlled trials enrolled 1,171 subjects with IBS-C who received Amitzia (8 mcg) twice daily or placebo for 12-weeks. The primary endpoint, overall response, was reached by 17.9% of the subjects treated with Amitzia compared to 10.1% of those on placebo (P=0.001). The incidence of adverse events was similar in both the treatment and placebo arms. Sucampo plans to submit a sNDA to the FDA by July of 2007.

February 19, 2007

Dynogen reported positive results from a phase II trial of DDP733 for the treatment of irritable bowel syndrome with constipation (IBS-c). This randomized, double-blind, placebo-controlled, parallel group trial enrolled 91 subjects in Canada. Treatment was well tolerated with adverse events mild to moderate in nature. The clinical response rate, measured using the Overall Subject Global Assessment (OSGA), reached statistical significance versus placebo. The overall clinical response rate was 54% in subjects receiving DDP733 at a dose of 1.4 mg t.i.d. compared to a 15% for those receiving placebo. Based on these results, Dynogen plans to initiate a phase IIb trial later in 2007.

May 29, 2006

Microbia issued positive results of a phase Ib trial of linaclotide, for the treatment of constipation-predominant irritable bowel syndrome (IBS-C) and chronic constipation (CC), at the DDW annual meeting. Preliminary data yielded evidence of pharmacodynamic activity in the gastrointestinal tract, as measured by markers of intestinal transit, stool consistency, stool weight, and time to first bowel movement. No evidence of systemic exposure was observed, and treatment was safe and well tolerated. Based on these data, the company announced plans to initiate phase II trials of the drug in the near future.

PDL BioPharma announced positive results of a phase I trial of Nuvion (visilizumab), for the treatment of Crohn's disease (CD), at the 2006 Digestive Disease Week (DDW) annual meeting. This multi-center open-label study enrolled 14 patients with moderate to severe non-penetrating CD, who received two doses of 10 mcg/kg Nuvion via IV bolus injection. Preliminary data yielded evidence of efficacy, with 10 of 14 subjects demonstrating clinical response (> 100 point decrease) on the CDAI diagnostic scale. 5 subjects achieved complete remission (total CDAI score <150 points) during the treatment period. Nuvion-responsive patients included 5 subjects who had relapsed on infliximab, and 2 subjects whose disease never responded. No lymphoproliferative, malignant or life-threatening adverse events were reported.

November 7, 2005

Microbia has issued positive results of a phase I trial of MD-1100, for the treatment of constipation-predominant irritable bowel syndrome (IBS-C), at the 70th annual scientific meeting of the American College of Gastroenterology. Primary safety data yielded no reported serious adverse events and a positive overall tolerability profile. Preliminary efficacy data indicated changes in intestinal transit and motility expected to supportive of IBS-C symptom amelioration. This study enrolled healthy volunteers, who received single doses of the drug. The company announced plans to move development of the drug into later stage trials based on these results.

January 10, 2005

Vela has reported results of a phase II trial of dextofisopam, for the treatment of irritable bowel syndrome (IBS). Trial data achieved their primary endpoint, with subjects receiving the drug reporting symptom relief significantly more often vs. subjects receiving placebo (57% vs. 43%; p=0.033). Data also met secondary endpoints, including improvements in stool frequency and consistency; these improvements occurred more often in subject with diarrhea-predominant IBS than subjects with alternating-type IBS. This double-blind, placebo-controlled trial enrolled 141 patients of both genders with diarrhea-predominant and alternating-type IBS, who were randomized to receive dextofisopam or placebo twice daily for 12 weeks. Vela announced that, based on these results, they planned to proceed into the next phase of development in the near future.

November 8, 2004

Solvay Pharmaceuticals reported positive data from a pair of phase III trials of cilansetron for the treatment of irritable bowel syndrome with diarrhea predominance (IBS-D) at the Annual Meeting of the American College of Gastroenterology. Combined study results have indicated that the drug produced significant improvements in health related quality of life in both male and female subjects, with significant improvements in symptom severity scores (17.7 for cilansetron vs. 9.6 for placebo; p<0.005). In addition, the drug met several efficacy endpoints, with a significantly greater portion of subjects reporting adequate overall symptom relief on more than half their visits with cilansetron than placebo (49% vs. 28%; p<0.001), especially with abdominal pain (52% vs. 37%; p<0.001), and abnormal bowel habits (51% vs. 26%; p<0.001). These data were collected from two phase III trials of the drug: a 6-month, multinational study which randomized 338 subjects (157 male, 181 female) to receive either thrice daily oral dosing if cilansetron three times daily or placebo; and a three month US study which enrolled 205 males and 487 females to receive cilansetron or placebo. These data were part of the data used to support Solvay’s NDA for the drug. If approved, it would become the first drug approved to threat IBS-D in both men and women.

October 20, 2003

Novartis reported positive results from a post-marketing trial investigating Zelnorm (tegaserod maleate), an approved drug for the treatment of irritable bowel syndrome with constipation. Results showed Zelnorm was significantly more effective than placebo in improving straining, stool consistency, frequency of bowel movements, and other symptoms of chronic constipation. Data demonstrated that Zelnorm-treated subjects experienced significantly more complete spontaneous bowel movements than subjects receiving placebo did. The multinational, randomized, double-blind, placebo-controlled study enrolled 1,264 subjects. Subjects had experienced chronic constipation for an average of 15 years. Results were presented today at the 68th Annual Scientific Meeting of the American College of Gastroenterology.

July 14, 2003

The BioBalance Corp. reported positive results from a pilot study investigating Probactrix, a probiotic oral suspension for the treatment of irritable bowel syndrome (IBS). Probactrix is a formulation of M-17 E. coli which is approved as an OTC pharmaceutical in Russia and as a food supplement in Israel. Results showed eight out of ten subjects that started on placebo dropped out because of infectivity compared with none of the subjects taking ProBactrix. Data demonstrated significant improvement in bowel movement and mucus in stools among subjects taking ProBactrix. The randomized, double blind study enrolled 20 subjects experiencing severe symptoms of diarrhea and constipation. Results were presented at the 2003 Annual Meeting of the American Society of Gastroenterologists.

June 9, 2003

Pain Therapeutics reported positive results from a phase I/II trial investigating PTI-901 (naltrexone), an opioid antagonist for the treatment of irritable bowel syndrome (IBS). Results showed a response rate of 76.2% after four weeks. PTI-901 was well tolerated by all subjects during the entire period. Data also demonstrated improvements in all secondary endpoints including, daily abdominal pains, bowel habits and stool consistency. In addition, subjects on PTI-901 reported a 193% increase in number of pain-free days at week 4 compared to baseline. Treatment consisted of a 0.5mg dose of PTI-901 daily over a four-week period. The open-label study enrolled 50 subjects who were diagnosed with IBS by a gastroenterologist according to Rome II Criteria. The study was conducted at the Sourasky Medical Center in Israel.

April 1, 2002

Results of a pilot phase II trial of ALX-0600 showed statistically significant improvement in intestinal function of 11 subjects with short bowel syndrome. Subjects received one of three doses of ALX-0600 by daily subcutaneous injections during a treatment period of 21 days. Results of three 72 hour balance studies measuring improvement in intestinal function showed significant improvements in the absorption of wet-weight from all dietary sources, decreases in fecal volume, increases in urine volume and decreases in fecal energy excretion. A result of this improved intestinal function was a statistically significant increase in body mass. NPS Pharmaceuticals also reported that histological examination of tissue from patient biopsies showed a significant increase in the number and size of epithelial cells that line the small bowel.