Aldafermin (NGM282) for Chronic Diarrhea Due to Bile Acid Malabsorption (BAM)

Inclusion Criteria

• Aged 18 to 75 years, inclusive at Visit 1 Screen.
• Clinical diagnosis of functional diarrhea or IBS with diarrhea according to Rome III or IV criteria at Visit 1 Screen.
• Clinical laboratory evidence of BAM (20-22), with at least one of the following results recorded in their past medical history:
• Serum C4 ≥ 52 ng/mL
• Fecal BA > 2337 µmoles / 48 hours
• Total fecal BA > 1000 µmoles / 48 hours + 4 % primary BA
• Fecal primary BA > 10% / 48 hours
• Body mass index (BMI) 18.0 to 45.0 kg/m2, inclusive at Visit 1 Screen
• Understands the study procedures, is willing and able to comply with the study procedures, and is able to give informed consent
• If treated with any of the following medications, dosing must be stable for 30 days prior to Visit 1 Screen. Patient must agree to maintain the same dose of medication throughout the study:
• Tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs).
• Bile acid sequestrants such as colestipol, cholestyramine and colesevelam.
• Participants must use one highly effective method of contraception for 30 days before the study through 90 days after study completion for males and through 30 days after study completion for females. Highly effective methods of contraception include: Oral, implantable, transdermal or injectable hormonal contraceptives; standard intrauterine device or vaginal ring; Male or female condoms and diaphragms used with spermicide; abstinence from heterosexual intercourse; female partners exclusively sexually active with a surgically sterilized male partner. Females who are surgically sterile having experienced a prior hysterectomy, bilateral salpingectomy, or bilateral oophorectomy or postmenopausal (defined as12 consecutive months with no menses) are not considered to be of childbearing potential.

Exclusion Criteria

• Pregnant or lactating
• Structural or metabolic diseases/conditions that affect the gastrointestinal system
• Use of the following medications at least 14 days prior to Visit 1 throughout the duration of the treatment period
• Patients may elect to withdraw from bile acid sequestrants such as colestipol, cholestyramine and colesevelam or they may continue but they must continue at the same dose throughout the study.
• GI medications including:
• Anti-nausea agents including trimethobenzamide, promethazine, prochlorperazine, dimenhydrinate, hydroxyzine
• Osmotic laxative agents including lactulose, sorbitol or PEG solutions as Miralax and Glycolax
• Prokinetic agents including tegaserod, metoclopramide, prucalopride, domperidone, erythromycin, clarithromycin and azithromycin.
• 5-HT3 antagonists including alosetron, ondansetron, tropisetron
• Drugs with a known pharmacological activity at 5-HT4, 5-HT2b or 5-HT3 receptors including tegaserod, ondansetron, granisetron and tropisetron
• All narcotics including codeine, morphine, and propoxyphene, either alone or in combination
• Anti-cholinergics including dicyclomine, hyoscyamine, propantheline.
• Antimuscarinics
• Tramadol
• Peppermint oil
• Systemic antibiotics and antibiotics directed at colonic flora including rifaximin and metronidazole
• Use of CNS stimulant medications, including methylphenidate, atomoxetine, modafinil, amphetamines or phentermine.
• Clinically relevant changes in dietary, lifestyle, or exercise regimen within 30 days prior to Visit 1 Screen and throughout the duration of the study
• Any colonic or major abdominal surgery including bariatric surgery, gastric banding, stomach surgery and intestinal or colonic surgery. Procedures such as appendectomy, cholecystectomy, hysterectomy, caesarean section, or polypectomy are allowed as long as they have occurred at least 3 months prior to Visit 1 Screen.
• .History of colorectal cancer, inflammatory bowel disease, diverticulitis, ischemic colitis, microscopic colitis or celiac disease
• History of organic abnormalities o