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

Inclusion Criteria:

1. Aged 18 to 75 years, inclusive at Visit 1 Screen.
2. Clinical diagnosis of functional diarrhea or IBS with diarrhea according to Rome IIIor IV criteria at Visit 1 Screen.
3. Clinical laboratory evidence of BAM (20-22), with at least one of the followingresults 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

4. Body mass index (BMI) 18.0 to 45.0 kg/m2, inclusive at Visit 1 Screen
5. Understands the study procedures, is willing and able to comply with the studyprocedures, and is able to give informed consent
6. If treated with any of the following medications, dosing must be stable for 30 daysprior to Visit 1 Screen. Patient must agree to maintain the same dose of medicationthroughout the study:

• Tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs),serotonin and norepinephrine reuptake inhibitors (SNRIs).
• Bile acid sequestrants such as colestipol, cholestyramine and colesevelam.

7. Participants must use one highly effective method of contraception for 30 days beforethe study through 90 days after study completion for males and through 30 days afterstudy completion for females. Highly effective methods of contraception include: Oral,implantable, transdermal or injectable hormonal contraceptives; standard intrauterinedevice or vaginal ring; Male or female condoms and diaphragms used with spermicide;abstinence from heterosexual intercourse; female partners exclusively sexually activewith a surgically sterilized male partner. Females who are surgically sterile havingexperienced a prior hysterectomy, bilateral salpingectomy, or bilateral oophorectomyor postmenopausal (defined as12 consecutive months with no menses) are not consideredto be of childbearing potential.

Exclusion Criteria:

1. Pregnant or lactating
2. Structural or metabolic diseases/conditions that affect the gastrointestinal system
3. Use of the following medications at least 14 days prior to Visit 1 throughout theduration 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 thesame 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 Miralaxand 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 receptorsincluding tegaserod, ondansetron, granisetron and tropisetron
• All narcotics including codeine, morphine, and propoxyphene, either alone or incombination
• Anti-cholinergics including dicyclomine, hyoscyamine, propantheline.
• Antimuscarinics
• Tramadol
• Peppermint oil
• Systemic antibiotics and antibiotics directed at colonic flora includingrifaximin and metronidazole

4. Use of CNS stimulant medications, including methylphenidate, atomoxetine, modafinil,amphetamines or phentermine.
5. Clinically relevant changes in dietary, lifestyle, or exercise regimen within 30 daysprior to Visit 1 Screen and throughout the duration of the study
6. 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 longas they have occurred at least 3 months prior to Visit 1 Screen.
7. .History of colorectal cancer, inflammatory bowel disease, diverticulitis, ischemiccolitis, microscopic colitis or celiac disease
8. History of organic abnormalities of the GI tract, intestinal obstruction, stricture,toxic megacolon, GI perforation, or impaired intestinal circulation.
9. Other GI diseases such as GI bleeding or ulcerations
10. History of cerebrovascular disease including stroke, TIA, acute coronary syndrome,myocardial infarction or unstable angina
11. Clinically significant cardiac history or presence of electrocardiogram (ECG) findingsat Visit 1 Screen:

• Abnormal heart rate < 40 or > 100 beats per minute
• QTc interval > 470 milliseconds (ms)
• QRS interval ≥ 110 ms
• PR interval ≥ 220 ms

12. Hepatic dysfunction including abnormal serum alanine aminotransferase [ALT] oraspartate transaminase [AST] > 3 × upper limit of normal [ULN]); total directbilirubin > 2 × ULN, or alkaline phosphatase > 2 × ULN at Visit 1 Screen
13. Clinically significant renal insufficiency including serum creatinine > 2.5 mg/dL atVisit 1 Screen
14. History of severe head injury or history of seizures
15. History of suicide attempt or a hospitalization for a major psychiatric conditionwithin 1 year prior to Visit 1 Screen. At Visit 1 Screen or during the optional remoteconsent and eligibility review, participants will complete the Hospital Anxiety andDepression questionnaire. If either score for anxiety or depression individuallyexceeds 8, the score will be discussed. The patient will be and advised whether toparticipate or whether to see their primary care physician.
16. History of alcohol use disorder or substance use disorder within 2 years of Visit 1Screen.
17. Significant history or clinical manifestation of any endocrine, allergic,dermatological, hepatic, renal, hematological, pulmonary, GI, neurological orpsychiatric disorder, malignancy (with the exception of treated basal cellcarcinomas), or any other condition that would prevent the individual fromparticipating in the study due to risk to the scientific validity of study assessmentsor to personal well-being of the patient.
18. Participated in another clinical study that includes an investigational drug or abiologic therapy within 30 days or 5 half-lives, whichever time period is longer,prior to Visit 1 Screen.