Eligibility Details:
Parts A and B Inclusion Criteria:
1. Males or females of nonchildbearing potential, of any race, 18 to 60 years of age,
inclusive, at Screening.
Females of nonchildbearing potential are defined as permanently sterile (ie, due to
hysterectomy, bilateral salpingectomy, or bilateral oophorectomy) confirmed by history
or postmenopausal (defined as at least 12 continuous months without menses and
follicle-stimulating hormone [FSH] ≥40 mIU/L and without an alternative medical
cause).
2. Body mass index between 18.0 and 30.0 kg/m2 , inclusive, with a minimum body weight of
50.0 kg at Screening.
3. In good health, determined by no clinically significant findings from medical history,
physical examination, 12-lead ECG, vital signs measurements, and clinical laboratory
evaluations (congenital nonhemolytic hyperbilirubinemia [eg, Gilbert's syndrome] is
not acceptable) at Screening or Check-in as assessed by the Investigator (or
designee).
4. Male subjects who are surgically sterile for at least 90 days will not need to use
contraception. Male subjects who are not surgically sterile for at least 90 days will
be required to use a male condom with spermicide when sexually active with female
partners of childbearing potential from Check-in until 90 days after the last dose of
study drug. Sexual intercourse with female partners who are pregnant or breastfeeding
should be avoided unless condoms are used from the time of the first dose until 90
days after the last dose of study drug. Male subjects are required to refrain from
donation of sperm from Check-in until 90 days after the last dose of study drug.
5. Has maintained stable weight (by history) for at least 4 weeks prior to Screening.
6. Agrees to the following:
- Not to initiate a weight-loss program from Screening until the Follow-up visit;
- To refrain from strenuous exercise from 7 days before Check-in until the
Follow-up visit;
- To maintain consistent dietary habits and exercise routines for the duration of
the study.
7. Must have transaminases (AST and ALT) and total bilirubin within the normal range at
Screening and Check-in. For other laboratory evaluations, the subject may be included
only if the Investigator judges the abnormalities or deviations from normal to be not
clinically significant.
8. Able to comprehend and willing to sign an ICF and to abide by the study restrictions.
Parts A and B Exclusion Criteria:
1. Significant history or clinical manifestation of any metabolic, allergic,
dermatological, hepatic, renal, hematological, pulmonary, cardiovascular,
gastrointestinal, neurological, respiratory, endocrine, or psychiatric disorder, as
determined by the Investigator (or designee).
2. Clinically significant ECG abnormalities or QTcF >450 milliseconds for males and >470
milliseconds for females at either Screening or Check-in, or any prior history of QT
abnormality.
3. Creatinine clearance of <90 mL/min at Screening, determined using the Cockcroft-Gault
(C-G) equation.
4. History of febrile illness within 7 days prior to the first dose of study drug or
subjects with evidence of active infection.
5. History of significant hypersensitivity, intolerance, or allergy to any drug compound,
food, or other substance, unless approved by the Investigator (or designee).
6. History of alcoholism or drug/chemical abuse within 2 years prior to Check-in.
7. Alcohol consumption of >21 units per week for males and >14 units for females. One
unit of alcohol equals 12 oz (360 mL) beer, 1½ oz (45 mL) liquor, or 5 oz (150 mL)
wine.
8. Positive urine drug screen (confirmed by repeat) at Screening or positive alcohol
breath or urine test result or positive urine drug screen at Check-in.
9. Positive hepatitis panel and/or positive human immunodeficiency virus test. Subjects
with serologic finding of immunity consistent with history of prior hepatitis B
vaccination may be enrolled.
10. Participation in a clinical study involving administration of an investigational drug
(new chemical entity) in the past 30 days prior to dosing or have received a
biological product within 3 months or 5 elimination half-lives (whichever is longer)
prior to dosing.
11. Use of prescription drugs, nonprescription drugs, dietary supplements including
Vitamin E, herbal supplements, hormonal therapy/replacement, or CYP3A4 substrates,
inducers and inhibitors within 14 days prior to the first dose of study drug unless,
in the opinion of the Investigator and Sponsor's Medical Monitor, the medication will
not interfere with the study procedures or compromise subject safety.
12. Use or intend to use slow-release medications/products considered to still be active
within 14 days prior to Check-in, unless deemed acceptable by the Investigator (or
designee).
13. Use or intend to use any nonprescription medications/products including vitamins,
minerals, and phytotherapeutic/herbal/plant-derived preparations within 14 days prior
to the first dose of study medication, unless deemed acceptable by the Investigator
(or designee).
14. Use of tobacco- or nicotine-containing products within 3 months prior to Check-in.
15. Receipt of blood products within 2 months prior to Check-in.
16. Donation of blood from 56 days prior to Screening, plasma from 2 weeks prior to
Screening, or platelets from 6 weeks prior to Screening.
17. Poor peripheral venous access.
18. Have previously completed or withdrawn from this study or any other study
investigating CB4211, and have previously received the investigational product.
19. Subjects who, in the opinion of the Investigator (or designee), should not participate
in this study.
Part C Inclusion Criteria:
1. Males or females of nonchildbearing potential, of any race, 18 to 60 years of age,
inclusive, at Screening.
Females of nonchildbearing potential are defined as permanently sterile (ie, due to
hysterectomy, bilateral salpingectomy, or bilateral oophorectomy) confirmed by history
or postmenopausal (defined as at least 12 continuous months without menses and FSH ≥40
mIU/L and without an alternative medical cause).
2. Body mass index between 30.0 and 38.0 kg/m2 , inclusive, and body weight ≤115 kg at
Screening.
3. History of Fatty Liver Index (FLI) score >60 or documented history of fatty liver with
imaging results (eg, standard positive ultrasound or Fibroscan CAP >300 dB/m)
indicating liver fat >10% within 6 months of Screening. A formal diagnosis of NAFLD is
not required.
4. Fibroscan CAP >300 dB/m within 6 weeks prior to Check-in.
5. Liver fat content ≥10% as determined by MRI-PDFF 7 to 10 days prior to Check-in.
6. No history of common causes of secondary hepatic steatosis such as:
1. Macrovesicular steatosis: excessive alcohol consumption, hepatitis C (genotype
3), Wilson's disease, lipodystrophy, starvation, parenteral nutrition,
abetalipoproteinemia, medications (eg, amiodarone, methotrexate, tamoxifen,
corticosteroids, or any drug known to affect hepatic steatosis or insulin
resistance)
2. Microvesicular steatosis: Reye's syndrome, medications (valproate,
anti-retroviral medicines), acute fatty liver of pregnancy, HELLP syndrome,
inborn errors of metabolism (eg, lecithin-cholesterol acyltransferase deficiency,
cholesterol ester storage disease, Wolman disease, lysosomal acid lipase
deficiency)
7. Glycosylated hemoglobin A1c of ≥4.0% to ≤6.4% at Screening.
8. Fasting blood glucose of ≥100 to <126 mg/dL at Screening.
9. Serum triglyceride level ≤500 mg/dL at Screening
10. Have INR <ULN and platelet count >150,000 at Screening and Check-in. For other
abnormalities, the subject may be included only if the Investigator judges the
abnormalities or deviations from normal to be not clinically significant.
11. Two BLMs of ALT, AST, ALP, and total bilirubin that were obtained approximately 4
weeks apart must both be less than the ULN or, if one of the measurements is >ULN,
must meet the following criteria prior to randomization:
1. ALT ≤3 x ULN for both measurements and the difference between the measurements
should be <20% of the lower value;
2. AST ≤3 x ULN for both measurements and the difference between the measurements
should be <20% of the lowest value;
3. ALP ≤3 x ULN for both measurements and the difference between the measurements
should be <20% of the lowest value;
4. Total bilirubin <ULN for both measurements and the difference between
themeasurements should be <20% of the lowest value.
12. In good health, determined by no clinically significant findings from medical history,
physical examination, 12-lead ECG, vital signs measurements, and clinical laboratory
evaluations (congenital nonhemolytic hyperbilirubinemia [eg, Gilbert's syndrome] is
not acceptable) at Screening or Check-in as assessed by the Investigator (or
designee).
13. Male subjects who are surgically sterile for at least 90 days will not need to use
contraception. Male subjects who are not surgically sterile for at least 90 days will
be required to use a male condom with spermicide when sexually active with female
partners of childbearing potential from Check-in until 90 days after the last dose of
study drug. Sexual intercourse with female partners who are pregnant or breastfeeding
should be avoided unless condoms are used from the time of the first dose until 90
days after the last dose of study drug. Male subjects are required to refrain from
donation of sperm from Check-in until 90 days after the last dose of study drug.
14. Has maintained stable weight (by history) for at least 4 weeks prior to Screening.
15. Agrees to the following:
- Not to initiate a weight-loss program from Screening until the Follow-up visit;
- To refrain from strenuous exercise from 7 days before Check-in until the
Follow-up visit;
- To maintain consistent dietary habits and exercise routines for the duration of
the study.
16. Able to comprehend and willing to sign an ICF and to abide by the study restrictions.
Part C Exclusion Criteria:
1. Significant history or clinical manifestation of any metabolic, allergic,
dermatological, hepatic (except for NAFLD), renal, hematological, pulmonary,
cardiovascular, gastrointestinal, neurological, respiratory, endocrine, or psychiatric
disorder, as determined by the Investigator (or designee).
2. Clinically significant ECG abnormalities or QTcF >450 milliseconds for males and 470
milliseconds for females at either Screening or Check-in, or any prior history of QT
abnormality.
3. Currently using any antidiabetic medication (eg, metformin, insulin, glucagon-like
peptide-1 analogs, agonist therapy).
4. Use of fibrates or statins within 6 weeks prior to Check-in.
5. Use of Vitamin E, agents associated with changes in liver fat, or agents used for
treatment of NAFLD or NASH within 3 months prior to Screening.
6. Change in body weight >5% within the 3 months prior to Check-in.
7. History of bariatric surgery and any other gastrointestinal surgery relative to weight
loss (eg, Roux-en-Y gastric bypass, laparoscopic adjustable gastric banding, sleeve
gastrectomy, duodenal switch with biliopancreatic diversion).
8. Claustrophobia or other contraindication to magnetic resonance imaging.
9. Creatinine clearance of <90 mL/min at Screening, determined using the C-G equation.
10. History of febrile illness within 7 days prior to the first dose of study drug or
subjects with evidence of active infection.
11. History of significant hypersensitivity, intolerance, or allergy to any drug compound,
food, or other substance, unless approved by the Investigator (or designee).
12. History of alcoholism or drug/chemical abuse within 2 years prior to Check-in.
13. Alcohol consumption of >14 units per week for males and >7 units for females. One unit
of alcohol equals 12 oz (360 mL) beer, 1½ oz (45 mL) liquor, or 5 oz (150 mL) wine.
14. Positive urine drug screen (confirmed by repeat) at Screening or positive alcohol
breath or urine test result or positive urine drug screen at Check-in.
15. Positive hepatitis panel and/or positive human immunodeficiency virus test. Subjects
with serologic finding of immunity consistent with history of prior hepatitis B
vaccination may be enrolled.
16. Participation in a clinical study involving administration of an investigational drug
(new chemical entity) in the past 30 days prior to dosing or have received a
biological product within 3 months or 5 elimination half-lives (whichever is longer)
prior to dosing.
17. Use of prescription drugs, nonprescription drugs, dietary supplements including
peroxisome proliferator-activated receptor-γ agonists, drugs known to affect insulin
sensitivity, herbal supplements, hormonal therapy/replacement, or CYP3A4 substrates,
inducers, and inhibitors within 14 days or 5 elimination half-lives (whichever is
longer) prior to the first dose of study drug unless, in the opinion of the
Investigator and Sponsor's Medical Monitor, the medication will not interfere with the
study procedures or compromise subject safety.
18. Use or intend to use slow-release medications/products considered to still be active
within 14 days prior to Check-in, unless deemed acceptable by the Investigator (or
designee).
19. Use or intend to use any nonprescription medications/products including vitamins,
minerals, and phytotherapeutic/herbal/plant-derived preparations within 14 days prior
to the first dose of study medication, unless deemed acceptable by the Investigator
(or designee).
20. Use of tobacco- or nicotine-containing products within 3 months prior to Check-in.
21. Receipt of blood products within 2 months prior to Check-in.
22. Donation of blood from 56 days prior to Screening, plasma from 2 weeks prior to
Screening, or platelets from 6 weeks prior to Screening.
23. Poor peripheral venous access.
24. Have previously completed or withdrawn from this study or any other study
investigating CB4211, and have previously received the investigational product.
25. Subjects who, in the opinion of the Investigator (or designee), should not participate
in this study.
common.study.methods.has-drugs-yes
common.study.methods.is-healthy-no
