A Phase 1, Randomized, Placebo-Controlled, Double-Blind Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Single-and Multiple-Ascending Subcutaneous Doses of DR10624

• Status: Not yet recruiting
• Trial end date: 2024-12-01
• Target enrollment: 0
• Participant gender: All

Summary

DR10624 is an Fc fusion protein tri-agonist with balanced GLP-1R/GCGR/FGF21R agonizing activities that complement each other in regulating blood glucose and weight. The GLP-1R agonizing activity lowers blood glucose, GCGR agonizing activity reduces body weight by increasing energy consumption, and FGF21R agonizing activity reduces blood glucose and lipid content. The development of DR10624 addresses an unmet medical need: lowering blood glucose and weight in T2D patients with a high safety margin. Additional indications, such as obesity and NASH, are also being considered.

The objectives of the planned clinical investigation will be to evaluate the safety, tolerability, PK, and pharmacodynamics (PD) of single- and multiple-ascending doses of DR10624 via SubQ injection in a randomized, placebo-controlled, double-blind study. The design and choice of the study population of the planned first-in-human (FIH) clinical Phase 1 study is based on the need to provide initial safety, tolerability, PK, and PD outcomes of DR10624 for future clinical studies. Analysis of serum concentrations from this study will characterize the single- and multiple-dose PK of DR10624 and help to refine the dosing strategy for subsequent Phase 2 multiple-dose studies.

• Phase: Phase 1
• Accepts Healthy Volunteers?: Accepts Healthy Volunteers

Details

• Lead Sponsor: Zhejiang Doer Biologics Corporation

Criteria

Inclusion Criteria:

Each subject must meet all of the following criteria to be enrolled in this study:

1. The subject is considered by the investigator to be in good general health as determined by medical history, clinical laboratory test results, vital sign measurements, 12-lead ECG results, and physical examination findings at Screening.

2. Female subjects (heterosexually active, of childbearing potential, not pregnant, not trying to become pregnant, and not lactating) are eligible to participate if they agree to total abstinence from heterosexual intercourse, or use of a highly effective method of birth control listed below, from Screening through until at least 30 days after the last study dose. Highly effective methods of contraception acceptable for use in this study include:

• Implant contraceptive (eg, Jadelle)

• Intra-uterine device (IUD) containing either copper or levonorgestrel (eg, Mirena)

• Male sterilization (vasectomy)

• Female sterilization (eg, by bilateral tubal ligation ['tying tubes'] or hysterectomy) second non-hormonal (barrier) method of contraception is required if a user dependent hormonal form of birth control is used:

• Injectable contraceptive (eg, Depo Provera)

• Oral contraceptive pill (combined hormonal pill or progestogen-only pill)

• Vaginal contraceptive ring (eg, NuvaRing)

Barrier methods of birth control acceptable for this study include:

• Male condom

• Female condom

• Female diaphragm Please note that barrier methods on their own are NOT highly effective methods of birth control. Females of childbearing potential must have negative pregnancy tests at Screening and on admission. Female subjects must refrain from egg donation throughout study and for 30 days after the last dose. Females who are postmenopausal (age-related amenorrhea for ≥12 consecutive months and increased follicle-stimulating hormone [FSH] ≥40 mIU/mL) or who have undergone permanent sterilization (hysterectomy, total bilateral salpingectomy, and bilateral oophorectomy [more than 3 months prior]) do not need to use any methods of contraception.

Male subjects with female partners of childbearing potential are eligible to participate if they are vasectomized, or agree to total abstinence from heterosexual intercourse, from Screening through until at least 90 days after the last study dose, or use of an effective method of birth control listed above, from Screening through until at least 90 days after the last study dose.

Male participants must refrain from sperm donation throughout the study and for 90 days after the last study dose.

3. The subject agrees to comply with all protocol requirements.

4. The subject is able to provide written informed consent. Additional inclusion criteria for healthy subjects or mildly obese but otherwise healthy adult subjects in Part 1, Cohorts A, B, C, D, E, and F: The subject is male or female 18 to 55 years of age, inclusive. The subject has a body weight ≥50 kg at Screening and a BMI of 18 to 32 kg/m2, inclusive, at Screening. Additional inclusion criteria for mildly obese but otherwise healthy adult subjects in Part 2,

Cohorts H and I:

1. The subject is male or female 18 to 60 years of age, inclusive.

2. The subject has a body weight ≥50 kg (≥45 kg for Chinese females only) at Screening and a BMI of 28 to 32 kg/m2, inclusive, at Screening.

3. The subject does not have an established diagnosis of T2D.

4. The subject has normal glucose tolerance (fasting glucose less than 5.6 mmol/L and/or 2-hour postprandial glucose tolerance of less than 7.8 mmol/L), does not have prediabetes status (impaired fasting glucose [≥5.6 and <6.9 mmol/L] or impaired glucose tolerance [≥7.8 and <11.1 mmol/L]), and has HbA1c ≤5.8%.

Additional inclusion criteria for mildly obese or obese subjects with features of MetS in

Part 1, Cohort G and Part 2, Cohorts J, K, and L:

The subject is male or female 18 to 60 years of age, inclusive. The subject has a body weight ≥50 kg (≥45 kg for Chinese females only) at Screening and a BMI of 30 to 40 kg/m2, inclusive, at Screening.

The subject has MetS defined as presence of any 3 of the following criteria:

• Waist circumference >90 cm (men), >80 cm (women)

• Triglycerides ≥1.69 mmol/L, or on Rx (pharmacologic treatment)

• High density lipoprotein cholesterol <1.03 mmol/L (men), <1.29 mmol/L women, or on Rx (pharmacologic treatment)

• Systolic blood pressure (BP) ≥130 mm Hg or diastolic BP ≥85 mm Hg, or on stable/treatment doses of antihypertension medication

• Fasting plasma glucose ≥5.6 mmol/L, or stable/treatment doses of anti-diabetic medication

Additional inclusion criteria for overweight or obese subjects with T2D in Part 2, Cohorts M, N, and O:

1. The subject is male or female 18 to 60 years of age, inclusive.

2. The subject has an established diagnosis of T2D of at least 3 months duration at Screening.

3. The subject has a body weight ≥50 kg (≥45 kg for Chinese females only) at Screening and a BMI of 25 to 40 kg/m2, inclusive, at Screening.

4. The subject has T2D managed by lifestyle modification (diet and exercise alone) or is on a stable daily dose of metformin of at least 1000 mg (1 g) for ≥12 weeks without use of other antidiabetic medications for >3 months prior to Screening and maintains the dose until the end of the study.

5. The subject has an HbA1c ≥53 mmol/mol (7.0%) and ≤80 mmol/mol (9.5%) at Screening.

6. The subject has at least 120 hours (equivalent to 5 days) of available blinded CGM data at Check-in and performed an average of at least 2 blood glucose meter checks per day during the screening phase.

Exclusion Criteria:

Subjects meeting any of the following criteria will be excluded from the study:

1. The subject has a positive test result for hepatitis B surface antigen, hepatitis C virus antibody, or human immunodeficiency virus types 1 or 2 antibodies at Screening.

2. The subject has a personal or family history of medullary thyroid cancer, or multiple endocrine neoplasia syndrome type 2, or with a Screening calcitonin ≥50 ng/L.

3. The subject has a history of chronic pancreatitis or episode of acute pancreatitis within 3 months of Screening.

4. The subject has used any prescription (excluding hormonal birth control, metformin for subjects with T2D, and stable/treatment doses of antihypertension and/or lipid for at least 3 months, or antidiabetic medication for subjects with features of MetS), or over-the-counter medications (except paracetamol [up to 2 g per day]), including herbal or nutritional supplements, within 14 days before the first dose of study drug.

5. The subject has consumed grapefruit or grapefruit juice, Seville orange or Seville orange-containing products (eg, marmalade), or alcohol-, caffeine-, or xanthine-containing products within 48 hours before dosing and during the study confinement period.

6. The subject has consumed alcohol within 48 hours before dosing and outpatient visits or during the confinement period.

7. The subject is a smoker or has used tobacco, nicotine, or nicotine-containing products (eg, snuff, nicotine patch, nicotine chewing gum, mock cigarettes, or inhalers) from start of the confinement period until after EOS.

8. The subject has a history of alcohol abuse or drug addiction within the last year or excessive alcohol consumption (regular alcohol intake >21 units per week for male subjects and >14 units of alcohol per week for female subjects) (1 unit is equal to approximately ½ pint [200 mL] of beer, 1 small glass [100 mL] of wine, or 1 measure [25 mL] of spirits) or use of alcohol 48 hours before the first dose of study drug.

9. The subject has a positive test result for drugs of abuse, alcohol, or cotinine (indicating active current smoking) at Screening or before the first dose of study drug.

10. The subject is involved in strenuous activity or contact sports within 48 hours before admission and for the duration of the study.

11. The subject has donated blood or blood products >450 mL within 30 days before the first dose of study drug.

12. The subject has total cholesterol >10.3 mmol/L or triglycerides >4.5 mmol/L at Screening.

13. The subject has clinically significant history or presence of ECG findings as determined by the investigator at Screening and Check-in, including any of the following:

• Abnormal sinus rhythm (heart rate lower than 45 bpm and higher than 100 bpm)

• Risk factors for torsades de pointes (eg, heart failure, cardiomyopathy, or family history of long QT syndrome)

• Sick sinus syndrome, second- or third-degree atrioventricular block myocardial infarction, pulmonary congestion, cardiac arrhythmia, prolonged QT interval, or conduction abnormalities

• QT interval corrected for heart rate using Fridericia's formula (QTcF) >450 msec (male subjects) or >470 msec (female subjects)

• QRS interval >110 msec, confirmed by manual over read

• PR interval <120 or >220 msec In the event a value is outside of the reference range, this will be confirmed by 2 further repeat measurements, which will then be calculated as a mean of the original value and the 2 repeat measurements.

• Repeated or frequent syncope or vasovagal episodes

• Hypertension, angina, bradycardia (if assessed as clinically significant by the investigator), or severe peripheral arterial circulatory disorders

14. The subject has a history of relevant drug and/or food allergies (ie, allergy to DR10624 or excipients, or any significant food allergy that could preclude a standard diet in the clinical unit).

15. The subject has a history of severe allergic or anaphylactic reactions.

16. The subject has experienced a >5% body weight loss over the past 2 months at Screening.

17. Female subjects who are pregnant or lactating.

18. The subject has a positive test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Note: Testing will be performed according to site procedures.

19. The subject has received study drug in another investigational study within 30 days of dosing.

20. In the opinion of the investigator, the subject is not suitable for entry into the study.

Additional exclusion criteria for overweight or obese subjects with T2D in Part 2, Cohorts M, N, and O:

1. The subject has a history of severe hypoglycemia within 6 months of Screening (Note:

the subject may have been on insulin or sulfonylureas).

2. The subject has a FPG of <5.6 mmol/L or >14.4 mmol/L at Screening; 1 repeat measurement will be allowed.

3. The subject has a skin reaction from adhesive that would preclude CGM during the study.

4. The subject requires systemic or daily inhaled corticosteroids in the last 6 months (intermittent treatment with inhaled corticosteroids does not exclude subjects from enrollment).