A Phase 1 Study of DD01 in Overweight/Obese Subjects With T2DM and NAFLD

Phase 1

Completed

• Conditions: NAFLD; Overweight and Obesity; Type2 Diabetes
• Interventions: Drug: DD01; Drug: Placebo

• Registration Number: NCT04812262
• Lead Sponsor: Neuraly, Inc.

Brief Summary

This is a Phase 1, first in human (FiH), randomized, double-blind, placebo-controlled, single ascending dose (SAD) and multiple ascending dose (MAD) study to investigate the safety, tolerability, PK and PD of DD01 administered by subcutaneous (SC) injection in overweight/obese subjects with type 2 diabetes (T2DM) and nonalcoholic fatty liver disease (NAFLD).

The study will be conducted in 2 Parts (Part A and B), with up to 8 cohorts included in each part (Part A; Cohorts A1 to A8 and Part B; Cohorts B2 to B8).

Detailed Description

Part A (SAD):

In Part A, subjects will receive a single dose of study drug, and the safety and efficacy of DD01 will be evaluated in overweight/obese subjects with T2DM.

Part B (MAD):

In Part B, subjects will receive once-weekly doses of the study drug for 4 weeks, and the safety and efficacy of DD01 will be evaluated in overweight/obese subjects with T2DM and NAFLD.

Study Timeline

• Study Start: 2021-02-24
• Study First Submitted: 2021-03-19
• Study First Submitted QC: 2021-03-22
• Study First Posted: 2021-03-23
• Primary Completion: 2022-12-20
• Study Completion: 2023-02-14
• Status Verified: 2024-04
• Last Update Submitted: 2024-04-26
• Last Update Posted: 2024-04-29

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 255

Inclusion Criteria

• Type 2 diabetes ≥ 12 months.
• Treatment with diet and exercise or metformin monotherapy on stable dose for 3 months prior to screening
• HbA1c ≤ 10%).
• Body Mass Index (BMI) ≥ 25 and ≤ 40.0 kg/m2

Part B Inclusion Criteria

• Type 2 diabetes ≥ 12 months.
• Treatment with diet and exercise or metformin monotherapy on stable dose for 3 months prior to screening
• HbA1c ≤ 10%
• BMI ≥ 30 kg/m2 and ≤ 40.0 kg/m2
• Waist circumference ≤ 57 inches
• Controlled attenuation parameter by FibroScan
• Liver fat fraction ≥ 10% by magnetic resonance imaging (MRI)

Part A

Exclusion Criteria

• History of type 1 diabetes mellitus (T1DM)
• History of acute proliferative retinopathy or maculopathy, severe gastroparesis, and/or severe neuropathy, in particular autonomic neuropathy, as judged by the Investigator.
• Uncontrolled hypertension
• Treatment with antihypertensive medication and statins not stable during the past 2 months prior to screening
• Treatment with thyroid hormones not stable during the past 3 months prior to screening
• History of any weight control treatment, including over-the-counter and herbal medication and supplements, or any medication with a labeled indication for weight loss or weight gain within 3 months prior to screening
• History of surgical treatment for obesity
• History of heart disease
• History of renal disease
• History or current diagnosis of acute or chronic pancreatitis or factors for pancreatitis, such as a history of cholelithiasis (without cholecystectomy) or alcohol abuse
• A history of or active chronic liver disease due to alcohol, auto-immune, HIV, HBV or active HCV-infection or NASH
• History of major depression, anxiety, suicidal behavior or attempts, or other psychiatric disorder requiring medical treatment
• Personal or family history of medullary thyroid carcinoma (MTC) or a genetic condition that predispose to MTC (i.e., multiple endocrine neoplasia type 2)
• Administration of Vaccines/Immunizations within 14 days prior to first dosing or if scheduled during the study. Vaccination for COVID-19 is allowed during the study if a washout period of 5 days after vaccine administration is followed before dosing.
• History of any major surgery within 6 months prior to screening
• Participation in any other clinical interventional study receiving active treatment within 30 days or 5 half-lives prior to screening, whichever is longer
• History of alcohol or illicit drug abuse including marijuana
• Existence of any surgical or medical condition that, in the judgment of the Investigator, might interfere with the investigational product

PART B Exclusion Criteria

• History of type 1 diabetes mellitus (T1DM)
• History of acute proliferative retinopathy or maculopathy, severe gastroparesis, and/or severe neuropathy, in particular autonomic neuropathy, as judged by the Investigator
• Uncontrolled hypertension (treatment with medications must be stable)
• History of any weight control treatment
• History of surgical treatment for obesity
• History of heart disease
• History of renal disease
• Subjects with a history or clinically significant active disease of the gastrointestinal, cardiovascular, hepatic, neurological, renal, pancreatic, immunological, dermatological, endocrine, genitourinary or hematological system.
• History or current diagnosis of acute or chronic pancreatitis
• History of major depression, anxiety, suicidal behavior or attempts, or other psychiatric disorder requiring medical treatment
• History of alcohol or illicit drug abuse including marijuana
• Existence of any surgical or medical condition that, in the judgment of the Investigator, might interfere with the investigational product
• Any history of clinically significant chronic liver disease

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Group A2, Single Ascending Dose	Placebo	DD01 Dose 2 (N=6) Placebo (N=2) Subcutaneous injection
Group B2 - Multiple Ascending Dose	DD01	DD01 Dose 2 (N=6) Placebo (N=2) Subcutaneous injection once weekly for 4 weeks
Group A1 - Single Ascending Dose	DD01	DD01 Dose 1 (N=6) Placebo (N=2) Subcutaneous injection
Group A2, Single Ascending Dose	DD01	DD01 Dose 2 (N=6) Placebo (N=2) Subcutaneous injection
Group A4, Single Ascending Dose	Placebo	DD01 Dose 4 (N=6) Placebo (N=2) Subcutaneous injection
Group B3 - Multiple Ascending Dose	DD01	DD01 Dose 3 (N=6) Placebo (N=2) Subcutaneous injection once weekly for 4 weeks
Group A5, Single Ascending Dose	Placebo	DD01 Dose 4 (N=6) Placebo (N=2) Subcutaneous injection
Group A6, Single Ascending Dose	DD01	DD01 Dose 4 (N=6) Placebo (N=2) Subcutaneous injection
Group A4, Single Ascending Dose	DD01	DD01 Dose 4 (N=6) Placebo (N=2) Subcutaneous injection
Group B3 - Multiple Ascending Dose	Placebo	DD01 Dose 3 (N=6) Placebo (N=2) Subcutaneous injection once weekly for 4 weeks
Group B6 - Multiple Ascending Dose	DD01	DD01 Dose 4 (N=6) Placebo (N=2) Subcutaneous injection once weekly for 4 weeks
Group B8 - Multiple Ascending Dose	Placebo	DD01 Dose 4 (N=6) Placebo (N=2) Subcutaneous injection once weekly for 4 weeks
Group A1 - Single Ascending Dose	Placebo	DD01 Dose 1 (N=6) Placebo (N=2) Subcutaneous injection
Group B2 - Multiple Ascending Dose	Placebo	DD01 Dose 2 (N=6) Placebo (N=2) Subcutaneous injection once weekly for 4 weeks
Group B4 - Multiple Ascending Dose	DD01	DD01 Dose 4 (N=6) Placebo (N=2) Subcutaneous injection once weekly for 4 weeks
Group A6, Single Ascending Dose	Placebo	DD01 Dose 4 (N=6) Placebo (N=2) Subcutaneous injection
Group B7 - Multiple Ascending Dose	DD01	DD01 Dose 4 (N=6) Placebo (N=2) Subcutaneous injection once weekly for 4 weeks
Group A3, Single Ascending Dose	DD01	DD01 Dose 3 (N=6) Placebo (N=2) Subcutaneous injection
Group A3, Single Ascending Dose	Placebo	DD01 Dose 3 (N=6) Placebo (N=2) Subcutaneous injection
Group B4 - Multiple Ascending Dose	Placebo	DD01 Dose 4 (N=6) Placebo (N=2) Subcutaneous injection once weekly for 4 weeks
Group B5 - Multiple Ascending Dose	Placebo	DD01 Dose 4 (N=6) Placebo (N=2) Subcutaneous injection once weekly for 4 weeks
Group A5, Single Ascending Dose	DD01	DD01 Dose 4 (N=6) Placebo (N=2) Subcutaneous injection
Group A7, Single Ascending Dose	DD01	DD01 Dose 4 (N=6) Placebo (N=2) Subcutaneous injection
Group A7, Single Ascending Dose	Placebo	DD01 Dose 4 (N=6) Placebo (N=2) Subcutaneous injection
Group A8, Single Ascending Dose	Placebo	DD01 Dose 4 (N=6) Placebo (N=2) Subcutaneous injection
Group B8 - Multiple Ascending Dose	DD01	DD01 Dose 4 (N=6) Placebo (N=2) Subcutaneous injection once weekly for 4 weeks
Group B6 - Multiple Ascending Dose	Placebo	DD01 Dose 4 (N=6) Placebo (N=2) Subcutaneous injection once weekly for 4 weeks
Group A8, Single Ascending Dose	DD01	DD01 Dose 4 (N=6) Placebo (N=2) Subcutaneous injection
Group B7 - Multiple Ascending Dose	Placebo	DD01 Dose 4 (N=6) Placebo (N=2) Subcutaneous injection once weekly for 4 weeks
Group B5 - Multiple Ascending Dose	DD01	DD01 Dose 4 (N=6) Placebo (N=2) Subcutaneous injection once weekly for 4 weeks

Primary Outcome Measures

Name	Time	Method
Heart Rate assessed by 24-hour ambulatory electrocardiography monitoring reader)	Part B - 57 days
Number of participants with clinically significant abnormalities in 12-lead ECGs	Part B - 57 days
Blood Pressure assessed by 24-hour ambulatory blood pressure monitoring (ABPM)	Part B - 57 days
Number of participants with treatment-related adverse events and serious adverse events	Part A - 43 days
Number of participants with clinically significant abnormalities in physical examinations	Part B - 57 days
Number of participants with clinically significant abnormalities in vital signs	Part B - 57 days
Number of participants with clinically significant abnormalities in clinical laboratory values	Part B - 57 days
Number of participants with treatment-related adverse events and serious adverse events (TEAEs)	Part B - 57 days

Secondary Outcome Measures

Name	Time	Method
Maximum observed blood/plasma concentration of DD01	Part B - 57 days	Maximum observed blood/plasma concentration (Cmax)
Termination elimination rate constant of DD01	Part B - 57 days	Termination elimination rate constant (kel)
Apparent total blood/plasma clearance of DD01	Part B - 57 days	Apparent total blood/plasma clearance (CL/F)
Time of the maximum observed blood/plasma concentration of DD01	Part B - 57 days	Time of the maximum observed blood/plasma concentration (Tmax)
Apparent blood/plasma terminal elimination half life of DD01	Part B - 57 days	Apparent blood/plasma terminal elimination half life (t1/2)
Area under the blood/plasma concentration time curve from time zero to 216 hours postdose of DD01	Part B - 57 days	Area under the blood/plasma concentration time curve from time zero to 216 hours postdose (AUC0-216)
Area under the blood/plasma concentration time curve from time zero to 168 hours postdose of DD01	Part B - 57 days	Part B only: Area under the blood/plasma concentration time curve from time zero to 168 hours postdose (AUC0-168)
Apparent volume of distribution of DD01	Part B - 57 days	Apparent volume of distribution(Vz/F)
Area under the blood/plasma concentration time curve from time zero to 144 hours postdose of DD01	Part B - 57 days	Area under the blood/plasma concentration time curve from time zero to 144 hours postdose (AUC0-144)
Number of participants with antidrug antibodies (ADAs)	Part B - 57 days
Area under the blood/plasma concentration time curve from time zero to the time of the last quantifiable concentration of DD01	Part B - 57 days	Area under the blood/plasma concentration time curve from time zero to the time of the last quantifiable concentration (AUC0-t)

Trial Locations

Locations (4)

Prosciento; 🇺🇸 Chula Vista, California, United States

Southwest General Healthcare Center; 🇺🇸 Fort Myers, Florida, United States

FDI Clinical Research; 🇵🇷 San Juan, Puerto Rico

Combined Research Orlando; 🇺🇸 Orlando, Florida, United States