A Phase 1/2 Study to Evaluate ALN-KHK in Overweight to Obese Healthy Volunteers and Obese Patients With T2DM

Study Overview
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Brief Summary
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To evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of single ascending doses of ALN-KHK and to evaluate the safety, tolerability, efficacy, PK and PD of multiple doses of KHK.

Official Title
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A Phase 1/2, Randomized, Double-blind, Placebo-controlled, 2-Part Study of the Safety, Tolerability, Efficacy, Pharmacokinetics, and Pharmacodynamics of Single Dose ALN-KHK in Overweight to Obese Adult Healthy Volunteers and Multiple Dose ALN-KHK in Obese Patients With Type 2 Diabetes Mellitus (T2DM)

Conditions
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Type 2 Diabetes Mellitus (T2DM)

Intervention / Treatment
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* Drug: ALN-KHK
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Stable euthyroid status (no known changes in thyroid function; stable hormone replacement for at least 4 months) at screening Part A: body mass index (BMI) ≥27 kg/m^2 and ≤34.9 kg/m^2 Part B: BMI ≥32 kg/m^2 to ≤39.9 kg/m^2, confirmed diagnosis of T2DM, and an HbA1c ≥7.5% to <10% Part B: Confirmed T2DM diagnosis (≤8 years) Exclusion Criteria: Parts A and B: has received an investigational agent within the last 30 days Part A: History of Type 1 or Type 2 diabetes Part B: History of Type 1 diabetes

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: The single ascending dose part of this study (Part A) will have a sequential interventional study model. The multi-dose part of this study (Part B) will have a parallel interventional study model and will begin after the completion of Part A.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A: ALN-KHK<br>Participants will be administered a single dose of ALN-KHK. | Drug: ALN-KHK<br>* ALN-KHK will be administered by subcutaneous (SC) injection.<br>|
| Placebo Comparator: Part A: Placebo<br>Participants will be administered a single dose of placebo. | Drug: Placebo<br>* Placebo will be administered by subcutaneous (SC) injection.<br>|
| Experimental: Part B: ALN-KHK<br>Participants will be administered a multiple doses of ALN-KHK. | Drug: ALN-KHK<br>* ALN-KHK will be administered by subcutaneous (SC) injection.<br>|
| Placebo Comparator: Part B: Placebo<br>Participants will be administered a multiple doses of placebo. | Drug: Placebo<br>* Placebo will be administered by subcutaneous (SC) injection.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A: Frequency of Adverse Events |  | Up to 9 Months | 
| Part B: Frequency of Adverse Events |  | Up to 12 Months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A: Area Under the Concentration-time Curve (AUC) of ALN-KHK and Potential Major Metabolite(s) |  | Up to 2 Days following dosing on Day 1 | 
| Part A: Maximum Observed Plasma Concentration (Cmax) of ALN-KHK and Potential Major Metabolite(s) |  | Up to 2 Days following dosing on Day 1 | 
| Part A: Time to Maximum Observed Plasma Concentration (Tmax) of ALN-KHK and Potential Major Metabolite(s) |  | Up to 2 Days following dosing on Day 1 | 
| Part A: Fraction of ALN-KHK Excreted in the Urine (fe) and Potential Major Metabolite(s) |  | Up to 2 Days following dosing on Day 1 | 
| Part A: Percent Change from Baseline in Circulating Fructose in Response to a Fructose Tolerance Test |  | Baseline up to Month 6 | 
| Part A: Percent Change from Baseline in Urinary Fructose in Response to a Fructose Tolerance Test |  | Baseline up to Month 6 | 
| Part A: Percent Change from Baseline in Circulating Fibroblast Growth Factor 21 (FGF21) in Response to a Fructose Tolerance Test |  | Baseline up to Month 6 | 
| Part B: Absolute Change from Baseline in Hemoglobin A1C (HbA1c) at 6 Months |  | Baseline and Month 6 | 
| Part B: Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) in Response to a Glucose Tolerance Test |  | Month 4 | 
| Part B: Fasting Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) |  | Month 4 | 
| Part B: Glucose and Insulin AUC in response to Tolerance Test |  | Month 4 | 
| Part B: Plasma Concentrations of ALN-KHK and Potential Major Metabolite(s) |  | Day 1 and Month 3 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Overweight, Obese, Fructose, siRNA, HbA1C, Insulin, Glucose