A Phase 1/2 Study of the Safety, Tolerability, and Efficacy of ALN-4324 in Overweight to Obese Healthy Volunteers and Patients With Type 2 Diabetes Mellitus

Trial ID: 2024-519005-35-00
Protocol: ALN-4324-001
Sponsor: Alnylam Pharmaceuticals Inc.

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Diseases & Conditions

Type 2 diabetes mellitus

Objectives

The primary objective is to evaluate the safety and tolerability of multiple doses of ALN-4324 in patients diagnosed with type 2 diabetes mellitus. Secondary objectives include:

Assessment of efficacy regarding HbA1c levels compared to placebo.
Characterization of pharmacodynamic effects following multiple doses.
Characterization of pharmacokinetics and potential metabolites.

Trial scope: 4, 5, 6, 7, 9.

Participants

This clinical trial involves 25 participants diagnosed with type 2 diabetes mellitus. The study population includes both male and female patients within specific age ranges. Eligible individuals must have a confirmed diagnosis for at least 6 months and present with an HbA1c level between 7.0% and 10.5%. Participants are required to maintain a stable euthyroid status and demonstrate a C-peptide level at or above the lower limit of normal. Inclusion criteria necessitate a body mass index within specified ranges, adjusted for Asian ancestry, and a 12-lead ECG showing no clinically significant abnormalities, including specific QTcF limits. The cohort consists of patients receiving stable doses of metformin or a combination of metformin and an SGLT2 inhibitor, such as dapagliflozin, empagliflozin, or canagliflozin, for at least 3 months prior to screening.

Plans and Procedures

This Phase 1/2, randomized, double-blind, placebo-controlled study consists of two parts designed to evaluate the safety, tolerability, efficacy, pharmacokinetics, and pharmacodynamics of ALN-4324. Part A involves a single dose administered to overweight or obese healthy volunteers, while Part B involves multiple doses administered to overweight or obese patients with Type 2 Diabetes Mellitus. The study utilizes ALN-4324 as the test product and phosphate buffered saline for subcutaneous administration as the placebo. The research sequence begins with a screening visit to assess eligibility based on criteria such as Body Mass Index, HbA1c levels, and stable euthyroid status. Following screening, participants proceed through scheduled study visits for dose administration and monitoring. Safety is assessed through the frequency of adverse events, vital signs, electrocardiogram, and clinical laboratory assessments. Secondary endpoints include changes in HbA1c, HOMA-IR, Matsuda index, and glucose AUC response. The total duration of the study is estimated to conclude by August 2027.

Treatment

The experimental medication is ALN-4324, provided as a solution for injection. This substance is administered via the subcutaneous route.

The control group receives a placebo consisting of phosphate buffered saline for subcutaneous administration.

Efficacy

Efficacy assessment in this study focuses on metabolic parameters in patients with Type 2 Diabetes Mellitus. The primary secondary endpoint is the change from baseline in HbA1c at Month 6. Additional assessments include the HOMA-IR, Matsuda index, and glucose AUC response following a glucose tolerance test.

Pharmacokinetic evaluation involves measuring plasma concentrations of ALN-4324 and its potential metabolite(s).

Inclusion and Exclusion Criteria

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Inclusion Criteria

Age 18 to 75 years, inclusive, at the time of initial informed consent.
Stable euthyroid status (no known changes in thyroid function or changes in dosing of exogenous thyroid or oral antithyroid medication in the last 4 months) at screening.
12-lead ECG within normal limits or with no clinically significant abnormalities at screening in the opinion of the Investigator. QTcF should be <450 msec in males or <470 msec in females.
HbA1c ≥7.0% to <10.5% at screening.
BMI: ≥25 kg/m2 to <45 kg/m2 at screening. a. if Asian background (both parents are Asian), BMI: ≥23 kg/m2 to <40 kg/m2.
Confirmed T2DM diagnosis based on medical history for at least 6 months before screening.
Patient must be on 1 of the following therapies, with no changes (in dose or therapy) for at least 3 months prior to screening and no expected changes in dose during the study. Metformin and the SGLT2i medications must be prescribed consistent with guideline recommendations and/or local labels. a. Metformin alone (≥500 mg daily dose) b. Metformin (≥500 mg daily dose) and an SGLT2i limited to 1 of the following: mpagliflozin, dapagliflozin, or canagliflozin
Patient is able to understand and is willing and able to comply with the study requirements and to provide written informed consent.

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Exclusion Criteria

Has known HIV infection or autoimmune hepatitis; known acute active hepatitis A virus infection; known active hepatitis E virus infection, or known current or chronic HCV or HBV infection.
Newly enrolled (started within 3 months of screening) in a weight loss program using diet and exercise, or plan to initiate such therapy before the end of the 6-month DB period of this study. If enrolled for longer than 3 months, the patient should intend to stay in the program during the study.
Is not willing to comply with the contraceptive requirements during the study period
History of type 1 diabetes, latent autoimmune diabetes, MODY, or self-reported family history of MODY.
Has known renovascular hypertension caused by renal artery stenosis.
History of any clinically significant or active gastrointestiHistory of any clinically significant or active gastrointestinal, cardiovascular, autoimmune (excluding autoimmune thyroid conditions), hematological, psychiatric, renal, hepatic, pancreatic or neurological abnormality (including malignancies) that could interfere with the safety or results of this study as judged by the Investigator. Note: Patients with suspected, possible, or confirmed metabolic-associated fatty liver disease may be enrolled if hepatic laboratory values are within acceptable limits (ie, ALT and AST are ≤2×ULN and total bilirubin is ≤1.5×ULN).
History of or acute significant gastrointestinal disorder (eg, peptic ulcers, severe gastroesophageal reflux disease), gastric surgery, gastric bypass or antrectomy or small bowel resection or any disorder that would interfere with the swallowing, absorption, distribution, metabolism, and excretion of food, and the oral glucose tolerance test during the study.
Has severe gastroparesis and/or severe neuropathy, especially autonomic neuropathy, as judged by the Investigator.
Cancer diagnosis (other than squamous or basal cell skin cancer, carcinoma in situ [breast], or positive polyp on colonoscopy with no recurrence) within 5 years of screening.
Surgery (except eye/skin, oral) within 3 months of screening.
Has undergone liver, lung, kidney, or heart transplantation or is anticipated to be on an active transplantation waiting list during the study.
Known food intolerance that may affect interpretation of the results at the discretion of the Investigator, or known intolerance to glucose loads.
Female patient is pregnant or breastfeeding.
History of multiple drug allergies or history of allergic reaction to any component of or excipient in the study drug.
History of intolerance to SC injection(s).
Has any of the following laboratory parameter assessments at screening: a. ALT or AST >2×ULN b. Total bilirubin >1.5×ULN. Patients with elevated total bilirubin that is secondary to documented Gilbert’s syndrome are eligible if the total bilirubin is <2×ULN. c. INR >2.0 (patients on oral anticoagulant [eg, warfarin] with an INR <3.5 will be allowed).
Background treatment with 3 or more lipid-lowering agents of different classes.
Has a history of seizures.
Has a history of ketoacidosis or hyperosmolar state/coma.
Has hypoglycemia unawareness or poor recognition of hypoglycemia symptoms in the Investigator’s opinion, has had any episode of severe hypoglycemia (according to American Diabetes Association criteria) within 3 months prior to screening, or has had more than 1 episode of severe hypoglycemia (according to American Diabetes Association criteria) within 6 months prior to screening.
History of any bariatric or gastric procedure (eg, gastrectomy), or plan for a bariatric or gastric procedure before the end of the Safety/PD Follow-up period of this study.
Has eGFR of <45 mL/min/1.73m2 at screening (calculation will be based on the CKD-EPI equation).
Has any hematological condition that may interfere with HbA1c measurement (for example, hemolytic anemias, sickle cell disease)
Has SBP ≥150 mmHg and/or DBP ≥95 mmHg after 10 minutes of sitting at rest at screening), or a change in antihypertensive medications within 30 days of screening.
Unwilling or unable to limit alcohol consumption throughout the course of the study. Alcohol intake of >2 units/day is excluded during the study (unit: 1 glass of wine [approximately 125 mL or 4 fluid ounces] = 1 measure of spirits [approximately 30 mL or 1 fluid ounce] = ½ pint of beer [approximately 240 mL or 8 ounces]).
History or clinical evidence of drug/chemical or alcohol use disorder, within the last 12 months before screening, in the opinion of the Investigator.
Received an investigational agent within the last 30 days or 5 half-lives, whichever is longer, before the first dose of study drug, or are in follow-up of another clinical study before study enrollment. Any agent that has received health agency authorization (including for emergency use) by local or regional regulatory authorities is not considered investigational.
Currently taking, taken within 30 days prior to randomization, or anticipated to receive during the study, sotagliflozin.
Currently taking, taken within 6 months before randomization, or anticipated to receive an RNAi therapeutic or antisense oligonucleotide (approved or investigational) other than ALN-4324.
Change in weight (±5%) within 3 months of screening (documented or known history) or between screening and Day 1.
Use of chromium picolinate or vanadate
Has received any of the following glucocorticoid regimens: a. Oral or inhaled systemic glucocorticoid therapy for 14 days or longer within 2 months before screening; b. Parenteral systemic glucocorticoid therapy (intravenous or intramuscular, any duration) or any intra-articular glucocorticoid injection within 3 months before screening c.Systemic glucocorticoids for active autoimmune abnormality (eg, lupus, rheumatoid arthritis) within 3 months before screening or is likely to be required, in the opinion of the Investigator, during the study. Note: Use of topical, ophthalmic, or intranasal glucocorticoid preparations are permitted.
Therapies for chronic weight management (eg, GLP-1RA such as semaglutide or liraglutide, GLP-1RA/glucose-dependent insulinotropic polypeptide receptor agonist [GIPRA] such as tirzepatide), anorectics (eg, phentermine or combination of phentermine and topiramate), orlistat (Xenical®), or other body weight loss medications within 3 months of screening, or plan to initiate such therapy within 6 months after the of first dose of study drug.
Has other medical conditions or comorbidities, which in the opinion of the Investigator, would interfere with study compliance or data interpretation; or, in the opinion of the Investigator, taking part in the study would jeopardize the safety of the patient, including the following: a. Acute myocardial infarction, unstable angina, coronary artery bypass graft, percutaneous coronary intervention (diagnostic angiograms are permitted), cerebrovascular accident (stroke), or hospitalization due to congestive heart failure (CHF) within 3 months of screening. b. History of New York Heart Association Functional Classification IV CHF c. Proliferative diabetic retinopathy or diabetic maculopathy or nonproliferative diabetic retinopathy that requires active treatment (within 3 months of screening)
Use of incretins, insulins, thiazolidinediones, or antidiabetics other than metformin and permitted SGLT2i within 3 months of screening.
Donation or loss of >500 mL of blood, donation of platelets or plasma, or receipt of blood products within 2 months before randomization, or expected donation of blood, platelets, or plasma or receipt of blood products during the study.