ALN-4324 for Type 2 diabetes mellitus

Inclusion criteria

• {"criterion_text":"- Age 18 to 75 years, inclusive, at the time of initial informed consent.\n- Stable euthyroid status (no known changes in thyroid function or changes in dosing of exogenous thyroid medication in the last 4 months) at screening.\n- 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.\n- HbA1c ≥7.0% to <10.5% at screening.\n- C-peptide ≥lower limit of normal at screening.\n- 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.\n- Confirmed T2DM diagnosis based on medical history for at least 6 months before screening.\n- 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\n- Patient is able to understand and is willing and able to comply with the study requirements and to provide written informed consent."}

Exclusion criteria

• {"criterion_text":"- 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).\n- Background treatment with 3 or more lipid-lowering agents of different classes.\n- Currently taking, taken within 30 days prior to randomization, or anticipated to receive during the study, sotagliflozin.\n- 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®), lorcaserin (Belviq®), or other body weight loss medications within 3 months of screening, or plan to initiate such therapy within 6 months after the first dose of study drug.\n- Use of GLP-1RA, insulins, thiazolidinediones, or antidiabetics other than metformin and permitted SGLT2i within 3 months of screening.\n- 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 safety/PD follow-up period of this study. If enrolled for longer than 3 months, subject should intend to stay in the program during the study.\n- Are receiving systemic glucocorticoid therapy (including oral or inhaled and excluding topical, intranasal and intraocular) for 14 days or longer or have received 14 days or longer of systemic glucocorticoid therapy or intra-articular glucocorticoid injection within 2 months of screening \n- Unstable dose or anticipated need for titration of dose of a diuretic medication.\n- History of type 1 diabetes, latent autoimmune diabetes, MODY, or self-reported family history of MODY.\n- Poorly controlled hypertension (ie, mean seated SBP ≥150 mmHg or mean seated DBP ≥95 mmHg after 5 minutes of sitting at rest at screening), or a change in antihypertensive medications within 30 days of screening, renal artery stenosis, or evidence of labile blood pressure including symptomatic postural hypotension.\n- 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) d. Autoimmune disease\n- Has known HIV infection; or known current or chronic HCV or HBV infection.\n- 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.\n- Has undergone liver, lung, kidney, or heart transplantation or is anticipated to be on an active transplantation waiting list during the study.\n- Known food intolerance that may affect interpretation of the results at the discretion of the Investigator, or known intolerance to glucose loads.\n- History of multiple drug allergies or history of allergic reaction to any component of or excipient in the study drug.\n- History of intolerance to SC injection(s).\n- Change in weight (±5%) within 3 months of screening (documented or known history) or between screening and Day 1.\n- Hyperthyroidism that is being treated with oral antithyroid medications.\n- Has a history of seizures.\n- Has a history of ketoacidosis or hyperosmolar state/coma.\n- Has hypoglycemia unawareness or poor recognition of hypoglycemia symptoms in the Investigator’s opinion or has had more than 1 episode of severe hypoglycemia (according to American Diabetes Association criteria) within 6 months prior to screening.\n- Has eGFR of <45 mL/min/1.73m2 at screening (calculation will be based on the CKD-EPI equation).\n- Have any hematological condition that may interfere with HbA1c measurement (for example, hemolytic anemias, sickle cell disease)\n- Is not willing to comply with the contraceptive requirements during the study period\n- Female patient is pregnant or breastfeeding.\n- 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] = 1 measure of spirits [approximately 1 fluid ounce] = ½ pint of beer [approximately 284 mL]).\n- History or clinical evidence of drug/chemical or alcohol use disorder, within the last 12 months before screening, in the opinion of the Investigator.\n- 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.\n- Currently taking, taken within 6 months before randomization, or anticipated to receive an RNAi therapeutic or antisense oligonucleotide other than ALN-4324 (approved or investigational).\n- Surgery (except eye/skin, oral) within 3 months of screening.\n- 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.\n- Use of chromium picolinate or vanadate\n- Use of injectable medications used for systemic immunosuppressive treatment."}

Primary endpoints

• {"endpoint_text":"- Frequency of AEs. Safety will also be evaluated through vital signs, ECGs, and clinical laboratory assessments.","definition_or_measurement_approach":"Frequency of adverse events (AEs); safety assessed via vital signs, 12‑lead ECGs (QTcF thresholds provided in inclusion), and clinical laboratory assessments."}

Secondary endpoints

• {"endpoint_text":"- Change from baseline in HbA1c at Month 6.","definition_or_measurement_approach":"Change from baseline in glycated hemoglobin (HbA1c) measured at Month 6 compared with baseline."}
• {"endpoint_text":"- HOMA-IR, Matsuda index, and glucose AUC response to glucose tolerance test.","definition_or_measurement_approach":"Assessment of insulin resistance and glucose tolerance using HOMA-IR and Matsuda index calculations and glucose area under the curve (AUC) from a glucose tolerance test."}
• {"endpoint_text":"- Plasma concentrations of ALN-4324 and potential metabolite(s).","definition_or_measurement_approach":"Measurement of plasma concentrations (PK) of ALN-4324 and any identified metabolite(s) via appropriate bioanalytical assays."}

Poland

Earliest CTIS Part Ii Submission Date

26-01-2026

Latest Decision Or Authorization Date

16-02-2026

Processing Time Days

21

Number Of Sites

4

Number Of Participants

20

Germany

Earliest CTIS Part Ii Submission Date

21-01-2026

Latest Decision Or Authorization Date

10-02-2026

Processing Time Days

20

Number Of Sites

2

Number Of Participants

15

Primary sponsor

Full Name

Alnylam Pharmaceuticals Inc.

Organisation Type

Pharmaceutical company

Country Of Registered Address

United States

Contract research organisations

Name

PPD Development LP

Responsibilities

Multiple roles including clinical supplies (multiple role codes listed)

Name

PPD International Holdings LLC

Responsibilities

Laboratory Logistics; additional role codes listed

Name

Advanced Clinical LLC

Responsibilities

Electronic Data Capture

Third parties

• {"country":"United States","full_name":"Proofpilot Inc.","duties_or_roles":"Study Site Communication Portal","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Suvoda LLC","duties_or_roles":"Code 3 (role code provided; specific role text not provided)","organisation_type":"Non-Pharmaceutical company"}
• {"country":"United States","full_name":"Advanced Clinical LLC","duties_or_roles":"Electronic Data Capture","organisation_type":"Pharmaceutical company"}
• {"country":"United Kingdom","full_name":"Neonstone Limited","duties_or_roles":"Electronic site-specific recruitment plans","organisation_type":"Non-Pharmaceutical company"}
• {"country":"United States","full_name":"Aliri USA Inc.","duties_or_roles":"Code 4 (role code provided; specific role text not provided)","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"Belgium","full_name":"PPD International Holdings LLC","duties_or_roles":"Laboratory Logistics; Code 4 (additional role codes present)","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Clario Medical Imaging Inc.","duties_or_roles":"Central Medical Reading of subjects' imaging (ECHO imaging reading)","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"PPD Development LP","duties_or_roles":"Multiple roles including Clinical supplies (many role codes listed)","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Greenphire LLC","duties_or_roles":"Patient travel and reimbursement","organisation_type":"Non-Pharmaceutical company"}