A Phase 1/2 Study to Evaluate ALN-4324 in Overweight to Obese Healthy Volunteers and in Overweight to Obese Patients With T2DM

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Alnylam Pharmaceuticals Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Hormonal diseases [C19]

Trial duration

9 Mar 2026 → ongoing

Decision date (initial)

2026-02-10

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Dose response, Efficacy, Pharmacodynamic, Safety

To evaluate the safety and tolerability of multiple doses of ALN-4324 in patients with T2DM

Secondary objectives 3

1. To evaluate the efficacy of ALN-4324 compared with placebo on HbA1c
2. To characterize the PD effects of multiple doses of ALN-4324
3. To characterize the multiple dose PK of ALN-4324 and potential metabolite(s)

Conditions and MedDRA coding

Type 2 Diabetes Mellitus

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

1. Age 18 to 75 years, inclusive, at the time of initial informed consent.
2. Stable euthyroid status (no known changes in thyroid function or changes in dosing of exogenous thyroid medication in the last 4 months) at screening.
3. 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.
4. HbA1c ≥7.0% to <10.5% at screening.
5. C-peptide ≥lower limit of normal at screening.
6. 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.
7. Confirmed T2DM diagnosis based on medical history for at least 6 months before screening.
8. 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
9. Patient is able to understand and is willing and able to comply with the study requirements and to provide written informed consent.

Exclusion criteria 37

1. 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.
2. Surgery (except eye/skin, oral) within 3 months of screening.
3. 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.
4. Change in weight (±5%) within 3 months of screening (documented or known history) or between screening and Day 1.
5. Use of chromium picolinate or vanadate
6. 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.
7. 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.
8. 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
9. Use of GLP-1RA, insulins, thiazolidinediones, or antidiabetics other than metformin and permitted SGLT2i within 3 months of screening.
10. 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.
11. Is not willing to comply with the contraceptive requirements during the study period
12. Unstable dose or anticipated need for titration of dose of a diuretic medication.
13. History of type 1 diabetes, latent autoimmune diabetes, MODY, or self-reported family history of MODY.
14. Has known renovascular hypertension caused by renal artery stenosis.
15. Hyperthyroidism that is being treated with oral antithyroid medications.
16. History of any clinically significant or active gastrointestinal, cardiovascular, 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, AST and AST are <2×ULN and total bilirubin is <1.5×ULN).
17. 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.
18. Has severe gastroparesis and/or severe neuropathy, especially autonomic neuropathy, as judged by the Investigator.
19. 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.
20. Has undergone liver, lung, kidney, or heart transplantation or is anticipated to be on an active transplantation waiting list during the study.
21. Known food intolerance that may affect interpretation of the results at the discretion of the Investigator, or known intolerance to glucose loads.
22. Female patient is pregnant or breastfeeding.
23. History of multiple drug allergies or history of allergic reaction to any component of or excipient in the study drug.
24. History of intolerance to SC injection(s).
25. 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).
26. Background treatment with 3 or more lipid-lowering agents of different classes.
27. Has a history of seizures.
28. Has a history of ketoacidosis or hyperosmolar state/coma.
29. 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.
30. Has eGFR of <45 mL/min/1.73m2 at screening (calculation will be based on the CKD-EPI equation).
31. Have any hematological condition that may interfere with HbA1c measurement (for example, hemolytic anemias, sickle cell disease)
32. Has SBP ≥150 mmHg or DBP ≥95 mmHg after 10 minutes of rest at screening, or a change in antihypertensive medications within 30 days of screening.
33. 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]).
34. History or clinical evidence of drug/chemical or alcohol use disorder, within the last 12 months before screening, in the opinion of the Investigator.
35. 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.
36. Currently taking, taken within 30 days prior to randomization, or anticipated to receive during the study, sotagliflozin.
37. 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).

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Frequency of AEs. Safety will also be evaluated through vital signs, ECGs, and clinical laboratory assessments.

Secondary endpoints 3

1. Change from baseline in HbA1c at Month 6.
2. HOMA-IR, Matsuda index, and glucose AUC response to glucose tolerance test.
3. Plasma concentrations of ALN-4324 and potential metabolite(s).

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Alnylam Pharmaceuticals Inc.

Sponsor organisation

Alnylam Pharmaceuticals Inc.

Address

300 3rd Street

City

Cambridge

Postcode

02142-1103

Country

United States

Scientific contact point

Organisation

Alnylam Pharmaceuticals Inc.

Contact name

Clinical Trial Information

Public contact point

Organisation

Alnylam Pharmaceuticals Inc.

Contact name

Clinical Trial Information

Third parties 9

Locations

2 EU/EEA countries · 6 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 24 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications