A Phase 1 Study of an Investigational Drug, ALN-AT3SC, in Healthy Volunteers and Hemophilia A or B Patients

Study Overview
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Brief Summary
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The purpose of this study is to determine the safety, tolerability, and pharmacokinetics of ALN-AT3SC in healthy volunteers and Hemophilia A or B patients.

Official Title
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A Phase 1 Single-ascending and Multiple-ascending Dose, Safety, Tolerability and Pharmacokinetics Study of Subcutaneously Administered ALN-AT3SC in Healthy Adult Volunteers and Hemophilia A or B Patients (Moderate or Severe Hemophilia)

Conditions
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Hemophilia A, Hemophilia B

Intervention / Treatment
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* Drug: ALN-AT3SC
* Drug: Sterile Normal Saline (0.9% NaCl)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Part A (SAD phase) inclusion: Healthy adult males aged 18 to 40 years inclusive at Screening. Subjects with adequate complete blood counts and liver function tests. Willing to provide written informed consent and willing to comply with study requirements. Part B & C (MAD & MD phase) inclusion: Adult male hemophilia patients aged 18 to 65 years inclusive at Screening. Patients with adequate complete blood counts and liver function tests. Patients with moderate or severe, clinically stable hemophilia A or B (Factor VIII or Factor IX ≤5%). Willing to provide written informed consent and willing to comply with study requirements Part D (MD Phase in patients with inhibitors) Inclusion: Same as Parts B/C A Bethesda inhibitor assay > 0.6 BU/mL Exclusion Criteria: Part A (SAD phase) exclusion: Subjects with a personal history and/or family history of venous thromboembolism (VTE) Subjects with a known co-existing thrombophilic disorder Subjects with a history of multiple drug allergies or history of allergic reaction to an oligonucleotide or GalNAc. Subjects with a history of serious mental illness that includes, but is not limited to schizophrenia, bipolar disorder, severe depression requiring hospitalization or pharmacological intervention. Subjects who have a clinically relevant history or presence of cardiovascular, respiratory, gastrointestinal, renal, hematological, lymphatic, neurological, musculoskeletal, genitourinary, immunological including osteoarthritis and other inflammatory diseases, dermatological including rash, eczema, dermatitis, or connective tissue diseases or disorders. Part B & C (MAD & MD phase) exclusion: Patients with a current serious mental illness that, in the judgment of the Investigator, may compromise patient safety, ability to participate in all study assessments, or study integrity. Patients who have a clinically relevant history or presence of cardiovascular, respiratory, gastrointestinal, renal, neurological, inflammatory or other diseases that in the judgment of the investigator precludes their participation in the study. Patients with a known co-existing thrombophilic disorder Patients with a history of multiple drug allergies or history of allergic reaction to an oligonucleotide or GalNAc. Patients who are known to be HIV positive and have a CD4 count <400 cells/μL Part D (MD Phase in patients with inhibitors) exclusion: Same as Parts B/C Patients who are known to be HIV positive and have a CD4 count <200 cells/μL

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

Sexes Eligible for Study
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Male

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: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: ALN-AT3SC<br> | Drug: ALN-AT3SC<br>* Ascending doses of ALN-AT3SC by subcutaneous (sc) injection<br>|
| Placebo Comparator: Sterile Normal Saline (0.9% NaCl)<br> | Drug: Sterile Normal Saline (0.9% NaCl)<br>* Calculated volume to match active comparator<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The safety of ALN-AT3SC evaluated by the proportion of subjects experiencing adverse events (AEs), serious adverse events (SAEs), dose-limiting toxicities (DLTs), and AEs leading to study drug discontinuation. |  | Part A (SAD phase): through day 56; Part B (MAD) phase: through Day 70; Part C (MD Phase) through Day 112; Part D (MD Phase in patients with inhibitors) through Day 112 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The pharmacokinetics (PK) of ALN-AT3SC as characterized by plasma PK profiles and urine samples. |  | Part A (SAD) phase: through day 56; Part B (MAD) phase: through Day 70; Part C (MD Phase) through Day 112; Part D (MD Phase in patients with inhibitors) through Day 112 | 
| The pharmacodynamic (PD) effect of ALN-AT3SC, evaluated by Plasma AT levels. |  | Part A (SAD) phase: through day 56; Part B (MAD) phase: through Day 70; Part C (MD Phase) through Day 112; Part D (MD Phase in patients with inhibitors) through Day 112 | 
| The pharmacodynamic (PD) effect of ALN-AT3SC, evaluated by Plasma TG. |  | Part A (SAD) phase: through day 56; Part B (MAD) phase: through Day 70; Part C (MD Phase) through Day 112; Part D (MD Phase in patients with inhibitors) through Day 112 |