A Phase 1 Study of Givosiran (ALN-AS1) in Patients With Acute Intermittent Porphyria (AIP)

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety and tolerability of givosiran (ALN-AS1) in AIP patients as well as to characterize pharmacokinetics (PK) and pharmacodynamics (PD) of ALN-AS1 in AIP patients.

Official Title
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A Phase 1, Single-ascending Dose, Multiple-ascending Dose, and Multi-dose Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics Study of Subcutaneously Administered ALN AS1 in Patients With Acute Intermittent Porphyria (AIP)

Conditions
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Acute Intermittent Porphyria

Intervention / Treatment
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* Drug: givosiran (ALN-AS1)
* Drug: Sterile Normal Saline (0.9% NaCl)


Participation Criteria
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Eligibility Criteria
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Parts A and B Inclusion Criteria: Diagnosis of AIP Urine PBG at Screening indicating patient is a high excreter No clinically significant health concerns Women of child bearing potential must have a negative pregnancy test, not be nursing, and use effective contraception Willing to provide written informed consent and willing to comply with study requirements. Exclusion Criteria: Porphyria attack within 6 months of screening Started a new prescription medication within 3 months of screening Clinically significant abnormal laboratory results Received an investigational agent within 90 days before the first dose of study drug or are in follow-up of another clinical study History of multiple drug allergies or intolerance to subcutaneous injection Part C Inclusion Criteria: Diagnosis of AIP Patient experienced a porphyria attack or was taking medication to prevent attacks recently No clinically significant health concerns Women of child bearing potential must have a negative pregnancy test, not be nursing, and use effective contraception Willing to provide written informed consent and willing to comply with study requirements. Exclusion Criteria: Stared a new prescription medication within 3 months of screening Clinically significant abnormal laboratory results Received an investigational agent within 90 days before the first dose of study drug or are in follow-up of another clinical study History of multiple drug allergies or intolerance to subcutaneous injection

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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No

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: givosiran (ALN-AS1)<br> | Drug: givosiran (ALN-AS1)<br>* Single or multiple doses of ALN-AS1 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 givosiran evaluated by the proportion of subjects experiencing adverse events (AEs), serious adverse events (SAEs), and AEs leading to study drug discontinuation |  | Part A (SAD phase): through day 42; Part B (MAD) phase: through Day 70; Part C (MD) phase: through Day 168 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Profile of Pharmacokinetics (PK) of givosiran | Cmax | Part A (SAD) phase: predose - 42 days post-dose; Part B (MAD) phase: predose - 70 days post-dose; Part C (MD) phase: predose - 168 days post-dose | 
| Profile of Pharmacokinetics (PK) of givosiran | tmax | Part A (SAD) phase: predose - 42 days post-dose; Part B (MAD) phase: predose - 70 days post-dose; Part C (MD) phase: predose - 168 days post-dose | 
| Profile of Pharmacokinetics (PK) of givosiran | AUC | Part A (SAD) phase: predose - 42 days post-dose; Part B (MAD) phase: predose - 70 days post-dose; Part C (MD) phase: predose - 168 days post-dose | 
| Profile of Pharmacokinetics (PK) of givosiran | t1/2 | Part A (SAD) phase: predose - 42 days post-dose; Part B (MAD) phase: predose - 70 days post-dose; Part C (MD) phase: predose - 168 days post-dose | 
| The change in delta-aminolevulinic acid (ALA) from baseline |  | Part A (SAD) phase: screening - 42 days post-dose; Part B (MAD) phase: screening - 70 days post-dose; Part C (MD) phase: screening - 168 days post-dose | 
| The change in Porphobilinogen (PBG) from baseline |  | Part A (SAD) phase: screening - 42 days post-dose; Part B (MAD) phase: screening - 70 days post-dose; Part C (MD) phase: screening - 168 days post-dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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RNAi therapeutic, Porphyria, AIP