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

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)

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.

Study Overview

• Status: Completed
• Conditions: Acute Intermittent Porphyria
• Intervention / Treatment: Drug: Sterile Normal Saline (0.9% NaCl); Drug: givosiran (ALN-AS1)

• Study Type: Interventional
• Enrollment (Actual): 40
• Phase: Phase 1

Contacts and Locations

Study Locations

• Sweden
  • Stockholm, Sweden
    • Clinical Trial Site
• United Kingdom
  • London, United Kingdom
    • Clinical Trial Site
• United States
  • Alabama
    • Birmingham, Alabama, United States
      • Clinical Trial Site
  • California
    • San Francisco, California, United States
      • Clinical Trial Site
  • New York
    • New York, New York, United States
      • Clinical Trial Site
  • Texas
    • Galveston, Texas, United States
      • Clinical Trial Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Sterile Normal Saline (0.9% NaCl)	Drug: Sterile Normal Saline (0.9% NaCl); calculated volume to match active comparator
Active Comparator: givosiran (ALN-AS1)	Drug: givosiran (ALN-AS1); Single or multiple doses of ALN-AS1 by subcutaneous (sc) injection

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Collaborators and Investigators

• Sponsor: Alnylam Pharmaceuticals
• Investigators: Study Director: Amy Simon, MD, Alnylam Pharmaceuticals

Publications and helpful links

General Publications

• Sardh E, Harper P, Balwani M, Stein P, Rees D, Bissell DM, Desnick R, Parker C, Phillips J, Bonkovsky HL, Vassiliou D, Penz C, Chan-Daniels A, He Q, Querbes W, Fitzgerald K, Kim JB, Garg P, Vaishnaw A, Simon AR, Anderson KE. Phase 1 Trial of an RNA Interference Therapy for Acute Intermittent Porphyria. N Engl J Med. 2019 Feb 7;380(6):549-558. doi: 10.1056/NEJMoa1807838.

Study record dates

Study Major Dates

• Study Start (Actual): May 6, 2015
• Primary Completion (Actual): September 6, 2017
• Study Completion (Actual): September 6, 2017

Study Registration Dates

• First Submitted: May 19, 2015
• First Submitted That Met QC Criteria: May 20, 2015
• First Posted (Estimate): May 22, 2015

Study Record Updates

• Last Update Posted (Actual): June 14, 2018
• Last Update Submitted That Met QC Criteria: June 13, 2018
• Last Verified: June 1, 2018

More Information

Terms related to this study

• Keywords: RNAi therapeutic; Porphyria; AIP
• Additional Relevant MeSH Terms: Digestive System Diseases; Metabolic Diseases; Skin Diseases; Liver Diseases; Genetic Diseases, Inborn; Skin Diseases, Genetic; Porphyrias, Hepatic; Porphyria, Erythropoietic; Porphyrias; Porphyria, Acute Intermittent
• Other Study ID Numbers: ALN-AS1-001