Safety, Tolerability and Pharmacodynamic Effect of Fazirsiran (TAK-999, ARO-AAT) (SEQUOIA)

Arrowhead Pharmaceuticals

Status and phase: Completed; Phase 2

Conditions: Alpha 1-Antitrypsin Deficiency

Treatments: Other: Placebo; Drug: Fazisiran Injection

Study type: Interventional

Funder types: Industry

Identifiers

NCT03945292

2018-003385-14 (EudraCT Number)

AROAAT2001

Details and patient eligibility

About

The purpose of AROAAT2001 (SEQUOIA) is to evaluate the safety, efficacy and tolerability of multiple doses of the investigational product, Fazirsiran Injection, administered subcutaneously to participants with alpha-1 antitrypsin deficiency (AATD).

Full description

Participants will be enrolled to receive multiple subcutaneous injections of Fazirsiran Injection (also referred to as TAK-999 Injection or ARO-AAT Injection) or placebo. Eligible participants will require a pre-dose biopsy completed as part of the study within the screening window. However, any participant with a biopsy result within 1 year of screening showing no fibrosis does not require a pre-dose biopsy. Only participants who have liver fibrosis will undergo a post-dose biopsy and may continue treatment in an open-label phase.

Enrollment: 40 patients

Sex: All

Ages: 18 to 75 years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Diagnosis of AATD
• Liver biopsy at Screening indicating liver fibrosis (score less than F4); a patient with no fibrosis may participate based on a previous biopsy conducted within one year
• Women of childbearing potential must have a negative pregnancy test, cannot be breastfeeding, and must be willing to use contraception
• Willing to provide written informed consent and to comply with study requirements
• Non-smoker for at least 1 year
• No abnormal finding of clinical relevance at Screening

Exclusion criteria

• Clinically significant health concerns other than AATD
• Previous diagnosis or diagnosis at Screening of definitive liver cirrhosis
• Previous lung or liver transplant due to AATD
• Regular use of alcohol within one month prior to Screening
• Use of an investigational agent or device within 30 days prior to dosing or current participation in an investigational study involving therapeutic intervention
• Use of illicit drugs within 1 year prior to Screening

NOTE: additional inclusion/exclusion criteria may apply, per protocol

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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40 participants in 4 patient groups, including a placebo group

Fazirsiran 25 mg DB/200 mg OL

Experimental group

Description:

Double-blind (DB) Period: Participants with no fibrosis: Administered on Day 1 and Week 4. Participants with fibrosis: Administered on Day 1, Week 4, and Week 16, then every 12 weeks up to 18 total doses. Open-label (OL) Period: Participants with fibrosis at Screening who received double-blind (DB) fazirsiran 25 mg and who completed the post-dose liver biopsy at Week 48 (or Week 72 or Week 96) entered the open-label phase and received fazirsiran 200 mg every 12 weeks for the duration of the study.

Treatment:

Drug: Fazisiran Injection

Fazirsiran 100 mg DB/200 mg OL

Experimental group

Description:

DB Period: Participants with no fibrosis: Fazirsiran 100 mg administered on Day 1 and Week 4. Participants with fibrosis: Fazirsiran 100 mg administered on Day 1, Week 4, and Week 16, then every 12 weeks up to 18 total doses. OL Period: Participants with fibrosis at Screening who received double-blind (DB) fazirsiran 100 mg and who completed the post-dose liver biopsy at Week 48 (or Week 72 or Week 96) entered the open-label phase and received fazirsiran 200 mg every 12 weeks for the duration of the study.

Treatment:

Drug: Fazisiran Injection

Fazirsiran 200 mg DB/200 mg OL

Experimental group

Description:

DB Period: Participants with no fibrosis: Fazirsiran 200 mg administered on Day 1 and Week 4. Participants with fibrosis: Fazirsiran 200 mg administered on Day 1, Week 4, and Week 16, then every 12 weeks up to 18 total doses. OL Period: Participants with fibrosis at Screening who received double-blind (DB) fazirsiran 200 mg and who completed the post-dose liver biopsy at Week 48 (or Week 72 or Week 96) entered the open-label phase and received fazirsiran 200 mg every 12 weeks for the duration of the study

Treatment:

Drug: Fazisiran Injection

Placebo DB / Fazirsiran 200 mg OL

Placebo Comparator group

Description:

DB Period: Participants with no fibrosis: Placebo administered on Day 1 and Week 4. Participants with fibrosis: Placebo administered on Day 1, Week 4, and Week 16, then every 12 weeks up to 18 total doses. OL Period: Participants with fibrosis at Screening who received double-blind (DB) placebo and who completed the post-dose liver biopsy at Week 48 (or Week 72 or Week 96) entered the open-label phase and received fazirsiran 200 mg every 12 weeks for the duration of the study.

Treatment:

Drug: Fazisiran Injection

Other: Placebo