Safety and Tolerability of Patisiran (ALN-TTR02) in Transthyretin (TTR) Amyloidosis

A Phase 2, Open-Label, Multi-Dose, Dose Escalation Trial to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Intravenous Infusions of ALN-TTR02 in Patients With TTR Amyloidosis

This was a multiple dose, dose escalation study designed to determine the safety, tolerability, pharmacokinetics and pharmacodynamics of patisiran (ALN-TTR02) in participants with transthyretin (TTR) mediated amyloidosis (ATTR).

Study Overview

• Status: Completed
• Conditions: TTR-mediated Amyloidosis
• Intervention / Treatment: Drug: Patisiran

• Study Type: Interventional
• Enrollment (Actual): 29
• Phase: Phase 2

Expanded Access

No longer available outside the clinical trial. See expanded access record.

Contacts and Locations

Study Locations

• Brazil
  • Rio de Janeiro, Brazil
    • Clinical Trial Site
• France
  • Le Kremlin-bicetre, France
    • Clinical Trial Site
  • Marseille Cedex, France
    • Clinical Trial Site
• Germany
  • Munster, Germany
    • Clinical Trial Site
• Portugal
  • Lisbon, Portugal
    • Clinical Trial Site
  • Porto, Portugal
    • Clinical Trial Site
• Spain
  • Barcelona, Spain
    • Clinical Trial Site
  • Palma De Mallorca, Spain
    • Clinical Trial Site
• Sweden
  • Umeå, Sweden
    • Clinical Trial Site
• United States
  • Massachusetts
    • Boston, Massachusetts, United States
      • Clinical Trial Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Body mass index must be between 17 kg/m^2 and ≤ 33 kg/m^2;
• Women of child-bearing potential must have a negative pregnancy test, cannot be breast feeding, and must use appropriate contraception;
• Males agree to use appropriate contraception;
• Diagnosis of TTR amyloidosis;
• Adequate blood counts, liver and renal function;
• Willing to give written informed consent and are willing to comply with the study requirements.

Exclusion Criteria:

• Known human immunodeficiency virus (HIV) positive status or known or suspected systemic bacterial, viral, parasitic, or fungal infection;
• Received an investigational agent, other than tafamidis or diflunisal, within 30 days prior to first dose study drug administration;
• Prior liver transplant;
• Poor cardiac function;
• Considered unfit for the study by the Principal Investigator;
• Employee or family member of the sponsor or the clinical study site personnel.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Patisiran (ALN-TTR02); Two administrations of patisiran will be administered once every 4 weeks [Q4W]) in 4 sequential cohorts with escalating doses followed by optional cohorts with an alternative dosing regimen (once every 3 weeks [Q3W]), and an alternative premedication regimen.	Drug: Patisiran; Participants received a single dose of patisiran as an intravenous (IV) infusion on Day 0 and Day 28 (Q4W). Optional cohorts received an alternative dosing regimen (once every 3 weeks [Q3W]: Day 0 and Day 21) and an alternative premedication regimen.; Other Names: ALN-TTR02

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and Study Drug Discontinuation	The number of participants experiencing at least one adverse event (AE), at least one serious adverse event (SAE) and study drug discontinuation (due to any reason).	Up to 56 days post first dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage Change From Baseline in Serum Transthyretin (TTR) Protein	Percentage change of TTR relative to pretreatment/baseline levels is reported. For arms with a dosing regimen of Q4W TTR protein samples were measured on Days 28 and 56. For the arms with a dosing regimen of Q3W TTR protein samples were measured on Days 21 and 42.	Baseline to Day 21/28 and Day 42/56 depending on dosing regimen (Q3W/Q4W)
Pharmacokinetic Parameters of Patisiran - Area Under the Concentration Curve From Time 0 to Last Measurable Time Point (AUC0-last)	Pharmacokinetic profiles for patisiran (ALN-TTR02) were determined based on dosage and dosing frequency only, not premedication regimens. For arms with a dosing regimen of Q4W PK samples were taken on Days 0 and 28. For the arm with a dosing regimen of Q3W PK samples were taken on Days 0 and 21.	Predose, end of infusion and post-infusion at 5 minutes (min), 10 min, 30 min, 1 hour (h), 2 h, 4 h, 6 h, 24 h and 48 h on Day 0 and Day 21/28 depending on dosing regimen (Q3W/Q4W)
Pharmacokinetic Parameters of Patisiran - Maximum Observed Plasma Concentration (Cmax)	Pharmacokinetic profiles for patisiran (ALN-TTR02) were determined based on dosage and dosing frequency only, not premedication regimens. For arms with a dosing regimen of Q4W PK samples were taken on Days 0 and 28. For the arm with a dosing regimen of Q3W PK samples were taken on Days 0 and 21.	Predose, end of infusion and post-infusion at 5 minutes (min), 10 min, 30 min, 1 hour (h), 2 h, 4 h, 6 h, 24 h and 48 h on Day 0 and Day 21/28 depending on dosing regimen (Q3W/Q4W)
Pharmacokinetic Parameters of Patisiran - Beta Elimination Half-life (t1/2 Beta)	Pharmacokinetic profiles for patisiran were determined based on dosage and dosing frequency only, not premedication regimens. For arms with a dosing regimen of Q4W PK samples were taken on Days 0 and 28. For the arm with a dosing regimen of Q3W PK samples were taken on Days 0 and 21.	Predose, end of infusion and post-infusion at 5 minutes (min), 10 min, 30 min, 1 hour (h), 2 h, 4 h, 6 h, 24 h and 48 h on Day 0 and Day 21/28 depending on dosing frequency
Pharmacokinetic Parameters of Patisiran - Systemic Clearance (CL)	Pharmacokinetic profiles for patisiran were determined based on dosage and dosing frequency only, not premedication regimens. For arms with a dosing regimen of Q4W PK samples were taken on Days 0 and 28. For the arm with a dosing regimen of Q3W PK samples were taken on Days 0 and 21.	Predose, end of infusion and post-infusion at 5 minutes (min), 10 min, 30 min, 1 hour (h), 2 h, 4 h, 6 h, 24 h and 48 h on Day 0 and Day 21/28 depending on dosing frequency
Pharmacokinetic Parameters of Patisiran - Apparent Volume of Distribution at Steady State (Vss)	Pharmacokinetic profiles for patisiran were determined based on dosage and dosing frequency only, not premedication regimens. For arms with a dosing regimen of Q4W PK samples were taken on Days 0 and 28. For the arm with a dosing regimen of Q3W PK samples were taken on Days 0 and 21.	Predose, end of infusion and post-infusion at 5 minutes (min), 10 min, 30 min, 1 hour (h), 2 h, 4 h, 6 h, 24 h and 48 h on Day 0 and Day 21/28 depending on dosing frequency
Pharmacokinetic Parameters of Patisiran - Renal Clearance (CLR)	Pharmacokinetic profiles for patisiran were determined based on dosage and dosing frequency only, not premedication regimens. For arms with a dosing regimen of Q4W PK samples were taken on Days 0 and 28. For the arm with a dosing regimen of Q3W PK samples were taken on Days 0 and 21.	Predose (within 1 h of planned dosing start) and post-infusion at 0-6 h (pooled) on Day 0 and Day 21/28 depending on dosing frequency

Collaborators and Investigators

• Sponsor: Alnylam Pharmaceuticals
• Investigators: Study Director: Jared Gollob, MD, Alnylam Pharmaceuticals

Publications and helpful links

General Publications

• Suhr OB, Coelho T, Buades J, Pouget J, Conceicao I, Berk J, Schmidt H, Waddington-Cruz M, Campistol JM, Bettencourt BR, Vaishnaw A, Gollob J, Adams D. Efficacy and safety of patisiran for familial amyloidotic polyneuropathy: a phase II multi-dose study. Orphanet J Rare Dis. 2015 Sep 4;10:109. doi: 10.1186/s13023-015-0326-6.

Study record dates

Study Major Dates

• Study Start: May 1, 2012
• Primary Completion (Actual): October 1, 2013
• Study Completion (Actual): January 1, 2014

Study Registration Dates

• First Submitted: June 7, 2012
• First Submitted That Met QC Criteria: June 11, 2012
• First Posted (Estimated): June 13, 2012

Study Record Updates

• Last Update Posted (Actual): April 19, 2024
• Last Update Submitted That Met QC Criteria: April 17, 2024
• Last Verified: October 1, 2018

More Information

Terms related to this study

• Keywords: RNAi therapeutic
• Additional Relevant MeSH Terms: Metabolic Diseases; Proteostasis Deficiencies; Amyloidosis
• Other Study ID Numbers: ALN-TTR02-002; 2012-000467-24 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Access to Anonymized individual participant data that support these results is made available 12 months after study completion and not less than 12 months after the product and indication have been approved in the US and/or the EU.

Data will be provided contingent upon the approval of a research proposal and the execution of a data sharing agreement. Requests for access to data can be submitted via the website www.vivli.org.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes