A Study of PRX004 in Subjects With Amyloid Transthyretin (ATTR) Amyloidosis

NCT03336580 | Terminated Phase 1 DMC FDA Drug

• 2 other identifiers: PRX004-1012017-003521-15
• Study Type: interventional
• Target: 21
• Locations: 4 countries
• Sites: 7

Brief Summary

A Phase 1, open-label study of intravenous (IV) PRX004 as a single agent in subjects with hereditary amyloid transthyretin (hATTR) amyloidosis. The study will consist of 3 phases and will enroll up to a total of 36 subjects. A 3+3 dose escalation component to determine the safety, tolerability, PK, PD, and MTD. An expansion component in anticipated PRX004 RP2D cohorts selected from the Dose Escalation Phase. An extended dosing component for eligible subjects from the Dose Escalation or Expansion phases.

Conditions

Amyloidogenic Transthyretin (ATTR) Amyloidosis

Outcome Measures

Primary Outcomes (2)

• Maximum Tolerated Dose of PRX004

  Maximum Tolerated Dose of PRX004

  28 days

• Number of subjects with treatment-emergent adverse events and clinically significant changes in ECGs, echocardiograms, cardiac telemetry, vital signs, and laboratory evaluations

  Number of subjects with treatment-emergent adverse events and clinically significant changes in ECGs, echocardiograms, cardiac telemetry, vital signs, and laboratory evaluations

  3 months

Secondary Outcomes (6)

• PRX004 pharmacokinetic parameters - Cmin

  3 months

• PRX004 pharmacokinetic parameters -Cmax

  3 months

• PRX004 pharmacokinetic parameters - T1/2

  3 months

• PRX004 pharmacokinetic parameters -AUClast

  3 months

• PRX004 pharmacokinetic parameters -AUCtau

  3 months

Study Arms (1)

PRX004

EXPERIMENTAL

Dose escalation in up to 6 dose levels Expansion of previously studied cohort(s) from Dose Escalation Extended dosing at RP2D

Drug: PRX004

Interventions

PRX004 DRUG

PRX004 (0.1, 0.3, 1, 3, 10, and 30 mg/kg) IV every 28 days PRX004 IV every 28 days at RP2D(s) PRX004 IV every 28 days at RP2D(s)

PRX004

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age ≥18 years
• Ability to understand and willingness to sign an informed consent form prior to initiation of any study procedures
• Diagnosis of amyloidosis determined by polarizing light microscopy of green birefringent material in Congo Red-stained tissue specimens; and confirmed diagnosis of ATTR amyloidosis by immunohistochemistry, mass spectrometry, documentation of an ATTR mutation by gene sequencing, or 99m technetium-3,3-diphosphono-1,2-propanodicarboxylic acid (99mTc-DPD) scans and/or technetium pyrophosphate (PYP) SPECT cardiac imaging. If scintigraphy is used for diagnosis then the grade must be 2 or greater, indicative of transthyretin amyloidosis-cardiomyopathy (ATTR-CM) (Gillmore, 2016)
• Known TTR mutation
• Patients receiving concomitant tafamidis or diflunisal may enroll in the study, providing the dose has been stable for the last 6 months
• Karnofsky Performance Status (KPS) ≥60%
• Adequate organ function, including all of the following:
• Adequate bone marrow reserve, defined as the following: absolute neutrophil count ≥1.0 × 109/L; platelet count ≥100 × 109/L; hemoglobin ≥10 g/dL
• Hepatic: total bilirubin ≤ 2 times the upper limit of normal (× ULN), transaminases (aspartate aminotransferase and/or alanine aminotransferase) ≤3 × ULN; alkaline phosphatase ≤5 × ULN
• Renal: estimated glomerular filtration rate (eGFR) ≥45 mL/min/1.73 m2
• If currently receiving a diuretic, must have been on a stable dose for at least 4 weeks prior to the first dose of study drug
• Systolic blood pressure ≥90 mmHg and ≤180 mmHg
• Subjects with cardiomyopathy must have an NT-proBNP ≥650 pg/mL and ≤5000 pg/mL (ie, ≥76.9 pmol/L and ≤591 pmol/L) or evidence of septal wall thickening \>1.2 cm on echocardiogram
• Must have a biopsy unless data are available from a previous one. The biopsy may be taken from any tissue or organ affected by ATTR amyloidosis (eg, skin, lip, abdominal fat pad, salivary gland), at the Investigator's discretion. Nerve biopsies are not required.
• Women of childbearing potential must have 2 negative pregnancy tests during Screening, the second within 24 hours prior to the first administration of study drug, and must agree to use highly effective physician-approved contraception from Screening to 90 days following the last study drug administration

You may not qualify if:

• Amyloid light chain or other non-ATTR amyloidosis
• Any past history of or present abuse of alcohol, diabetes, B12 or folate deficiencies, autoimmune diseases, hereditary disorders other than transthyretin (eg, Charcot-Marie-Tooth), uncontrolled hypothyroidism, or other etiologies for the peripheral neuropathy
• Received prior liver transplant
• Planned liver transplant during the study
• Modified body mass index (mBMI) ≤600 kg/m2 × g/L
• New York Heart Association (NYHA) Functional Class III-IV (Appendix 2)
• LVEF ≤45%
• Uncontrolled symptomatic orthostatic hypotension
• Myocardial infarction, unstable or uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia, within 6 months prior to the first dose of study drug
• Any history of clinically significant sinus pauses on ECG
• Sinus pauses \>3 seconds in the day or sinus pauses \>5 seconds at night during the 48-hour pre-dose cardiac monitoring (ie, prior to first dose of study drug)
• Arrhythmia requiring treatment diagnosed during the 48-hour pre-dose cardiac monitoring (ie, prior to first dose of study drug). Note: subject could be reconsidered for entry into the study if appropriate treatment is obtained
• Hospitalized for heart failure within the 12 weeks prior to the first dose of study drug
• Uncontrolled infection, or active malignancy with the exception of the following:
• Adequately treated basal cell carcinoma, squamous cell carcinoma of the skin, or in situ cervical cancer

Sponsors & Collaborators

• Prothena Biosciences Limited: lead

Study Sites (7)

Tufts Medical Center

Boston, Massachusetts, 02111, United States

Location

Mayo Clinic Minnesota

Rochester, Minnesota, 55905, United States

Location

Oregon Health and Science University

Portland, Oregon, 97239, United States

Location

Penn Presbyterian Medical Center

Philadelphia, Pennsylvania, 19104, United States

Location

Centro Hospitalar do Porto

Porto, Portugal

Location

Hospital Universitario Puerta de Hierro - Majadahonda

Majadahonda, Madrid, 28222, Spain

Location

Umeå University Hospital

Umeå, Sweden

Location

Related Publications (1)

• Capustin M, Frishman WH. Transthyretin Cardiac Amyloidosis and Novel Therapies to Treat This Not-so-rare Cause of Cardiomyopathy. Cardiol Rev. 2021 Sep-Oct 01;29(5):263-273. doi: 10.1097/CRD.0000000000000387.

  PMID: 34397539 DERIVED

MeSH Terms

Conditions

Amyloidosis

Condition Hierarchy (Ancestors)

Proteostasis Deficiencies; Metabolic Diseases; Nutritional and Metabolic Diseases

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Dose Escalation Study

Study Record Dates

• First Submitted: October 23, 2017
• First Posted: November 8, 2017
• Study Start: April 5, 2018
• Primary Completion: July 23, 2020
• Study Completion: July 23, 2020
• Last Updated: August 20, 2020

Record last verified: 2020-08

Data Sharing

• IPD Sharing: Will not share

Locations

US (4); ES (1); SE (1); PT (1)