Efficacy and Safety of CSL222 (Etranacogene Dezaparvovec) Gene Therapy in Adults With Hemophilia B With Pretreatment Adeno-associated Virus Serotype 5 (AAV5) Neutralizing Antibodies (Nabs)

Official title

Phase 3b, Open-label, Multicenter, Single-dose Study Investigating Efficacy and Safety of CSL222 (Etranacogene Dezaparvovec) Gene Therapy Administered to Adult Subjects With Severe or Moderately Severe Hemophilia B With Detectable Pretreatment AAV5 Neutralizing Antibodies

Overview

The purpose of this study is to assess the risk of bleeding due to failure of expected pharmacological action of CSL222 in adults with severe or moderately severe hemophilia B with detectable pretreatment AAV5 Nabs.

Interventions

• Genetic CSL222 (AAV5-hFIXco-Padua)
  Administered as a single IV infusion.

Primary outcome measures

• Annualized Bleeding Rate (ABR) [Time frame: Months 7 to 18 after CSL222 treatment]

Secondary outcome measures (12)

• Number of participants with Treatment Emergent Adverse Events (TEAEs) [Time frame: Up to 60 months after CSL222 treatment]
• Percentage of participants with TEAEs [Time frame: Up to 60 months after CSL222 treatment]
• Number of TEAEs [Time frame: Up to 60 months after CSL222 treatment]
• Change in Liver ultrasound [Time frame: Up to 60 months after CSL222 treatment]
• Number of participants who develop Factor IX (FIX) Inhibitors [Time frame: Up to 60 months after CSL222 treatment]
• Percentage of participants who develop FIX Inhibitors [Time frame: Up to 60 months after CSL222 treatment]
• Change in hematology and biochemistry parameters [Time frame: Up to 60 months after CSL222 treatment]
• Number of participants with clinically significant increase in Alanine Aminotransferase (ALT) or Aspartate Aminotransferase (AST) [Time frame: Up to 60 months after CSL222 treatment]
• Percentage of participants with clinically significant increase in ALT or AST [Time frame: Up to 60 months after CSL222 treatment]
• Corticosteroid use for ALT or AST increases after CSL222 treatment [Time frame: Up to 60 months after CSL222 treatment]
• Number of participants with clinically significant Alpha-fetoprotein (AFP) [Time frame: Baseline and up to 60 months after CSL222 treatment]
• Percentage of participants with clinically significant AFP [Time frame: Baseline and up to 60 months after CSL222 treatment]

Eligibility criteria

Inclusion criteria

• Considered legally an adult, as defined by country regulations.
• Has congenital hemophilia B with known severe or moderately severe FIX deficiency (less than or equal to \[<=\] 2% of normal circulating FIX) for which the participant is on continuous routine FIX prophylaxis.
• Has 2 consecutive detectable AAV5 NAb titer results between Screening and Visit L-Final using a validated AAV5 NAb assay (based on central laboratory results).
• Has greater than (>) 150 previous exposure days to FIX replacement therapy.
• Has been on stable FIX prophylaxis for at least 2 months before Screening.
• Has demonstrated capability to independently, accurately, and in a timely manner complete the eDiary during the Lead-in Period, as judged by the investigator.
• Acceptance to adhere to contraception guidelines.
• Able to provide informed consent after receipt of verbal and written information about the study.
• Investigator believes that the participant (or the participant's legally acceptable representative\[s\]) understands the nature, scope, and possible consequences of the study and is able to adhere to the study procedures.

Exclusion criteria

• History of FIX inhibitors or positive FIX inhibitor test at Prescreening, Screening or Visit L-Final (based on central laboratory results).
• Screening or Visit L-Final laboratory values (based on central laboratory results) of total bilirubin > 2 × the upper limit of normal (ULN) (except if caused by Gilbert's syndrome).
• Screening or Visit L-Final laboratory values (based on central laboratory results) of any of the following laboratory abnormalities:

• ALT > 2 × the ULN
• AST > 2 × the ULN
• Alkaline phosphatase > 2 × the ULN
• Serum creatinine > 2 × the ULN
• Hemoglobin less than (<) 8 g/dL
• Any condition other than hemophilia B resulting in an increased bleeding tendency.
• Thrombocytopenia, defined as a platelet count <50 × 10\^9/L, at Screening or Visit L Final (based on central laboratory results).
• Any uncontrolled or untreated infection (human immunodeficiency virus \[HIV\], hepatitis B virus \[HBV\] and hepatitis C virus \[HCV\], or any other significant concurrent, uncontrolled medical condition including, but not limited to, renal, hepatic, cardiovascular, hematological, gastrointestinal, endocrine, pulmonary, neurological, cerebral or psychiatric disease, alcoholism, drug dependency, or any other psychological disorder evaluated by the investigator to interfere with adherence to the clinical study protocol procedures or with the degree of tolerance to CSL222.
• Known history of allergy to corticosteroids or known medical condition that would require chronic administration of oral corticosteroids.
• Known uncontrolled allergic conditions or allergy / hypersensitivity to any component of the CSL222 excipients (ie, sucrose, potassium chloride, potassium dihydrogen phosphate, sodium chloride, and disodium hydrogen phosphate).
• Previous AAV5 gene therapy treatment.
• Receipt of an experimental agent or device within 60 days before Screening until the end of the study.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

Taiwan · 5 centers

• Tri-Service General Hospital — Taipei
• Kaohsiung Medical University Chung-Ho Memorial Hospital (KMUH) — Kaohsiung City
• Changhua Christian Hospital (CCH) — Chang-hua
• Taichung Veterans General Hospital - — Taichung
• National Taiwan University Hospital — Taipei

Australia · 4 centers

• Royal Prince Alfred Hospital — Camperdown
• Royal Brisbane Hospital — Herston
• Royal Adelaide Hospital — Adelaide
• The Alfred Hospital — Melbourne

United States · 3 centers

• University of California, San Diego (UCSD) — San Diego
• University of Michigan — Ann Arbor
• Hemophilia Center of Western Pennsylvania (HCWP) — Pittsburgh

South Korea · 3 centers

• Kyungpook National University Hospital — Daegu
• Kyung Hee University Hospital at Gangdong — Seoul
• Severance Hospital, Yonsei University Health System — Seoul

Turkey (Türkiye) · 3 centers

• Ege University Medical Faculty — Bornova
• Gaziantep University Sahinbey Research and Practice Hospital — Gaziantep
• Özel Acibadem Adana Hastanesi — Seyhan

Brazil · 2 centers

• Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo — São Paulo
• UNICAMP Universidade Estadual de Campinas — São Paulo

Hong Kong · 2 centers

• Queen Mary Hospital — Hong Kong
• Prince of Wales Hospital Chinese University of Hong Kong — Shatin

Singapore · 2 centers

• National University Hospital — Singapore
• Singapore General Hospital — Singapore

Bulgaria · 1 center

• Specialized Hospital for Active Treatment of Hematological Diseases — Sofia

Canada · 1 center

• McMaster University - Hamilton — Hamilton

Israel · 1 center

• Sheba Medical Center — Tel Litwinsky

Mexico · 1 center

• Centro de Investigacion Clinica GRAMEL S.C. — Mexico City

Poland · 1 center

• Klinika Zaburzen Hemostazy i Chorob Wewnetrznych — Warsaw

Saudi Arabia · 1 center

• King Faisal Specialist Hospital and Research Center — Riyadh

South Africa · 1 center

• Haemophilia Comprehensive Care Centre — Johannesburg

Identifiers

NCT: NCT06003387 · CSL222_3005 · 2023-509590-23-00

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗