Efficacy and Safety of Etranacogene Dezaparvovec Gene Therapy in Adults with Severe or Moderately Severe Hemophilia B and Pre-existing AAV5 Neutralizing Antibodies

Trial ID: 2023-509590-23-00
Protocol: CSL222_3005
Sponsor: CSL Behring LLC

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Diseases & Conditions

Factor IX deficiency

Objectives

The primary objective of this Phase 3b, open-label, multicenter study is to evaluate the **efficacy** and **safety** of CSL222 (Etranacogene Dezaparvovec) gene therapy in adult subjects with severe or moderately severe **Hemophilia B** who have detectable pretreatment AAV5 neutralizing antibodies. Specifically, the study aims to assess whether there is a clinically significant correlation between pretreatment AAV5 neutralizing antibody titers and the risk of bleeding during the 52 weeks following CSL222 treatment. This evaluation will occur after the establishment of stable Factor IX (FIX) expression, from months 7 to 18 post-dose, compared to the standard of care continuous routine FIX prophylaxis during a lead-in period of at least 6 months. The clinical relevance of this study lies in its potential to provide insights into the impact of pretreatment antibody levels on the therapeutic outcomes of gene therapy in Hemophilia B, which could inform treatment strategies and improve patient management.

Participants

The clinical trial involves a total of **32 participants** diagnosed with **Hemophilia B**, a condition characterized by a deficiency in clotting factor IX (FIX). The study population includes both male and female adults, aged 18 years and older, who are considered legally adults according to their respective country regulations. Participants were selected based on their congenital hemophilia B with severe or moderately severe FIX deficiency, defined as ≤ 2% of normal circulating FIX, and their current regimen of continuous routine FIX prophylaxis. All participants have a history of more than 150 exposure days to FIX replacement therapy and have been on stable FIX prophylaxis for at least two months prior to screening. The trial also considers lifestyle factors, requiring participants to demonstrate the capability to independently and accurately complete an electronic diary during the lead-in period. The study includes a vulnerable population, and participants must agree to use barrier contraception for one year starting from the day of CSL222 treatment. The sponsor has not provided additional information regarding specific lifestyle considerations such as diet or physical activity.

Plans and Procedures

The clinical trial is a **Phase 3b**, open-label, multicenter study designed to evaluate the efficacy and safety of **CSL222 (Etranacogene Dezaparvovec)** gene therapy in adult subjects with severe or moderately severe **Hemophilia B** who have detectable pretreatment AAV5 neutralizing antibodies. The trial will involve a single-dose administration of the investigational product, delivered via **intravenous infusion**. The primary objective is to assess the correlation between pretreatment AAV5 neutralizing antibody titers and the risk of bleeding during the 52 weeks following treatment, compared to standard care continuous routine FIX prophylaxis during a lead-in period of at least six months.

The trial is expected to commence recruitment on March 25, 2025, and conclude by October 4, 2028. Participants will be involved in the study for a maximum treatment period of one year. The study will include several key visits: an initial screening visit to confirm eligibility, followed by the administration of the gene therapy. Subsequent follow-up visits will be scheduled to monitor the participants' health, assess the treatment's efficacy, and record any adverse events. The end-of-study visit will mark the completion of the participant's involvement, where final assessments will be conducted.

Participants are expected to meet specific inclusion criteria, such as being 18 years or older, having congenital Hemophilia B with severe or moderately severe FIX deficiency, and having a history of more than 150 exposure days to FIX replacement therapy. They must also demonstrate the ability to complete an electronic diary during the lead-in period and agree to use barrier contraception for one year post-treatment. Conditions that may lead to early termination from the study include the development of clinically significant adverse events or the inability to adhere to study procedures.

The primary endpoint of the study is the annualized bleeding rate (ABR). Secondary endpoints include the number and percentage of participants with treatment-emergent adverse events, changes in liver ultrasound, and the development of Factor IX inhibitors. Additional assessments will include changes in hematology and biochemistry parameters, the use of corticosteroids for liver enzyme increases, and the evaluation of infusion-related reactions. The study will also analyze the correlation between FIX activity levels and baseline AAV5 neutralizing antibody titers.

Treatment

The clinical trial involves the administration of **Hemgenix**, a gene therapy product containing **etranacogene dezaparvovec**. This experimental medication is formulated as a **concentrate for solution for infusion**. The active substance, etranacogene dezaparvovec, is a non-replicating, recombinant adeno-associated virus serotype 5 (AAV5) based vector. It contains a codon-optimized cDNA of the human coagulation Factor IX variant R338L (FIX-Padua) gene, which is under the control of a liver-specific promoter (LP1). The pharmaceutical form is a concentrate for solution for infusion, and the route of administration is via **intravenous infusion**. The dosage is specified as 1x10^13 genome copies/mL, with a maximum daily and total dose of 2 millilitres per kilogram. The treatment is administered as a single dose, with a maximum treatment period of one day.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The trial is designed to assess the efficacy and safety of the gene therapy in adult subjects with severe or moderately severe **hemophilia B** who have detectable pretreatment AAV5 neutralizing antibodies. Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the protocol. The trial aims to establish a stable expression of Factor IX and evaluate the correlation of pretreatment AAV5 neutralizing antibody titers with the risk of bleeding during the follow-up period.

Efficacy

The efficacy of the clinical trial will be assessed primarily through the **Annualized Bleeding Rate (ABR)**, which serves as the primary endpoint. This parameter will be used to evaluate the effectiveness of CSL222 (Etranacogene Dezaparvovec) gene therapy in adult subjects with severe or moderately severe hemophilia B. The trial aims to determine the correlation between pretreatment AAV5 neutralizing antibody titers and the risk of bleeding during the 52 weeks following treatment, compared to standard care during the lead-in period.

Secondary endpoints include a comprehensive range of parameters to further assess efficacy and safety. These include the number and percentage of participants with Treatment Emergent Adverse Events (TEAEs), changes in liver ultrasound, the development of Factor IX (FIX) inhibitors, and changes in hematology and biochemistry parameters. Additionally, the trial will monitor the number of participants with clinically significant increases in Alanine Aminotransferase (ALT) or Aspartate Aminotransferase (AST), corticosteroid use for ALT or AST increases, and changes in endogenous FIX activity. Other secondary measures include the annualized consumption and infusion rate of FIX replacement therapy, the number and percentage of participants remaining free of continuous routine FIX prophylaxis, and various bleeding episode rates.

Data collection will involve validated laboratory tests and patient-reported outcomes, with specific timepoints for assessment not explicitly detailed. The trial will also include correlation analyses of FIX activity levels with baseline AAV5 NAb titers and evaluate changes in quality of life using the EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) Visual Analogue Scale (VAS) and Index Scores. These assessments will provide a comprehensive evaluation of the gene therapy's impact on the participants' health and quality of life.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Age ≥ 18 years and 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 subject 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
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.

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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: • Alanine aminotransferase (ALT) > 2 × the ULN • Aspartate aminotransferase (AST) > 2 × the ULN • Alkaline phosphatase > 2 × the ULN • Serum creatinine > 2 × the ULN • Hemoglobin < 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 gene therapy treatment.
Receipt of an experimental agent or device within 60 days before Screening until the end of the study.