In Brief | Blood Disorders | Haemophilia
Breakthrough gene therapy, fidanacogene elaparvovec, shows promise for adults with Haemophilia B
Time to read: 04:09 minutes
Time to listen: 06:01 minutes
Published on MedED: 21 October 2024
Originally Published: 25 September 2024
Sourced: NEJM
Type of article: In Brief
MedED Catalogue Reference: MHIB001
Category: Blood Disorders
Cross Reference: Novel drugs, Trauma, Critical Care
Keywords: haemophilia, gene therapy, novel drugs
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Originally Published: 25 September 2024
Sourced: NEJM
Type of article: In Brief
MedED Catalogue Reference: MHIB001
Category: Blood Disorders
Cross Reference: Novel drugs, Trauma, Critical Care
Keywords: haemophilia, gene therapy, novel drugs
Key Takeaway
The phase 3 study demonstrated that fidanacogene elaparvovec offers an effective benefit-risk profile, delivering efficacy at one of the lowest doses of AAV-based gene therapy for haemophilia B. An extended follow-up study will continue for 15 years to provide additional insights into the therapy's long-term effects.
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Originally published in NEJM 25 September 2024
The management of haemophilia B typically requires episodic intravenous infusions of plasma-derived or recombinant factor IX replacement therapies.
Despite recent advancements that have reduced infusion frequency, these therapies remain non-curative and often fail to alleviate symptoms, often leading to joint damage.
Gene therapy has emerged as a promising alternative, potentially freeing patients from continuous treatment.
Fidanacogene elaparvovec is the first gene therapy for haemophilia B to be approved by the FDA (April 2024). This therapy employs an adeno-associated virus (AAV) serotype 5 vector to deliver a high-activity factor IX - FIX-R338L - into the body.
In earlier phase 1–2a studies, fidanacogene elaparvovec demonstrated sustained factor IX activity levels ranging from mild to normal, with low rates of bleeding and a reduced need for exogenous factor IX.
These results were achieved using one of the lowest vector doses reported in gene therapy trials (5×10^11 vector genome copies per kilogram)..1
This phase 3 open-label study (BENEGENE-2) enrolled 45 participants with severe haemophilia B, 44 of whom completed at least 15 months of follow-up.
Inclusion Criteria
Severe haemophilia B was indicated by factor IX levels ≤2%, and these patients had received factor IX prophylaxis for at least six months during the BENEGENE-1 study.
Severe haemophilia B was indicated by factor IX levels ≤2%, and these patients had received factor IX prophylaxis for at least six months during the BENEGENE-1 study.
Exclusion Criteria
Patients were excluded on the basis of detectable anti-AAV neutralizing antibodies, a history of factor IX inhibitors, significant unstable diseases, elevated liver enzymes, active hepatitis B or C, or HIV infection.
Patients were excluded on the basis of detectable anti-AAV neutralizing antibodies, a history of factor IX inhibitors, significant unstable diseases, elevated liver enzymes, active hepatitis B or C, or HIV infection.
Primary Endpoint
The primary endpoint of the study was the annualized bleeding rate from week 12 to month 15 after treatment, compared to the prophylaxis lead-in period.
The primary endpoint of the study was the annualized bleeding rate from week 12 to month 15 after treatment, compared to the prophylaxis lead-in period.
Secondary Endpoints
Secondary endpoints included the annualized rate of treated bleeding episodes and factor IX activity levels, with safety assessments involving annual liver ultrasounds and immune response evaluations.
The following findings were recorded:
The mean age was of the participants was 33.2 years
At baseline, 2% had controlled HIV, 29% had positive serologic tests for previous hepatitis B, and 33% were positive for previous hepatitis C. 29% of the patients had target joints.
- Participants suspended prophylaxis after receiving a single intravenous fidanacogene elaparvovec infusion on Day 1
- During the prophylaxis period, the average rate of total bleeding episodes was 4.42
- After treatment with fidanacogene elaparvovec, this rate dropped significantly to 1.28 from week 12 to month 15, showing a 71% reduction (P<0.001).
- For treated bleeding episodes, the average rate decreased from 3.34 to 0.73, indicating a 78% reduction (P=0.002)
- Following gene therapy, the average infusion rate decreased 92.3%, and total factor IX consumption decreased 92.4%, highlighting its effectiveness
- Following gene therapy, the average infusion rate decreased 92.3%, and total factor IX consumption decreased 92.4%, highlighting its effectiveness
- Before treatment, 29% of participants had no bleeding episodes, but this increased to 64% after therapy. Similarly, the proportion of participants with no treated bleeding episodes rose from 36% to 73%
- Of the 45 participants, 38 (84%) reported 206 adverse events, including seven serious cases
- The most common adverse event was a mild increase in aminotransferase levels, affecting 24 participants (53%).
- A total of 28 participants (62%) received glucocorticoids for elevated aminotransferase or decreased factor IX levels, with 6 (21%) resuming prophylaxis.
- The median time to start glucocorticoids was 37.5 days, with a median treatment duration of 95.0 days
In conclusion
Fidanacogene elaparvovec reduced bleeding and stable factor IX expression. Based on these findings, the researchers concluded that it was superior to prophylaxis for treating participants with hemophilia B.
This trial was funded by Pfizer and registered as BENEGENE-2 ClinicalTrials.gov number NCT03861273
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