• ClinicalTrials.gov Identifier: NCT02484092¹
• Phase 3, Open-label, Single-arm Study to Evaluate Efficacy and Safety of FIX Gene Transfer With PF-06838435 (rAAV-Spark100-hFIX-R338L) in Adult Male Participants With Moderately Severe to Severe Hemophilia B (FIX:C =2%) (BeneGene-2)

• Active, not recruiting
• Last Update Posted: 2024-08-23
• Approval status: According to a supporting document⁶ on the FDA page, fidanacogene elaparvovec was approved by the FDA on May 20, 2024

• Males ≥18 y.o. with confirmed diagnosis of hemophilia B (≤2 IU/dL or ≤2% endogenous factor IX)
• Had ≥50 prior EDs to any FIX protein products
• A minimum average of 4 bleeding events per year requiring episodic treatment of factor IX infusions or prophylactic factor IX infusions

• Neutralizing antibodies reactive with AAV-Spark100 above and/or below a defined titre
• Participated in a gene transfer trial within the last 52 weeks or in a clinical trial with an investigational drug within the last 12 weeks

Bioengineered capsid AAV-Spark100³ / HEK293 cells

Codon-opimized FIX-Padua / FIX-R338L^2, 3

The FIX expression cassette³ includes:

• APOE gene hepatic-control region (APOE-HCR) enhancer and the
• ​​​​Liver-specific human α1 -antitrypsin (hAAT) promoter

Systemic⁴

Single dose cohort: 5e11 (45) ²

44 of 45 pts. completed at least 15 months²

One-stage SynthASil assay²

At 15 months, the mean FIX activity was 26.9% (median of 22.9%; range from 1.9% to 119.0%)²

Not yet reported

The ABR for all bleeding episodes decreased by 71%, from 4.42 (95% confidence interval [CI], 1.80 to 7.05) at baseline to 1.28 (95% CI, 0.57 to 1.98) after gene therapy, a treatment difference of −3.15 episodes (95% CI, −5.46 to −0.83; P=0.008)²

Not yet reported

No infusion-related serious adverse events observed²

No thrombotic events, development of factor IX inhibitors were observed²

Not yet reported

A total of 28 participants (62%) received glucocorticoids for increased aminotransferase levels or decreased factor IX levels (or both) starting between 11 and 123 days²

A total of 28 participants (62%) received glucocorticoids for increased aminotransferase levels or decreased factor IX levels (or both) starting between 11 and 123 days²

Not yet reported

Not yet reported

A total of 28 participants (62%) received glucocorticoids for increased aminotransferase levels or decreased factor IX levels (or both) starting between 11 and 123 days²

No malignant conditions were observed²

1. A Study to Evaluate the Efficacy and Safety of Factor IX Gene Therapy With PF-06838435 in Adult Males With Moderately Severe to Severe Hemophilia B (BENEGENE-2). Available at: Study Details | A Study to Evaluate the Efficacy and Safety of Factor IX Gene Therapy With PF-06838435 in Adult Males With Moderately Severe to Severe Hemophilia B | ClinicalTrials.gov
2. Cuker A, Kavakli K, Frenzel L, Wang JD, Astermark J, Cerqueira MH, Iorio A, Katsarou-Fasouli O, Klamroth R, Shapiro AD, Hermans C, Ishiguro A, Leavitt AD, Oldenburg JB, Ozelo MC, Teitel J, Biondo F, Fang A, Fuiman J, McKay J, Sun P, Rasko JEJ, Rupon J; BENEGENE-2 Trial Investigators. Gene Therapy with Fidanacogene Elaparvovec in Adults with Hemophilia B. N Engl J Med. 2024 Sep 26;391(12):1108-1118. doi: 10.1056/NEJMoa2302982. PMID: 39321362. Gene Therapy with Fidanacogene Elaparvovec in Adults with Hemophilia B - PubMed (nih.gov)
3. George, L.A., et al., Hemophilia B Gene Therapy with a High-Specific-Activity Factor IX Variant. N Engl J Med, 2017. 377(23): p. 2215-2227. Hemophilia B Gene Therapy with a High-Specific-Activity Factor IX Variant | NEJM
4. Nathwani, A.C., Gene therapy for hemophilia. Hematology Am Soc Hematol Educ Program, 2019. 2019(1): p. 1-8. Gene therapy for hemophilia - PMC (nih.gov)

AAV, Adeno-associated virus; ABR, Annualized bleeding rate; AEs: adverse events; AIR, Annualized FVIII/FIX infusion rate; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CH, Chromogenic Assay; Co., cohort; DOACs, Direct oral anticoagulants; D, days; EDs, exposure days; FIX, factor IX; FIX-Padua, gain of function FIX variant; FVIII, factor VIII; gc, genome copies; HEK cells, human embryonic kidney cells; IQR, interquartile range; IRR, Infusion-related reaction; NAbs, neutralizing antibodies; OS, One-stage clotting assay; Pop., population; pt., patient/participant; pts., patients/participants; P1, Participant 1; PI, phase I; PBGD, porphobilinogen deaminase; PBMC, peripheral blood mononuclear cells; SAEs, serious adverse events; SFU, spot-forming units; TAC, tacrolimus; ULN, upper limit of normal; VCN, vector copy number; vg, vector genomes; W, weeks; WT, wild type; Y, year