Medical Policy

This document addresses gene therapy for hemophilia, a congenital bleeding disorder.

Note: For a high-level overview of this document, please see “Summary for Members and Families” below.

Medically Necessary:

Etranacogene dezaparvovec-drlb is considered medically necessary in individuals who meet all of the following criteria:

1. Diagnosis of hemophilia B; and
2. Age 18 years or older; and
3. Baseline factor IX level is less than 2 international units (IU)/deciliter (dL) (or 2% endogenous factor IX); and
4. No contraindications to infusion (if any of the following are present, treatment is contraindicated):
   1. Active infection; or
   2. Immunosuppressive disorder; or
   3. Liver cirrhosis; or
   4. Active hepatitis B or C; or
   5. Alanine transaminase (ALT) greater than 3 times the upper limit of normal; or
   6. Bilirubin greater than 3 times the upper limit of normal; or
   7. Alkaline phosphatase greater than 3 times the upper limit of normal; or
   8. International normalized ratio (INR) greater than 1.4; or
   9. Prior infusion of gene therapy for hemophilia B (for example, etranacogene dezaparvovec-drlb or fidanacogene elaparvovec-dzkt);
      and
5. Poor disease control meeting one or more of the following:
   1. One or more episodes of spontaneous bleeding into a joint or the central nervous system while receiving routine prophylaxis factor replacement therapy; or
   2. Four or more episodes of soft tissue bleeding in an 8-week period while receiving routine prophylaxis factor replacement therapy; or
   3. At least 12 bleeding episodes over the previous year while receiving on-demand therapy.

Fidanacogene elaparvovec-dzkt is considered medically necessary in individuals who meet all of the following criteria:

1. Diagnosis of hemophilia B; and
2. Age 18 years or older; and
3. Baseline factor IX level is less than 2 international units (IU)/deciliter (dL) (or 2% endogenous factor IX); and
4. No contraindications to infusion (if any of the following are present, treatment is contraindicated):
   1. Neutralizing antibodies to adeno-associated virus serotype Rh74var (AAVRh74var) capsid; or
   2. Active infection; or
   3. Immunosuppressive disorder; or
   4. Liver cirrhosis; or
   5. Active hepatitis B or C; or
   6. Alanine transaminase (ALT) greater than 3 times the upper limit of normal; or
   7. Bilirubin greater than 3 times the upper limit of normal; or
   8. Alkaline phosphatase greater than 3 times the upper limit of normal; or
   9. International normalized ratio (INR) greater than 1.4; or
   10. Prior infusion of gene therapy for hemophilia B (for example, etranacogene dezaparvovec-drlb or fidanacogene elaparvovec-dzkt);
       and
5. Poor disease control meeting one or more of the following:
   1. One or more episodes of spontaneous bleeding into a joint or the central nervous system while receiving routine prophylaxis factor replacement therapy; or
   2. Four or more episodes of soft tissue bleeding in an 8-week period while receiving routine prophylaxis factor replacement therapy; or
   3. At least 12 bleeding episodes over the previous year while receiving on-demand therapy.

Valoctocogene roxaparvovec-rvox is considered medically necessary in individuals who meet all of the following criteria:

1. Diagnosis of hemophilia A; and
2. Age 18 years or older; and
3. Baseline factor VIII level is less than 1 international unit (IU)/deciliter (dL) (or 1% endogenous factor VIII); and
4. No contraindications to infusion (if any of the following are present, treatment is contraindicated):
   1. Detectable pre-existing immunity to the AAV5 capsid as measured by AAV5 transduction inhibition or AAV5 total antibodies; or
   2. History of factor VIII inhibitor; or
   3. Active infection; or
   4. Immunosuppressive disorder; or
   5. Liver cirrhosis; or
   6. Active hepatitis B or C; or
   7. Alanine transaminase (ALT) greater than 3 times the upper limit of normal; or
   8. Bilirubin greater than 3 times the upper limit of normal; or
   9. Alkaline phosphatase greater than 3 times the upper limit of normal; or
   10. International normalized ratio (INR) greater than 1.4; or
   11. Prior infusion of valoctocogene roxaparvovec-rvox;
       and
5. Poor disease control meeting one or more of the following:
   1. One or more episodes of spontaneous bleeding into a joint or the central nervous system while receiving routine prophylaxis factor replacement therapy; or
   2. Four or more episodes of soft tissue bleeding in an 8-week period while receiving routine prophylaxis factor replacement therapy; or
   3. At least 12 bleeding episodes over the previous year while receiving on-demand therapy.

Investigational and Not Medically Necessary:

Gene therapy for hemophilia is considered investigational and not medically necessary when the criteria above are not met and in all other situations.

This document describes clinical studies and expert recommendations, and explains whether gene therapy for hemophilia is clinically appropriate. The following summary does not replace the medical necessity criteria or other information in this document. The summary may not contain all of the relevant criteria or information. This summary is not medical advice. Please check with your healthcare provider for any advice about your health.

Key Information

Hemophilia is an inherited bleeding disorder. People with hemophilia do not have enough clotting proteins in their blood, so bleeding can last longer and may happen inside joints, muscles, or the brain. There are several types of hemophilia, A, B, and C, caused by faulty genes that make blood proteins that cause blood to clot. A type of treatment called gene therapy has become available, where the gene that makes the faulty gene can be replaced with a new one and allow the treated person’s body to make working clotting proteins. At this time gene therapy is available to treat hemophilia A and hemophilia B. The goal is to lower abnormal bleeding and reduce the need for regular treatments with replacement clotting proteins and blood transfusions.

What the Studies Show

The studies for hemophilia gene therapy suggest that some gene therapies can lower bleeding rates and reduce clotting protein use, but they also have risks. These risks include liver test changes, infusion reactions, need for steroid use, serious side effects, and uncertainty about how long treatment benefits last. Some products are U.S. Food and Drug Administration (FDA) approved, while others are still being developed.

Etranacogene dezaparvovec-drlb (Hemgenix^® CSL Behring, King of Prussia, PA) is a gene therapy for hemophilia B. Studies showed lower bleeding rates and less need for routine factor IX treatment after 1 dose. In follow-up lasting up to 5 years after treatment, many adults continued to make the correct version of the corrected protein. Side effects included liver test changes that may be a problem, infusion reactions, headache, fatigue, and flu-like illness. Some people needed corticosteroids, which are steroid medicines, for liver test changes indicating liver damage. Studies also noted that the long-term cancer risk is still not fully known.

Fidanacogene elaparvovec-dzkt (Beqvez^™ Pfizer Inc, New York, NY) is another gene therapy for hemophilia B. A study found fewer bleeding episodes after treatment and higher clotting protein levels in many treated adults. Common side effects included liver enzyme increases, and many people needed glucocorticoids, which are steroid medicines. There were two people who received glucocorticoids and had bleeding in their gut. Long-term follow-up is still underway, so more information is needed about how long benefits last and about long-term safety.

Valoctocogene roxaparvovec-rvox (Roctavian^® Biomarin Pharmaceuticals, Baltimore, MD) is a gene therapy for hemophilia A. Studies found fewer bleeding episodes and much less use of clotting protein replacement treatment after 1 infusion. Clotting protein levels increased after treatment, but they often went down over time. Some people did not respond to treatment at all, and some who did respond lost response later. Side effects included liver test changes and some serious side effects. The long-term durability of benefit is still uncertain.

Is this Clinically Appropriate?

Etranacogene dezaparvovec-drlb and fidanacogene elaparvovec-dzkt may be clinically appropriate when a person has hemophilia B, is age 18 years or older, has a baseline clotting protein factor IX level less than 2 international units (IU) per deciliter (dL), or 2% endogenous factor IX and does not have any listed contraindication to infusion, such as active infection, immunosuppressive disorder, liver cirrhosis, active hepatitis B or C, certain abnormal liver blood tests, international normalized ratio (INR) greater than 1.4, or prior hemophilia B gene therapy.

Valoctocogene roxaparvovec-rvox may be clinically appropriate when a person has hemophilia A, is age 18 years or older, has a baseline clotting protein factor VIII level less than 1 IU per dL, or 1% endogenous factor VIII and does not have any listed contraindication to infusion, such as detectable pre-existing immunity to the AAV5 capsid (type of virus used in the therapy), history of factor VIII inhibitor, active infection, immunosuppressive disorder, liver cirrhosis, active hepatitis B or C, certain abnormal liver blood tests, INR greater than 1.4, or prior gene therapy.

When is this not Clinically Appropriate?

Gene therapy for hemophilia is not clinically appropriate in scenarios other than those listed above.

(Return to Description/Scope)

Summary

Gene therapies for hemophilia A and B aim to deliver working factor VIII or IX genes using viral vectors. Approved products, such as Hemgenix, Beqvez, and Roctavian, have generally reduced bleeding rates and decreased or eliminated the need for prophylactic factor replacement in many individuals. However, the evidence also shows important limitations, including variable durability of response, liver enzyme elevations and other adverse events, small or uncontrolled early studies for some products, and ongoing uncertainty about long-term safety. As a result, these treatments are often framed as best suited for carefully selected adults with poorly controlled disease despite optimal standard therapy. Some products remain investigational, and market status has shifted for others, with certain therapies being withdrawn from the market.

Discussion

Hemophilia is a congenital medical condition in which the blood does not clot normally due to lack of sufficient blood-clotting proteins known as clotting factors. There are several forms of hemophilia, the most common of which are hemophilia A, which involves a deficiency in clotting factor VIII, and hemophilia B, which involves a deficiency in clotting factor IX. Gene therapy products for hemophilia use a virus vector with a working copy of the missing gene attached (factor VIII and factor IX for hemophilia A and B, respectively).

Hemophilia B

Etranocogene dezaparovec-drlb (Hemgenix)

Etranacogene dezaparvovec-drlb, previously known as AMT-061, is a gene therapy product for hemophilia B that has received approval from the U.S. Food and Drug Administration (FDA). It uses an adeno-associated virus serotype 5 (AAV5) vector that carries the Padua gene variant of Factor IX. Etranacogene dezaparvovec-drlb is indicated for the treatment of adults with hemophilia B (congenital Factor IX deficiency) who currently use Factor IX prophylaxis therapy, or have current or historical life-threatening hemorrhage, or repeated, serious spontaneous bleeding episodes.

In 2019, von Drygalski and colleagues published data from a Phase IIb trial of 3 adults with moderate to severe hemophilia B (factor IX activity ≤ 2% per year) who received a single dose of etranocogene dezaparvovec-drlb (AMT-061). The trial aimed to collect preliminary data on the safety and efficacy of the 2×10¹³ genome copies (gc)/kilogram (kg) dose of the product prior to further study in the HOPE-B (Health Outcomes With Padua Gene; Evaluation in Hemophilia-B) phase III trial. At week 26, mean factor IX activity was 47% (range, 33% to 57%). There were no reported bleeds during the 26 weeks of follow-up and there were no reported serious adverse events.

von Drygalski and colleagues (2023) reported additional follow-up data from the Phase IIb trial, discussed above. Data were available for participants 1 and 2 at 3 years and participant 3 at 2.5 years. Factor IX activity at follow-up was over 40% (in the non-hemophilic range) for participants 1 and 2 and was 32.3% (in the mild hemophilic range) for participant 3. All 3 participants remained prophylaxis-free. Overall, participants had annualized bleeding rate of 0.22 and 2 of the 3 participants did not experience any bleeds. The publication reported 1 serious adverse event that occurred in the first year after treatment; this was worsening avascular necrosis requiring hip surgery.

In 2025, von Drygalski published the final analysis (5-years post gene therapy) results of the Phase IIb trial discussed above of etranacogene dezaparvovec given for severe or moderately severe hemophilia B. From year 1, elevations in factor IX activity remained stable (mean, 40.77 international unit [IU]/deciliter [dL]; standard deviation [SD], 9.45; range, 31.3-50.2) to year 5 (mean, 45.7 IU/dL [SD, 6.18; range, 39.0-51.2]). At 5 years, participants 1 and 3 were maintaining factor IX activity in the nonhemophilia range (≥40 IU/dL), at 46.8 IU/dL and 51.2 IU/dL, respectively, while participant 2 was close to the nonhemophilia range at 39 IU/dL. Bleeding rates decreased with none of the participants experiencing bleeding events after year 2. There were 84 treatment-emergent adverse events reported during the study. None of the serious adverse events were considered related to the gene therapy. All participants in the study have enrolled in the extension study for an additional 10 years.

FDA approval in November 2022 was based on an 18-month interim analysis of data from the HOPE-B trial. A total of 54 of the 67 enrolled individuals were dosed with etranacogene dezaparvovec-drlb and were included in the analysis. The FDA product label (2022) reported efficacy data up to 18 months post treatment; 53 of the 54 dosed individuals completed the 18-month follow-up. The person who did not complete follow-up died at month 15 after dosing for reasons deemed unrelated to treatment. The primary efficacy outcome was a non-inferiority analysis of the annualized bleeding rate from months 7 to 18 after treatment, and this was compared to the annualized bleeding rate during the initial lead-in period. Individuals were permitted to continue their prophylaxis treatment up to 6 months after being dosed with etranacogene dezaparvovec-drlb. The mean annualized bleeding rate during months 7 to 18 were 1.9 bleeds per year (95% confidence interval [CI], 1.0 to 3.4). During the lead-in period, the estimated mean annualized bleeding rate was 4.1 (95% CI, 3.2 to 5.4). The ratio of the annualized bleeding rate in months 7 to 18 post-treatment compared with during the lead-in period was 0.46 (95% CI, 0.26 to 0.81). There were 2 participants who were unable to stop routine prophylaxis after gene therapy treatment, and a third individual, who stopped prophylaxis at 6 months per study protocol, received it again during days 396 to 534. Limitations of this analysis include that the study was uncontrolled (no comparison with individuals on factor replacement therapy) and conducted in a relatively small number of people. Moreover, in this analysis, not all individuals were able to stop prophylaxis after treatment and 1 of 54 individuals resumed prophylaxis use after stopping for approximately 6 months, suggesting variable efficacy and a possible waning effect of the treatment.

In a safety analysis combining data from the 2 clinical studies included in the FDA documents (n=3 and n=54), no serious adverse events were reported. The most common adverse events were alanine aminotransferase (ALT) elevations (42%), aspartate aminotransferase (AST) elevations (42%), blood creatine kinase elevations (42%), infusion-related reactions (33%), headache (18%), flu-like symptoms (14%), fatigue (12%) and malaise (12%). In 1 individual with an infusion-related reaction, infusion was stopped and not resumed. There were 9 of the 24 individuals with ALT elevations who were treated with corticosteroids for a mean duration of 81 days and 19 of the 24 individuals with ALT elevations also had AST elevations.

There was 1study participant with preexisting risk factors for developing hepatic cancer who developed hepatocellular carcinoma, which was assessed as not likely related to etranacogene dezaparvovec-drlb (based on vector integration site analyses and whole genome sequencing). As noted in FDA prescribing information: “the integration of liver-targeting AAV vector deoxyribonucleic acid (DNA) into the genome may carry the theoretical risk of hepatocellular carcinoma development.” Although AAV is a non-integrating vector, it can integrate into the nuclear genome in small amounts; the clinical significance and risk of malignancy in the long-term is not known.

Coppens and colleagues (2024) reported on a post-hoc analysis of 24-month data from the HOPE-B trial. An analysis of all 54 participants found that the adjusted annualized bleeding rate for all bleeding episodes decreased significantly from 4.18 (95% CI, 3.21 to 5.44) during the lead-in period to 1.51 (95% CI, 0.83 to 2.75, p=0.0002) during months 7 to 24. No new safety signals were identified between the 18- and 24-month follow-ups. Adverse events were reported in all participants during the course of the study; 38 of 54 (70%) were determined to have gene-therapy-related adverse events. Treatment-related adverse events with at least a 10% incidence included headache, influenza-like illness, and increased ALT. There were 3 new serious adverse events between months 18 and 24 and none of these were considered to be related to treatment. There was one case each of severe blood loss anemia, diverticular hemorrhage, and peripheral artery aneurysm. All of these individuals recovered, and no new deaths were reported.

In 2026, Pipe published the 5-year final analysis data (phase 3) from the HOPE-B study. A total of 67 individuals with severe or moderately severe hemophilia B were enrolled in the study (54 who were included in the final analysis) with 50 participants who completed the 5-year follow-up. All participants received a single intravenous infusion of gene therapy (etranacogene dezaparvovec). Inclusion criteria included being male, at least 18 years old, having severe or moderately severe congenital hemophilia B, currently on factor IX prophylaxis and exposure to factor IX protein for at least the past 150 days. Key exclusion criteria include a history of factor IX inhibitors or a positive factor IX inhibitor test at screening, select liver screening laboratory test values over 2 times the upper limit of normal or history of hepatitis B or C or active infection (given the risk of potential hepatotoxicity), a positive human immunodeficiency virus (HIV) test that is not controlled with anti-viral therapy, and previous gene therapy treatment. Study outcomes included adjusted annualized bleeding rates, factor IX expression, and safety outcomes. The adjusted bleeding rate was 4.16 during the lead-in period and 1.52 at 7-60 months following the gene therapy. Following gene therapy, 52 participants (96%) had endogenous transgene-derived factor IX expression and were considered to have had a response to treatment; 80% of the participants had a factor IX activity level of at least 12 IU/dL at the 5-year follow-up. There were 912 adverse events reported during the 5-year study period. Serious adverse events included hypertensive urgency, procedure-related bleeding, and cardiac amyloidosis which resulted in death. None of the serious adverse events were considered related to the gene therapy treatment.

Given ongoing unknowns related to the long-term durability and safety of etranacogene dezaparvovec-drlb, and the highly established and robust efficacy of prophylactic therapy in reducing bleeding and long-term complications of bleeding, consideration for treatment should be limited to individuals with poor disease control despite optimal management (in the absence of contraindications to therapy such as presence of factor IX inhibitor, active infection, immunosuppressive disorder or significant liver dysfunction or disease).

Fidanacogene elaparvovec-dzkt (Beqvez)

Fidanacogene elaparvovec-dzkt (formerly known as SPK-9001 and PF-06838435) uses a bioengineered AAV capsid and a high-activity variant of the human coagulation factor IX gene. In 2018, following a licensing agreement between the two companies, Spark Therapeutics transferred responsibility for the phase III program evaluating this product to Pfizer.

As of February, 2025, Pfizer is no longer marketing fidanacogene elaparvovec-dzkt in the U.S.

Fidanacogene elaparvovec-dzkt received approval from the FDA in 2024. The FDA-approved indication for fidanacogene elaparvovec-dzkt is for the treatment of adults with moderate to severe hemophilia B (congenital Factor IX deficiency) who currently use Factor IX prophylaxis therapy, or have current or historical life-threatening hemorrhage, or repeated, serious spontaneous bleeding episodes, and do not have neutralizing antibodies to adeno-associated virus serotype Rh74var (AAVRh74var) capsid.

A phase III trial evaluating fidanacogene elaparvovec-dzkt was published by Cuker and colleagues in 2024.

Eligibility criteria are as follows:

Inclusion Criteria

• Males who completed 6 months of Factor IX prophylaxis therapy during the lead-in study (C0371004) prior to providing consent at the screening visit for this study
• Documented moderately severe to severe hemophilia B (Factor IX activity < =2%)
• Previous experience with FIX therapy (=>50 documented exposure days to a FIX protein product)
• Suspension of prophylaxis therapy for hemophilia B after administration of the study drug
• Laboratory values (hemoglobin, platelets and creatinine) within study specified limits
• Agree to contraception until components of the drug are eliminated from their body
• Capable of giving signed informed consent

Exclusion Criteria

• Anti-AAVRh74var neutralizing antibodies (nAb) titer above the established threshold (ie, positive for nAb).
• History of inhibitor to Factor IX or inhibitor detected during screening. Clinical signs or symptoms of decreased response to Factor IX
• Hypersensitivity to Factor IX replacement product or IV immunoglobulin administration
• History of chronic infection or other chronic disease
• Any conditions associated with increased thromboembolic risk
• Concurrent clinically significant major disease or condition unsuitable for participation and/or may interfere with the interpretation of study results
• Laboratory values at screening visit that are abnormal or outside acceptable study limits
• Current unstable liver or biliary disease
• Currently on antiviral therapy for hepatitis B or C
• Planned surgical procedure requiring Factor IX surgical prophylactic factor treatment 15 months from screening visit
• Use of restricted therapies (e.g., blood products, acetylsalicylic acid [aspirin] or ibuprofen, other investigational therapy, and by-passing agents)
• Previously dosed in a gene therapy research trial at any time or in an interventional clinical study within 12 weeks of screening visit
• Active hepatitis B or C; hepatitis B surface antigen, hepatitis B virus deoxyribonucleic acid positivity, or hepatitis C virus ribonucleic acid positivity
• Significant liver disease
• Serological evidence of HIV1 or HIV2 infection with either CD4+ cell count <=200 mm3 and/or a viral load >20 copies/mL
• Study and sponsor staff involved in the conduct of the study and their families
• Unable to comply with study procedures
• Sensitivity to heparin or heparin induced thrombocytopenia
• Sensitivity to any of the study interventions, or components thereof, or drug or other allergy

A total of 45 men were enrolled in the study and treated with fidanacogene elaparvovec-dzkt. The primary study outcome was annualized bleeding rate for total bleeds (treated and untreated) between week 12 and month 15 after infusion, compared with prophylaxis use during the baseline run-in period. At the time of data cutoff, 44 of the participants had completed 15 months of follow-up and the remaining individual had completed 12 months of follow-up. The annualized bleeding rate for total bleeding episodes at follow-up was 1.28 (95% CI, 0.57 to 1.98) from week 12 to month 15, compared with 4.42 (95% CI, 1.80 to 7.05) during the baseline lead-in period The represents a treatment difference of -3.15 episodes (95% CI, -5.46 to -0.83; p=0.008). Considering only treated bleeding episodes, the annualized bleeding rate was 0.73 at follow-up (95% CI, 0.23 to 1.23), compared with 3.34 during the prophylaxis period (95% CI, 1.70 to 4.98), a treatment difference of −2.61 (95% CI, −4.27 to −0.96; p=0.002). Mean factor IX activity at month 15 was 26.9% (median, 22.9; range, 1.9 to 119.0). A total of 38 of the 45 participants (84%) reported 206 adverse events; the study serious adverse events were reported for 7 (16%) individuals. The most common adverse event associated with treatment therapy was an increased level of aminotransferase (n=24 participants, 53%), most of which was mild. A total of 28 participants (62%) received glucocorticoids for an increased aminotransferase level, decreased factor IX levels, or both. There were 2 participants who had glucocorticoid therapy and experienced gastrointestinal hemorrhage. No treatment-related thrombotic events, or hepatic or other cancers were reported. All participants developed anti-AAV-neutralizing antibodies after therapy; none developed Factor IX inhibitors. Following completion of the study, participants are eligible to participate in a long-term follow-up study in which they will be followed up to 10 years post-infusion.

A phase I/II trial evaluating SPK-9001 (PF-06838435) enrolled 15 males aged 18 and older with factor IX coagulant activity ≤ 2% of normal. Interim data reporting on 10 of the study participants who received a dose of 5E11 vector genome (vg)/kg were published by George and colleagues (2017b). The primary objective was to assess the safety of gene therapy. Exploratory efficacy endpoints included change from baseline in the annualized bleeding rate, consumption of favor IX replacement therapy and infusions. After a follow-up period ranging from 28-78 weeks, the annualized bleeding rate was significantly reduced from pre-infusion (mean rate: 11.1 events per year) to post-infusion (mean rate: 0.4 events per year). At follow-up, 8 of 10 participants (80%) did not use factor IX replacement therapy and 9 of 10 (90%) did not have any bleeds after gene therapy infusion. No serious adverse events were reported.

Rasko (2025) reported data from the phase I/II trial in 14 men who had completed at least 3 years of follow-up after infusion. Median follow-up duration was 5.5 years. None of the 14 participants reported adverse events after year 1 that were deemed to be treatment-related. There were 4 participants who reported a total of 9 serious adverse events, but none were determined to be related to the vector-related therapy. There were 10 participants who had liver abnormalities identified during surveillance ultrasounds, 7 of the 10 had not had baseline assessments. The mean annualized bleeding rate decreased from 8.9 at baseline to 0.4 in year 1, 0.9 in year 2, 0.4 in year 3, 0.1 in year 4, 0.2 in year 5 and 0.4 in year 6. The median annualized bleeding rate was 0.

Hemophilia A

Valoctocogene roxaparvovec-rvox (Roctavian)

Valoctocogene roxaparvovec-rvox, is an AAV5 vector gene therapy product, which received FDA approval in 2023. The FDA-approved indication (FDA, 2023) is “treatment of adults with severe hemophilia A (congenital factor VIII deficiency with factor VIII activity < 1 IU/dL) without pre-existing antibodies to adeno-associated virus serotype 5 detected by an FDA-approved test”. Contraindications include active infections, known significant hepatic fibrosis or cirrhosis, and known hypersensitivity to mannitol.

As of February, 2026, Biomarin Pharmaceuticals is no longer marketing valoctocogene roxaparvovec-rvox in the U.S.

Data from a phase I/II dose-escalation study evaluating valoctocogene roxaparvovec (a previous name) for hemophilia A (NCT02576795) have been published. The study included 15 males aged 18 and older with severe hemophilia A disease (base factor VIII level ≤ 1 IU/dL who had no history of factor VIII inhibitor development. Individuals who used on-demand therapy were required to have had ≥ 12 bleeding episodes in the previous 12 months. Individuals were excluded if they had detectable pre-existing immunity to the AAV5 capsid, evidence of active infection, any immunosuppressive disorder or any bleeding disorder other than hemophilia A, were HIV positive or had significant liver dysfunction. Study participants were required to discontinue using prophylactic factor VIII replacement therapy but were permitted to use factor VIII therapy if they experienced a bleeding episode during the study. Participants received a single intravenous injection of 1 of 4 doses of gene therapy: 6x10¹² vg/kg (n=1), 2x10¹³ vg/kg (n=1), 6x10¹³ vg/kg (n=7) or 4x10¹³ (n=6). The primary aims of the study were to assess the number of participants with treatment-related adverse events over 5 years and to determine the dose of gene therapy needed to achieve expression of factor VIII ≥ 5% of normal activity (> 5 IU/dL) 16 weeks after infusion. Factor VIII activity levels were performed at a central laboratory and were measured in two ways; by a one-stage activated partial thromboplastin time-based clotting assay and a chromogenic factor Xa assay.

Individuals were sequentially enrolled in the study, with those enrolled first receiving the lowest dose of gene therapy. Rangarajan and colleagues (2017) reported 1-year data on the first 3 cohorts (n=9). In 6 of 7 individuals in the higher-dose cohort (6x10¹³ vg/kg), factor VIII activity increased to a normal level (> 50 IU/dL) and this level was maintained at 1 year. In 6 individuals in the higher-dose cohort who had received factor VIII prophylaxis before trial entry, the median annualized bleeding rate decreased from 16 events per year to 1 event per year. There was one serious adverse event, progression of chronic arthropathy, which was reported.

Pasi and colleagues (2020) reported on all 4 cohorts (n=15) and up to 3 years of follow-up data. At 3 years after infusion, the 2 individuals in the lowest-dose cohorts (6x10¹² vg/kg, n=1 and 2x10¹³ vg/kg, n=1), had factor VIII expression below IU/dL. There was 3-year data also available for the 7 individuals in the third cohort, those who received the 6x10¹³ vg/kg dose. At the end of years 1, 2 and 3, the mean factor VIII activity levels as measured by chromogenic assay were 64 IU/dL, 36 IU/dL and 33 IU/dL, respectively. Mean factor VIII values at the same time points using the one-stage assay were 104 IU/dL, 59 IU/dL and 52 IU/dL, respectively. After reaching a peak factor VIII level, the mean factor VIII expression decreased by 43% during year 2 and by 10% during year 3. In the third cohort, the mean annualized rate of bleeding events decreased by 96%, from a mean of 16.3 (SD, 15.7) events per year at baseline to a mean of 0.7 (SD, 1.6) events per year at the end of year 3. At baseline, only 1 of 6 participants who were receiving prophylaxis was free from breakthrough bleeding events. At the end of the third year of follow-up, 6 of 7 participants (86%) were free from bleeding events.

There was 2-year follow-up data available on the 6 participants in the fourth cohort who received the highest dose of gene therapy, 4x10¹³. The mean factor VIII activity level, according to the chromogenic assay, was 21.0 IU/dL at the end of year 1 and 15 IU/dL at the end of year 2. Mean factor VIII levels according to the one-stage assay were 31 IU/dL at the end of year 1 and 23 IU/dL at the end of year 2. In this cohort, Factor VIII level decreased by 30% during the second year after infusion. None of the individuals in the third or fourth cohorts were using prophylactic factor replacement at the end of year 3. In cohort 4, the annualized rate of bleeding events decreased by 92%, from a mean of 12.2 (SD, 5.4) events per year in the year before study entry to a mean of 1.2 (SD, 2.4) events per year at the end of year 2. All 6 individuals in cohort 4 were using prophylactic replacement therapy at baseline. In the year before study entry, 1 of these 6 individuals (17%) was free from breakthrough bleeding events. At the 2-year follow-up, 4 of 6 individuals (67%) were free from bleeding events.

All of the study participants had at least 1 adverse event. The most common adverse event was elevation of the ALT level with 14 events; 13 were grade 1 and 1 was a grade 2 event. The elevations in the ALT level were managed with glucocorticoid treatment. Three participants experienced serious adverse events at some point during the study. These included 1 case of grade 2 pyrexia, along with myalgia and headache that occurred within 24 hours of gene therapy infusion. Symptoms resolved within 48 hours. Two participants had serious adverse events associated with pre-existing hemophilic arthropathies; these were determined by investigators to be unrelated to treatment.

There was 6-year data were reported by Symington and colleagues in 2024. Data were available for all 7 participants in the 6x10¹³ vg/kg dose cohort and the 6 participants in the 4x10¹³ vg/kg  dose cohort. No new treatment-related serious adverse events were reported after the first year of follow-up. Two serious adverse events determined to be unrelated to treatment emerged in the final year of follow-up. These included grade 2 parotid gland acinar cell carcinoma (6x10¹³ vg/kg) and an exacerbation of Crohn disease (4x10¹³ vg/kg dose cohort). Regarding efficacy, there was a sustained reduction from baseline in annualized bleeding rate. Over the entire study period, mean annualized bleeding rate was 0.7 treated bleeds per year (median 0.0) in the 6x10¹³ vg/kg dose cohort and 1.1 treated bleeds per year (median, 0.6) in the 4x10¹³ vg/kg dose cohort. Over this same time period, the mean FVIII infusion rate was 4.5 infusions per year (median 1.5) in the 6x10¹³ vg/kg dose cohort and 9.6 infusions per year in the 4x10¹³ vg/kg dose cohort.

Data from a phase III trial evaluating a single 6x10¹³ vg/kg dose of valoctocogene roxaparvovec were published in 2022 by Ozelo and colleagues. Eligibility included being at least 18 years old with severe congenital hemophilia A (factor VIII activity level ≤ 1 IU/dL), having received prophylaxis with factor VIII concentrates for at least 1 year prior to enrollment and being negative for factor VIII inhibitors. Key exclusion criteria were the presence of anti-AAV5 capsid antibodies, HIV infection, and substantial liver dysfunction, fibrosis or cirrhosis. The primary efficacy outcome was change from baseline in factor VIII activity at 1 year. A total of 181 men were screened, 144 were enrolled in the study and 134 were dosed with 6x10¹³ vg/kg of valoctocogene roxaparvovec and completed the week 49-52 visit. Anti-AAV5 capsid antibodies were present in most (26 of 37) of the men who were ineligible after screening. Of the 134 individuals who received a dose of gene therapy, 132 were HIV-negative and were included in a modified intention-to-treat (ITT) population. In the modified ITT analysis, the mean change from baseline in the factor VIII activity level at 1 year was 41.9 IU/dL (95% CI, 34.1 to 49.7). The median change was 22.9 IU/dL. There were 17 participants who had at least 2 years of follow-up. This group had mean factor VIII activity levels of 42.2 IU/dL at week 49-52 and 24.2 IU/dL at week 104. Median factor VIII activity levels in this group were 23.9 IU/dL at week 49-52 and 14.7 IU/dL at week 104. In the modified ITT population, the mean and median annualized rates of treated bleeding episodes were 4.8 per year and 2.8 per year, respectively, at baseline and 0.8 bleeds per year and 0 bleeds per year, respectively, after week 4. In terms of safety, all 134 participants had at least 1 adverse event; most were grade 1 or grade 2. A total of 22 participants (16.4%) reported any serious adverse event; 5 serious adverse events were determined by the investigators to be related to the study drug. All of the serious adverse events resolved and there were no reported deaths and none of the participants withdrew due to adverse events or developed factor VIII inhibitors.

Mahlangu (2023) reported 2-year findings of the Phase III trial. After a median follow-up of 110.9 weeks (range 66 to 194 weeks), the mean change in the annualized bleeding rate, compared with baseline (when the participants were receiving prophylaxis), was -4.1 bleeding events per year (95% CI, -5.3 to -4.1). The annualized rate of factor VIII use decreased by 98.2% from baseline. The factor VIII activity increased from baseline by a mean of 22.0 IU/dL (95% CI, 26.9 to 43.). There were 9 individuals who had an adverse event in year 2, none of which were serious adverse events.

The 4-year findings of the Phase III trial were reported by Leavitt and colleagues in 2024. The median length of follow-up was 214 weeks (range, 66 to 266). Mean annualized bleeding rate in year 4 was 0.9 (SD, 2.3) bleeds per year, which was an 81.3% reduction from baseline. Mean FVIII activity increased from the baseline value of 1.0 IU/dL to 16.1 (2.5) IU/dL at week 208 in the modified ITT population (n=130); this represented a 3.5% mean decrease from year 3. At the end of year 4, 10 (7.7%) participants had median FVIII activity in the non-hemophilia range (≥ 40 IU/dL), 68 (52.3%) participants were in the mild hemophilia range (< 40 and ≥ 5 IU/dL), 18 (13.8%) participants were in the moderate hemophilia range (< 5 and ≥ 3 IU/dL), and 34 (26.2%) had FVIII activity in the moderate to severe hemophilia range, < 3 IU/dL). During year 4, 106 (80.9%) participants experienced an adverse event and 13 (9.9%) participants had a serious adverse event. None of the serious adverse events were related to treatment. There was 1 death, which occurred during week 183; this was caused by head trauma following a fall and was deemed by the investigators unrelated to treatment. No participants had thromboembolic events or were diagnosed with malignancies, and none developed inhibitors.

The FDA product insert (2023) for valoctocogene roxaparvovec reported data in individuals in the phase III study who were followed for at least 3 years. The primary efficacy outcome for the analysis was a non-inferiority evaluation of the difference in annualized bleeding rate during the post-treatment evaluation period compared with baseline. The investigators established a non-inferiority margin of 3.5 bleeds per year. The mean annualized bleeding rate was 2.6 bleeds per year post-treatment, compared to a mean baseline annualized bleeding rate of 5.4 bleeds per year. The mean difference pre- and post-treatment was -2.8 bleeds per year (95% CI, -4.3 to -1.2), meeting the pre-specified non-inferiority margin.

The rollover population (n=122) consisted of individuals with at least 6 months of prospectively collected data on factor VIII prophylaxis prior to receiving valoctocogene roxaparvovec. In this group (n=122), a total of 5 participants (4%) did not respond to treatment and 17 participants (15%) lost response to treatment over a median time of 2.3 years (range: 1.0 to 3.3 years). Among the remaining study participants with a longer follow-up (n=22), a total of 1 participant (5%) did not respond to treatment and 6 participants (27%) lost response to treatment over a median time of 3.6 years (range: 1.2 to 4.3 years).

Given ongoing unknowns related to the long-term durability and safety of valoctocogene roxaparvovec-rvox, and the highly established and robust efficacy of prophylactic therapy in reducing bleeding and long-term complications of bleeding, consideration for treatment should be limited to individuals with poor disease control despite optimal management (in the absence of contraindications to therapy such as presence of factor VIII inhibitor, active infection, immunosuppressive disorder or significant liver dysfunction or disease).

Other products

Giroctocogene fitelparvovec (SB-525) (Pfizer [under license from Sangamo], New York, NY) has not received approval from the FDA. Data from a phase I/II dose-ranging study were published in 2024 by Leavitt. The study included males aged at least 18 years with severe hemophilia A (FVIII activity < 1% of normal). In addition, eligibility including having at least 150 prior treatment or exposure days to FVIII concentrates or cryoprecipitate and, if using on-demand treatment, having at least 12 bleeding episodes during the year before screening. The study used escalating doses of giroctocogene fitelparvovec, starting at 9x10¹¹, to achieve a FVIII activity of 40% to 100% of normal. The primary efficacy endpoint was change in circulating FVIII activity. There were 11 of the 37 screened candidates who were enrolled and dosed in 1 of 4 cohorts. In the 12 months prior to enrollment, study participants had a mean of 7.5 (SD, 8.8) bleeding episodes. A total of 10 of the 11 participants were receiving FVIII prophylaxis. A total of 103 treatment-emergent adverse events were reported; 26 of these were considered to be related to treatment. All of the participants reported at least 1 treatment-related adverse event. The most common of these were increase in ALT levels (13 events in 5 participants), increase in AST levels (5 events in 3 participants). A total of 4 serious adverse events were reported in 3 participants. There were 2 serious adverse events which were considered related to treatment and occurred in a participant who received the highest dose (3x10¹³ vg/kg); these were grade 3 hypotension and grade 2 pyrexia that occurred 2 hours after dosing and resolved within 24 hours of treatment. Circulating FVIII activity increased as dose increased. All 5 participants in the highest dose cohort achieved peak FVIII in the normal range (> 50%) by week 9. The mean FVIII activity level in this cohort (using the chromogenic assay) was 52.6% at week 52 and 25.4% at week 104. In cohort 4, the mean total ABR was 8.8 (SD, 8.3) in the year before dosing versus 0.7 (SD, 1.4) after dosing.

A phase III single-arm trial known as AFFINE (NCT04370054) is underway. The first participant was dosed in October 2020 and the estimated enrollment is 63 individuals. The primary outcome of the study is annualized bleeding rate at 12 months.

Verbrinacogene setparvovec, also known as FLT180a, uses an AAVS3 synthetic capsid vector that carries a gain-of-function Padua gene variant (R338L) of Factor IX. It has not been approved by the FDA.

Results of a phase I/II study evaluating verbrinacogene setparvovec (the B-AMAZE study) were published by Chowdary and colleagues in 2022. The study included 10 males at least 18 years old with hemophilia B that was categorized as severe (factor IX level < 1%) or moderately severe (factor IX level, 1-2%) with a severe bleeding phenotype. Individuals with evidence of inhibitors to factor IX were not eligible to participate. None of the participants had evidence of AAVS3 neutralizing antibodies. Participants were treated with 1 of 4 doses of vg/kg of body weight; 3.84x10¹¹ (n=2), 6.40x10¹¹ (n=2), 8.32x10¹¹ (n=4). or 1.28x10¹² (n=2). All 10 individuals completed the 26-week trial. In the total study population, the mean annualized bleeding rate at baseline was 2.93 events per year (range, 0 to 7.3) and was 0.71 events per year (range, 0 to 1.7) after treatment. Annualized factor IX consumption decreased from a mean at baseline of 226,026 IU per year to a mean of 9723 IU per year after receiving gene therapy. There were 12 serious adverse events that were thought to be related to gene therapy; 9 of these were an increase in liver aminotransferase levels.

Hemophilia is an inherited bleeding disorder that impairs the blood clotting process. The disease results in prolonged bleeding after an injury or surgery, easy bruising, and an increased risk of bleeding, including inside joints, muscles and/or the brain.

Hemophilia A, the most common type, involves a deficiency in blood clotting factor VIII and is caused by mutations in the F8 gene whereas hemophilia B (also called Christmas disease) involves a deficiency in factor IX and is caused by mutations in the F9 gene. The F8 and F9 genes provide instructions for making proteins called coagulation factor VIII and IX, respectively, which are necessary for the blood clotting process. Mutations in the F8 or F9 genes lead to reduction in the level of these coagulation factors, or production of abnormal versions of these proteins.

Both hemophilia A and B are x-linked recessive genetic disorders; that is, the genes associated with the conditions are located on the X-chromosome. Hemophilia more commonly affects males because they have only one copy of the X-chromosome. Females have two copies of the X-chromosome; when they have a single altered copy of the F8 or F9 gene, the mutation results in about half the normal level of coagulation factor VIII or IX, which is generally not sufficient to cause hemophilia. Most females (about 90%) with a single altered copy of the F8 or F9 gene are asymptomatic carriers who have a 50% chance of passing on the disease to their sons. It is possible for females to have two altered copies of the gene causing hemophilia, but this occurs very rarely (Genetics Home Reference, 2022).

Baseline factor level is often determined at the time of diagnosis (preceding factor replacement therapy). Assessment of baseline factor activity during therapeutic management with factor replacement therapy may pose laboratory challenges. For purposes of applying this document, baseline factor level measurement can be based on a previously documented test result, for example, at the time of diagnosis (Nardi, 2019).

The prevalence of hemophilia B is about one-fifth that of hemophilia A. In the United States, the birth prevalence of hemophilia A is approximately 1 in 6500 live male births and the birth prevalence of hemophilia B is about 1 in 30,000 live male births (GeneReviews, 2025 and 2025). For both hemophilia A and B, approximately 60% of individuals have severe disease, 15% have moderate disease and 25% have mild disease (National Hemophilia Foundation).

The current medical management strategy for hemophilia is prevention and treatment of bleeding with infusions of replacement blood clotting factors. A variety of replacement products are available. All of the available prophylaxis products are considered effective, but may vary by individual response, safety profile (e.g., risk of inhibitor development), and product characteristic (e.g., product half-life, effects on monitoring). Prophylactic use of factor replacement therapy is recommended for individuals with severe hemophilia due to the high risk of spontaneous bleeding. Even a small increase in factor clotting activity can significantly reduce clinical bleeding rates. For moderate or mild hemophilia, recommendations regarding prophylactic use of factor replacement therapy are individualized depending on the person’s clinical situation and preferences. Repeated intravenous infusions can be burdensome and involve risks such as infection from a central venous catheter. Other hemophilia management strategies include avoiding activities likely to cause trauma, exercising regularly to stimulate normal psychomotor development and improve fitness, practicing good oral hygiene and avoiding medications that increase bleeding risk.

Various gene therapy products for hemophilia A and hemophilia B exist and others are currently being investigated. These products use a virus vector with a working copy of the missing gene attached (factor VIII and factor IX for hemophilia A and B, respectively). The virus vector is the outer structure (capsid) of an adeno-associated virus (AAV) which is incapable of replicating and thus unlikely to cause disease (Chuah, 2013). The gene therapy is infused intravenously where it selectively targets hepatocytes (liver cells), the site where factor VIII and factor IX production primarily takes place. Several hemophilia B gene therapy products use AAVs that carry the Padua gene variant of Factor IX. The Padua variant is a naturally occurring missense mutation in the factor IX gene that increases its activity approximately 4- to 40-fold. This can potentially increase the efficacy of the treatment without using higher doses of vector (VandenDriessche, 2018) and may have implications for treatment durability. AAV vector-based gene therapy is intended to be a one-time treatment.

Pre-existing AAV neutralizing antibodies (NAbs) are a contraindication to receiving gene therapy as it is currently formulated, limiting the number of individuals potentially eligible for treatment. A review article identified found prevalences of anti-AAV NAbs ranging from 3% to 50% in individual studies (Louis Jeune, 2013). Pre-clinical studies have been conducted to evaluate gene therapy for inducing immune tolerance in individuals with hemophilia, but to date, clinical data are lacking (Arruda, 2016; Borsotti, 2018).

Some individuals with hemophilia may develop an inhibitor (an antibody directed against infused factor that inhibits the function of the factor). Individuals who develop inhibitors can often no longer use standard factor replacement to treat bleeding or to provide prophylaxis against bleeding. Individuals who have developed an inhibitor to factor have been excluded from gene therapy trials due to concerns about reduced efficacy.

There are a number of unanswered questions concerning gene therapy for hemophilia. It is unclear how certain characteristics, such as age at treatment, duration of disease and severity of disease, affect the likelihood that individuals with hemophilia would benefit from gene therapy. It is also unknown whether gene therapy for hemophilia will provide durable long-term benefit in individuals who initially benefit. Hepatocytes, the target of hemophilia gene therapy, have the capability to undergo cell division (Miyaoka, 2013). However, the scope and rate of hepatocellular turnover is variable, and in the context of gene therapy, it is unclear whether long-term liver regeneration will dilute the therapeutic effect of gene therapy (particularly in children, where ongoing proliferation of liver cells may dilute the number of viral genomes). Given this, current vectors are designed to target adult postmitotic hepatocytes (George, 2017a).

Adeno-associated virus (AAV): A small virus that infects humans and is not known to cause disease. Modified (non-replicating) AAVs are frequently used as viral vectors for gene therapy.

Gene replacement therapy: A medical treatment that introduces or alters genetic material to replace the function of a missing or dysfunctional gene with the goal of lessening or eliminating a disease process that results from genetic dysfunction.

Mild hemophilia (factor clotting activity level 5-40%): Mild disease is often not diagnosed until later in life, depending on the individual’s exposure to surgical procedures or serious injury. Individuals with mild hemophilia do not have spontaneous bleeding episodes. Abnormal bleeding occurs with surgery or tooth extractions. The frequency of bleeding varies from once a year to once every 10 years.

Moderate hemophilia (factor clotting activity level 1-5%): Usually diagnosed before age 5 to 6 years. These individuals rarely have spontaneous bleeding, but do have prolonged bleeding or delayed oozing after relatively minor trauma. Frequency of bleeding episodes varies but generally occurs between once a month and once a year.

Phenotype: Observable traits or characteristics in an individual that result from having particular genes (i.e., genotype) and from the interaction of the genotype with the environment.

Severe hemophilia (factor clotting activity level < 1%): Usually diagnosed within the first 2 years of life. Without prophylactic treatment with factor replacement, individuals with severe hemophilia A or B may average 2 to 5 spontaneous bleeds per month. Spontaneous bleeding can occur into the joints, can lead to joint destruction, as well as into the brain, a dangerous and life-threatening event. Delayed bleeding after trauma is also common in individuals with severe hemophilia. Bleeding can be massive or persist as continuous oozing for days or weeks.

X-linked recessive trait: A mutation in the gene on the X-chromosome. The phenotype is always expressed in males (who have only one X chromosome) and in females who have mutations in both of their X chromosomes.

The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

Hemophilia B gene therapy
When services may be Medically Necessary when criteria are met:

When services are Investigational and Not Medically Necessary:
For the procedure and diagnosis codes listed above when criteria are not met or for all other diagnoses not listed.

Hemophilia A gene therapy
When services may be Medically Necessary when criteria are met:

When services are Investigational and Not Medically Necessary:
For the procedure and diagnosis codes listed above when criteria are not met or for all other diagnoses not listed.

Other therapies
When services are also Investigational and Not Medically Necessary:
When the code describes any other gene therapy product for hemophilia.

Peer Reviewed Publications:

1. Arruda VR, Samelson-Jones BJ. Gene therapy for immune tolerance induction in hemophilia with inhibitors. J Thromb Haemost. 2016; 14(6):1121-1134.
2. Borsotti C, Follenzi A. New technologies in gene therapy for inducing immune tolerance in hemophilia A. Expert Rev Clin Immunol. 2018; 14(12):1013-1019.
3. Chowdary P, Shapiro S, Makris M, et al. Phase 1-2 trial of AAVS3 gene therapy in patients with hemophilia B. N Engl J Med. 2022; 387(3):237-247.
4. Chuah MK, Evens H, Vandendriessche T. Gene therapy for hemophilia. J Thromb Haemost. 2013; 11(Suppl. 1):99-110.
5. Coppens M, Pipe SW, Miesbach W, et al. Etranacogene dezaparvovec gene therapy for haemophilia B (HOPE-B): 24-month post-hoc efficacy and safety data from a single-arm, multicentre, phase 3 trial. Lancet Haematol. 2024; 11(4):e265-e275.
6. Cuker A, Kavakli K, Frenzel L, et al. Gene therapy with fidanacogene elaparvovec in adults with hemophilia B. N Engl J Med. 2024; 391(12):1108-1118.
7. George LA. Hemophilia gene therapy comes of age. Blood Adv. 2017a; 1(26):2591-2599.
8. George LA, Sullivan SK, Giermasz A, et al. Hemophilia B gene therapy with a high-specific-activity factor IX variant. N Engl J Med. 2017b; 377(23):2215-2227.
9. Leavitt AD, Konkle BA, Stine KC, et al. Giroctocogene fitelparvovec gene therapy for severe hemophilia A: 104-week analysis of the phase 1/2 Alta study. Blood. 2024a; 143(9):796-806.
10. Leavitt AD, Mahlangu J, Raheja P, et al. Efficacy, safety, and quality of life 4 years after valoctocogene roxaparvovec gene transfer for severe hemophilia A in the phase 3GENEr8-1 trial. Res Pract Thromb Haemost. 2024b; 8(8):102615.
11. Louis Jeune V, Joergensen JA, Hajjar RJ, et al. Pre-existing anti-adeno-associated virus antibodies as a challenge in AAV gene therapy. Hum Gene Ther Methods. 2013; 24(2):59-67.
12. Mahlangu J, Kaczmarek R, von Drygalski A, et al. Two-year outcomes of valoctocogene roxaparvovec therapy for hemophilia A. N Engl J Med. 2023; 388(8):694-705.
13. Miyaoka Y, Miyajima A. To divide or not to divide: revisiting liver regeneration. Cell Div. 2013; 20;8(1):8.
14. Ozelo MC, Mahlangu J, Pasi KJ, et al. Valoctocogene roxaparvovec gene therapy for hemophilia A. N Engl J Med. 2022; 386(11):1013-1025.
15. Pasi KJ, Rangarajan S, Mitchell N, et al. Multiyear follow-up of AAV5-hFVIII-SQ gene therapy for hemophilia A. N Engl J Med. 2020; 382(1):29-40.
16. Pipe SW, Miesbach W, Recht M, et al. Final analysis of a study of etranacogene dezaparvovec for hemophilia B. N Engl J Med. 2026; 394(5):463-474.
17. Rangarajan S, Walsh L, Lester W, et al. AAV5-Factor VIII gene transfer in severe hemophilia A. N Engl J Med. 2017; 377(26):2519-2530.
18. Rasko JEJ, Samelson-Jones BJ, George LA et al. Fidanacogene elaparvovec for hemophilia B - a multiyear follow-up study. N Engl J Med. 2025; 392(15):1508-1517.
19. Symington E, Rangarajan S, Lester W, et al. Long-term safety and efficacy outcomes of valoctocogene roxaparvovec gene transfer up to 7 years post-treatment. Haemophilia. 2024; 30(5):1138-1147.
20. VandenDriessche T, Chuah MK. Hyperactive factor IX Padua: a game-changer for hemophilia gene therapy. Mol Ther. 2018; 26(1):14-16.
21. von Drygalski A, Giermasz A, Castaman G, et al. Etranacogene dezaparvovec (AMT-061 phase 2b): normal/near normal FIX activity and bleed cessation in hemophilia B. Blood Adv. 2019; 3(21):3241-3247.
22. von Drygalski A, Gomez E, Giermasz A, et al. Completion of phase 2b trial of etranacogene dezaparvovec gene therapy in patients with hemophilia B over 5 years. Blood Adv. 2025; 9(14):3543-3552.
23. von Drygalski A, Gomez E, Giermasz A, et al. Stable and durable factor IX levels in hemophilia B patients over 3 years post etranacogene dezaparvovec gene therapy. Blood Adv. 2023; 7(19):5671-5679.

Government Agency, Medical Society, and Other Authoritative Publications:

1. Beqvez™ (Product Information), New York, NY. Pfizer Inc. May 2024. Available at: https://labeling.pfizer.com/ShowLabeling.aspx?id=20452. Accessed on April 8, 2026.
2. BioMarin Pharmaceutical. Gene therapy study in severe haemophilia A patients (270-201). NLM Identifier: NCT02576795. Last updated on April 10, 2025. Available at: https://clinicaltrials.gov/study/NCT02576795?tab=study. Accessed on April 23, 2026.
3. DiMichele DM. Inhibitors in hemophilia: a primer. World Federation of Hemophilia. November 2018. Available at: http://www1.wfh.org/publication/files/pdf-1122.pdf. Accessed on April 8, 2026.
4. Genetics Home Reference. U.S. National Library of Medicine. Hemophilia. Last updated May 6, 2022. Available at: https://ghr.nlm.nih.gov/condition/hemophilia. Accessed on April 8, 2026.
5. Hemgenix^® (Product Information), King of Prussia, PA. CSL Behring LLC, November 2022.  Available at: https://labeling.cslbehring.com/PI/US/Hemgenix/EN/Hemgenix-Prescribing-Information.pdf. Accessed on April 8, 2026.
6. Konkle BA, Huston H, Fletcher SN. Hemophilia A. GeneReviews^® [Internet]. 2025. Available at: https://www.ncbi.nlm.nih.gov/books/NBK1404/. Accessed on April 8, 2026.
7. Konkle BA, Huston H, Fletcher SN. Hemophilia B. GeneReviews^® [Internet]. 2025. Available at: https://www.ncbi.nlm.nih.gov/books/NBK1495/. Accessed on April 8, 2026.
8. Nardi MA. Laboratory monitoring of factor VIII and factor IX in hemophilia patients. American Society for Clinical Laboratory Science. 2019; 32(1):27-35.
9. Roctavian^® (Product Information), Baltimore, MD. BioMarin Pharmaceutical Inc. June 2023. Available at: https://www.fda.gov/media/169937/download. Accessed on April 8, 2026.
10. Sharma A, Easow Mathew M, Sriganesh V, Reiss UM. Gene therapy for haemophilia. Cochrane Database Syst Rev. 2020;4(4):CD010822.
11. Srivastava A, Santagostino E, Dougall A et al. WFH guidelines for the management of hemophilia, 3rd edition. Haemophilia. 2020;26 Suppl 6:1-158.

1. National Hemophilia Foundation. Hemophilia A. Available at: https://www.hemophilia.org/Bleeding-Disorders/Types-of-Bleeding-Disorders/Hemophilia-A. Accessed on February 13, 2025.
2. National Hemophilia Foundation. Hemophilia B. Available at: https://www.hemophilia.org/Bleeding-Disorders/Types-of-Bleeding-Disorders/Hemophilia-B. Accessed on February 13, 2025.

Beqvez
Etranacogene dezaparvovec-drlb
Fidanacogene elaparvovec-dzkt
Hemgenix
Roctavian
Valoctocogene roxaparvovec-rvox

The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

Applicable to Commercial HMO members in California: When a medical policy states a procedure or treatment is investigational, PMGs should not approve or deny the request. Instead, please fax the request to Anthem Blue Cross Grievance and Appeals at fax # 818-234-2767 or 818-234-3824. For questions, call G&A at 1-800-365-0609 and ask to speak with the Investigational Review Nurse.

Federal and State law, as well as contract language, including definitions and specific contract provisions/exclusions, take precedence over Medical Policy and must be considered first in determining eligibility for coverage. The member’s contract benefits in effect on the date that services are rendered must be used. Medical Policy, which addresses medical efficacy, should be considered before utilizing medical opinion in adjudication. Medical technology is constantly evolving, and we reserve the right to review and update Medical Policy periodically.

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