Coverage Policy Manual - Arkansas Blue Cross and Blue Shield

Coverage Policy Manual
Policy #:	2023050
Category:	Pharmacy
Initiated:	December 2023
Last Review:	December 2024

Valoctocogene roxaparvovec-rvox (e.g., Roctavian)

Description:

Valoctocogene roxaparvovec-rvox (e.g., Roctavian) is an AAV5 based gene therapy vector, designed to introduce a functional copy of a transgene encoding the B-domain deleted SQ form of human coagulation factor VIII (hFVIII-SQ). Transcription of this transgene occurs within the liver, using a liver-specific promoter, which results in the expression of hFVIII-SQ. The expressed hFVIII-SQ replaces the missing coagulation factor VIII needed for effective hemostasis.

Regulatory Status

Valoctocogene roxaparvovec-rvox (e.g., Roctavian) was approved by the U.S. Food and Drug Administration (FDA) on June 29, 2023, for the 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.

Coding

See CPT/HCPCS Code section below.

Policy/
Coverage:

Prior Approval is required for valoctocogene roxaparvovec-rvox (e.g., Roctavian).

The initial use of this drug requires documentation of direct physician involvement (MD/DO) in the ordering and evaluation, as well as signature, in the medical records submitted for prior approval.

Approval timeframes may differ for members/participants of Self-Insured plans.

Effective December 13, 2023

Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria

Valoctocogene roxaparvovec-rvox (e.g., Roctavian) meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes when ALL the following criteria are met:

1. Individual is 18 years of age or older (FDA, 2023); AND

2. Individual was assigned male at birth (FDA, 2023); AND

3. Individual has severe or moderately severe hemophilia A as defined by residual Factor VIII activity levels ≤ 1 IU/dL (Ozelo, 2022); AND

4. Individual has been treated with or exposed to Factor VIII concentrates or cryoprecipitate for a minimum of 150 exposure days (FDA, 2023); AND

5. Individual meets one of the following:

a. Current or historical life-threatening hemorrhage; OR

b. Repeated, serious spontaneous bleeding episodes; AND

6. Individual does not have a history of Factor VIII inhibitors or a positive screen result of ≥ 0.6 Bethesda Units (BU) using the Nijmegen-Bethesda assay (Ozelo, 2022); AND

7. Individual does not have detectable pre-existing antibodies to the adeno-associated virus serotype 5 (AAV5) capsid (FDA, 2023); AND

8. Individual is HIV negative (FDA, 2023); AND

9. Absence of active infection at the scheduled infusion (FDA, 2023); AND

10. Individual has received a liver health assessment including enzyme testing and is absent of significant liver dysfunction or disease, defined as one or more of the following (FDA, 2023):

a. Liver cirrhosis of any etiology; OR

b. Active hepatitis B or C infection; OR

c. Alanine transaminase (ALT) greater than or equal to 3 times the upper limit of normal; OR

d. Bilirubin greater than or equal to 3 times the upper limit of normal; OR

e. Alkaline phosphatase greater than or equal to 3 times the upper limit of normal; OR

f. International normalized ratio (INR) greater than or equal to 1.4; AND

11. Individual should be able to receive corticosteroids and/or immunosuppression therapy (FDA, 2023); AND

12. Individual has no history of receiving gene therapy or under consideration for treatment with another gene therapy for hemophilia A (FDA, 2023); AND

13. Valoctocogene roxaparvovec-rvox (e.g., Roctavian) is being prescribed by or in consultation with a hematologist or a prescriber who specializes in hemophilia A, and is being administered by or in consultation with a Hemophilia Treatment Center (HTC), and post-administration monitoring per the manufacturer recommendations is planned by or in consultation with an HTC; AND

14. Must be dosed in accordance with the FDA label.

**Please note, for certain identified gene and cellular therapies such as valoctocogene roxaparvovec-rvox (e.g., Roctavian), when coverage is available and the individual meets member benefit certificate primary coverage criteria, distribution from a specialty pharmacy provider due to cost (distribution channel restriction) may be required for coverage to be provided.

Dosage and Administration

Dosing per FDA Guidelines

The recommended dose of valoctocogene roxaparvovec-rvox (e.g., Roctavian) is 6 x 10 trillion vector genomes (vg) per kg of body weight. The prescribing information includes information on calculating the dose and number of vials required depending on the individual’s weight.

Valoctocogene roxaparvovec-rvox (e.g., Roctavian) is available as a single-dose vial (NDC 68135-927-01) with an extractable volume of not less than 8 mL, containing 16 × 10 trillion vg.

Valoctocogene roxaparvovec-rvox (e.g., Roctavian) should be administered as an IV infusion by a healthcare professional.

Dosing Limits

One injection per lifetime.

Please refer to separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.

Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria

Valoctocogene roxaparvovec-rvox (e.g., Roctavian), for any indication or circumstance not described above, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.

For members with contracts without primary coverage criteria, valoctocogene roxaparvovec-rvox (e.g., Roctavian), for any indication or circumstance not described above, is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Rationale:

The efficacy of valoctocogene roxaparvovec-rvox (e.g., Roctavian) was evaluated in a prospective, phase 3, open-label, single-dose, single-arm, multinational study in 134 adult males (18 years of age and older) with severe hemophilia A, who received a single intravenous dose of 6 × 1013 vg/kg body weight of valoctocogene roxaparvovec-rvox (e.g., Roctavian) and entered a follow-up period of 5 years. Patients previously treated with prophylactic factor VIII replacement therapy, but not emicizumab, were enrolled in the study. The study population was 72% White, 14% Asian, and 11% Black with a median age of 30 (range: 18 to 70) years. Twenty patients had a history of hepatitis B and 41 patients had a history of hepatitis C. All except 2 patients were HIV-negative.

Only patients without detectable, pre-existing antibodies to AAV5 capsid were eligible for therapy. Presence of pre-existing antibodies to AAV5 capsid was identified during screening using the ARUP Laboratories AAV5 DetectCDx™ total antibody assay, which is the FDA-approved test for selection of patients for valoctocogene roxaparvovec-rvox (e.g., Roctavian) therapy. Other key exclusion criteria included active infection, chronic or active hepatitis B or C, immunosuppressive disorder including HIV, current or prior history of factor VIII inhibitor, stage 3 or 4 liver fibrosis, cirrhosis, liver function test abnormalities, history of thrombosis or thrombophilia, serum creatinine ≥ 1.4 mg/dL, and active malignancy.

Of the 134 patients who received valoctocogene roxaparvovec-rvox (e.g., Roctavian) in the clinical trial, 112 patients had baseline annualized bleeding rate (ABR) data prospectively collected during a period of at least six months on factor VIII prophylaxis prior to receiving valoctocogene roxaparvovec-rvox (e.g., Roctavian) (rollover population). The remaining 22 patients had baseline ABR collected retrospectively (directly enrolled population). All patients were followed for at least 3 years.

The primary efficacy outcome was a non-inferiority (NI) test of the difference in ABR in the efficacy evaluation period (EEP) following valoctocogene roxaparvovec-rvox (e.g., Roctavian) administration compared with ABR during the baseline period in the rollover population. The NI margin was 3.5 bleeds per year. All bleeding episodes, regardless of treatment, were counted towards ABR. The EEP started from Study Day 33 (Week 5) or the end of factor VIII prophylaxis including a washout period after valoctocogene roxaparvovec-rvox (e.g., Roctavian) treatment, whichever was later, and ended when a patient completed the study, had the last visit, or withdrew or was lost to follow-up from the study, whichever was the earliest.

The NI comparison between the mean ABR after valoctocogene roxaparvovec-rvox (e.g., Roctavian) treatment and the mean baseline ABR while patients were on factor VIII prophylaxis in the rollover population (N = 112). The mean EEP ABR was 2.6 bleeds/year, compared to a mean baseline ABR of 5.4 bleeds/year. The mean difference in ABR was -2.8 (95% confidence interval: -4.3, -1.2) bleeds/year. The NI analysis met the pre-specified NI margin, indicating the effectiveness of valoctocogene roxaparvovec-rvox (e.g., Roctavian).

Overall, 134 participants received an infusion and completed more than 51 weeks of follow-up. Among the 132 human immunodeficiency virus–negative participants, the mean factor VIII activity level at weeks 49 through 52 had increased by 41.9 IU per deciliter (95% confidence interval [CI], 34.1 to 49.7; P<0.001; median change, 22.9 IU per deciliter; interquartile range, 10.9 to 61.3). Among the 112 participants enrolled from a prospective noninterventional study, the mean annualized rates of factor VIII concentrate use and treated bleeding after week 4 had decreased after infusion by 98.6% and 83.8%, respectively (P<0.001 for both comparisons). All the participants had at least one adverse event; 22 of 134 (16.4%) reported serious adverse events. Elevations in alanine aminotransferase levels occurred in 115 of 134 participants (85.8%) and were managed with immune suppressants. The other most common adverse events were headache (38.1%), nausea (37.3%), and elevations in aspartate aminotransferase levels (35.1%). No development of factor VIII inhibitors or thrombosis occurred in any of the participants.

The safety data described in this section reflect the exposure of 134 adult patients with severe hemophilia A (defined as residual factor VIII activity ≤ 1 IU/dL) to a single dose of 6 × 1013 vg/kg of body weight of valoctocogene roxaparvovec-rvox (e.g., Roctavian). Patients with detectable pre-existing antibodies to AAV5, active infections, history of thrombosis, immunosuppressive disorders, and liver dysfunction were excluded. All patients had a median follow-up of 162 weeks (range: 66 to 255 weeks). The most common adverse reactions (≥ 5%) to valoctocogene roxaparvovec-rvox (e.g., Roctavian) were nausea, fatigue, headache, infusion-related reactions, vomiting, and abdominal pain. The most common laboratory abnormalities (≥ 10%) to valoctocogene roxaparvovec-rvox (e.g., Roctavian) were ALT, AST, LDH, CPK, factor VIII activity levels, GGT, and bilirubin > ULN. Over 80% of patients treated with valoctocogene roxaparvovec-rvox (e.g., Roctavian) received immunosuppressive medications, including steroids, to control elevations in transaminases and to prevent loss of transgene expression.

2024 Update

Valoctocogene roxaparvovec transfers a human factor (F)VIII coding sequence into hepatocytes of people with severe hemophilia A to provide bleeding protection.

To present 3-year efficacy and safety in the multicenter, open-label, single-arm, phase 3 GENEr8-1 trial.

GENEr8-1 enrolled 134 adult males with severe hemophilia A who were receiving FVIII prophylaxis. Efficacy endpoints included annualized bleeding rate, annualized FVIII utilization, FVIII activity (chromogenic substrate assay; imputed as 1 IU/dL at baseline and 0 IU/dL after discontinuation), and the Haemophilia-Specific Quality of Life Questionnaire for Adults. Safety was assessed by adverse events (AEs).

At week 156, 131 of 134 participants remained in the study; overall, 17 of 134 resumed prophylaxis. Mean annualized bleeding rate for treated bleeds decreased from 4.8 (SD, 6.5) bleeds/y at baseline to 0.8 (SD, 2.3; P < .0001) bleeds/y after prophylaxis (prophylaxis cessation to last follow-up) and 0.97 (SD, 3.48) bleeds/y during year 3. Annualized FVIII utilization decreased 96.8% from baseline after prophylaxis and 94.2% during year 3. At week 156, mean and median FVIII activity were 18.4 (SD, 30.8) and 8.3 IU/dL, respectively. FVIII activity decrease was lower between years 2 and 3 than between years 1 and 2. At the end of year 3, clinically meaningful improvements in the Haemophilia-Specific Quality of Life Questionnaire for Adults Total Score were observed (mean change from baseline, 6.6; 95% CI, 4.24-8.87; P < .0001). Mild alanine aminotransferase elevations remained the most common AE during year 3 (23.7% of participants). A serious AE of B-cell acute lymphoblastic leukemia was considered unrelated to treatment.

Hemostatic efficacy was maintained, and safety remained unchanged from previous years. (Madan B, Ozelo MC, Raheja P, et.al., 2024)

CPT/HCPCS:

References:

Curry MP, Afdhal NH.(2023) Noninvasive assessment of hepatic fibrosis: Overview of serologic and radiographic tests. In: UpToDate, Runyon BA, (Ed), UpToDate, Waltham, MA, 2023.

Hoots WK, Shapiro AD.(2023) Inhibitors in hemophilia: Mechanisms, prevalence, diagnosis, and eradication. . In: UpToDate, Leung LLK, Mahoney DHS (Ed), UpToDate, Waltham, MA, 2023.

J Thromb Haemost(2024) Three-year outcomes of valoctocogene roxaparvovec gene therapy for hemophilia A. Jul;22(7):1880-1893. doi: 10.1016/j.jtha.2024.04.001. Epub 2024 Apr 12. PMID: 38614387.

Mahlangu J, Kaczmarek R, von Drygalski A, et al.(2023) Two-Year Outcomes of Valoctocogene Roxaparvovec Therapy for Hemophilia A. N Engl J Med. Feb 23 2023; 388(8): 694-705. PMID 36812433

Ozelo, M. C., Mahlangu, J., Pasi, K.J., et al.(2023) Valoctocogene Roxaparvovec Gene Therapy for Hemophilia A. N Engl J Med. 386(11), 1013–1025.

Pasi KJ, Rangarajan S, Mitchell N, et al.(2020) Multiyear Follow-up of AAV5-hFVIII-SQ Gene Therapy for Hemophilia A. N Engl J Med. 2020;382:29-40.

Rangarajan S, Walsh L, Lester W, et al.(2017) AAV5-factor VIII Gene Transfer in Severe Hemophilia A. N Engl J Med. 2017;377:2519-2530.

Roctavian [package insert]. Novato, CA: Biomarin Pharmaceuticals Inc, June 2023

Single-Arm Study To Evaluate The Efficacy and Safety of Valoctocogene Roxaparvovec in Hemophilia A Patients (BMN 270301). Clinicaltrials.gov website https://clinicaltrials.gov/study/NCT03370913. Accessed October 25, 2023

Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants.