Valoctocogene Roxaparvovec-rvox (Roctavian)

Number: 1037

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

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Policy

Scope of Policy

This Clinical Policy Bulletin addresses valoctocogene roxaparvovec-rvox (Roctavian) for commercial medical plans. For Medicare criteria, see Medicare Part B Criteria.

Note: Requires Precertification: 

Precertification of valoctocogene roxaparvovec-rvox (Roctavian) is required of all Aetna participating providers and members in applicable plan designs. For precertification of valoctocogene roxaparvovec-rvox (Roctavian), call (866) 752-7021 or fax (888) 267-3277. For Statement of Medical Necessity (SMN) precertification forms, see Specialty Pharmacy Precertification.  

Note: Unless member's health plan has elected not to require, gene and cellular therapies must be administered at an Aetna Institutes^® Gene Based, Cellular and Other Innovative Therapy (GCIT^®) Network. For valoctocogene roxaparvovec-rvox (Roctavian), see Aetna Institutes® GCIT Designated Centers.  

1. Prescriber Specialties

   This medication must be prescribed by or in consultation with a hematologist.

2. Criteria for Initial Approval

   Hemophilia A

   Aetna considers valoctocogene roxaparvovec-rvox (Roctavian) medically necessary for one dose total for treatment of severe hemophilia A (congenital factor VIII deficiency) when all of the following criteria are met:

   1. Member must be 18 years of age or older; and 
   2. Member has severe disease with factor VIII activity levels less than or equal to 1 IU/dL; and
   3. Absence of pre-existing antibodies to AAV5 was confirmed by an FDA-approved test (e.g., AAV5 DetectCDX™); and
   4. Member meets both of the following:
      
      
      1. Member does not have a history of Factor VIII inhibitors (greater than or equal to 0.6 Bethesda units [BU]); and
      2. Member has a negative Factor VIII inhibitor test result within the past 30 days (less than 0.6 Bethesda units [BU]); and

   5. Member meets all of the following:

      1. Member is currently using Factor VIII prophylaxis therapy (e.g., Advate, Adynovate, Eloctate); and
      2. Member has a history of prophylactic Factor VIII use for at least 150 exposure days; and
      3. Member has uncontrolled disease despite the use of prophylactic Factor VIII or has a clinical reason to avoid therapy with Factor VIII prophylaxis; and

   6. Member has the following laboratory values at baseline:

      1. Platelets greater than or equal to 100,000 cells/microL; and
      2. Creatinine less than 1.5 mg/dL; and
   7. Member does not have alanine transaminase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT) levels and total bilirubin (unless there is a diagnosis of Gilbert’s Syndrome and member is otherwise stable) greater than 1.25 times the upper limit of normal (ULN); and
   8. Member does not have an INR (international normalized ratio) greater than or equal to 1.4; and
   9. Member does not have stage 3 or 4 liver fibrosis; and
   10. Member has undergone a hepatic ultrasound and/or elastography to rule out radiological liver abnormalities and/or sustained liver enzyme elevations; and
   11. Member meets both of the following:
       
       
       1. Member does not have a chronic or active infection with hepatitis B virus or hepatitis C virus; and
       2. Member is not currently receiving antiviral therapy for a prior hepatitis B virus or hepatitis C virus exposure; and
   12. Member does not have uncontrolled human immunodeficiency virus (HIV) infection; and
   13. Member does not have an active infection or other immunosuppressive disorder; and
   14. Member does not have an active malignancy; and
   15. Member does not have a history of arterial or venous thromboembolic events (e.g., deep vein thrombosis, non-hemorrhagic stroke, pulmonary embolism, myocardial infarction, arterial embolism); and
   16. Member does not have a known inherited or acquired thrombophilia, including conditions associated with increased thromboembolic risk (e.g., atrial fibrillation); and
   17. Member has not received Roctavian or any other gene therapy previously; and
   18. Prophylactic use of Factor VIII products will not be given after Roctavian administration once adequate Factor VIII levels have been achieved (note: Factor VIII therapy may be given in case of surgery, invasive procedures, trauma, or bleeds in the event that Roctavian-derived Factor VIII activity is deemed insufficient for adequate hemostasis); and
   19. Provider attests that liver enzymes and Factor VIII activity will be followed per the protocol outlined in the prescribing information following receipt of Roctavian infusion.

   Aetna considers all other indications as experimental, investigational, or unproven.

3. Continuation of Therapy

   See Dosage and Administration information.

4. Related Policies

   1. CPB 0131 - Clotting Factors

Dosage and Administration

Valoctocogene roxaparvovec-rvox is supplied as Roctavian suspension for intravenous infusion and has a nominal concentration of 2 x 10¹³ vg valoctocogene roxaparvovec-rvox per mL, each vial contains an extractable volume of not less than 8 mL (16 × 10¹³ vg).

Roctavian is for one-time single-dose intravenous use only.

• Perform baseline testing to select patients, including testing for pre-existing antibodies to adeno-associated virus serotype 5 (AAV5), factor VIII inhibitor presence, and liver health assessments.
• The recommended dose of Roctavian is 6 × 10¹³ vector genomes (vg) per kg of body weight.
• Start the infusion at 1 mL/min. If tolerated, the rate may be increased every 30 minutes by 1 mL/min up to a maximum rate of 4 mL/min.

Refer to full prescribing information for Roctavian for preparation and administration instructions.

Source: BioMarin Pharmaceutical; 2023

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Other CPT codes related to the CPB:
AAV5 Detect CDX –no specific code
76705	Ultrasound, abdominal, real time with image documentation; limited (eg, single organ, quadrant, follow-up) [Liver]
82247	Bilirubin; total
82248	Bilirubin; direct
82565	Creatinine; blood
82570	Creatinine; other source
82977	Glutamyltransferase, gamma (GGT)
84075	Phosphatase, alkaline
84450	Transferase; aspartate amino (AST) (SGOT)
84460	Transferase; alanine amino (ALT) (SGPT)
85049	Blood count; platelet, automated
85335	Factor inhibitor test
85240	Clotting; factor VIII (AHG), 1-stage
85610	Prothrombin time
85730	Thromboplastin time, partial (PTT); plasma or whole blood
85732	Thromboplastin time, partial (PTT); substitution, plasma fractions, each
88720	Bilirubin, total, transcutaneous
91200	Liver elastography, mechanically induced shear wave (eg, vibration), without imaging, with interpretation and report
96365 - 96368	Intravenous infusion
HCPCS codes covered if selection criteria are met:
J1412	Injection, valoctocogene roxaparvovec-rvox, per mL, containing nominal 2 × 10^13 vector genomes
Other HCPCS codes related to the CPB:
J7182	Injection, factor viii, (antihemophilic factor, recombinant), (novoeight), per iu
J7185	Injection, factor viii (antihemophilic factor, recombinant) (xyntha), per i.u
J7186	Injection, antihemophilic factor viii/von willebrand factor complex (human), per factor viii i.u
J7188	Injection, factor viii (antihemophilic factor, recombinant), (obizur), per i.u
J7190	Factor viii (antihemophilic factor, human) per i.u
J7191	Factor viii (antihemophilic factor (porcine)), per i.u
J7192	Factor viii (antihemophilic factor, recombinant) per i.u., not otherwise specified
J7204	Injection, factor viii, antihemophilic factor (recombinant), (esperoct), glycopegylated-exei, per iu
J7205	Injection, factor viii fc fusion protein (recombinant), per iu
J7207	Injection, factor viii, (antihemophilic factor, recombinant), pegylated, 1 i.u
J7208	Injection, factor viii, (antihemophilic factor, recombinant), pegylated-aucl, (jivi), 1 i.u
J7209	Injection, factor viii, (antihemophilic factor, recombinant), (nuwiq), 1 i.u
J7210	Injection, factor viii, (antihemophilic factor, recombinant), (afstyla), 1 i.u
J7211	Injection, factor viii, (antihemophilic factor, recombinant), (kovaltry), 1 i.u
S9345	Home infusion therapy, anti-hemophilic agent infusion therapy (e.g., factor viii); administrative services, professional pharmacy services, care coordination, and all necessary supplies and equipment (drugs and nursing visits coded separately), per diem
ICD-10 codes covered if selection criteria are met:
D66	Hereditary factor VIII deficiency
ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):
A00.0 – B99.9	Certain infectious and parasitic diseases
C00.0 – D49.9	Neoplasms
D68.51 – D68.59	Primary thrombophilia
D68.69	Other thrombophilia [acquired]
I25.2	Old myocardial infarction
I48.0 – I48.92	Atrial fibrillation and flutter
K74.02	Hepatic fibrosis, advanced fibrosis [stage 3 or 4]
Z86.711 – Z86.718	Personal history of venous thrombosis and embolism
Z86.73	Personal history of transient ischemic attack (TIA), and cerebral infarction without residual deficits

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Background

U.S. Food and Drug Administration (FDA)-Approved Indications 

• Roctavian is indicated for the treatment of adults with severe hemophilia A (congenital factor VIII deficiency with factor VIII activity < 1 IU/dL) without antibodies to adeno-associated virus serotype 5 (AAV5) detected by an FDA-approved test.

Valoctocogene roxaparvovec-rvox is available as Roctavian (BioMarin Pharmaceutical Inc) and is an adeno-associated virus (AAV) vector-based gene therapy product. It is derived from naturally occurring adeno-associated virus and is produced using Sf9 insect cells and recombinant baculovirus technology. Roctavian is designed to introduce a functional copy of a transgene encoding the B-domain deleted SQ form of human coagulation factor VIII (hFVIIII-SQ). The expression of the B-domain deleted recombinant human factor VIII under the control of a liver-specific promoter results in the replacement of missing coagulation factor VIII required for effective hemostasis (BioMarin Pharmaceutical; 2023).

According to the prescribing information, Roctavian carries the following contraindications:

• Active infections, either acute or uncontrolled chronic.
• Known significant hepatic fibrosis (stage 3 or 4), or cirrhosis.
• Known hypersensitivity to mannitol.

Per the prescribing information, Roctavian carries the following warnings and precautions:

• Infusion-related reactions: Infusion reactions, including hypersensitivity reactions and anaphylaxis, have occurred. Monitor during and for at least 3 hours after Roctavian administration. If symptoms occur, slow or interrupt administration and give appropriate treatment. Restart infusion at slower rate once symptoms resolve. Discontinue infusion for anaphylaxis.
• Hepatotoxicity: Monitor alanine aminotransferase (ALT) weekly for at least 26 weeks and institute corticosteroid treatment in response to ALT elevations as required. Continue to monitor ALT until it returns to baseline. Monitor factor VIII activity levels since ALT elevation may be accompanied by a decrease in factor VIII activity. Monitor for and manage adverse reactions from corticosteroid use.
• Thromboembolic events: Thromboembolic events may occur in the setting of elevated factor VIII activity above the upper limit of normal (ULN). Factor VIII activity above ULN has been reported following Roctavian infusion. Evaluate for risk factors for thrombosis including cardiovascular risk factors prior to and after Roctavian use and advise patients accordingly.
• Monitoring laboratory tests: Monitor for factor VIII activity and factor VIII inhibitors.
• Malignancy: Monitor for hepatocellular malignancy in patients with risk factors for hepatocellular carcinoma (e.g., hepatitis B or C, non-alcoholic fatty liver disease, chronic alcohol consumption, non-alcoholic
  steatohepatitis, advanced age). Perform regular liver ultrasound (e.g., annually) and alpha-fetoprotein testing following administration.

Per the prescribing information, Roctavian carries the following adverse reactions:

• Most common adverse reactions (incidence ≥ 5%): Nausea, fatigue, headache, infusion-related reactions, vomiting, and abdominal pain.
• Most common laboratory abnormalities (incidence ≥ 10%): ALT, aspartate aminotransferase (AST), lactate dehydrogenase (LDH), creatine phosphokinase (CPK), factor VIII activity levels, gamma-glutamyl
  transferase (GGT) and bilirubin > ULN.

On June 29, 2023, the U.S. Food and Drug Administration approved valoctocogene roxaparvovec-rvox (Roctavian), an adeno-associated virus vector-based gene therapy for the treatment of adults with severe hemophilia A without pre-existing antibodies to adeno-associated virus serotype 5 detected by an FDA-approved test. The FDA approval was based on supporting data from the GENEr8-1 study (FDA, 2023).

In the GENEr8-1 study, a prospective, phase 3, open-label, single-dose, single-arm, multinational trial, Ozelo and colleagues (2022) evaluated the efficacy and safety of valoctocogene roxaparvovec-rvox (Roctavian) in 134 adult males (18 years of age and older) with severe hemophilia A. Patients receiving prior prophylactic factor VIII replacement therapy, but not emicizumab, were enrolled in this study. Only patients without detectable, pre-existing antibodies to AAV5 capsid were eligible for Roctavian therapy. The AAV5 DetectCDx™ total antibody assay (i.e., the FDA-approved test for selection for Roctavian therapy) was used to screen the presence of pre-existing antibodies to AAV5 capsid. Patients received a single intravenous dose of 6.x 10¹³ vg/kg body weight of Roctavian and entered a follow-up period of 5 years. The primary efficacy end point was a non-inferiority (NI) test of the difference in annualized bleeding rate (ABR) in the efficacy evaluation period (EEP) following Roctavian administration compared with ABR during the baseline period in the rollover population. Efficacy was determined from the results of a cohort of 112 patients followed up for at least 3 years after Roctavian treatment. Compared to their baseline, patients experienced an average ABR reduction of 52% after receiving Roctavian, or roughly 2.6 bleeds/year, through to the end of a median three years of follow-up. Their baseline ABR while receiving routine FVIII prophylaxis was about 5.4 bleeds/year (FDA, 2023). Among this cohort of 112 patients, 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). An increase in alanine aminotransferase levels occurred in 115 of 134 individuals (85.8%) and were managed with immune suppressants. Other most common adverse events included headache (38.1%), nausea (37.3%), and elevations in aspartate aminotransferase levels (35.1%). No development of factor VIII inhibitors or thrombosis was noted in any of the participants. 

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References