Oscar Roctavian (valoctocogene roxaparvovec-rvox) (PG163) Form

Hemophilia A

Hemophilia A is a rare, X-linked genetic bleeding disorder caused by coagulation factor VIII deficiency. Based on the level of clotting factor (factor VIII) activity detected in the blood, hemophilia A severity is classified into the following categories:

1. Severe disease - Factor VIII activity less than 1% of normal (less than 1 unit/dL)
2. Moderate disease - Factor VIII activity between 1% to 5% of normal (1 to 5 units/dL)
3. Mild disease - Factor VIII activity more than 5% but less than 40% of normal (more than 5 but less than 40 units/dL)

Patients with severe hemophilia A are at high risk for spontaneous bleeding episodes, particularly into joints and muscles, leading to chronic pain, joint damage, and disability. The current standard of care is routine intravenous prophylactic infusions of factor VIII concentrate to prevent bleeding events. However, breakthrough bleeding still occurs due to the short 8-12 hour half-life of factor VIII products.

Roctavian (valoctocogene roxaparvovec-rvox)

is the first gene therapy approved for adults with severe hemophilia A. It delivers a functional F8 gene via an AAV5 viral vector to enable endogenous factor VIII production. It 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

• It is administered as a one-time intravenous infusion.
• It provides an alternative to intravenous factor VIII prophylaxis, but is not a cure for hemophilia A.

In the phase 3 trial, Roctavian (valoctocogene roxaparvovec-rvox) reduced annualized bleeding rates by 52% over 3 years. However, factor VIII activity wanes over time.

Definitions

• AAV5 Viral Vector is a tool used in gene therapy to deliver a functional F8 gene to cells. AAV5 is a specific type of adeno-associated virus.
• Annualized Bleeding Rates refers to the expected number of bleeding episodes within a year.
• Antibodies to AAV5 are proteins produced by the immune system that recognize and neutralize the AAV5 virus, potentially impacting the efficacy of Roctavian.
• Bethesda Assay is a laboratory test used to measure the level of factor VIII inhibitors in the blood.
• Factor VIII Inhibitors are proteins produced by the immune system that neutralize factor VIII, making treatment less effective.
• Factor VIII is a protein involved in blood clotting. Its deficiency leads to Hemophilia A.
• FDA refers to the United States Food and Drug Administration, responsible for approving drugs and medical treatments.
• Hemophilia A is a rare, X-linked genetic bleeding disorder resulting from a deficiency in coagulation factor VIII.
• Prophylactic Infusions refers to preventive treatment given to avoid the onset of a disease or condition, in this case, bleeding episodes.
• Thrombocytopenia is a condition characterized by low platelet count, leading to increased risk of bleeding.
• Vector Genomes are complete sets of viral DNA. In this context, it's used to measure the dosage of Roctavian.
• Von Willebrand Disease is a genetic disorder caused by missing or defective von Willebrand factor (VWF), a clotting protein.
• X-linked refers to a gene carried on the X chromosome. In the context of hemophilia, it primarily affects males since they have only one X chromosome.

Medical Necessity Criteria for Authorization

The Plan considers Roctavian (valoctocogene roxaparvovec-rvox) medically necessary when ALL of the following criteria are met:

1. Prescribed by or in consultation with a physician experienced in the treatment of hemophilia and/or bleeding disorders (e.g., hematologist); AND
   • a. IF there is documentation indicating any radiological liver irregularities or liver function test anomalies (ALT, AST, GGT, ALP or total bilirubin > 1.25 × ULN or INR ≥ 1.4), a consultation with a hepatologist is required.
2. The member is 18 years of age or older; AND

The member has a diagnosis of severe hemophilia A, defined as congenital factor VIII deficiency with factor VIII activity level less than or equal to (≤) 1 IU/dL; AND

4. Documentation of ALL of the following:
   1. baseline testing for BOTH of the following:
      • factor VIII inhibitor titer; and
      • preexisting antibodies to adeno-associated virus serotype 5 (AAV5); and
   2. at least 6 months prophylactic use of factor VIII before considering Roctavian; and
   3. liver health assessments, which include:
      1. Liver function tests, i.e., ALT, AST, GGT, ALP, total bilirubin, and INR; and
      2. Liver condition evaluations through ultrasound, elastography, or laboratory assessments for liver fibrosis; and
   4. A comprehensive review of the member’s concurrent therapy considerations, inclusive of:
      1. alcohol consumption AND the member has received guidance to refrain from alcohol consumption for a minimum of one year after Roctavian administration and is encouraged to moderate their alcohol intake thereafter; and
      2. herbal products and dietary supplements; and
      3. medications that might induce hepatotoxicity, reduce factor VIII activity, or alter plasma corticosteroid levels which can influence liver enzymes or factor VIII activity; and
      4. member’s capability to undergo prolonged corticosteroids and/or other immunosuppressive treatments; AND
5. The member does NOT have ANY of the following:
   1. Active infections, either acute (such as acute respiratory infections or acute hepatitis) or uncontrolled chronic (such as chronic active hepatitis B); and/or
   2. Known hypersensitivity to mannitol; and/or
   3. Presence of antibodies to AAV5 capsid, as confirmed by an FDA-approved/cleared or CLIA-compliant test, such as ARUP Laboratories' AAV5 DetectCDx™; and/or
   4. presence of factor VIII inhibitors (i.e., results from a Bethesda assay or Bethesda assay with Nijmegen modification of less than 0.6 Bethesda Units (BU)); and/or
   5. Stage 3 or 4 liver fibrosis, or cirrhosis; AND
6. Authorization is for no more than:
   1. 6 × 10¹³ vector genomes per kilogram (vg/kg) body weight, administered as a single intravenous infusion; or
   2. one dose of Roctavian (valoctocogene roxaparvovec-rvox) per lifetime.

If the above criteria are met, one dose of Roctavian (valoctocogene roxaparvovec-rvox) will be approved for the one-time treatment.

Experimental or Investigational / Not Medically Necessary

Roctavian (valoctocogene roxaparvovec-rvox) for any other indication or use is considered not medically necessary by the Plan, as it is deemed to be experimental, investigational, or unproven. Non-covered indications include, but are not limited to, the following:

1. hemophilia A (congenital factor VIII deficiency):
   1. Retreatment after receiving one prior dose
   2. dosage exceeding the FDA-approved dose of 6 × 10¹³ vector genomes per kilogram (vg/kg) body weight
   3. Use in females
   4. Use in patients with pre-existing antibodies to adeno-associated virus serotype 5 (AAV5)
   5. Use in patients with current or prior factor VIII inhibitors
   6. Use in pediatric patients
   7. Mild or moderate hemophilia A:
      1. Mild: Factor VIII level >5% to <40%
      2. Moderate: Factor VIII level 1% to 5%
2. Treatment of other coagulation factor deficiencies (e.g. factors IX, XI, XII)
3. Treatment of thrombocytopenia or platelet dysfunction
4. Treatment of vitamin K deficiency
5. Treatment of von Willebrand disease