Valoctocogene roxaparvovec


Approved by the European Commission (EC) in August 2022, valoctocogene roxaparvovec is also poised to be the first gene therapy to launch in the United States for severe hemophilia A. Treatment benefit is expected to last for years, reduce the number of bleeding events, minimize the need for replacement factor VIII (FVIII) and negate the use of otherwise burdensome prophylaxis treatment.

About valoctocogene roxaparvovec

  1. BioMarin Pharmaceutical Inc.
  2. AAV5-based gene transfer therapy
  3. Single intravenous infusion to treat severe hemophilia A
  4. ~16,500 cases of severe hemophilia A in the G7 markets in 2021

Why is it a drug to watch?

  1. By restoring the expression of endogenous FVIII, valoctocogene roxaparvovec reduces the number of bleeding events experienced by people with hemophilia A, converting the patient from having severe hemophilia to mild disease.
  2. The EC approval and resubmission to the U.S. Food and Drug Administration (FDA) were supported by data from a phase 1/2 trial and the phase 3 GENEr8-1 trial, including additional long-term follow-up data to confirm the duration of effect, as requested in the complete response letter (CRL) from the FDA.
  3. In the GENEr8-1 trial, valoctocogene roxaparvovec decreased the annualized bleeding rate and improved the annualized FVIII infusion rate.
  4. BioMarin Pharmaceutical Inc has constructed, commissioned and validated a gene therapy manufacturing facility that will produce the therapy.
  5. BioMarin Pharmaceutical Inc is developing a companion diagnostic with ARUP Laboratories Inc.

Review and approval status

March 2021:
• Regenerative medicine advanced therapy (RMAT) designation: U.S. FDA

August 2022:
• Marketing authorization: EC

September 2022:
• Marketing authorization for AAV5 DetectCDx™ Kit companion diagnostic: EC
• Biologics License Application (BLA) resubmitted: U.S. FDA

March 31, 2023:
• PDUFA date

Actual and expected launch:
2022: Europe
2023: United States

Patents estimated to expire beginning in 2033

How will valoctocogene roxaparvovec impact the market for hemophilia A?

  1. Gene therapies potentially offer curative treatment, but FVIII levels do not appear to be sustained with the first generation of gene transfer therapies.
  2. Initial uptake will be very slow but gradually increase as more safety data, postmarketing real world data and data on the pretreatment parameters that determine individual responses become available.
  3. By the time these data are available, the hemophilia A competitive landscape is likely to change drastically, and FVIII gene therapy may be a much less attractive alternative.
  4. Payer decisions for valoctocogene roxaparvovec could set the tone for future gene therapies, with many key opinion leaders and payers stating that pay-for-performance is the only viable, ethical way for society to afford an expensive, potentially ineffective treatment when other safe, efficacious therapies already exist.
  5. Payers also suggest that the cost of valoctocogene roxaparvovec could result in coverage for only patients most likely to benefit (young without joint damage vs an older person who already has severe joint damage).

What gaps in treatment does valoctocogene roxaparvovec fill?

Approximately 43% of people with hemophilia A experience painful, spontaneous bleeds into their muscles and joints that contribute to progressive, debilitating joint damage that can have a major impact on quality of life. Standard of care consists of 100 to 150 intravenous infusions (two to three times a week) of replacement FVIII a year and does not always prevent joint damage. Correction of the coagulation system can be life-changing, and valoctocogene roxaparvovec could potentially be the first treatment to accomplish this with a single infusion, eliminating the need for blood transfusions and FVIII replacement therapy.

What hurdles might it need to overcome to reach blockbuster status?

There are a number of factors that could influence whether valoctocogene roxaparvovec will be broadly adopted within the target population including the presence of safe, efficacious therapies; use restricted to patients older than 18 years; and loss of FVIII expression over time, as observed in clinical trials. In addition, the combination of this loss of efficacy, unpredictable and variable individual responses to the treatment and a lack of long-term safety data might make both patients and physicians hesitant to use, and payers hesitant to cover, a novel gene therapy. Coverage could depend on a set of predetermined conditions, and the patient copay might be high.

expected sales in 2027
probability of success for valoctocogene roxaparvovec in the United States.

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