Food and Drug Administration

Hemophilia Gene Therapy—is the US Next?

Paul Clement

Last week we discussed Roctavian, the brand name of BioMarin Pharmaceutical’s gene therapy product, valoctocogene roxaparvovec, to treat patients with severe hemophilia A, and the European Commission’s August 24, 2022, conditional marketing authorization for the therapy. Two big questions on everyone’s mind are: when will it be approved in the US and what will it cost?

US Approval Soon?

BioMarin submitted a biologics license application (BLA) to the U.S. Food and Drug Administration (FDA) for approval to market Roctavian back in 2019. In August 2020, the FDA responded by issuing a Complete Response Letter (CRL) to BioMarin, delaying their approval request and requiring two more years of additional safety and efficacy data from the company’s Phase 3 GENEr8-1 clinical trial.

Why did the FDA delay approval of BioMarin’s gene therapy? Its primary concern was the trend in clinical trial data showing decreasing efficacy of Roctavian over time, which could potentially render the therapy ineffective after several years.

At the end of September, BioMarin resubmitted its BLA for Roctavian with the requested additional data, and in a press release, announced that the FDA had accepted its resubmission of the BLA on October 12, 2022. Similar to the therapy’s conditional approval in Europe, the BLA resubmission includes a proposed long-term extension study to follow all trial participants for up to 15 years, plus two post-approval registry studies to follow patients dosed in a real-world setting.

According to BioMarin, BLA resubmissions are typically are followed by a six-month review process. However, the company anticipates that an additional three months of review may be necessary to review the new data—bringing the approval date to sometime in mid-2023. The approval of Roctavian is likely to proceed fairly rapidly: the FDA had previously granted Roctavian Breakthrough Therapy as well as Regenerative Medicine Advanced Therapy designations, both FDA programs designed to speed up the development and review process of therapies. And Roctavian also received an orphan drug designation from the FDA, granting it seven years of market exclusivity after approval. If approved, Roctavian would be the first commercially-available gene therapy in the U.S. for the treatment of severe hemophilia A.

How Much Will It Cost?

This is the million dollar question. Cell and gene therapies are extraordinarily expensive, ranging in cost from $373,000 (Yescarta, a cell therapy for lymphoma) to $2.8 million (Zynteglo, a cell therapy for beta-thalassemia). Pharmaceutical companies would like a one-time payment for the therapy up front, but health insurance companies balk at the high cost, citing concerns about efficacy (what if it does not work?), durability (how long will it last?) and patient mobility (why should we pay for a therapy that may last a lifetime, when the patient is likely to have a policy with us only three to six years?).

In response to these concerns and “failure to launch” for several gene therapies in Europe due to their high cost, pharmaceutical and health insurance companies have been exploring 16 different reimbursement models to make these expensive therapies more palatable to both parties. Two models stand out: the annuity model in which insurers make payments in installments over time; and the outcomes/milestone-based contract model in which the payment amount is adjusted depending on whether a pre-specified health outcome is achieved (i.e., the patient’s factor level will remain above a certain level for a certain number of years) if the outcome is not met, the pharmaceutical company might provide large rebates for patients that fail to respond to a therapy in a predetermined way). Both of these payment models may also be combined, in which an outcome-based contract with the manufacturer is connected to an annuity payment for the therapy, contingent on a positive health outcome.

BioMarin expects Roctavian’s list price in Europe to be roughly $1.5 million, after all discounts. They are currently in payment negotiations with Germany and will then move to France, Italy, and Spain, and then to other countries. (The healthcare systems in France, Germany, Italy, Spain and England are predominantly single-payer systems, with public health insurance covering either the entire, or the vast majority of the population, making payment negotiations easier than in the highly fragmented health insurance industry in the US). In Europe, BioMarin is negotiating outcomes-based agreements, with the goal of guarding against the risk of a “non-response” to treatment for at least five to eight years.

What about the cost in the US? BioMarin has not set a price for Roctavian in the US, but has suggested it will be between $2 and $3 million. How this new therapy will be greeted by health insurance industry in the US remains to be seen. So far, the effect of cell and gene therapies on the US health insurance landscape has been minimal, because there are currently only a handful of products licensed in the US. However, major changes are on the horizon: there are about 3,000 cell and gene therapy therapies in the pipeline, and by 2025, the FDA predicts they will be approving between 10 and 20 cell and gene therapy products per year. And these therapies will require the adoption of new payment models if they are to reach  consumers.

Hemophilia Gene Therapy wins Conditional Approval

Part 1

Paul Clement

It has been almost 30 years since the New York Times in 1994 ran the headline “Cure for Hemophilia Is Seen by Year 2000,” regarding a prediction by the World Health Organization. But the first approval of a gene therapy for hemophilia has finally arrived!

In June, the European Medicines Agency (EMA), the European equivalent of the US Food and Drug Administration (FDA), recommended granting a conditional approval to BioMarin’s ROCTAVIANTM, the brand name of its gene therapy product, valoctocogene roxaparvovec, to treat patients with severe hemophilia A.1 On August 24, 2022, the European Commission (the EC is the executive arm of the European Union or EU) granted conditional marketing authorization to Roctavian. The EC also endorsed EMA’s recommendation for Roctavian to maintain orphan drug designation, thereby granting a 10-year period of market exclusivity, and the EC is further requiring patients treated with Roctavian to be monitored for 15 years, to ensure the long-term efficacy and safety of this gene therapy.

How does it work?

Roctavian is a single injection of trillions of copies of an adeno-associated virus (AAV) which have had their genetic material removed and replaced by a good copy of the gene for factor VIII. Once the AAV has had its genetic material removed, it can no longer replicate itself and it does not cause disease—it is now merely a transport vehicle called a “vector,” designed to get good copies of the factor VIII gene into liver cells where the liver can then produce functional factor VIII. There a many different varieties of AAV, which are given numbers to distinguish one variety from another. Roctavian uses AAV5 as a vector, which has a relatively low (4% to 50%) incidence of natural immunity (antibodies) against the vector. Roctavian does not become part of the individuals DNA and it cannot be passed on to children.

Who is eligible?

  • Only adults (18 years or older) with severe hemophilia A (factor VIII deficiency) are eligible. (In children, the liver is rapidly increasing in size as the child grows, which would dilute the effect of the gene therapy).
  • Only individuals who do not have factor VIII inhibitors.
  • Only individuals without detectable antibodies to the vector, AAV5. The incidence of antibodies to AAV5 can vary widely, from 4% to 50%, and varies with geographic region and increases with age. (Unless the individual is immuno-suppressed, antibodies will neutralize the gene therapy treatment, rendering it ineffective.) BioMarin is running a Phase 1/2 trial, called 270-203 (ClinicalTrials.gov #NCT03520712), evaluating a single dose of Roctavian in about 10 men with severe hemophilia A who carry pre-existing antibodies against the AAV5 viral vector.
  • Only individuals who do not have liver disease. (This will likely eliminate many older people with hemophilia who were infected with hepatitis C through contaminated factor products in the 1970s and early 1980s.)

Are there risks involved?

  • Roctavian can cause transient inflammation of the liver, which can trigger the immune system to destroy liver cells which have the new factor VIII gene and are producing functional factor VIII. Obviously, this is not good, as it may potentially neutralize the gene therapy treatment or reduce its efficacy. This immune response can be tamped by using a corticosteroid in combination with the Roctavian infusion. BioMarin has recently completed a clinical trial, called “GENEr8-3,” of this combination treatment (Clinicaltials.gov # NCT04323098), with results expected in early 2023.
  • A person’s response to Roctavian can vary widely. For many, Roctavian will not be a “cure,” but will convert a person’s severe hemophilia to mild hemophilia (factor levels between 6% and 40%).
  • In clinical trials, the efficacy of Roctavian has decreased over time. This could potentially render the treatment ineffective after several years. And because the body produces antibodies against the vector after treatment, this will likely prevent the individual from receiving another gene therapy treatment using the same vector.

The very high cost of Roctavian will present challenges to its uptake, and it will also face severe competition with Hemlibra, a bispecific antibody that mimics the function of factor VIII and can be injected under the skin as infrequently as once a month. However, according to a report by the newsletter Fierce Pharma, recent market research showed that healthcare professionals in EU estimated Roctavian could capture 35% of eligible patients, in line with BioMarin’s own projection. Plus, about 80% of surveyed doctors in both EU and the U.S. expect to treat at least one patient with Roctavian within 12 months of an approval.2

In the second of this two-part series, we will look at the timeline for approval of Roctavian in the US and what it might cost.

  1. BioMarin is a California-based biopharmaceutical company, known as BioMarin Pharmaceutical Inc. in the US and BioMarin International Limited in Europe.
  2. https://www.fiercepharma.com/pharma/biomarins-hemophilia-gene-therapy-roctavian-wins-conditional-eu-backing-fda-plan-delayed
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