Gene Therapy

Stunning Breakthrough: Hemgenix

Last week we shared an essay by Paul Clement about the approval for gene therapy for hemophilia A, approved only in Europe, and asked, when for the US?

While that question is still valid for hemophilia A, the stunning news this week was that gene therapy–at long last—is approved, for hemophilia B!

The news straight from CSL Behring: “This historic approval provides a new treatment option that reduces the rate of annual bleeds, reduces or eliminates the need for prophylactic therapy and generates elevated and sustained factor IX levels for years after a one-time infusion.”

The news was so startling, it made front page on CNN.com. But I suspect not for the scientific reason but for the economic reason: it comes with a $3.5 million price tag, making it the most expensive drug on earth currently.

Hemophilia Economics 101

While high prices are nothing new in hemophilia—factor therapy has always been among the world’s most expensive drugs—the sticker price was shocking to many. So many people have asked me through the years when is the price of factor going to come down, as if it were a high-tech consumer item like camcorders, Walkmans or DVD players. Remember those? They get mass produced, offshored, and millions upon millions of consumers buy them, which eventually drives the price down. And don’t forget competition. Basic supply and demand.

Hemophilia drugs are nothing like that. There are many factors that determine price but here are three: the research and development (R&D) that was spent to create the drug; the finite marketplace; and whether insurance will cover the cost.

R&D for drugs such as Roctavian, the brand name of BioMarin Pharmaceutical’s gene therapy product approved in Europe for hemophilia A, and Hemgenix, the brand name of CSL Behring’s gene therapy product approved by the U.S. FDA for hemophilia B, can surge to the hundreds of millions, if not billions, of dollars. The money needs to be recouped, and reinvested in the company, and to investors.  

The smaller the target audience, the higher the price. How can you recoup the R&D with such a small consumer audience as hemophilia B? In the U.S., there are approximately 20,000 with hemophilia, of which about 15% have hemophilia B. Not everyone of these patients will want gene therapy; not everyone can afford it.

By afford it, I mean have insurance cover it, which is the final piece of the pricing puzzle. Who will pay the $3.5 million per patient? State Medicaid plans? Commercial insurance? What if a patient on Blue Cross Blue Shield is approved, gets the gene therapy, has it reimbursed, but the following year switches plans? How does this benefit the bottom line at BCBS? Will insurance companies say no to gene therapy based on these concerns?

Advocacy is Key

This is where our decades of strong advocacy in the hemophilia community will make a difference. In a way, we’ve been preparing for this moment our whole lives. While the new drugs are not being touted as a cure, those of us old enough remember the slogan “A Cure by 2000!” We have fought for compensation for those infected by HIV and hepatitis from unsafe blood products. We fought for the new recombinant drugs, when insurance denied us. We fought for longer half-life drugs, for prophy, for bi-specific antibody products. All of these came with higher price tags, and eventually we prevailed.

And now?

We will all need to be educated about this new gene therapy, and how to approach our insurance companies, if we want it. As we have been preaching since 2005, when everything changed in insurance for hemophilia, you need to learn to speak the insurance company’s language; debate with them in a way they are used to; work with your healthcare team; stand with your state hemophilia group.

There are so many excellent products available to treat hemophilia, will insurance companies use this to deny gene therapy? At this point, no one knows, but we do know we need to get prepared. Why?

BioMarin is actively working on getting Rotavian approved for hemophilia A in the US. And that will impact thousands more in our community. How the insurance reimbursement of Hemgenix plays out could be a harbinger of things to come.

Read CSL Behring’s press release here.

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

Will Insurance Cover Gene Therapy?


There’s been a lot of news lately about gene therapy. Just Google “hemophilia and gene therapy” to catch up on what’s happening.

A big concern is how will payers react to gene therapy when it does become available, given how much they try to contain costs?

We covered this topic in a previous issue of PEN’s Insurance Pulse (now discontinued) and it might be good to revisit

First, payers (insurance companies, state Medicaid programs, self-insured employers, and others) will probably pay for new therapies, including gene therapy, but the payers will very likely have prior authorization criteria that define which patients can access these products.

Second, new therapies probably won’t be available immediately after FDA approval. Why? Gene therapy products will probably be expensive. Payers will want time to understand how they work and for whom they will be appropriate. For example, one gene therapy clinical trial excludes patients with inhibitors. Another excludes patients with HIV. If a product hasn’t been tested in a segment of patients, then payers and physicians probably won’t use it for those patients; it’s a matter of safety.

Now, let’s go back to cost: Payers don’t have endless buckets of money. A commercial insurance company’s “income” is made up of the monthly premiums, copays, coinsurances, and deductibles that we pay. Its “expenses” are the medical claims paid to providers (including doctors, hospitals, pharmacies, and labs) and everything else it takes to run the business (employee salaries, building rent, and so on).

What does this mean to our community? Everyone who is eligible for any expensive therapy may not be able to get it immediately.

What can you do if they want to receive a new therapy?

• Talk to your hemophilia treatment center (HTC) team or hematologist. They can help you understand if a particular therapy might work for you.

• If you and your medical team decide to move forward, you’ll have to justify to your payer why this is the right therapy for you. This takes time, and your insurance company may or may not approve it.

• Be prepared to help your medical team make the case for you. That might include extra tests, accurate factor logs, and other documentation.

Remember that insurance companies are not the enemy! To get the best care, you and your healthcare team need to work with them, not against them.

National Hemophilia Foundation and Hemophilia Federation are good places to turn to for information on educating payers on bleeding disorders and also to enhance the relationship between these payers and HTCs. As a community, we need to be responsible stewards of healthcare dollars while getting excellent care. Fortunately, every advanced therapy for bleeding disorders has eventually been covered by most insurance plans–let’s hope this happens fro gene therapy across the board for all.

Cell Therapy Hits a Stumbling Block

by Paul Clement

Paul Clement, author

Despite the heightened anticipation of the development of a successful gene or cell therapy for hemophilia, sometimes things hit stumbling blocks.

Sigilon Therapeutics has paused development of its hemophilia A cell therapy candidate, SIG-001, after one of three patients enrolled in their Phase 1/2 clinical trial developed inhibitors and the implanted cells were found to be dead.

What exactly is SIG-001? It’s a modified form of cell therapy in which live human cells—not derived from the patient—are genetically engineered to express factor VIII and implanted into a patient.

Normally, foreign cells implanted in a person would be rapidly killed by the person’s immune system. In SIG-001, the genetically engineered cells are encased in tiny spheres of a proprietary synthetic biomaterial, which not only protects them from attack by the immune system, but also allows nutrients and waste to flow through the spheres, allowing the cells inside the spheres to survive. The synthetic spheres also allow factor VIII to flow out, making them little factor VIII “factories.”  

How is this different than say, gene therapy? Sigilon’s cell therapy technology—and other similar cell therapies such as Sernova’s “cell pouch”—could have several advantages over gene therapy:

(1) most people with hemophilia would not qualify for gene therapy—it’s not for children, and they tend to be unsuitable for liver or kidney disease patients, those with inhibitors, or those with pre-existing antibodies to the viral vector used in the gene therapy (vectors are modified viruses used to deliver genes, such as the factor VIII gene, to cells).

(2) Gene therapies cannot be re-dosed if their efficacy starts to wane because, once dosed, the patient develops antibodies to the vector, which would rapidly destroy another dose, unless the patient was put on a regimen of immunosuppressive drugs. However, because SIG-001 protects the engineered cells from the immune system, patients could be re-treated if necessary–or have some spheres removed if the dose is too high. (The spheres are administered by injecting them into the patient’s abdomen through a large syringe.)

And (3), the most important potential advantage is cost. Gene therapies are hugely expensive (estimated to cost between $2-$2.5 million) and no satisfactory payment model has so far been worked out. SIG-001 would be off-the-shelf and easily scalable, making it more cost-effective.

So, what happened to SIG-001? In July 2021, the FDA put a clinical hold on the SIG-001 study after a patient developed inhibitors. Inhibitors in hemophilia A patients are common—as many as one-third of people with hemophilia A develop inhibitors, and they usually develop within the first few dozen infusions of factor. However, participants in the SIG-001 clinical trial were pre-screened to be at low risk of inhibitors. In order to qualify for participation in the clinical trial, prospective participants were required to have had at least 150 exposure days to factor, making the risk of developing inhibitors very low. So, a patient developing inhibitors in the clinical trial was concerning.

In November 2021, the inhibitor patient underwent a laparoscopic procedure to retrieve the implanted spheres, which were found to be fibrosed (covered with scar tissue) and the cells within them dead. For SIG-001, its proprietary synthetic biomaterial, specifically designed to prevent fibrosis which occurs when our body detects a foreign object, had failed.

In December 2021, Sigilon decided to pause SIG-001 development in a “strategic reprioritization” in which they laid off approximately 38% of their workforce and refocused their efforts for now on developing a cell therapy for a rare lysosomal disease.

Sigilon has an excellent concept, but unfortunately, its product met an unexpected stumbling block. With each stumbling block though, we also learn, and get one step closer to a successful “cure” for hemophilia.

Paul Clement is a science writer for the hemophilia community who enjoyed a long career as a high school science teacher. He is especially adept at translating complex topics into easy-to-understand language. He is the chief science writer and editor for LA Kelley Communications’ publications, including the Parent Empowerment Newsletter from 1998-2021 and PEN’s Insurance Pulse magazine from 2009-2020. He is co-author of the books Managing Your Child’s Inhibitor and A Guide to Living with von Willebrand Disease. He holds a bachelor’s degree in biology and a master’s degree in science education from California State Polytechnic University. Paul lives in southern California with his wife Linda. They have two adult children, Erika and Brett, who has severe hemophilia A.

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