The Age of Gene Therapy: Why Plasma?

It’s happened: gene therapy is available, at least for hemophilia B patients in the US. The idea that hemophilia can be treated as a “cure,” or at least using one shot to cover your bleeding episodes for at least a few years, is tantalizing. And if not that, we still have recombinant products that have never touched human blood.

We just updated our factor chart here, which compares all the products available on the market for hemophilia A and B. You have lots of treatments to consider! But why are we still making plasma-derived products?

A few reasons. But first, understand where plasma-derived products come from.

Plasma-derived products come from human blood plasma. Plasma donors undergo strict screening for disease risk factors, and their plasma is tested for several viral diseases. Recombinant products are not derived from blood; they originate from genetically engineered mammalian cells containing the human gene for factor. Recombinants are produced in large bioreactors, with human and animal proteins used in the culture medium in first- and second-generation recombinant factor. Third-generation products contain no human or animal proteins in the culture medium or the final product. Fourth-generation products are made from human cell lines.

Although plasma-derived products potentially risk transmitting blood-borne viruses, all US factor products, whether plasma derived or recombinant, are considered safe by the FDA.

Why would anyone intentionally choose a plasma-derived product instead of recombinant? After all, recombinant factor is the product recommended by NHF’s MASAC. And now we have gene therapy for hemophilia B. Why inject anything other than the missing factor into your child?

For some people, it’s all about cost. Plasma-derived factor is less expensive than recombinant factor. And gene therapy is expected to cost about $3.5 million per shot. People who have high out-of-pocket expenses need safe products, but may choose less expensive ones. Sometimes, the decision depends on the type of bleeding disorder being treated. For example, intermediate purity factor VIII products contain factor VIII combined with VWF (the way it’s naturally found in the blood) and are useful in treating von Willebrand disease.

When choosing your factor therapy, always discuss options with your HTC! Use our factor product guide here, which now includes bispecific antibody products and gene therapy, and bring it with you, and ask what’s best for your loved one or you.

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

Safety versus Science: Do We Allow Blood Donations by Gay Males?

Remember the 1980s? For those with hemophilia, we remember fear, lack of understanding, being labeled part of the “Four-H Club”: the groups who seemed to get AIDS most predominantly were heroin users, homosexuals, hemophiliacs and Haitians. Fast forward to the Millennium and one group still seems to be held under a microscope: homosexuals. A lifetime ban was placed on homosexuals in 1983 due to the spread of AIDS through blood donations. Homosexuals were social activists and quite altruistic. They often donated blood. Before HIV was identified, their donations contributed to the spread of HIV to those with hemophilia.

So why are they still banned from donating blood? Is there a scientific or medical reason–or just plain discrimination?

Apparently 18 senators think it’s discrimination. A letter signed by all was sent to the Food and Drug Administration (FDA) last week, requesting the FDA to modify its policies on donors. They asked the FDA for the same deferral policies for heterosexuals engaged in high-risk behavior–usually a 12 month waiting period. In plain language: if you are a gay or bisexual man, you could donate blood if you have not had sex with a man in the past 12 months.

What do the nation’s blood bank organizations have to say about that? They’ve been open to changing policy since 2006. The AABB, America’s Blood Centers and American Red Cross all support a 12 month deferral. And the CDC says transmission of HIV through blood donations are extremely rare – less than 1% of all new HIV infections.

But Mark Skinner, president of the World Federation of Hemophilia, cautions that the focus should be on the safety of the recipient, not the altruistic needs of the donor. Blood-donor rules are discriminatory by design, Skinner says in the Washington Times. He noted that people with hemophilia can’t give blood, so it’s not about discrimination; it’s about scientific vigilance.

The FDA reports that homosexual males have an HIV prevalence 60 times higher than the general population, 800 times higher than first-time blood donors, and 8,000 times higher than repeat blood donors.

In a statement released February 19, the WFH stated that donation policy must be based on the Precautionary Principle, which asks that in the absence of scientific consensus, decisions must err on the side of caution. Here, not to cause any unnecessary risk to recipients of blood donations.

This is a fascinating discussion about safety and science, and one that has not ended yet. Surely it is difficult to be a gay male and not to be allowed to donate blood, which is a highly altruistic and socially conscious act. But due to our history, the hemophilia community may defeat efforts to change the current blood donation policies.

For more info, see: Washington Times – Senators ask FDA to lift gay blood donor ban
http://www.washingtontimes.com/news/2010/mar/05/senators-ask-fda-to-lift-gay-blood-donor-ban//print/[3/6/2010 10:50:41 PM]

Wilate: a New VWD Product

This is big news for von Willebrand Disease patients: there’s a new product on the market. Wilate® just got approved by the US FDA for “treatment of spontaneous and trauma-induced bleeding episodes in patients with all types of von Willebrand disease (VWD),” according to a press release. Wilate is a high-purity plasma-derived product, which uses a double viral inactivation process in manufacturing: solvent/detergent (S/D) process and a special terminal dry-heating (TDH) system. No albumin is added as a stabilizer. Wilate is exclusively derived from large pools of human plasma collected in U.S. FDA approved plasma donation centers. Wilate will be available in the market in early 2010.

Wilate is produced by Octapharma, a Swiss-based company. This is the first time Octapharma has entered the US bleeding disorders market. Wilate will be in direct competion with Humate-P, manufactured by CLS Behring.

One thing interesting I learned is that this is the first product developed and manufactured specifically for VWD.

Here’s a quote from Octapharma: “Octapharma’s worldwide commitment to coagulation disorders dates back to Octapharma Group’s formation 25 years ago,” said Octapharma USA President Flemming Nielsen.”We are thrilled that U.S. patients will now have access to Wilate following its significant success in Europe as a next generation therapy. Octapharma is committed to providing the U.S. market with life-enhancing therapies.”

VWD patients now have more choices for treatment options. For more information, please visit www.octapharma.com.

Great Book I Just Read
Final Voyage: A Story of Arctic Disaster and One Fateful Whaling Season by Peter Nichols

Massachusetts (my home state) gave birth to the American Revolution and also the global whaling industry. This fascinating book recounts a terrible story of scores of whaling ships trapped in the Arctic region, as the captains tried to score as many whales as possible before the ice closed in for the winter. Nichols deftly parallels that story with the beginning of the whaling industry, which has direct ties to Puritans coming to the new world, religious intolerance in Massachusetts in the 1700s, and the Quakers, who almost single-handedly created this lucrative industry. Whale oil soon was lighting the homes of Massachusetts and then lubricating the machines of the Industrial Age, making some Quakers millionaires, even then. Nichols also details the decline of the industry: the discovery of crude oil in Titusville, Pennsylvania, which soon replaced whale oil; the decimation of so many whales left hunting lean. All these events culminate into a dreadful outcome for the ambitious captains of the whaling ships that last season of hunting, as they searched for the last whales in an early and fearsome storm. This book will enlighten you about many subjects, from religion and commerce, to whales and history. Three stars.

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