Gene Therapy Historical Approval

Gene therapy is the process of inserting new, functional factor IX genes into the body to allow it to produce its own factor IX.

The U.S. Food and Drug Administration (FDA) approved CSL Behring’s gene therapy for hemophilia B. The drug name is etranacogene dezaparvovec-drlb, and the trade name is HEMGENIX®. The treatment was originally developed by uniQure and will be commercialized globally by CSL. We want to congratulate them for their years of work and the success of this exciting breakthrough.

HEMGENIX consists of an adeno-associated virus, type 5 (AAV5) vector that delivers the high-activity Padua factor IX gene to cells in the liver. The transformed liver cells can then produce the Padua version of factor IX along with the mutated factor IX that they usually produce.

Although HEMGENIX was only tested clinically in adult males with severe or moderately-severe hemophilia B, the FDA gave it a fairly broad indication:

HEMGENIX is an adeno-associated virus vector-based gene therapy indicated for treatment of adults with Hemophilia B (congenital Factor IX deficiency) who:

•Currently use Factor IX prophylaxis therapy, or

•Have current or historical life-threatening hemorrhage, or

•Have repeated, serious spontaneous bleeding episodes

That means that it can be used in adult (18 and older) men or women who fit the above criteria, not just in those with severe (<1% FIX) or moderately-severe (up to 2% FIX) disease. However, it is not indicated for inhibitor patients.

The clinical studies showed a wide range of responses to the treatment with factor IX levels ranging from factor IX levels of 4.9% of normal to 99.2% after 24 months in 50 patients. The average factor IX level after 24 months was 36.7%. Thus, the treatment will move many patients up into the mild hemophilia range, with some patients even obtaining normal factor IX levels.

Such a widespread in results, 4.9 to 99.2%, would normally doom a product. Manufacturers want to know that a product can be depended on to work for as many patients as possible. However, the clinical study results suggest that the product will work well in many patients, so it was probably worth approving for those patients’ benefit.

The approval was actually based on the decrease in annualized bleeding rate (ABR) rather than factor level. The average ABR during the lead-in portion of the study while the subjects were still on prophylaxis (months 0 to 6) was 4.1 bleeds/year. The average ABR during months 7 to 18 after treatment decreased to 1.9 bleeds/year. All but two of 54 subjects in the studies were able to discontinue prophylaxis.

Pre-testing is required for patients considering HEMGENIX. Patients will be tested for inhibitors and for liver health. It is also recommended, but not required, that potential recipients be tested for pre-existing antibodies against the AAV5 vector. The clinical studies showed that the treatment still works in people with pre-existing antibodies, except for those with extremely high levels.

Presence of an inhibitor will preclude using HEMGENIX. We don’t know what would happen if an inhibitor patient were given gene therapy, but there is a potentially significant risk. The inhibitor patient would start producing factor IX, but the immune system would also still be producing inhibitor antibodies. This could set up an ongoing war between the immune system and the transformed liver cells that now make factor IX. That could be a possibly fatal situation.

Patients with liver damage can still potentially receive HEMGENIX. FDA only requires that a liver specialist be consulted before going ahead. If the specialist thinks the patient will still do all right with the treatment, they could still be treated.

Possible adverse reactions include infusion-site reactions, liver toxicity, immune reactions against the AAV vector that could render the treatment ineffective and liver cancer. Other common reactions include headache, flu-like symptoms, fatigue and malaise.

After treatment, regular testing for factor IX level, new inhibitors and liver enzymes will continue. It can take several weeks for the treatment to take hold, so factor IX infusions may need to continue during the first weeks after treatment. Patients with elevated liver enzymes (ALT and AST) after treatment may be given corticosteroids to manage the liver inflammation. In patients with liver conditions, periodic ultrasound and tests for alpha-fetoprotein will continue at least annually for five years.

One real question is how long the treatment will last. This is a one-time treatment that is intended to last a lifetime, but we don’t really know for sure – only time will tell. Last year uniQure reported results from a series of patients who had had the treatment for at least five years. They still had sustained production of factor IX, reductions in ABR, and were still off prophylaxis. However, those subjects had been treated with an earlier version of the product that did not use the Padua factor IX gene. So, this provides some assurance, but not proof that the treatment will last a substantial amount of time.

Much of the media coverage of the approval of HEMGENIX overlooked the fact that this is a real breakthrough treatment for hemophilia B and only focused on the cost. HEMGENIX is now the most expensive drug in the world at $3.5 million per dose. That could be a real burden. We will have to see how payers react. CSL will also want patients to use their new product, so they might provide some financial incentives as have become common for other high-priced drugs.

We don’t yet know how HEMGENIX will be marketed and administered. There has been talk of only providing the product through a few major medical centers and HTCs. If you are interested in being treated, talk to your hemophilia provider or HTC. You should also explore what is known so far about HEMGENIX before you make a decision. Much of this article is based on the FDA-approved Package Insert (also called Prescribing Information or Direction Insert), which can be downloaded for free at https://www.fda.gov/vaccines-blood-biologics/vaccines/hemgenix. In addition, there will probably be ongoing evaluation of HEMGENIX as the product is rolled out to patients, and we get more real-world experience with it.

This is an exciting development for hemophilia B treatment. It is the first gene therapy approved anywhere for treatment of hemophilia B. It represents a major leap in the development of an eventual cure for all patients with hemophilia B. [FDA approval information and press releases from CSL and uniQure]