Q&A: What’s Next for Hemophilia Gene Therapy?

In December, Children’s Hospital Los Angeles treated its third patient with Hemgenix gene therapy—a young adult with hemophilia B. The first two patients were treated on the clinical trial that led to the drug’s approval by the Food and Drug Administration.

International hemophilia expert Guy Young, MD, led CHLA’s participation in that trial, as well as the trial for Roctavian gene therapy, which is FDA approved for hemophilia A. Dr. Young leads the Hemostasis and Thrombosis Center in the Cancer and Blood Disease Institute at CHLA— which has been caring for hemophilia patients for almost 50 years and is a national leader in gene therapy for children and young adults.

He shares his thoughts on the success and challenges of today’s gene therapies, why more patients haven’t yet opted to receive them, and how two clinical trials starting this year at CHLA will take novel approaches.

How effective are today’s gene therapies for hemophilia?

They’re not a cure. But for Hemgenix, after three years, 51 out of 54 patients from the clinical trials have stayed off factor treatment. Two patients who had to resume factor therapy had special circumstances: One received only a partial infusion, and another had a very high antibody level to the viral vector.

So the response has been really, really good with Hemgenix. I have two patients who are five years out from their treatment, and both are doing well.

For Roctavian, factor levels peak around six months, then drop off and plateau. About 15% of Roctavian patients have had to resume factor therapy. But the other 85% have not. And around 5% of Roctavian patients have factor levels that are in the normal range. So there is upside with Roctavian as well.

For patients who want to pursue gene therapy, I do think now is the time. We are at least five to seven years away from next-generation therapies potentially being approved for either hemophilia A or B.

As more people choose gene therapy, I think they will later say: Why did I wait so long? Because what we hear from our patients who receive gene therapy is that it’s life-changing.

Guy Young, MD

What are the limits of current gene therapies?

As I mentioned, they’re not a cure—most patients will still have factor levels below normal. But another issue is that some patients aren’t eligible.

You need to have a healthy liver, for example. For Roctavian, patients also can’t have any antibodies to the virus that’s used to deliver the therapy. Hemgenix patients can have some antibodies, but if the levels are too high, they’re not eligible. At CHLA we have had some patients who were not eligible to receive these drugs based on results of these screenings.

Some people’s immune systems attack the viral vector as well. We then need to administer steroid treatment to prevent the patient’s immune system from destroying the gene therapy.

Are you concerned about the drop-off in factor levels with Roctavian? How do you counsel patients?

There has been some reluctance among physicians around Roctavian because of this question of durability. The way I approach it with patients is to be very transparent. I go through all the data—what we know and what we don’t know.

And then it’s a shared decision-making process. We look at how well the patient is currently managing their disease and what works best for their life. Some patients tell me, ‘If I could just be off my treatment for three years, I’ll take it.’

Demand for hemophilia gene therapy has been lower than gene therapies for some other conditions. Why?

One possible reason is that, unlike some of those other conditions, the standard treatments for both hemophilia A and B are quite good. For hemophilia B, you need infusions every week, and for hemophilia A, we have subcutaneous treatments. But these treatments work well.

In addition, gene therapy is a completely new way to treat diseases. Patients want to know, ‘What is this? Is it safe?’ There’s a learning curve. But I also think many patients don’t know what they’re missing out on.

As more people choose gene therapy, I think they will later say: Why did I wait so long? Because what we hear from our patients who receive gene therapy is that it’s life-changing. For the first time, they can live their life without worrying about their hemophilia.

CHLA will be the site of two hemophilia gene therapy trials starting in 2025. How are these drugs different from current treatments?

They are very different, and neither uses a viral vector. One of the study drugs, known as REGV131-LNP1265, uses CRISPR-Cas9 gene editing technology to insert the corrected gene directly in the patient’s chromosomes. That will be a phase 1 trial for hemophilia B and should launch at CHLA early this year.

The second phase 1 trial is for BE-101, which should launch later this year at CHLA, takes a cell therapy approach to hemophilia B. We’ll take blood from the patient, isolate the B-cells, and then insert the gene for factor IX into those B-cells. We’ll then infuse them back into the patient as plasma cells, which hopefully will produce factor IX.

One benefit of cell therapy is that you could potentially titrate the dose and re-dose patients later if their factor levels dropped too much. That’s not possible with today’s gene therapies.

What makes CHLA an ideal place for hemophilia gene therapy?

CHLA has a long history as a center of excellence for treating children and young adults with hemophilia, and we’re one of the top centers in the nation for gene therapy for young people. Our first gene therapy trial for hemophilia was nearly 10 years ago.

But our biggest strength is our team. We have a strong multidisciplinary team of physicians, nurses, social workers, physical therapists, and psychologists—including some who have received national awards for hemophilia care. We all work together to share our expertise and help each patient achieve the best possible outcomes.