Could a Cure for Hemophilia Be Personalized?

Has your hematologist ever asked that your child have pharmacokinetic (PK) testing? Chances are, the doctor wants to know how factor behaves in your child’s body, so factor dosing can be tailored to get the maximum factor coverage on your child’s most active days. Personalized medicine is the tailoring of medical treatment to your individual biological characteristics, and to your lifestyle, for the best therapeutic results. Personalized medicine in hemophilia often refers not only to when you dose with factor concentrate, but also to PK testing to discover your child’s half-life—how long factor lasts in his body—so you can choose the right dose, dosing schedule, and product.

This article focuses on gene therapy, which may be available commercially in the next few years. Is it possible that gene therapy—or any form of a cure—could be personalized to meet the needs of individual patients? To find out, we asked the experts at three biotech companies involved in gene therapy research: uniQure, Spark Therapeutics, and Sigilon Therapeutics.*

What About Gene Therapy Could Be Personalized?

Personalization for a cure in hemophilia starts with the hemophilia diagnosis. Dr. Rogerio Vivaldi, CEO of Sigilon, says, “Gene therapy is, by its nature, personalized to a patient’s genetic profile. It seeks to deliver healthy copies of the specific gene that is dysfunctional in a given patient. The healthy genes are paired with a promoter that prompts them to express the specific enzyme, protein, or factor that the patient is missing. Restoring the balance in expression of that enzyme, protein, or factor should reduce or even eliminate symptoms and improve the patient’s health.” He adds, “However, it’s important to note that these therapies aren’t customized to individual patients. They are designed to cover all patients with a specific genetic mutation—for example, all patients with low factor VIII levels.”

Clearly, the diagnosis matters, notes Dr. Leonard Valentino, Medical Strategy Lead at Spark Therapeutics. “We don’t have a universal approach to apply to the diagnosis of hemophilia in general. There are differences in trials for hemophilia A and B.” So your diagnosis will determine how your gene therapy might work.

Another influence is factor levels. Danielle Day, Medical Science Liaisons, GlobalMedical Affairs at uniQure, notes, “With gene therapy, we’ve identified the missing or altered gene, and can deliver a functional copy of it…but across all gene therapy studies, there appears to be variability in how much factor is produced.”

Challenges to Personalization

A major challenge to personalizing gene therapy is the “neutralizing antibody profile.” That is, does the patient have an antibody (inhibitor) to the vector (the virus being used to deliver the gene therapy into the liver)? According to Vivaldi, more than 40% of patients who might benefit from gene therapy have preexisting antibodies to the vector. This makes them ineligible for treatment. Also, patients who have liver disease, as well as pediatric patients (who have rapidly growing livers), are ineligible for gene therapy.

“Right now investigational gene therapies are ‘one and done,’” notes Valentino. “Currently you can’t redose gene therapy after the initial dose, due to the neutralizing inhibitor. Maybe down the road, if you used an AAV8 vector and it didn’t work, you could go back and try an AAV5 vector, but this is not really a reality right now in clinical trials. Currently, you can’t personalize based on different vectors. You can only personalize based on your personal antibody profile. So we still need to resolve the redosing issue.”

Another puzzle to solve is why some patients in clinical trials show higher factor level expression than others. Could this become an area of personalization someday? Could patients pick their gene therapy based on how much factor expression they want? “When using wild type factor IX,” Day reports, “levels were increased but not to the near-normal seen with the hyperactive Padua factor IX gene. We were just trying at that time to get levels above 1%. And then some were getting over 10%. That variability is important. In the current factor IX trials, using the hyperactive Padua factor IX gene, you see a range of 14%–80% across trials. Now you wonder, does gene therapy even need to be personalized if patients are no longer bleeding, without having to be infused?”

Is Cell Therapy a Personalized Cure?

Vivaldi points out that Sigilon is developing a different approach to a genetic cure, called cell therapy: “It’s another form of personalized medicine.”

He explains, “First, we’ve engineered human cells to produce the specific enzyme, protein, or factor that the patient is missing, like a living protein factory. Separately, we’ve engineered a biomaterial that is meant to protect these cells. Normally when you implant any foreign tissue into a patient, the patient’s immune system

will identify it as a threat and attack it. Our biomaterial are tiny spheres capable of shielding our therapeutic cells from immune attack. The spheres are also designed to ward off fibrosis, which is a scarring process that normally occurs as part of the body’s reaction to a foreign implant.”

In this therapeutic cure, thousands of the engineered cells are nestled into the special spheres. Nutrients and oxygen flow through the sphere’s matrix-like walls and nourish the cells. The proteins, enzymes, or factors that the engineered cells produce are able to flow out of the spheres and circulate through the patient’s bloodstream. The spheres are implanted into the patient’s abdomen in a simple laparoscopic procedure.

“We believe this will vastly improve [patients’] symptoms, delivering a functional cure for hemophilia,” says Vivaldi.

This functional cure can be personalized. “A key advantage to our approach is that you can redose the patient by adding more cells loaded into spheres, if he or she needs more therapy,” Vivaldi notes. The spheres also have the potential to be removed, if needed. In contrast to gene therapy, there’s no issue with preexisting antibodies. “And because our cells don’t integrate into the patient’s DNA,” he adds, “there’s no concern about off-target integration causing side effects.”

Future of a Personalized Cure

“We don’t know what we want from gene therapy yet,” says Valentino. “Do we want a cure? Freedom from spontaneous bleeding? Freedom from infusions, or maybe normal factor levels? The community needs to put a stake in the ground for what they are looking for in potential gene therapies. We’ve heard that it will correct genetic defects, but what will that mean practically?”

Whether gene or cell therapy, Vivaldi notes, “Both should be far more durable than today’s standard of care [infusions of factor concentrate]. A single treatment should last years. Another important advantage is that both therapies should result in a steady production of the protein, enzyme, or factor the patient is missing. There should not be spikes or plateaus, unless they are deliberately designed to be part of the therapy.”

Day adds, “Some patients want a guarantee; they never want to infuse again. Everyone has different expectations. What do parents, spouses, and partners think about gene therapy? It’s a big decision to make, a family decision—and that’s a big part of personalization, choosing what’s right for the patient and their family.”

Vivaldi sums it up: “This is a very exciting time where we’re seeing the future of medicine unfold before us. There’s still a lot of work to be done, but there are a lot of terrific ideas and promising technologies.”

November 2019

Source: LA Kelley Communications, Inc. Reprinted with permission.

*Biomarin could not be reached for comment.

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