Dr. Katherine High, M.D. is the President and Head of Research and & Development at Spark Therapeutics, maker of LUXTURNA® (voretigene neparvovec-rzyl), a gene therapy to treat a rare an inherited form of vision loss and the first directly administered gene therapy approved in the U.S. that targets a disease caused by mutations in a specific gene. We’re very excited to welcome her as a speaker on the Gene Therapy panel at the 2020 Wharton Health Care Business Conference.

The Pulse: Can you give an overview of how gene therapy works?

Dr. High: Gene therapy involves using a modified virus to deliver a healthy copy of a gene to make up for a gene that’s deficient in a way that causes disease.

Your body’s cells copy portions of DNA to make messenger RNA, which is transcribed into proteins. Many diseases are caused by missing or defective proteins. Proteins are short-lived and many biologic therapies are manufactured proteins that have to be administered repeatedly.

Because DNA is long-lived, gene therapy aims to be a more long-term solution. The therapy transfers therapeutic DNA to the relevant cell in your body, where it provides instructions to make a missing or defective protein over a long period of time.

The Pulse: Gene therapy has held promise for many decades but has only recently begun coming to market. What obstacles did Spark Therapeutics overcome to bring LUXTURNA® to patients?

Dr. High: It may seem to have taken a long time, but ten to twenty years in clinical development is typical for new classes of therapies.

New classes of therapeutics always have a number of hurdles to overcome. First, we had to master the process of manufacturing the gene therapy material, which is a viral vector patterned off a normal virus, but with all the viral DNA removed and replaced with therapeutic DNA.

Another very important hurdle when making a new type of therapeutic is to develop the regulatory science infrastructure to evaluate molecules for safety, purity, and potency.

An issue specific to gene therapy is the interference from human immune responses to the viral vectors. It took a while to understand how to manage the immune responses and preserve the activity of the donated gene, especially since animal studies had not predicted those immune responses.

The Pulse: What regulatory challenges are unique to gene therapy and how did you navigate them?

Dr. High: In 2018 the FDA released draft guidance for six areas of gene therapy and in January 2020 they released the final guidance draft plus an additional draft guidance. But when we were doing our initial work, we had no guidance at that level of detail.

We engaged in many discussions with the FDA, which they used to help develop their guidelines. We developed a novel clinical endpoint to measure in clinical trials because there had never been treatment for inherited retinal dystrophy, and there was no consensus on what to measure to prove that our drug worked. We were in constant dialogue with the FDA as we developed that novel endpoint and did clinical studies to validate it.

Some of the FDA’s guidance documents now refer specifically to the work that we did, and we’re proud to have helped them codify their thinking and make drug development easier for future innovators.

The Pulse: Spark Therapeutics is pioneering several innovative models in pricing and access – can you talk about your experience with outcomes-based pricing?

Dr. High: Spark is a trailblazer in championing innovative reimbursement models for one-time gene therapies. Sarah Pitluck, who manages pricing and reimbursement at Spark is really a trailblazer. She has deep experience in pricing and reimbursement for rare diseases. and she really helmed these efforts.

We use outcomes-based pricing because we are confident in the efficacy of our treatment. In this model, we share some risk with the insurance companies. For payers who have agreed to outcomes, They bring patients in for ophthalmologist testing to measure their vision 30-90 days after treatment, and if the patient has not gotten a beneficial effect, then the insurance company is eligible for a rebate.

We also stand behind the durability of the product in long-term. Patients can get re-tested 30-33 months after their treatment and if no durable effect can be is observed, then the insurance company is eligible for a rebate.

The Pulse: You also have a partnership with Express Scripts that offers insurers a way to purchase LUXTURNA® directly from you. What are the benefits of this model?

Dr. High: A number of existing medications use the “buy and bill” purchasing model, where hospitals buy medication and then bill insurers for it at what usually is a substantial markup. As an alternative, we allow insurers to buy our therapy directly from us.

This has major benefits for both hospitals and insurers: it saves hospitals the need to make substantial outlays of money and eliminates the risk of having a surgery be cancelled and being left with rare disease medicines they can’t use. Insurers also benefit by not having to pay markups.

In exchange, they agree to only treat patients based on the FDA-approved labeling, to not exclude any eligible patients, and to cap patients’ out of pocket expenses at in-network levels. This is especially important since LUXTURNA® is only administered at 10 a limited number of treatment centers in the U.S. , so most people would be considered out of network.

The Pulse: Is your vision to continue having these 10 academic centers of excellence administer the therapy?

Dr. High: We offer’ve ensured financial and logistical support for patient travel to these sites where possible, and we’re willing to remain flexible on whether LUXTURNA® is only administered at these hospitals. When we started, we wanted to make sure the patient experience with this first licensed gene therapy in the U.S. was consistent with the experiences in clinical trials. Because we had to educate surgeons and pharmacies, the best way to ensure consistency was to start with a limited number of treatment centers and expand from there. We have since added some treatment centers, and that may evolve over time.

The Pulse: What do you think the future of gene therapy holds?

Dr. High: It’s a very exciting time for the field. At Spark, we’re developing a gene therapy treatment for hemophilia, which has the potential to be a “one-and-done” treatment. This would be a dramatic improvement over the existing standard of care treatment, which is a substantial burden for patients because they have to get recurring intravenous infusions.

We’re also developing a treatment for Huntington’s Disease, which currently only has a treatment to address symptoms, not to actually modify the disease.

There are also exciting developments across the industry. For example, Duchenne Muscular Dystrophy has historically been fatal for patients at a fairly young age, but there are exciting new findings coming out in gene therapy trials.

While this discussion has focused on single-gene disorders, eventually gene therapy may be able to address more complex disorders like age-related macular degeneration, congestive heart failure, or even Alzheimer’s. Other classes of therapeutics haven’t been able to address all the patients in those populations, but eventually we may be able to devise genetic strategies for those diseases.

It’s early days for gene therapy and we have to see how things evolve, but the potential to treat diseases that have never before had good treatments is really exciting.

Interviewed by Michele Dragoescu, January 2020