Meet The Company: Spark Therapeutics

Posted on at October 6, 2017
911 71

NAME: Spark Therapeutics

STOCK SYMBOL: ONCE   

SHARE PRICE AS OF 8/22/17: $74.59

52-WEEEK RANGE AS OF 2/17/17: $35.07-$80.89

MARKET CAPITALIZATION: $2.36 billion

U.S. HEADQUARTERS: Philadelphia, PA

Dr. Katherine High, president and chief scientific officer at Spark Therapeutics, and Emeritus Professor of Pediatrics at the University of Pennsylvania’s Perelman School of Medicine, spoke with HD Insights about the company’s program to develop and acquire FDA BLA approval for a gene therapy to treat a rare form of congenital blindness. The therapy has implications for HD.

HD INSIGHTS: Dr. High, congratulations on your biologics license application (BLA) to the FDA. [A BLA is a request for permission to introduce, or deliver for introduction, a biologic product into interstate commerce.] 

HIGH: Thank you very much. This is a milestone for Spark, but as a former president of the American Society of Gene and Cell Therapy, I can tell you it is also a milestone for American gene therapy because it is the first application filed for an adeno-associated virus (AAV) vector for a genetic disease, in this case a rare form of congenital blindness.

For those of us who work in gene therapy for genetic disease, creating therapeutic options for people who are born with inherited diseases, many of whom have had very restricted therapeutic options, has been a long-standing goal. To file an application for an AAV product for a rare form of congenital blindness is very exciting for us.

HD INSIGHTS: This is the first FDA BLA application for a gene therapy to be eventually approved for use for a genetic condition?

HIGH: Yes, in the USA. The European Medicines Agency has approved two applications for gene therapy for genetic disease. One was an AAV vector approved in 2012 for lipoprotein lipase deficiency, a very rare lipid disorder, and the other was a retroviral vector for ADA SCID, a rare form of immunodeficiency.

But neither of those therapies are FDA-approved in the USA, therefore, this BLA for the rare form of congenital blindness, if granted, will be the first FDA-licensed product for gene therapy for a genetic disease. For me, that would be the fulfillment of a career spent trying to establish a basis for gene therapy for genetic diseases.

HD INSIGHTS: Can you tell us about this genetic therapy, and then how it might be applicable to HD?

HIGH: This genetic therapy is developed for a rare form of inherited blindness. There are over 220 genes involved in vision, and mutations in any one of those genes might interfere with vision. This particular gene encodes an enzyme that is needed to regenerate 11-cis retinol, a critical component of a light-sensing molecule required in the photoreceptors to convert light energy to an electrical signal.

When light strikes the retina, a reaction occurs that changes cis-retinal to trans-retinal. But that trans-retinal must then be regenerated to the cis form, and that occurs under the activity of the regenerative enzyme, RPE65, (which stands for retinal pigment epithelial 65 kilodalton protein), an isomerohydrolase. A mutation in this enzyme leads to loss of activity of the enzyme, and a break in the visual cycle.

An attractive feature of this disease for gene therapy is that normal retinal anatomy is preserved for a long period of time, so that if the normal gene can be introduced, and the visual cycle restored before there has been extensive degeneration of the retina, vision can be restored.

The work that underlies all this was first conducted in a naturally occurring dog model of the disease. Dr. Jean Bennett in the Department of Ophthalmology at the Perelman School of Medicine of the University of Pennsylvania had shown that subretinal injection of an AAV vector expressing the isomerohydrolase would restore vision in the dogs. That was the basis of the clinical studies in 12 subjects, which began in 2007 at the Children’s Hospital of Philadelphia. Child and adult patients who met all the entrance criteria for the study would have the worse of their two eyes injected. Using several different visual endpoints, we were able to show that their vision improved.

The next study we did was to inject the contralateral eye. At the beginning, we were concerned this might generate an immune response, like a prime and boost of a vaccine, because the patients’ immune system had now been exposed to the vector—but that did not occur. Based on the safety data from injecting the first eye, and then the second eye a couple of years later, we were able to move forward to a Phase Three study, which began in 2012 and read out toward the end of 2015. We spent 2016 and the first part of 2017 preparing the BLA, which we filed in May 2017.

Additionally, we have preclinical programs going on in diseases that target the CNS—one is Batten’s disease, a pediatric neurodegenerative condition, and the other is HD.

These programs are still at preclinical stages, and there is relatively less clinical experience with introducing AAV vectors into the CNS, although the PD trials have been going on for some time, and there is experience in a couple of other indications as well. There has been an early trial for Batten’s disease that involved focal intraparenchymal injections of AAV. We are looking at a different approach where we are hoping to get more extensive global distribution of the gene product.

HD INSIGHTS: The idea that you could have a one-time injection and cure a retinal disease, and that you could have a one-time injection and maybe not cure, but at least have substantial benefit for HD patients, is very appealing. Can you tell us about the status of your work in HD?

HIGH: We have been collaborating for some time now with Dr. Beverley Davidson from the Children’s Hospital of Philadelphia, and we have worked to develop a convincing package of safety data in dogs as well as preclinical efficacy data in mouse models.

Much of the work in the mouse models is already published. Some of the safety data in non-human primates has been presented in various forums. Dr. Jodi McBride at Oregon Health and Science University has done a lot of that work. Dr. Davidson’s group and ours have worked together to generate additional data in non-human primates.

HD INSIGHTS: Can you estimate when you expect Sparks’ therapeutic compounds to go to clinical trials for HD?

HIGH: I cannot give you a date for that. As you know, once we believe that we have a convincing package of safety and efficacy data, we would need to submit that to both FDA (an IND application) and local regulatory groups (the clinical protocol and supporting documents to the local IRB, details of the vector to the local Institutional Biosafety Committee), and get their agreement. We have not yet completed all the studies required to be ready to submit to the FDA.

HD INSIGHTS: As you look at HD from an outside perspective, what is missing? What would make it easier to develop a new drug for HD?

HIGH: I will tell you what I think are the good things about HD as an indication for gene therapy. While working with neurologists, I have been very impressed that the clinical rating scales, and the natural history data in HD seem very robust. And you guys have impressive genotype-phenotype correlation data. I think that the endpoints for such a study have been well studied. All those things are important.

When I contrast that with these rare blindness conditions, a situation where when we started our work, there were no FDA-approved pharmacologic products for the treatment of any of those conditions. That means that you have to really think about what you would use for endpoints. In the case of RPE65 deficiency, we had to develop a new endpoint, in the form of a mobility test that assesses functional vision, and then validate it.

One of the advantages of HD is that you have good natural history data, and in the UHDRS, an outstanding clinical rating scale that can be used across multi-site studies. This gives confidence that the UHDRS can be used to follow the effect of any kind of therapeutic intervention.

In terms of gene therapy, I think another good thing about HD is that we are contemplating focal delivery to the CNS, at least in the initial studies. I think there are very good safety data from the PD trials about focal delivery of AAV to the CNS.

A bigger challenge for situations where you want to have global delivery to the CNS is that there is less experience with that. I think that initial studies in HD will probably involve focal delivery to the CNS, and then you have some reasonable expectation that if you can knock down the mHTT without having any off-target effects, you can see clinical benefit from that.

HD INSIGHTS: Dr. High, thank you very much for your time, and congratulations again on your application to the FDA. I know this is a great moment for you, and it reflects not only your leadership at Spark, but also a long career as a successful academic and researcher pursuing gene therapies. We look forward to the day of celebrating the success of the first application to the FDA for a genetic therapy for HD.

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