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Spark's LCA2 gene therapy is likely to have greater benefit for younger patients

Biopharmaceutical Report I

Issue6_April 2015

Spark Therapeutics' (NASDAQ:ONCE) subretinal gene therapy injection of SPK-RPE65, is likely to restore vision most effectively in younger Leber's Congenital Amaurosis (LCA2) patients, experts agreed.

Younger patients are likely to experience better treatment results because they tend to have more viable retinal area to salvage, some experts said.

However, the greater the salvageable retinal region and the younger the patient, the higher the risk of performing surgery, two experts noted. Experts are nonetheless cautiously optimistic about a potential treatment for a disease that eventually results in certain blindness. The treatment is worth the risk despite uncertain durability, most experts agreed.

The 28-patient Phase III randomized, open-label, safety and efficacy study, with a subretinal injection of 1.5E11 vector genomes of human RPE65 to each eye, includes patients aged four to 44, all of whom have now received the treatment, according to a company spokesperson. He declined to discuss the distribution of ages in the Phase III trial, but noted that it was "balanced among treatment arms." Nine patients were in the control group for one year prior to having the option to receive the treatment; all nine opted to receive treatment, he said.

Pediatric patients have more restorable cells

The nine control patients received no sham injection, but received the same monitoring as the active arms for one year, according to the spokesperson.

The Phase III, which initiated in November 2012, is expected to complete in 2H15, according to company information.

LCA is a group of hereditary retinal dystrophies characterized by the loss of retinal and visual functions early in life with progressive cellular degeneration. These functions include papillary light reflexes (PLRs), involuntary eye fixation instability and fundus abnormalities. LCA is usually inherited, and LCA2 accounts for 10% of all LCA. LCA2 is caused by mutations in the RPE65 gene. [Simonelli F et al. Molecular Therapy (March 2010) 18(3): 643-650].

Spark's therapy received breakthrough designation by the FDA, according to a November 2014 company press release. SPK-RPE65 comprises the AAV2 vector which carries the human RPE65 gene.

Viable photoreceptors

For gene therapy, one of the necessary conditions is that photoreceptors be there before threatment, explained Dr. Jijing Pang, research professor, Department of Ophthalmology, University of Florida College of Medicine.

In most cases, the younger the patient, the more photoreceptors there are, he added.

If all photoreceptors are already gone before starting treatment, then the current gene replacement therapy cannot restore vision, said Pang, nothing that in clinical trials for LCA2, most patients are typically younger than 18 years old.

"We cannot cure or restore vision from late-stage patients," said Pang.

The process is not regenerative; you want to save what is already present, explained Dr. Demetrios Vavvas, co-director, Ocular Regenerative MEdical Institute, Boston, Massachusetts. That doesn't mean it will have no restorative capacity, he added. The cell will still receive the gene and work better than it was working before, he explained. The treatment will still slow down the degenerative process, Vavvas said, adding that later stage patients still receive some benefit.

The inclusion criteria for Spark's Phase III lists "sufficient viable retinal cells as determined by non-invasive means," and the location of the subretinal injection of product is determined based on the location of viable cells, however, it can be difficult to establish when photoreceptor cells are too far gone, noted Dr. Wadih Zein, staff clinician, Ophthalmic Genetics and Visual Function Branch, National Eye Institute. Researchers are still trying to come up with the best methods to identify areas of the retina with viable photoreceptors, that would allow for the best outcome following a subretinal injection, he added.

Age is a factor and benefit is expected to be more prominent for the younger patients who would have a larger aread of viable retina, agreed Zein.

The optimal retinal sites for subretinal gene delivery to achieve efficacy are also likely to change with disease progression. [Jacbson S et al. Investigative Ophthalmology & Visual Science (May 2009) 50(5): 2368-2375].

Age may influence efficacy in other ways, remarked Vavvas, citing a depressed immune system, environmental factors, less resilience and other factors associated with aging as possible reasons pediatric patients may fare better in Spark's trial. The photoreceptor cells may also degenerate at a faster rate in older people, he noted.

In Spark's Phase I trial, improvements in at least one measurement - pupillary light response (PLR) sensitivity - in the treated eye, was more notable among the youngest patients. [Maguire A et al. The Lancet (November 2009) 374(9701): 1597-1605].

Safety risk highest in most salvageable cases


Subretinal surgery remains a major concern, and safety presents a contradiction in this trial, noted Pang. The injection involves detaching the retina, he added. If you don't transfect a large area, you don't see a dramatic improvement, but detaching too much retina can be harmful to the macula and foveal area, he explained. Giving the patient too much solution can also cause damage, Pang added.

Sometimes subretinal injections are too close to the fovea and can cause central vision loss, or the area doesn't respond as well as other areas, explained Pang.

Pediatric patients may have the most to gain, but they also have the most to lose, explained Vavvas, nothing that the trial is definitely high risk. There is a risk of infection and detachment, which is especially high in pediatric patients who are at greater risk for proliferative vitreoretinopathy (PVR), a blinding condition, he said. A patient who is 44 and already nearly blind has much less to lose than a four-year-old, he added.

Acceptable high risk despite uncertain durability

There are also major risks with gene therapy, agreed investigator Dr. Stepehn Russell, professor, Department of Ophthalmology and Visual Sciences, University of Iowa Hospital.

The biggest concern is that by inserting the therapy into a gene, it may become integrated into the DNA and into a tumor suppressor gene, resulting in the development of tumors, explained Russell. The AAV2 vector is non-integrating, so it's less likely to result in tumor production, but it's still a worry, he said.

It's a non-integrating virus, but you never know whether there will be an alteration in other genes, and you might induce tumors or you might induce another type of malfunction in a different gene, explained Vavvas.

There was one significant adverse event in the Phase I trial, which was determined to be non-drug related, and was connected to the surgery itself, said the company spokesperson.

It's naive to think we can treat patients with gene therapy and not also protective therapies, noted Vavvas. If you think there is a gene mutation disease and you can supply the gene back, then that's the end of the disease, that's wrong, he said.

We have to use neuroprotective therapy at the same time as gene therapies, he said. Even after therapy for gene degradation, there is continued degeneration happening in patients. We need protective therapies in addition to the gene therapy, he said, adding that this is an area that is still being researched and not largely understood.

According to research, a second approach to coping with photoreceptor cell death, in addition to gene therapy, involves the use of neurotrophic growth factors to limit further damage. The aim is to provide a protective environment to prolong the viability of the photoreceptors by their effect on the secondary biochemical pathways. This can be achieved either by delivering neurotrophic growth factors, or inhibiting pro-apoptotic pathways, or implementing viability factors such as the rod-derived cone viability factor (RdCVF). [Sahni J et al. Current Genomics (June 2011) 12(4): 276-284].

Doctors are a ways off from having the perfect treatment, according to Pang. Researchers are working on developing novel generations of AAVs that can eventually penetrate the whole retina to reach RPE or photoreceptor cells, he explained. Research to find the best vectors to deliver gene therapy products is ongoing, and a major consideration in any study, agreed Zein. The ideal would be to have an IVT injection, which is safer and easier, said Pang.

There have been no adverse events reported in Phase III, according to the company spokesperson.


Durability is difficult to estimate at this stage, said Zein. There is some evidence in the literature that the functional benefit in the treated area regresses after a number of years, he added.

It's possible that in 10 to 15 years, patients will lose what visual acuity gain they had with this therapy, said Vavvas. The benefits still outweigh the risks despite safety concerns and uncertainty about durability, said Vavvas. The alternative is blindness, he remarked.

The risk to benefit ratio of performing this treatment will have to be determined per individual patient, depending on age, viable retina and retinal thickness at the area of projected delivery, just to consider a few factors, noted Zein.

It would be great if it were "one and done," said Russell, but the data right now on AAV2 is that the longest human treatment we know of is seven years, at which point it's still effective. Dogs, which have the same naturally occuring genetic mutation as humans, were treated in preclinical studies and the therapy's effectiveness has been maintained for 15 years, he said.

Additional research also needs to be conducted on determining the best vector in each case, experts agreed.

Spark's market cap is USD 1.50bn.

Alissa Fleck

Reporter, New York

Alissa is a former freelance editor and journalist who has been a regular contributor for Bankrate, the Huffington Post, Truthout, Global Post and three Straus News publications in Manhattan. She has written medical and health copy for websites including SF Gate (the San Francisco Chronicle online) and Livestrong as well as for private clients.

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