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 4 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.
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 in the RPE65 gene.
[Simonelli F et al. Moleculary 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 treatment, 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 photoreceptor are already gone before
starting treatment, then the current gene replacement therapy cannot restore
vision, said Pang, noting 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 if 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 area 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
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, noting 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.
There are also major risks with gene therapy,
agreed investigator Dr. Stephen 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 that
deliver gene therapy products are 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
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 not 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 occurring 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.