Innovation in Retina

EDITED BY EMMETT T. CUNNINGHAM, JR, MD, PhD, MPH, AND PRAVIN U. DUGEL, MD

Spark Therapeutics: Gene Therapy for Blinding Diseases

The focus is on a range of inherited retinal dystrophies, beginning with mutations in the RPE65 gene.

JERRY HELZNER, CONTRIBUTING EDITOR

The retinal community came to recognize gene therapy as a promising way to treat serious eye diseases 14 years ago when the blind sheepdog Lancelot showed dramatic improvement in vision following RPE65 gene therapy. Lancelot even appeared before Congress as part of a research funding effort by the scientists at the University of Pennsylvania, the University of Florida, and Cornell — the collaborative teams who cured him of the congenital canine form of Leber’s congenital amaurosis (LCA).

That work, initially conducted at the University of Pennsylvania by the team of Jean Bennett, MD, PhD, and Albert Maguire, MD, has since advanced into a phase 3 clinical program sponsored by Spark Therapeutics (Philadelphia), a late clinical-stage gene therapy company that was spun out of the Children’s Hospital of Philadelphia (CHOP) in 2013.

CHOP MAKES A COMMITMENT

“CHOP made a significant investment in gene therapy based on a belief that this treatment paradigm had great potential to benefit children, who are disproportionately impacted by genetic diseases,” says Jeffrey D. Marrazzo, cofounder and CEO of Spark.

Mr. Marrazzo said that the hospital’s 2004 decision to form the Center for Cellular and Molecular Therapeutics (CCMT) was “visionary,” noting that the field of gene therapy was in a firestorm at that time, following a tragic fatality in one of the first human trials in the late 1990s.

Dr. Bennett concurred with Mr. Marrazzo’s assessment.

Jeffrey Marrazzo, cofounder and CEO, Spark Therapeutics

Jean Bennett, MD, PhD

“It was a very brave move because, at the time, other gene therapy programs were being shut down, and good researchers were being let go and were available for hire,” she recalled.

Dr. Bennett credited Katherine A. High, MD, a world-renowned pioneer in the study of gene therapy for the treatment of hemophilia and the former director of CCMT at CHOP, for bringing her and Dr. Maguire into the new CHOP program.

“Kathy liked our data, and invited us to bring our research program into clinical development as part of the work being undertaken at CCMT,” said Dr. Bennett. “This was a chance to move beyond studying the impact of gene therapy in animal models and demonstrate that our promising results could help people as well.”

CREATING A SPARK

Mr. Marrazzo said that as CHOP’s gene therapy program grew and made significant progress over the years, hospital and program leaders began to see it as “more than a project.”

“Based on greatly promising results from the first phase 1 study — which suggested that one-time treatment with our gene therapy product, SPK-RPE65, could produce meaningful and potentially long-lasting effects in improving patients’ functional vision — we determined that a commercial structure would be needed to deliver this potentially transformative treatment to patients in need,” he said.

In 2013, with a $50 million commitment from CHOP, Spark Therapeutics launched, with Mr. Marrazzo as cofounder and CEO; Dr. High joined shortly after as cofounder, president, and chief scientific officer. While not employed by Spark, Dr. Bennett remained a scientific advisor to the company. (Drs. Bennett and Maguire maintain their primary affiliation with the University of Pennsylvania, Department of Ophthalmology).

Of the three major US-based gene therapy companies working on therapies to treat ophthalmic conditions (Avalanche Biotechnologies [Menlo Park, CA] and Applied Genetic Technologies Corp. [Alachua, FL] are the other two), Spark is the closest to a potential FDA approval. Spark is currently completing a fully enrolled phase 3 clinical trial of its proprietary SPK-RPE65 product in 28 children and adults who have inherited retinal dystrophies caused by mutations in the RPE65 gene, including forms of LCA. Trial data are expected to be reported later this year.

“Inherited retinal dystrophies have traditionally been diagnosed based on clinical distinctions, such as the age of onset of symptoms, but we now understand that these diseases are caused by more than 200 distinct genetic mutations. Gene therapy represents an opportunity to treat, for the first time, the underlying genetic mutation, making it vital for patients to be genotyped, so they can access appropriate treatment through clinical studies or, eventually, approved products,” said Mr. Marrazzo.

MANUFACTURING AND FORMULATION

Spark is leveraging its approach in RPE65 to address a broad spectrum of inherited retinal dystrophies, beginning with an ongoing dose-escalating, phase 1/2 clinical trial of its first follow-on program, SPK-CHM, for the treatment of choroideremia, also stemming from research carried out by Drs. Bennett and Maguire. The company has also been recognized for its innovations in manufacturing and formulation of its gene therapy products. Spark said traditional formulations of gene therapy products result in up to 80% of the gene-delivery vector failing to reach the site of impact. Through intensive device studies, Spark’s team (while at CHOP) developed a final formulation that prevents vector from being lost on the walls of the delivery device and syringe, an important advance given the dose-dependent nature of therapy.

DIFFERENTIATING THE SPARK APPROACH

As a result of these innovations, Spark believes that its approach to AAV delivery cannot be compared directly to other gene therapy platforms, including the first-generation RPE65 AAV vector used by the groups at the University of Pennsylvania and University College London to treat LCA and recently reported in the New England Journal of Medicine to show waning efficacy over time, with a peak benefit occurring at between six and 12 months in one study and at three years in a second.

In contrast, subjects reported to date from Spark’s phase 1 trial have maintained improvements in functional vision and retinal sensitivity through their latest follow-up visit, ranging from two to four years postinjection.

“The clinical profile of each gene therapy product is highly influenced by subtle changes in manufacturing, formulation, vector design, and immune management, so we are not surprised that our clinical results are strikingly different from those reported in NEJM earlier this year. Physicians caring for participants in other trials appear to be recognizing these differences as well, as we have received multiple requests to treat their patients’ other eye,” said Mr. Marrazzo. “I think it is also important to note that unlike our phase 1 and phase 3 programs, the studies published in NEJM did not use endpoints designed to measure patients’ functional vision, making it very difficult to draw conclusions about clinically meaningful results.”

Dr. Bennett added, “Both studies had significant limitations, from lack of proper controls to incomplete data, which make it difficult to draw strong conclusions from their analyses. The good news here is that — despite challenging conditions — both papers support safety of AAV2 gene therapy and, in the case of work conducted at Penn, the data are actually pretty promising with respect to persistence of efficacy, given that patients’ retinal sensitivity six years after one treatment is still much higher than baseline.”

SPARK’S RECENT STOCK OFFERING

That Spark’s program is so advanced helped the company’s stock offering receive a warm reception from Wall Street earlier this year, when the stock almost doubled on the first day of trading. The stock trades under the symbol ONCE, an indication that an ideal outcome should only require a single injection of a corrective gene delivered by a benign adeno-associated virus (AAV).

“Going public enabled us to raise more capital to fund our pipeline,” asserted Mr. Marrazzo. “We are building a global team and developing a fully integrated company capable of delivering our gene therapy product candidates to patients affected by a range of debilitating genetic diseases.”

In addition to its programs in eye diseases, Spark has a partnership with Pfizer (New York, NY) in a gene therapy program for the treatment of hemophilia B, and is advancing other preclinical programs to address other hematologic and neurodegenerative disorders.

LOOKING AHEAD WITH CONFIDENCE

Mr. Marrazzo views the field of gene therapy as “truly transformative, with the potential to deliver one-time, potentially curative therapies for severe genetic diseases.”

Both he and Dr. Bennett are encouraged that other well-funded and highly credible companies are now helping advance the science behind gene therapy for serious retinal disease.

“It’s encouraging to see several companies working in this field,” said Mr. Marrazzo. “There are more than 200 different genes causing inherited retinal dystrophies with the potential to be treated through gene therapy, so there’s a lot of work to be done.”

“I think the competition is fantastic,” added Dr. Bennett. “It’s an affirmation of the exciting results we have achieved. The goals of the various companies are pretty different. There are plenty of targets to go around.” RP