Thursday, October 24, 2013

Gene Therapy in Ophthalmology Update 21: New Gene Therapy Company, Spark Therapeutics, Launches

Children’s Hospital of Philadelphia (CHOP) announced that it had spun off its work in gene therapy to a new, fully integrated company, Spark Therapeutics, that will assume control over two current gene therapy clinical trials: a Phase III study for Leber’s Congenital Amaurosis, an inherited disease that results in blindness caused by mutations of the RPE65 gene, and a Phase I/II study for hemophilia B. The new company is also advancing toward the clinic with gene therapy programs to address neurodegenerative diseases and additional hematologic disorders and other forms of inherited blindness. One such program, in the latter category, already in pre-clinical development at CHOP, could be its study for the treatment of Choroideremia, a rare inherited disorder that causes progressive loss of vision due to degeneration of the choroid and retina.

Editors Note: It should be noted that one clinical trial using gene therapy to treat Choroideremia is already underway at Imperial College London and Oxford University, in conjunction with Moorfields Hospital in London.

The new company has been launched with a $50 million capital commitment from Children’s Hospital to advance and commercialize multiple ongoing programs with clinical proof of concept.

As noted by Susan Young, writing about the launch in Technology Review, “Spark has a chance to be the first gene-therapy company to obtain FDA approval. Results for a late-stage trial of a gene therapy for Leber's Congenital Amaurosis ... are expected by mid-2015. That treatment is one of several gene therapies in or nearing late-stage testing contending to be the first gene therapy approved by the FDA for sale in the U.S.”

The Phase III trial was initiated late last year, and CHOP has made significant progress in enrolling patients. Spark will be sharing additional details on its progress and encouraging results in the very near future.

And, as shown in my table of Ongoing Clinical Trials in Ophthalmology, it is the only gene therapy trial (in ophthalmology) that has advanced to Phase III.

Editors Note: For clarity, is should be noted that there are five other clinical trials underway to treat Leber’s, as shown in my table, but all are currently Phase I or Phase I/II studies. The Spark Therapeutics trial is the farthest advanced.

“The creation of Spark is the culmination of a decade-long commitment by CHOP and our founding team to drive the field of gene therapy forward during a time when many in the industry had moved away,” said Jeffrey D. Marrazzo, co-founder, president and chief executive officer of Spark Therapeutics. “Their vision and long-term dedication have enabled us to effectively address many of the key challenges facing the field and to emerge with one of the industry’s most robust clinical-stage gene therapy pipelines; as well as exclusive rights to commercialize a proprietary manufacturing platform, supply from a world-class manufacturing facility and a founding team with a proven track record of executing safe and effective gene therapy trials for nearly two decades. We are working with great urgency and care to deliver gene therapy products with the potential to transform the lives of those affected by severe genetic diseases.”

Spark builds on the work of CHOP’s Center for Cellular and Molecular Therapeutics (CCMT), established in 2004 as a world-class center for gene therapy translational research and manufacturing. Many of the CCMT’s leaders will assume management roles within Spark or engage with the company as scientific advisors, including Katherine A. High, M.D, a gene therapy pioneer who has served as the director of the CCMT since its inception.

“Gene-based medicines are among the most complex therapeutics ever developed,” said Dr. High. “We at CCMT have persevered through more than a decade of scientific and clinical development and are now closer than ever to realizing the ambitious vision of one-time, potentially curative therapies to address serious genetic conditions. The team at Spark has incredible goals for the treatment of diseases including hemophilia B and inherited blindness, and we look forward to working with them to deliver groundbreaking new treatments to patients in need.”

Spark has entered into agreements with multiple academic institutions to assemble the technology, programs and capabilities needed to deliver its pioneering gene therapy products. Notably, Spark has exclusive rights to commercialize CHOP’s proprietary manufacturing technology and will use clinical-grade gene therapy vectors produced by the CCMT’s state of the art good manufacturing practices (cGMP) clinical facility.

Pioneers in AAV delivery

Over the past two decades, the Spark leadership team has developed unrivaled expertise in the design, manufacturing and delivery of gene therapies using adeno-associated virus (AAV) vectors. AAV has been demonstrated in clinical studies to be a safe and effective vehicle for the delivery of genetic material into targeted cells and provides unique advantages over alternative delivery approaches. The Spark team was among the first to demonstrate human clinical proof of concept in two distinct organ systems — the eye and the liver — establishing a strong foundation for the company’s current programs, and has clinical experience in 15 studies across diverse genetic and non-genetic diseases and five distinct routes of administration.

Spark’s most advanced clinical program is a Phase III study to address blindness caused by mutations in the RPE65 gene. There is currently no pharmacologic treatment for this form of inherited retinal degeneration, which ultimately causes irreversible blindness.

The open-label, randomized, controlled study builds on an earlier clinical study in which 12 patients with RPE65-related blindness demonstrated notable improvement in visual function, moving in some cases from being profoundly blind to being able to recognize faces and ambulate independently. All school-age patients enrolled in the trial were able to transfer from Braille classrooms to sighted classrooms.

One such patient was Corey Haas, whose story is related in the book “The Forever Fix: Gene Therapy and the Boy Who Saved It”.
Corey Haas, his parents, and the CHOP team that treated his Leber’s and gave him back his vision. 
Read Corey’s story in Ricki Lewis’ book, The Forever Fix: Gene Therapy and the Boy Who Saved It.

The team's experience in the clinical study of gene therapy – from designing and manufacturing vectors to conducting studies that have shown strong potential for safety and efficacy – is unparalleled in the field. Clinical-grade vectors prepared by the team have been used to safely treat more than 100 human subjects in 12 clinical trials in the U.S. and EU, across five parenteral routes of administration in genetic and non-genetic diseases. No other group can claim this breadth of expertise and experience in human gene therapy.

The adeno-associated virus (AAV) vectors used in the clinical programs have been demonstrated to be safe and effective vehicles for delivering genetic material into targeted cells, providing unique advantages over alternative therapeutic approaches. The team has established human proof of concept in two organ systems – the eye and the liver – and are advancing a Phase III program in blindness caused by mutations of the RPE65 gene; a Phase I/II program in hemophilia B; and preclinical programs in neurodegenerative diseases and other hematologic disorders and forms of inherited blindness.

Thursday, October 17, 2013

Gene Therapy in Ophthalmology Update 20: Oxford BioMedica Clinical Trials Resume

Back in June, Oxford BioMedica announced that it had voluntarily paused recruitment for its clinical trials for wet AMD  (RetinoStat Phase I), Stargardt’s Disease (StarGen Phase I/IIa) and Usher’s Syndrome (UshStat Phase I/IIa). The company had halted recruitment of the aforementioned studies, as a precautionary measure, while it investigated the detection of very low concentrations of a potential impurity in its clinical trial material derived from a third party raw material.

Oxford has since performed extensive characterization studies using its newly developed, state-of-the-art analytical methods to identify the impurity as highly fragmented DNA derived from fetal bovine serum (FBS), the most widely-used growth supplement for cell culture media.  In light of these findings, Oxford remains convinced of the safety, integrity and quality of its LentiVector platform products and no safety concerns relating to any of the ocular products have been identified in any pre-clinical and clinical data generated to date.

Today, the company announced that following the submission of a comprehensive data package to the FDA and the French regulatory agency, ANSM, it has received agreement from both agencies to resume recruitment into its ocular clinical trials using the existing clinical trial material. The company will continue to use highly sensitive, state-of-the-art analytical methods to ensure the quality and integrity of its lentiviral vector products and will work with FDA and ANSM to define the necessary specifications for future batches of clinical trial material.

Oxford is now working closely with the clinical trial centers to obtain the necessary ethics committee approvals in order to resume recruitment into the clinical studies.

(For a list of the clinical site centers in the U.S. and France involved in the three studies, please take a look at my Gene Therapy Ongoing Clinical Trial Table at

John Dawson, Chief Executive Officer of Oxford BioMedica, said: "We value our relationships with the regulatory authorities and are pleased that, on the basis of our extensive technical investigations to demonstrate the integrity of our products, FDA and ANSM agree with our proposal to resume treating patients in our ocular trials as soon as possible.

"We place the highest importance on safety, and our analytical methods and quality assurance processes are continuously evolving to ensure that we remain at the forefront of gene therapy development and manufacture. I am confident that, with significant opportunities ahead such as the recently-announced AMSCI project win, Oxford BioMedica will continue to lead the way in delivering novel gene therapies to patients."

For your information, Oxford BioMedica has reported that 9 of the 18 patients to be treated in the wet AMD clinical trial had been treated; 12 of the 28 patients in the Stargardt’s trial; and 3 of 18 patients in the Usher Syndrome trial had been treated prior to the halt in recruitment in June.

Coincidently, Genzyme, who is also running a gene therapy clinical trial to treat the wet form of AMD, also announced a halt in recruitment for its trial in July. No reason for the stoppage has been given and all attempts to determine why the halt in recruitment occurred have been rebuffed. As of the last time I had obtained reliable information about the Genzyme trial, 6 of 34 patients to be treated had been treated.

Genzyme Update – October 25, 2013

After many attempts to determine why Genzyme halted its clinical trial recruitment, I have finally received the answer. Here is the statement received from a spokesperson from Genzyme:

“We enrolled 19 patients in this clinical trial, all of whom have been treated. The protocol stated that we would enroll "up to 34" patients, but that number accounted for the possibility of replacing patients who withdrew early from the trial. Since no patients withdrew from the trial, we did not need to recruit 34 patients in order to meet the target enrollment numbers. The protocol specified that we planned to enroll 12 patients in the dose escalation part of the trial, and 10 patients in the second part of the trial, for a total of 22 patients. We stopped enrollment at 19 (three short of this target) purely because our clinical material was coming to the end of its stability protocol. There were no safety or product quality issues. We continue to monitor the 19 patients who were treated in our trial.”

Thank you Genzyme for providing this update.