Can Gene Therapy Deliver on its Promise?

Now that the first gene therapies have been approved and have become bona fide commercial products, innovative therapies have reached a crucial threshold and proven what can be achieved. Spark Therapeutics, for example, received “breakthrough therapy” status for its retinal dystrophy treatment, Luxturna, which was approved by FDA in 2017 and has been viewed favorably by the European Medicine Agency’s Committee for Medicinal Products for Human Use (CHMP). The company is also working on treat­ments for hemophilia B, and is currently collaborating with Pfizer on Phase III clinical trials. 

At this point, better manufacturing processes will be crucial. “Sustained, reliable manufacturing will be required to bring gene therapy to patients worldwide,” Mikael Dolsten, president of worldwide R&D at Pfizer, told attendees at a panel discussion of gene therapy at the 2018 Galien Forum on October 25, 2018 in New York City.

As one audience member whose relative suffers from a genetic rare disease put it, “You’d better hurry up.” Currently, FDA has approved one directly-administered and two cell-based gene therapies, but has received over 700 investigational new drug (IND) applications in the gene therapy field, said Peter Marks, director of FDA’s Center for Biologics Evaluation and Research. 

“We will need a one-to-two orders of magnitude improvement in our ability to manufacture quantities of gene therapy vectors and a one-to-two orders of magnitude reduction in costs in order to do this,” said Marks, who cited the development of Apple’s iPhone as an example of why this won’t be impossible. 

Agreed Brian Kaspar, scientific founder and chief scientific officer of AveXis, Inc., which was recently acquired by Novartis, “We need to think about global regulatory strategies and the cost of goods and manufacturing so that batch 1 acts like batch 3 and batch 303,” he said.  

AveXis, which was acquired by Novartis in April 2018, is focusing on the rare pediatric disease spinal muscular atrophy, a condition that affects 500 children born in the United States each year, and normally ends their lives before their second birthday. In Phase I clinical trials of AveXis’ one-time gene therapy treatment, Kaspar said, all participants survived, and many are now over five years old and thriving, enjoying a greatly improved quality of life. The company has grown to more than 500 employees and is now moving into other research areas such as Rett syndrome, a condition on the autistic spectrum, as well as a genetic form of amyotrophic lateral sclerosis (ALS), said Kasper.

Improving vector delivery

Kathy High, president, cofounder, and head of R&D at Spark Therapeutics and Philip Gregory, chief science officer at Bluebird Bio, discussed their companies’ histories, their different approaches to one-time gene therapy treatments, and the work that they are doing to improve vector yield.

Where Spark uses in-vivo adeno-associated viral vectors (AVV) and is focusing on diseases that involve tissues of the retina, the liver, and the central nervous system, Bluebird uses an ex-vivo approach involving Lentivirus vectors, which carry genetic payloads that modify cells that have been removed from a patient, adding them to stem cells and then injecting them back into the patient.  The company is focusing on severe genetic diseases that include sickle cell anemia and thalassemia.  Bluebird’s approach can also be used to treat cancer, with vectors carrying redirection technologies that teach chimeric antigen receptor (CAR) T cells to see specific targets on the surface of tumor cells, said Gregory.

Progress only demonstrates the inextricable link between good clinical work and good process development, said High. “We’re already up by logs from where we were when we started our research,” she said. 

Bluebird, meanwhile, has recently made some major improvements to its manufacturing processes for the vectors, Gregory said. “The latest generation of our thalassemia therapy features a different manufacturing process that massively improves transduction efficiency and the amount of vector we need to use,” he said. 

In addition, on the CAR-T side, Bluebird has developed a new process that greatly improves cell durability, said Gregory, noting “Generation 1.0 processes need to be updated if we are to get these treatments to more patients.” 

Gene therapy: quiet childhood, stormy adolescence

High sketched the history of clinical gene therapy research, which began in the 1990s at the National InstituteS of Health (NIH).  The research that was to drive Spark began during that decade at Children’s Hospital in Philadelphia. The field was considered controversial and some companies that had begun research programs, including a partner that had worked with Spark’s founders at Children’s Hospital, left the field later, noted High. “Gene therapy has had a quiet childhood but a difficult adolescence,” she said.

After its collaborator left the field, the research group had to manufacture its own clinical-grade vector in order to do regulatory work, said High. As more programs succeeded, the company had to determine how to move its retinal dystrophy product, Luxturna, through Phase III and approval. The company decided to spin off the Children’s Hospital research group’s activities as a separate company, founding Spark in 2013. The company currently has 350 employees, and its research is focusing on diseases that affect tissues within the retina, liver, and central nervous system.

As High explained, Spark’s two lead programs represent different challenges with gene therapy. Luxturna treats a condition that has not had any successful cures so far, so it involved developing and validating a novel primary endpoint.  The company worked very closely on this with FDA, she said. The company’s work in hemophilia, meanwhile, has highlighted the difficulties of understanding and managing the human immune system’s response to a recombinant that has been engineered from a virus. 

Collaborating with FDA

FDA has also developed programs designed to help speed the development of gene therapies, said Marks. The agency offers expedited programs such as Breakthrough Therapy, priority review, which can reduce review period by four months, and accelerated approval provisions.

“We have also started to help de-risk development by allowing innovator companies to talk with reviewers in early non-binding regulatory meetings through the Interact program, which provides an informal opportunity to talk about preclinical and clinical issues and plans,” he said.

“From our vantage point, the next step in development of these therapies will require a quantum leap in manufacturing. Gene therapy also has the potential to address issues, not only in high income but in low- and middle-income countries, which don’t currently have the infrastructure required,” he said.

Don’t make the perfect the enemy of the good

Focus has been a crucial enabler of gene therapy innovation so far, and the process of focusing on areas where improvements have been shown and refining them. At some point, for example, High says, Spark researchers found that enough problems had been solved to enable AAV delivery to a few target tissue types that would allow development work to proceed.  “Have we solved everything we need to solve? No, but I do believe that good clinical results drive better process development, which expands manufacturing capability and allows you to approach clinical areas that you could not approach before,” she says.  High predicts that the industry will continue to see an expansion of feasible targets in gene therapies. “Do not make the perfect the enemy of the good,” she advised. 

Marks emphasized the importance of regulatory harmonization in speeding development of gene therapies, noting that dialogue has been ongoing. “High-income countries and the E[uropean] U[nion] understand that it is really challenging for developers to follow different global standards,” he said.  “We are starting to encourage people very early on to come to us, and even to invite E[uropean] M[edicines] A[gency] to listen to their discussions,” he said. This approach will be very important in dealing with surrogate endpoints. 

Marks noted that FDA is currently very comfortable with the use of surrogate endpoints in some areas, and believes that the agency can help drive acceptance throughout the global regulatory community. 

During a question and answer session, an audience member asked about treatments for polygenic diseases. Getting there will take time, panelists noted. “The field has progressed in thinking about very advanced targets, and in how to establish safety and dosing parameters and to design clinical trials,”said Kaspar. Developers will now need to take that knowledge and use those tools to start working on therapies for larger diseases such as Alzheimer’s and congestive heart failure, he said.

There will be challenges in developing treatments for conditions such as cystic fibrosis and Huntingtons. “For in-vivo delivery of AAV, every target tissue is essentially a different problem, and part of this has to do with the immune response, which is also tissue-specific,” said High. With cystic fibrosis, she explained, there is a need to reach the basal respiratory epithelium, but the cells above it continually turn over. “AAV is not an integrating vector, so it would be lost from cells at the top of the respiratory tract that are sloughed off. There are many complexities that have to be dealt with as you branch out to all the different types of target tissues,” she said.

Dolsten suggests that focus continue to guide development work. “Once you branch into polygenic diseases, in which environmental influences are also at work, it will be hard to tease apart technology shortcomings and delivery issues.  It is better to approach the problem stepwise and gain confidence with monogenic diseases first,” he said.