Experts came together to speak at a WCG Rare Disease Day webinar on the main scientific and ethical considerations of research in rare and ultra-rare diseases, the majority of which are driven by hereditary genetic mutations.

Institutional review boards continue to face the same challenges in clinical research as the industry begins to explore novel gene therapies, said Lindsay McNair, WCG’s chief medical officer. The theoretical risks of cutting-edge technologies, and the challenges of conducting trials in smaller patient populations, are much more concentrated in a gene therapy setting, she added.

“It’s always a consideration if the risks of a therapy are reasonable, in relation to potential benefits,” McNair said. “But this can be really difficult to assess with new mechanisms and new therapeutic approaches that we just don’t know much about.”

Citing previous cases of secondary cancers that developed in patients as the result of errant placement of introduced genetic material, McNair described the task of weighing a treatment’s short- and long-term risks against the unknown.

“If you’re treating a cancer, the risk of secondary cancer may be a risk that you’re very much willing to take. But if you’re treating a rare disease that causes progressive deafness over several decades, and one of the potential theoretical risks is a secondary cancer, where do you find the balance?”

“We think with the newer vectors that risk is reduced, but we don’t have a lot of long-term data to be able to really understand that,” she said.

In addition, protocol designers need to work to avoid misconceptions about their products, and balance optimism and realism when dealing with patients or families seeking effective treatments, to avoid IRB issues and streamline ethics reviews.

Sponsors should adhere to the descriptions “study drug,” “study regimen” and “participant or volunteer” in their protocols and informed consent documents, to avoid confusion over what is experimental and what is medical care, McNair said.

New is not always better, she added, warning that the majority of products in development don’t make it to approval. It’s important that patients have a realistic understanding of potential risks, and not just hope for the benefits.

For sponsors looking for a place to start in developing gene therapies, experts said retinal diseases provide an attractive early target for testing in vivo technology.

Treatments for the retina, including indications that cause progressive blindness, present good test cases for a variety of convergent reasons, said Daniel Kavanagh, WCG’s senior director of biosafety and gene therapy.

Primarily, risk to the patient is mitigated because the therapies do not target a vital organ, and treatment can be administered one eye at a time, Kavanagh said. In addition, sponsors are not required to produce a large amount of vector to deliver the therapeutic genetic material.

The eyes are also immune-privileged — they are isolated from the body’s immune system as a whole, so any injections are less likely to cause an inflammatory response in the patient, he said. Meanwhile, the retina itself is a highly specialized tissue; the targeted genes and proteins may not be expressed elsewhere in the body and have no function, which can help contain the effects of the treatment.

Clinical trials in these indications can be very attractive to researchers worried about their statistical power, Kavanagh said.

“It turns out it’s much more powerful to test one person in one eye, and have a comparator eye untreated, than it is to have a control in the form of a placebo-treated person,” he said. “These clinical trials tend to use both kinds of controls built-in — but it’s a significant, practical advantage to be able to treat one eye first and the other eye later, and to do your statistical comparison that way.”

The risk-benefit ratio also can be more favorable because study participants are already at a high risk for blindness or advanced disease.

“If you can fix the retina, and if the target protein is uniquely expressed in the retina, then you’ve cured the patient,” Kavanagh said. “So it’s an attractive prospect for your first indications for novel gene therapies.”

While the precise definition of what makes a gene therapy a gene therapy can vary depending on who you talk to in the industry, the FDA describes Spark Therapeutics’ retina-targeting Luxturna (voretigene neparvovec-rzyl) as one of the first gene therapies, and the first approved to treat an inherited disease caused by mutations in a specific gene.

In August 2017, the FDA approved what it described as the first gene therapy, Novartis’ CAR-T immunotherapy Kymriah (tisagenlecleucel), for younger patients with B-cell precursor acute lymphoblastic leukemia.

Last December, Luxturna was approved in biallelic RPE65 mutation-associated retinal dystrophy, which can cause complete blindness, and affects approximately 1,000 to 2,000 patients in the U.S.

After launch, the one-time treatment was widely described as the most expensive medicine available, with a $850,000 price tag that Spark justified with the therapy’s durable, long-term benefits to vision.

Luxturna uses a naturally occurring adeno-associated virus as a vector to deliver a normal copy of the RPE65 gene directly to retinal cells, spurring production of the protein that helps convert light to an electrical signal and restore vision. The FDA requires the therapy be administered in each eye at least six days apart.

Safety and efficacy were established in a clinical development program accruing a total of only 41 patients. A Phase III trial with 31 participants measured the change in a subject’s ability to navigate an obstacle course in low light, with 90 percent experiencing improvement over one year.

“We’re at a turning point when it comes to this novel form of therapy and at the FDA, we’re focused on establishing the right policy framework to capitalize on this scientific opening,” said FDA Commissioner Scott Gottlieb following Luxturna’s approval. Currently, the vast majority of gene therapy studies are in early phases, with 75 percent in Phase I and 20 percent in Phase II, compared to less than 5 percent in Phase III.

In 2018, the agency plans to issue a suite of disease-specific guidance documents on the development of gene therapy products, Gottlieb said, including new clinical measures for evaluation and review, starting with hemophilia before more common single-gene disorders.