Panelists from three biotechnology companies -- Enzyvant, Generation Bio, and Miromatrix -- provided insights on how to navigate the regulatory process and benefit from dialogue with regulators to inform the development of cell and gene therapy programs.

A not-so-typical approach

Enzyvant received its first U.S. Food and Drug Administration (FDA) approval on October 8 for Rethymic, a novel tissue-based therapy indicated for immune reconstitution in children with an ultrarare disease called pediatric congenital athymia.

"Rethymic is based on clinical data from 105 patients over the course of decades of research, and I think that is where the story starts for us -- for Enzyvant, that is when we licensed this interesting technology," said Enzyvant CEO Rachelle Jacques.

Babies with pediatric congenital athymia are born without a thymus and thus cannot make functioning T cells. Children with this disease are severely immunodeficient and can suffer from fatal infections. Most of them die by two or three years of age.

Enzyvant saw potential for clinically treating this fatal disease after looking at the life's work of a researcher who had been studying the disease and how to treat it, Jacques explained.

"Essentially, we felt that the data was there to support a clinical package for a BLA [biologics license application] submission," explained Jacques. "But as we know, that is not a typical approach to take data out of academia and studies that weren't necessarily designed for this purpose of filing a BLA and putting that into a package that would be acceptable to the regulators."

With the data in hand, the company reached out to the FDA, leapfrogging the traditional regulatory process.

"We did make a proposal to the FDA; they were open to seeing what we had, and that is how we went forward," Jacques said. "From an innovative regulatory standpoint, that was definitely a unique approach that we took and with very strong clinical data."

Early engagement with regulators

The FDA and other regulatory bodies offer early engagement meetings with cell and gene therapy developers. But utilizing these opportunities may require a balancing act.

One specific FDA initiative is the Initial Targeted Engagement for Regulatory Advice on CBER products (INTERACT) program, which offers informal nonbinding consultation with the FDA's Center for Biologics Evaluation and Research (CBER). INTERACT meetings are opportunities to meet with regulators and ask questions at an early development phase, before candidates are at the preinvestigational new drug application (IND) phase.

"For us, the INTERACT meeting has been tremendous and beneficial," Miromatrix CEO Jeff Ross, PhD, said. Miromatrix bioengineers livers and kidneys for patients with end-stage liver disease or patients with end-stage renal disease.

Ross cautioned that nailing down the timing on when to use the FDA INTERACT meeting option can be difficult.

"The challenge of the INTERACT meeting is really trying to figure out what is that timing, because today you only get one," Ross said, adding that companies need to be careful not to take the meeting too early or too late in their cell and gene therapy programs.

The INTERACT meeting allows the FDA to offer valuable but nonbinding guidance, Ross explained.

"They certainly can say, 'In the next step, this is something ... we are going to be asking,'" said Ross. "So now, you can come really well-prepared, knowing exactly what those issues will be to strengthen your position."

Generation Bio found the INTERACT meeting to be a good way to build a relationship with the FDA, said Jennifer Dittman, vice president of regulatory affairs at the company. The opportunity was especially valuable given that Generation Bio is focused on nonviral gene therapies, a novel area in the cell and gene therapy space.

Dittman explained that for Generation Bio the benefit of INTERACT was in "starting to build that relationship with agency, helping us really prepare for the pre-IND and strategically timing that discussion as well to get the most out of it so that we are well-positioned for the initial IND filing."

INTERACT helped Generation Bio think beyond the initial conversation, Dittman added.

"It's been really useful for us to think about how we pursue that with our products, but then also thinking about our platform overall and how we might leverage some of those discussions ... to make the best use of our time and the agency's time for some of these early interactions," she said.

Communication with regulators

While regulatory agencies offer these early engagement frameworks, sometimes, the timelines do not necessarily match up with the pace of the science.

Asked what kinds of changes she would like to see in the development process, Jacques offered two: greater speed and the ability to reach out and ask follow-up questions.

In terms of speed, Jacques would like to see regulators provide faster feedback on things like protocols without having to request a formal meeting.

"[For those] of us working in innovative programs, you cannot just have one piece of the program waiting for a potential answer ... we have a lot of things to be integrated in a synchronized manner," Jacques explained. "We need the answers as quickly as possible."

Speed is particularly critical when a company is working with patients with rare diseases, she explained.

"Any time we can have clarity quickly it is going to be beneficial for our patients without sacrificing safety," Jacques said.

The second change she would like to see is access to regulators for follow-up questions during substantial changes in product development.

"We might get some feedback in a formal meeting that is potentially creating a substantial change that we need to make," she explained. "You go back and you work on it as a team and you digest it. ... Inevitably, you have follow-up questions."

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