“We may not believe in miracles. But there are things that are miraculous, and this is one.” — Peter Marks

San Diego —At the Cell & Gene Meeting on the Mesa, keynote speaker Peter Marks, MD, PhD, director at the Center for Biologics Evaluation and Research, U.S. Food and Drug Administration (FDA), spoke about the agency’s efforts to take cell and gene therapy to the next level.

Marks delivered his remarks after a busy morning taking part in the FDA’s authorization of the Moderna and Pfizer-BioNTech bivalent COVID-19 vaccines for use as a booster dose in younger age groups.

There are currently ten FDA-approved gene therapies. Although most are CAR-T cell-based therapies, Marks thinks the future is bright for cell-based and directly administered gene therapies.

“There is a robust global pipeline of products,” said Marks. “In the genetically modified T-cell space for cancers, we see more complex products. We’re seeing allogeneic products make their way through and using CRISPR-Cas9 and other genome editing technologies.” The global pipeline addresses several indications: solid tumors, hemoglobinopathies (including sickle cell disease), hemophilia A and B, lysosomal storage disorders, neuromuscular diseases, retina disorders, and others.

Rare diseases

Marks is most excited about the success stories for rare diseases such as spinal muscular atrophy (SMA) type 1, which leads to a loss of motor function early in life and premature death.

“The introduction of this gene therapy [Zolgensma] has transformed [SMA treatment],” said Marks. “Rather than having repeated injections of an oligonucleotide, this has led to a once-and-done intravenous treatment that has led to remarkable responses with children now developing normally. A child running around with SMA type 1 at age three is just not possible without something like [gene therapies]. We may not believe in miracles, but there are things that are miraculous, and this is one.”

While gene therapies for these rare diseases might not treat many patients, they are critical. “When you take all these diseases and put them together, they affect quite a number of people,” he said.

The challenge in treating very rare diseases with precision genome editing is to develop paradigms where a particular base-pair correction will affect only 20 or 30 individuals.

“Getting this paradigm for making gene therapies that touch a small number of people right is important,” said Marks. “If we want to get large-scale gene therapy right for lots of people, this is the correct place to start—where the need is incredibly great, and we can potentially look at various applications and learn a lot. The therapies we’re talking about now are in this space of individualized medicine where we are creating the right drug to treat the patient.”


Without going into the large-scale production of gene therapies, besides noting the need for better vector production methodologies, Marks focused on issues with small-scale production for commercial viability. While some would say that this is something philanthropic groups should tackle, Marks doubted that philanthropic groups would pay the bill for these gene therapies for the hundreds of diseases to be addressed. “We’re going to have to find a way to make this commercially viable so that industry can find a way forward,” said Marks.

One solution might be automation. For example, for AAV, much of the manufacturing process can be automated, an area the FDA is exploring with various collaborators. The goal would be to develop a device akin to a soda dispenser.

“I know a soda dispenser isn’t a gene therapy manufacturing device, but it’s a stand-in for what might help here,” Marks said. “If one could spend most of the time worrying about the actual constructs that one was generating and less time about the manufacturing, including the purification and formulation of the product, we might see this reach commercial viability more rapidly.”

Relatedly, Marks said that the FDA is progressing toward putting together a cookbook-type approach for developing and manufacturing gene therapies.

“We believe that if academics, where a lot of the innovation comes from, could follow the same playbook more of the time, it would be easier for them to transfer work to contract manufacturing organizations without having to rework everything that would be mutually beneficial,” said Marks.

“It would likely add value on both ends of the equation to the investigators who are potentially licensing out technologies as well as to those who are recipients, who would like to have more surety that the technology will transfer smoothly.” Here, the FDA looks at how to use its regulations to leverage non-clinical and manufacturing data from one application to another.

“We’d start by allowing an individual company to leverage the information from one application to another, and then, if that’s working well, we can consider expanding that concept further,” said Marks. “There are certain pieces of gene therapies that are not like your typical small molecule drug because they’re reused repeatedly. Provided you don’t either under- or over-stuff [AAVs], you can probably get a similar result when putting a similar type of insert that produces a similar type of either secreted or membrane protein. If we could get this paradigm to work, rather than having a manufacturer go back and do all of the preclinical toxicology and give us all the manufacturing information each time they submit something, they would just cross reference. That would allow us to focus on innovation that’s going to bring benefit to people.”


Marks laid out the paths to providing new drug access to deliver innovation to patients more rapidly. Traditional access works through investigational new drug (IND) applications or expanded access programs, with either traditional or accelerated approval.

The expanded access program is for serious diseases or conditions when patients can’t end up being treated in clinical trials. “Individuals who might be treated on an expanded access program with gene therapy who have serious diseases may be different enough from those who are being treated in the protocol,” said Marks.

“Adverse events that might occur with those on an expanded access program don’t necessarily count against you in the traditional development plan.” But not every event can be brushed under the regulatory rug, such as serious effects seen in all treated patients. Marks thinks that often there is a hesitancy for expanded access programs because of that concern.

The FDA is facilitating individual patient access through single-patient IND requests. “There’s a pretty simplified form, and the bar for this is reasonably low,” said Marks. “We have intermediate-size population access, which is where most sponsors decide to go because it can be run under a protocol, and it fits once there’s some evidence that a product has an effect.”

Then there are biologics license applications (BLAs), where products have to be shown to be safe, pure, potent, and effective, with substantial evidence of efficacy from adequate and well-controlled trials.

Full approval can only be achieved with a clinical endpoint, such as how patients feel, function, or survive. “But we recognize increasingly that for gene therapies, we may need to rely on our accelerated approval authorities where we’re looking at either intermediate or surrogate endpoints,” said Marks. “That’s because… one will have to look at some biomarker or intermediate endpoint to get the products across the finish line to an approved product that can be looked at over time by either longer clinical studies or real-world evidence to convert them to full approval.”

This is particularly true for progressive diseases that still impair people’s quality of life for years to do a clinical trial in a timely manner. The FDA will have more to say about this in the future, Marks said.

Going global

What may be a tiny patient population in the United States could become a more sizable population when you look globally. For instance, the difference between 30 and 100 patients could be the difference for commercial viability, which, according to Marks, is roughly 100-200 gene therapy treatments a year.

To do this, Marks suggests enlisting low-, middle-, and high-income countries. Take hemoglobinopathies, where individuals in low and middle-income countries may benefit the most from gene therapies because the current standard of care for individuals with these disorders is not good. “Many individuals die in childhood or live very challenging lives because of the lack of access to supportive care,” said Marks. “Gene therapies could transform that without this constant need for supportive care.”

But Marks suggested that a harmonized regulatory framework would be needed because many countries don’t have experience regulating cell and gene therapies. This concept of global regulatory convergence might enable, at least for some rare diseases, delivery of such therapies to more patients. As companies often operate in multiple regulatory jurisdictions, convergence shouldn’t be that difficult. While the preclinical requirements, especially for toxicology studies, environmental assessments, and the required amount of manufacturing information, are different, the regulatory bodies may not be that far off.

“From some of our experience and the experience of our sponsors between the EMA and FDA, we think we’re pretty close together,” said Marks. “Sometimes there are different clinical outcome requirements, so hopefully, if we could converge here on these, especially around these very small populations, we could make a difference for people.”

FDA reorganization

The FDA has undergone some reorganization, the last region being the Office of Tissue Advanced Therapies (OTAT), which was converted into the Office of Therapeutic Products. “We’ll have an office devoted to the manufacturing of gene therapies, an office devoted to the manufacturing of cell therapies, a large clinical review branch that will be able to deploy clinical reviewers across where they’re needed, and a group focusing on more traditional plasma therapeutics,” said Marks.

“All of that will help us increase the interactions we need with various stakeholders, both patients, and industry. Most importantly is to improve the timeliness of our responses and meetings… and also enhance the consistency of our responses by having offices focused.”

Marks closed by pledging the FDA’s commitment to cell and gene therapy development. “We want to ensure that we get it right with smaller populations, but then hopefully see this grow to bring the benefits of cell and gene therapy to larger populations. We’ll use all the tools in our toolbox to help make that happen.”

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