CBER Helping to Speed Gene Therapies: Marks
CBER director Peter Marks says his Center has high hopes to speed gene therapy development through the harmonization of manufacturing protocols. This effort is mainly being led by the Bespoke Gene Therapy Consortium, a partnership between NIH, FDA and various public and private organizations, and it includes pilot programs that are trying to “align manufacturing and clinical protocols to see if we can help small gene therapies move forward more readily,” Marks said during a 12/5 Alliance for a Stronger FDA update.
“We think that automation of the manufacturing process could be quite helpful,” Marks said, because it’s already working in the cell therapy space “and we know it has the potential to work in the gene therapy space. It’s just a matter of someone putting through the work to apply it.” He said automation can potentially bring more certainty to the process than doing the steps by hand.
“Ultimately,” Marks continued, “what you're trying to look for is to get to a device … [that] will have disposables that will be used to make the therapies. The idea is if you had a much more facile process to make small-batch gene therapies, you can imagine companies that might have portfolios of rare disease gene therapies where since they could handle the manufacturing more easily, they could have 20 or 40 of these and then make a reasonable business of it.”
Marks said that the other issue for getting manufacturing right in the gene therapy space is that the products are very well-tuned for platform technologies because “whether they are virally vectored or otherwise vectored they generally have some backbone into which the gene of interest is put.”
Marks told the Alliance that the idea of being able to leverage nonclinical and manufacturing information from one application to another could be quite helpful under the platform technologies provision in the Omnibus Appropriations Act of 2023, which allows a pathway like this. He said a future guidance document is under development to assist stakeholders, and it will “allow sponsors to reference or rely on data or information from previous applications to hopefully help move things forward.”
Additionally, Marks said he sees the move to platform technologies as perfect timing for CRISPR Cas9 and the advancing improvements being made to the original CRISPR constructs. CRISPR-Cas9 is a genome editing tool that is faster, cheaper and more accurate than previous techniques of editing DNA and has a wide range of potential applications. “These are now able to essentially not just correct a single letter in our DNA but potentially correct stretches in our DNA,” Marks explained, adding that these products are the ultimate real platform technologies.
Another promising area being looked at is leveraging accelerated approval for gene therapies. With gene therapies, the idea is to replace something that's either missing or is present in excess or is deranged, Marks said, and this “means since you know what you're looking for, particularly if it's an enzyme activity or structural protein that can be measured, you can correlate what you're seeing with the administration of that gene therapy with what you're seeing in an animal model or in, what sometimes we are lucky enough to have, a natural human experiment.”
With gene therapies, Marks said a biomarker that would fulfill the accelerated approval provision of “reasonably likely to predict” a benefit could likely be shown in an animal model where 10% of a gene expression is demonstrated, and if that level can be achieved in a human, “then you have a good linkage. So this is one of the ideas that we will try to leverage. It’s not always as easy as it sounds, because sometimes we’re dealing with structural proteins that are inside the cell, which require biopsies, etc., but it is a way of trying to thread the needle and get there using our accelerated approval provisions potentially faster than one would otherwise.”
Marks also reminded the Alliance audience about a new pilot program, “Support for Clinical Trials Advancing Rare Disease Therapeutics (START),” that will begin in January. The pilot will offer rare disease product sponsors frequent advice and regular ad-hoc communication with FDA staff to address product-specific development issues, including clinical study design, choice of control group and fine-tuning the choice of patient population (see earlier story). It is modeled after the agency’s successful Operation Warp Speed communications offered to vaccine makers and others during the Covid-19 pandemic.
If the pilot is successful, Marks said expanding the communication opportunities will require dozens of additional staff members, which Congress and industry may balk at, as the program would fall under increased user fees. “Well, if this really does reduce the time to development by 25 to 50%, I’ve spent enough time around MBAs to show that probably won't take industry too long to do a net present value calculation to say” ‘oh, you know, it's worth making sure that they have their extra 20 or 30 or 40 reviewers because that translates into benefits for patients so much more rapidly.’” He also noted that increased communications will give companies the ability to cross the “finish line faster.”