The US Food and Drug Administration’s (FDA’s) new pathway for gene therapies could be “groundbreaking” if applied broadly, though the extent of its scope remains unclear.
In a New England Journal of Medicine article authored by FDA commissioner, Martin Makary, and Center for Biologics Evaluation and Research (CBER) director, Vinay Prasad, the new pathway could allow new, personalised therapies to be accelerated and bypass certain requirements.
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The pathway is based on the case of Baby KJ, a male newborn, who was diagnosed with a severe form of carbamoyl-phosphate synthetase 1 (CPS1) deficiency, an inherited rare disorder that causes an inability to process protein during digestion.
With a single-patient, expanded-access investigational new drug (IND) application processed in one week by the FDA, Baby KJ’s care team was able to manufacture and infuse a customised CRISPR gene editing therapy that repaired the gene mutation. In May 2025, KJ became the world’s first patient treated with a bespoke CRISPR-based therapy.
There are certain criteria for this pathway to be used. One is that a specific molecular or cellular abnormality needs to be present, as opposed to diseases defined by broad and unclear causes. The therapy must also target the underlying biological origin. This strategy would negate the need for a clinical trial ahead of the FDA approving its use; however, the agency will need some preclinical safety data ahead of patient dosing.
While certain elements of the pathway have been made clear, Terry Pirovolakis, CEO of Elpida Therapeutics, a rare disease company that acquires dropped gene therapy programmes, said that some questions remain as to what kinds of gene therapies will be eligible for this programme. He emphasised that if broad enough, this could be “groundbreaking” for the cell and gene therapy (CGT) landscape.
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By GlobalDataThis interview has been edited for length and clarity.
Abigail Beaney (AB): How does this new guidance impact gene therapy development?
Terry Pirovolakis (TP): It wasn’t really guidance, because it was a paper submitted to Nature Medicine. Despite that, it’s a good starting point and reference point for us to use when we’re filing rare disease programs. Hopefully, it will lead to more rare disease changes, because currently, I feel we are being categorised within larger diseases. Ultra-rare diseases that impact one to 5,000 patients need their own pathway.
AB: What kind of programmes do you think this will impact?
TP: This paper referenced baby KJ’s programme, and while it was a big programme, it was an N=1, N=2 maybe. I think this leaves the framework open more to programs that are affecting again, 5, 10, or 1000 patients, because there is more of an unmet need there.What we are hoping for is that leniency and that support and guidance that was provided for ultra rare conditions will be followed through, not just for gene editing, but for gene replacement therapies and antisense oligonucleotides (ASOs) and the other therapies that are available to us in our tool set.
AB: Do you think this might impact how biotech and pharma company views the viability of their gene therapy candidates?
TP: I hope so – I think the problem that we have is that the programs are not being dropped because there wasn’t a pathway to the clinic, but because the pathway to commercialisation and the priority review voucher (PRV) were gone. As a result, I don’t think this paper is going to help us here, as it doesn’t fix that commercial pathway. It is, however, a stepping stone to get into the clinic, so I hope we get another document to provide more leniency into the commercialisation aspect plus the renewal of the PRV.
AB: Could this pathway provide savings for companies in the clinical period?
TP: For those using the exact same pathway, then yes, but if your gene therapy is a different promoter, a different capsid, potentially not. Most of the time, you can’t use the same promoter on two different diseases. If the FDA accepts different capsids within this, then we will be much better off.
AB: So, do you think that this guidance is currently limited?
TP: I think the FDA has already been more lenient on broader pathways, but I don’t know how limited this will be, because it wasn’t very clear in the documentation. My question is, how broad will it be? Will thecapsid be the pathway forward, or will it be the promoter? There’s always going to be a missing transgene or a different code to put it in. If we can get the capsid and the promoter, then that would be groundbreaking, but again, we just don’t know, because the guidance wasn’t that definitive.
AB: This development from the FDA comes shortly after the UK’s Medicines and Healthcare products Regulatory Agency (MHRA) announced a similar pathway for single gene therapy development. Does this reflect that there’s finally some global harmonisation in the rare disease gene therapy space?
TP: I’m not sure if they were working with each other or separately. I know that Dr Makary and Dr Prasad have been talking about supporting rare diseases, and I personally think they just came on the heels of each other, because they are slightly different. In regard to the FDA, even without this development, for the submission process, the FDA has been very supportive of all of our programmes and they understand the urgency and unmet need.
AB: Do you think gene therapy development needs more programmes like this?
TP: I think it needs more programmes that help push to commercial, because the reality is right now that we have very few approved therapies. If we end up having 100, then the cost of goods reduces, which is a big factor in gene therapy development. It will also hopefully see the administration become more supportive of approving more programmes, even if there’s like an inkling of efficacy versus a larger indication of efficacy. By having a larger pool of approved products, the whole dynamic will change, but unfortunately, with only a handful or a dozen programs approved, it’s not enough to kickstart the whole industry.
Cell & Gene Therapy coverage on Pharmaceutical Technology is supported by Cytiva.
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