It was five years ago that Jeff Marrazzo, CEO of Spark Therapeutics, first stood in front of a crowd at the J.P. Morgan Healthcare Conference to outline his company's path forward. Fast forward to today, and the biotech is now a year removed from securing the first ever U.S. approval of a gene therapy for an inherited disease.
To do that, Spark had to take on clinical, regulatory and, in particular, manufacturing hurdles — challenges that in some ways still persist.
BioPharma Dive sat down with Marrazzo to discuss Spark's journey in gene therapy manufacturing and the questions left to answer in the next five years.
This interview has been condensed and edited for clarity.
BIOPHARMA DIVE: What sticking points are there still to get past in gene therapy manufacturing?
MARRAZZO: This has been no small task to go from scratch to a first-approved gene therapy facility. We have not only gone through and understood how to establish the validation of your process, but established validation of the methods that you use to confirm your process is what you said it is.
We developed 41 different assays to test and release Luxturna; the large majority of those are going to be applicable to every other thing that we do. We aren't going to have to do that again.
Our [Biologics License Application], when we filed it with the FDA and similarly with the EMA, was like 60,000 pages. The vast majority of it wasn't about the clinical data. It was about CMC, or chemistry, manufacturing and controls, which is all about how our process works, how we control for it and how we show reproducibility.
One of the really important developments beyond Luxturna for us over the last 18 months has been the development of a process where we could take the same cell line that has been approved with Luxturna and apply it to a suspension.
[To manufacture Luxturna] we use these things called roller bottles. What you do is attach the cells to the side of the surface of these vessels. In order to increase the amount of capacity, you need to double the number of vessels and you need more people or more time in the facility to increase the capacity because it's a linear scale-up.
We've been able to take those cells and give them a completely different soup, if you will, where they can live and grow up inside the vessel. As opposed to attaching to the side, they can actually sit in solution. If you go from 10 liters to 100 liters, you don't increase the number of operators, you don't increase the number of time, but you all of a sudden went ten-fold larger.
This is the way most biologics have been scaled. We're at an essentially 400-liter system that we have [tested] multiple times now.
There is work that we will need to do to continue to show the reproducibility of that. That is one of the areas of focus for us over '19 and '20, but the scale that we're at is already sufficient to meet the commercial demand for what we're projecting in hemophilia.
Has there been an area of gene therapy manufacturing — supply chain, acquiring talent, etc. — that stands out as having been particularly difficult?
MARRAZZO: This stuff all ultimately comes down to people.
I know and remember all the scars of getting here to there. We had to bring together people that knew these molecules really well, who were phenomenal scientists.
But in order to be able to bring these to patients at commercial scale, you also need the operational know-how to be able to replicate this over and over and over again. [At the time] there was no commercial-scale gene therapy manufacturing talent.
We had to basically make that up from the people who knew monoclonal antibodies or enzymes. We had to bring them together with the scientists who really knew gene therapy and get them to work together.
That cross-learning and cross-pollination is one of the most complex [pieces]. I knew it from the beginning and there's no silver bullet for that.
That's the biggest challenge, but also the biggest success when you make your way through.
How was the process of dealing with regulators, at least from a manufacturing perspective?
MARRAZZO: The really unique thing about this whole first application was we were not just breaking ground around gene therapy, we were also breaking ground around an area of medical need in these blinding diseases where there were no existing drugs, period.
The regulators, to their credit, collaborated well with us on development of a novel endpoint. Our primary endpoint was not an endpoint ever used before, and it was because these diseases had never been studied in a Phase 3 trial before.
In hemophilia we have precedents of what are the right endpoints. But with Luxturna we had to basically develop the clinical development course as well as the manufacturing development course.
Both of those were extremely collaborative. We had Breakthrough Therapy Designation, but regulators also wanted to see these succeed. If you think about it from a human perspective, these are people who have worked, in some cases, at the FDA for 25 years in this group and never had seen an approved product. They genuinely want to do the right thing for public health in the United States, but they're also human and they would love to see these things make their way to patients.
It was a great collaboration, and it is also one of the areas that we think is an intrinsic value about the company — that we have that relationship and we know how to work our way through a new territory that they've never been in and we've never been in. Bringing scientific rationale and explanation to regulatory questions, they appreciate that.
And how much is there left to iron out with the FDA as far as manufacturing guidance for gene therapies?
MARRAZZO: There's still plenty to work through. The area of a CMC is still one that, while we have cracked a lot of it, I think first of all there are people who are going to be going through with different systems — maybe an insect cell line versus a mammalian cell line. Someone might go through it with a system that is not actually these bottles but flasks on a stack. There are things that ultimately will still need to be worked through in that context.