Robert Finke : This is Robert on for Debjit. Congrats on the financing. From the perspective of the next mega financing, can you speak to the confidence in the pre-BLA meeting outcome and how a positive outcome is defined for the next leg?
Frank Thomas : Yes. Maybe I’ll speak to the sort of how the financing is tied to that. And then Bobby and Leslie can comment on sort of confidence level. So yes, the deal, as you saw in the press release, is structured success-based. So as we make progress and derisk the program, more and more capital comes in to fund the growth and strategy for the business. So the second milestone is tied to essentially a successful pre-BLA meeting and defining what exactly that means. I think as long as there’s nothing in the minutes that precludes us from moving forward to a submission, then that second tranche of financing is obligated to come in. It’s an obligation, not a right. So as long as we have a successful meeting, then we would expect that money to come in, and we’re expecting that because the meeting is scheduled in the second quarter to happen, sometime before midyear.
So that’s sort of the technical aspects of it, but I’ll let Bobby comment further on the meeting itself.
Bobby Gaspar : Yes. I think as far as our confidence is in the pre-BLA meeting and how we — and what happens off of that, I think we feel that we’re in a very good place. I’d say we’ve been in a lot of discussions with the FDA over the past essentially 3 years as far as this file is concerned. And I think what we’ve been able to do during that time period, we filed the IND, we had an RMAT designation. We talked through a number of different questions with the FDA, both on the clinical side and on the CMC side. We’ve agreed on things like what measures to use, such as the GMFC score to look at motor function. We’ve agreed on the primary endpoint that is clinically meaningful. We’ve developed a composite score called severe motor free survival.
We had detailed conversations with the FDA, what else needed to be addressed on the clinical side, the predictability of the clinical course is presymptomatic patients, the robustness of the natural history comparator cohort, the use of an independent review committee to review all the clinical data, both of treated patients and of the natural history cohort and had a constructive type B clinical meeting where these items were clear. So all of that has been very positive and has given us confidence to move forward to this pre-BLA meeting. On the CMC side, we’ve again started — we started with a lot of questions that needed to be addressed. We addressed a number of those through a written response only documentation. The CMC comparator package is under review, we’re answering questions as they come through.
And again, as I say, there was a multidisciplinary view that we could proceed to a pre-BLA meeting. And so I think with all of that, that’s where we stand. And I’m being kind of very transparent with you as to where we are. Obviously, we have to get through that meeting. But those are the things that have led up to us having that meeting and why we feel we’re in a good place to move forward after that.
Operator: And the next question comes from the line of Pete Stavropoulos from Cantor Fitzgerald.
Pete Stavropoulos : So recently on WORLD, you had a number of presentations for MLD newborn screening, which is going to be important to identify patients. Can you just sort of discuss the assay used? How sensitive is it? How easy or difficult is it to implement? And how specific is it to MLD patients? In other words, they get hit from the screen, but genetically couldn’t confirm?
Bobby Gaspar : Yes. Maybe I’ll start, and Leslie may be able to add detail on this. So the screen that is used is — uses a tandem mass spec and is basically looking for an increase in sulfatides levels. And so sulfatides are the substrate that accumulate in patient cells as a result of deficiency of the ARSA enzyme. So that is the first thing that is measurable. And what you can do is you can take a shot from the — a little punch from the dried blood spot, you process that. And from the eluate, you run that on the tandem mass spec and you can look for the rise in sulfatide. Now in MLD patients, you will see a high level of sulfatide accumulation compared to the natural history, natural normal children. But this is always a spread.
And you have to kind of define threshold above which you consider individuals to have a positive screen. And that threshold can be set over time. But of course, that is just the screening test. After that, you need to confirm whether that rise in sulfatides is actually associated with MLD. And in fact, you can use 2 subsequent events. One, you can look at or activity itself or you could go to genetic analysis. And Leslie maybe correct me, but I think different pilots are using either both of those second-tier tests or just one of those tests. But the gold standard is to get to a genetic diagnosis. So I’ll hand it over to Leslie.
Leslie Meltzer : Yes, I think that’s right. And an important point, Pete, is that these are research pilots. And part of the goals of these pilots is to really narrow down and make precise the screening methodology that would be intended to be the shared methodology worldwide as screening becomes universal at the country or state level. And there’s a regular collaboration between all of the different research groups that are conducting these pilots to share results and share improvements in methodological testing that will inform how that takes place. But in the ideal scenario, you have either a 2-tier or a 3-tier testing that starts with sulfatides, as Bobby mentioned, and in patients or in subjects who have elevated sulfatides could either go directly to genetic confirmation or you could first do in the same dry blood spot an assessment of ARSA levels.
You don’t start with ARSA directly because there’s actually a high rate in the general population of people who have what they call pseudo deficiency of ARSA. If you were to just screen for ARSA, first you get a lot of false positives. But the idea is by testing first for sulfatides, and then for ARSA, you can dramatically reduce the incidence of potential false positives to the point where you get to roughly 1 in 10,000 to 1 in 20,000 samples being referred for confirmatory genetics, which is what the de-identified pilot in Washington state showed. So those specific details of the methodology are being worked out in the pilots as we speak, and I would anticipate some significant improvement in that alignment over the course of this year as more pilots are coming online.
Pete Stavropoulos : And also, I don’t know if you answered this earlier, but any color on the CMC interaction for 200? Has the agency inspected the site or visited it? And does the agency have any experience with the site from other companies?
Bobby Gaspar : Yes, just so on the interaction. I think I’ve outlined in previous questions that we’re in the process of answer questions from the FDA on the CMC comparability package. On the site inspection front, so AGC Milan, which is the manufacturer that we use, you’ll know that they are obviously — they’re approved for commercial manufacture in the EU. We have done a pre-inspection monitoring with them using ex-FDA inspectors and there are questions that were asked and we are putting those processes and procedures in place for an FDA inspection. So I think we will only understand once we get nearer as to when the pre-inspection readiness will actually instill actually occur. So I’d say we can comment on that at a later stage.
