Leslie Meltzer : Yes. There’s not a whole lot to add with regard to safety as it was presented at WORLD, which is very consistent with everything that we’ve presented to date, in addition to all the points that Bobby made about the fact that we see no evidence of malignancy, no evidence of insertional oncogenesis or clonal expansion, a very robust safety profile. We’ve got over 232 cumulative patient, years of exposure. It’s been very — OTL-200 has been very well tolerated, no treatment-related SAEs or deaths. We see some instances of anti la antibodies, but these are not associated with any sort of impact on clinical outcomes. And we also see robust engraftment in all patients treated. The efficacy data that we present at WORLD is an update from previous presentations that includes all 39 patients treated in the clinical development program as well as patients treated in some compassionate use programs.
And again, we consistently see significantly improved clinical outcomes on motor impairment, on survival, on cognitive impairment on all of the clinical manifestations of the disease. And these results were, among other results that were discussed with the FDA as part of our Type B meeting and supported our movement to the next stage of the process, which is a pre-BLA meeting.
Hartaj Singh : And Bobby, and just to follow-up to that. I was actually just going to ask a quick question on the Type B and going into the pre-BLA meeting. Is that just the pre-BLA meeting, I would imagine, is sort of a — and I don’t want to use the term lightly sort of a check box exercise in the sense that the Type B meeting was where you had in-depth discussions around safety and the efficacy, the integrated mass all the other pieces of data that Orchard has and the pre-BLA sort of preparing for the actual BLA filing and getting that going. Is that the way to think about it? And that’s the core of the question.
Bobby Gaspar : I think so. I think generally, that is the case. And especially on the clinical front, as I said previously, they did have clinical questions that they wanted to address. And I think the fact that we’ve gone to a pre-BLA meeting, I think we feel that those clinical questions have been addressed. And so this is now — a lot of it will be procedural. We are waiting for feedback on the CMC comparability package. And that, again, is just about the comparability package. And that is a process that we are — that is ongoing with the FDA where they’re making comments to us, we are responding, et cetera, and there may be still a discussion of that at the pre-BLA meeting.
Operator: And your next question comes from the line of Yaron Werber from Cowen.
Brendan Smith : This is Brendan on for Yaron. Congrats on a great progress. Maybe just a quick one from us. You mentioned that the IND filing for MPS I still pending after which you expect you would be able to initiate a pivotal study. Can you remind us if you filed an IND for the MPS IIIA program? And if not, maybe what the timing for that is kind of relative to the Crohn’s IND? And then in MPS IIIA, assuming things proceed as expected, should we maybe expect to start a pivotal study sometime next year? Or is that still a little bit in flux?
Bobby Gaspar : Yes. So let me just take those one by one, and I’ll ask Leslie to comment on the path forward for MPS IIIA. But let me comment on MPS I, first of all. And so remember, we announced at the beginning of the year that the study design for a registrational study for MPS I has been cleared, and we gave some details around that. It’s going to be a randomized study against allogeneic transplant, approximately 40 patients with a composite endpoint that includes both safety and efficacy features. And our plan for that with the IND having been filed and cleared by the FDA is to open the pivotal registrational study by the end of the year. On the Crohn’s program, we are in the first half of the year, we’re going to announce preclinical proof-of-concept data, and we are anticipating moving forward on IND-enabling studies with the aim of submitting an IND by the end of 2024.
And so that — those are the milestones for these 2 programs. But I’ll ask Leslie to comment specifically on MPS IIIA.
Leslie Meltzer : Sure. So for MPS IIIA, we presented at the end of last year and then recently presented an at WORLD, results from the 5-patient study, 5 patient proof-of-concept study where we have at least year follow-up in all patients, in 4 out of 5 patients. And what we’ve shown is that in 4 out of 5 patients, we see cognitive outcomes that either are improved relative to natural history or are consistent with normal development in patients that are still early in the follow-up. So we see gain of constative skills in these patients, and we see some encouraging signs on clinical outcomes. However, this is still quite early in the disease course. If you recall from some previous discussions, patients with Sanfilippo Type A will go through a period of normal development and until around the age of 3, at which point they’ll plateau and then quickly decline around the ages of 4 to 5.
So we’re looking for some additional follow-up in this proof-of-concept study as the data matures. And as these patients reach an age where if things are working, we would start to expect a deviation from natural history. And as this data matures and as we see additional presentations of clinical data from this program, this will inform our discussion with regulators on potential study designs for a potential pivotal study.
Frank Thomas : Brendan — sorry, Brendan, it’s Frank. I mean just to follow up on your question about how soon could a pivotal study. I would anticipate that if we have the data this year that supports moving into a pivotal study that we would need a period of time to develop some of the CMC work. So I don’t think we’d be in a position to start a registrational study next year. But certainly, we’d be more working as quickly as we can to get that design and in parallel working on the CMC.
Operator: And your next question comes from the line of David Hoang from SMBC.
David Hoang : Congrats on the –on pulling together this financing. So I had a question or two just around a potential approval and launch of Libmeldy in 2024. Assuming that, that is possible, could you just talk a little bit about what prelaunch commercial activities you may need to pursue in the U.S. to develop the U.S. market? And then how would — do you have any, I guess, expectations as to how the cadence of a potential U.S. launch may look compared to what’s currently ongoing in the EU?
Bobby Gaspar : Okay. I’ll hand that straight over to Braden.
Braden Parker : Sure. Thanks for the question, David. In the U.S., the prelaunch activities would mirror somewhat the European activities in the sense of identification of treatment centers that we would want to qualify in advance of an approval to be prepared to have access for patients overall. Also working with a number of payers to educate them on MLD, as you might imagine, as a rare disease, there’s quite an education process that has to take place from the payer side on the disease state as well as the clinical impact of Libmeldy overall in preparation for access as well. And then as Leslie mentioned and others, there’s certainly some newborn screening activities that are taking place in the U.S. There will be other patient identification efforts that would be taking place as well leading up to a potential approval and launch.
So those are some of the major buckets that we’re looking at in addition to at the right time, building out the team to cover the region. Those are some of the activities we’ll be looking at from a prelaunch perspective in the U.S. In terms of the cadence of launch, if you look at the size of the opportunity in the U.S., it’s roughly similar to the EU, again, taking kind of the current estimates of 1 in 100,000 births, live births in the U.S., you’re looking at anywhere between 40 and 50 potential new patients each year that we would have to try to find and identify. So it’s a similar type of opportunity in terms of sizing but the access and the reimbursement side is where you see the real difference in the U.S. So in Europe, we see quite a lengthy process in terms of health technology assessments followed by reimbursement negotiations in the U.S., I would expect reimbursement to happen much more quickly than what we’ve seen in Europe.
So once we get approval, if we get approval in the U.S., we would be able to start to identify and recognize revenue a lot sooner than we have in Europe.
Operator: And your next question comes from the line of Robert Finke from Guggenheim.
