Sukumar Nagendran: So this first patient had a large deletion, which resulted in a severe phenotype. But to my knowledge, I don’t think — the severity of the genotype is necessarily correlated with the severity of the sleep abnormalities that correlation doesn’t seem to be clear. So — but this patient and Patient 1 had serious sleep abnormalities. And if your question also is that what is the actual pathophysiology behind it, I don’t think anybody fully understands that. But all I can tell you is the clinical observation is that the gene therapy appears to have restored normal sleep patterns. Does that help?
Kristen Kluska: Yes. Thank you so much. Appreciate it.
Sukumar Nagendran: Thank you.
Operator: Our next question comes from the line of Gil Blum with Needham & Company. Please proceed with your question.
Gil Blum: Good afternoon. Let me also add my congratulations on progress. So just one from us. Can you may be put into context the burden experience by adult red patients from being on steroids on a daily basis? And are steroid ever tapered during the standard of care for adult patients during the natural course of the disease?
Sukumar Nagendran: Yes. So that’s another good question. So immunosuppression or immuno modulation, in general, is not used to treat Rett patients in a disease-modifying fashion. It has been tried in the past using drugs like sirolimus or prednisolone or hydrocortisone to treat Rett syndrome, but it hasn’t had any positive impact on disease duration, severity or outcome. So what we’re seeing in our trial though is because it’s a gene therapy trial, steroids and [Indiscernible] being used as immunomodulatory agents to allow us to get all that initial period where there might be some theoretical risk of the treatment itself.
Operator: Our next question comes from the line of Joon Lee with Truist. Please proceed with your question.
Mehdi Goudarzi: Hi, good afternoon. This is Mehdi on for Joon and congrats on the quarter, and that for taking our questions. We have a couple, if I may. First, could you please elaborate on the safety and efficacy of using a fixed dose for patients as young as three years old to adults. And if you expect to achieve a comparable exposure level in the CNS of these patients?
Sean Nolan: The answer to that, I can start would be that the overall CNS fluid volume between a three-year-old and an adult actually is very — there’s very little difference, which is why we’re comfortable the IDMC is comfortable the regulators have all been comfortable based on the preclinical data using that fixed dose in the same — across patient populations, essentially.
Mehdi Goudarzi: And the other question is how do you envision a registrational trial would look like if data supports. And if you think MDRI, as a measure could be considered given the nature of the disease requiring multiple domain improvement analysis.
Sean Nolan: I would say a couple of things. As it relates to clinical trial design, I think the headline is we feel like there’s multiple pathways that we can go down and multiple endpoints that are there for consideration, which is a good place to be at this particular juncture. We’ve always been very steadfast in our view that we were going to use Part A to get to a better informed view and that we would have a discussion with the FDA prior to starting Part B of the study if we wanted to refine endpoints and refine our trial design. So that was one of the reasons we put out a press release out a few weeks ago when we announced that the IDMC had allowed us to go to the higher dose earlier because we think that step will hopefully provide more clarity to us relative to endpoints and potentially trial design as well.
So we can’t say anything declared right now about what exactly we’re going to do. I would say we’re — we continue to be very encouraged of the pathway that we’re on to be further informed in the coming quarters that can help us with the FDA. And I think in terms of the endpoints, again, we know that there’s a pathway there with CGI and RSBQ and there may be additional endpoints for consideration that, again, we think we’ll be better informed on as we continue to step through dosing patients, particularly at the high dose. Hopefully, that makes sense.
Mehdi Goudarzi: Thank you.
Sean Nolan: Thank you.
Mehdi Goudarzi: Yes, thanks for taking our questions.
Operator: Our next question comes from the line of Yanan Zhu with Wells Fargo. Please proceed with your question.
Yanan Zhu: Oh, great. Thank you for taking our questions. Congrats on the progress. So I was wondering since the first patient seeing a pediatric trial has gone through the six-week safety monitoring committee evaluation, wondering is there any color from that patient in terms of improvement that could be consistent with what you are seeing in the adult trial or in general, potential for such improvement in the pediatric population?
Sean Nolan: Really appreciate the question. I just would — I’d go back to — we dosed the first patient, the pediatric patient at the very end of December. And about a week later, we put out a press release saying that we wanted to begin to disclose data on a cohort basis and that we felt that was the most appropriate thing to do versus going patient by patient. And so all I can tell you at this point in time is that the IDMC saw the initial pediatric data as well as the data that we just reported on the two adults. And that was in their calculus as they decided that we could go to the high dose in the adolescent in an adult study, and we could proceed to dosing the second adolescent patients. So beyond that, we really prefer not to comment and foresee our path forward to disclosing that data in a more fulsome manner at midyear.
