Ultragenyx Pharmaceutical Inc. (RARE) Earnings Call Transcript & Summary

Ladies and gentlemen, thank you for standing by. And welcome to Ultragenyx GTX-102 Data Update. [Operator Instructions] I will now hand the conference over to your speaker today, Joshua Higa. You may begin.

Good afternoon. And welcome to the Ultragenyx conference call to discuss preliminary data from the ongoing Phase I/II study of GTX-102 in Angelman Syndrome sponsored by our partner, GeneTx Biotherapeutics. We issued a joint press release earlier detailing the results from the study. Slides covering the study update can be found in our corporate presentation posted in the Investors section of our website at ultragenyx.com. I am Joshua Higa, Director of Investor Relations. With me today is Emil Kakkis, Chief Executive Officer and President of Ultragenyx; and Scott Stromatt, Chief Medical Officer of our partner company, GeneTx. I would like to remind investors that this call will include forward-looking statements, including those related to management's outlook or predictions for future results. These forward-looking statements represent our views only as of the date of this call and involve substantial risks and uncertainties, including many that are beyond our control. Please note that actual results could differ materially from those projected in any forward-looking statement. For a further description of the risks and uncertainties that could cause actual results to differ materially from those expressed in the forward-looking statements as well as risks related to our business, see our periodic reports filed with the SEC. I'll now turn the call over to Emil.

Good afternoon, everyone, and thank you for joining us. Earlier today, we jointly released an interim positive data from the ongoing Phase I/II study of the investigational product, GTX-102, in Angelman Syndrome. I'll provide a brief overview before handing it over to Scott to give more detail. Ultragenyx first started working on Angelman in this program last year when we entered into a collaboration with our partner, GeneTx, to fund and support their extraordinary work and received an option to acquire the company. The GeneTx team is rooted in the Angelman community and was found by multiple leaders of the Angelman patient advocacy group, FAST, including leadership by Paula Evans and Allyson Berent. The critical development work was also managed by Jennifer Panagoulias and Scott Stromatt, GeneTx' Head of Regulatory and CMO, respectively. The FAST foundation, related to the company, GeneTx, funded the seminal research of Dr. Scott Dindot at Texas A&M. His laboratory established a deeper understanding of the antisense RNA regulation of the Angelman locus. This work, a tour de force of molecular biology and detailed molecular analysis, led to the identification of the ideal antisense regions to target with the GTX-102 oligo to unlock the expression of sufficient protein in Angelman. These fundamental data will be published very soon. There are few times when research comes forward, from discovery to a potential therapeutic, in just a few years and even rarer for families affected by the disease to pull together the community and find a potential treatment. Further, to find an investigational treatment that has the potential to change the symptoms of a neuro development disorder like Angelman is unprecedented and provides dramatic encouragement to families and foundations globally that even these rare complex neurologic diseases have the potential to be treated. While the Ultragenyx role has been in funding and support, we are honored to have had that opportunity to help these families reach this important milestone in the development of treatment for a disorder like Angelman Syndrome. We are pleased to report today the first preliminary interim clinical data for the GTX-102 that support the concept that symptoms of Angelman Syndrome may be at least partially reversible by targeting the underlying biology of the disease. In the ongoing Phase I/II study, all the first 5 patients treated have shown substantial improvements in the Clinical Global Impression Scale, or CGI, tailored for some of the key domains of Angelman as described in the press release issued today. The improvements observed spans domains of communication, behavior, motor skills and sleep and are supported by other key measures of development and reports from the principal investigator and caregivers. The improvements began after just a few weeks to a few months of treatment and after the lowest dose in some patients. These are very promising early indication of the activity and provide us with great confidence in moving GTX-102 forward. While we are incredibly encouraged by the early substantial efficacy we have seen in these patients, the study also identified a safety issue that we'll be working to address. At the 2 highest doses, all 5 patients experienced a grade 1 or grade 2 event of lower extremity weakness despite improvements in other domains. Fortunately, all of the patients have fully recovered from this issue, with dosing positive in treatment, while the clinical improvements are generally sustained. Based on the analysis of clinical data and laboratory results, the SAE appears to be related to local exposure to GTX-102, very close to the intrathecal administration site in the lower back and has not been connected to any other SAEs. We believe, based on these data, that we can dose at the lower end of the range and make certain adjustments to the administration regimen to reduce local exposure. We aim to meet with the FDA to discuss our protocol MEM to start research, enrollment and dosing soon. We're very excited about what we've seen to date and are thrilled for the patients of the families in the Angelman community. I will now hand it over to Scott to provide more detail on the interim clinical results and our next steps.

Thank you, Emil, and good afternoon, everyone. As Emil mentioned, I will provide additional detail on the results that are reported today. The study was an inter-patient dose escalation trial to learn about dosing, safety and preliminary efficacy, with the dose range starting very low and ramping up into the projected therapeutic range. 5 patients were enrolled between 5 and 15 years of age, and all of them had deletions in maternal UBE3A gene region, which is the most common genotype in the clinically severe phenotype of this disorder. The 5 patients were treated with a low starting dose and titrated up at each monthly administration, going from the first low dose, to the highest dose that was tenfold greater. 4 patients from the first 2 cohorts received between 3 and 5 total doses, and the fifth patient from the third cohort received a single dose before dosing enrollment was paused due to the serious adverse event. The assessments we are reporting are from day 128 relative to their baseline for patients 1 through 4 and for day 86 for patient 5. Starting with the efficacy results. All 5 patients treated to date have shown a clinically significant response in the CGI-I-AS scale adapted for Angelman Syndrome. This is a 7-point scale that ranges from minus 3 on the low end, to a plus 3 on the high end, with a score of 0 indicating no change. All of these first 5 patients -- excuse me, among these first 5 patients, all had a global rating of much improved or very much improved, the top 2 scores of plus 2 and plus 3. The main change in the global score across all patients was a plus 2.4. Looking at specific domains, the Angelman CGI-I-AS is comprised of 5 domains: communication, behavior, fine motor skills, gross motor skills and sleep. All patients showed some improvement, defined by a score of plus 1 or better on at least 3 of the 5 CGI domain scores. The communication and behavior domains have the greatest overall improvements, with all 5 patients showing a positive change; 3 out of 5 patients improved on the fine motor domain; and 2 of 5 on the sleep domain; with no patients worsened on either of these. The gross motor domain had 2 positive responders; and 3 patients that worsened due to the ongoing lower extremity weakness adverse event at the time of the gross motor assessment. These CGI data are consistent with the results seen from other domain-oriented end points that were implemented in the clinical trial. According to the daily scales of infant and toddler development, all patients have had increases in the expressive communication or receptive communication scores, and 3 of the 5 patients improved to various aspects and communication based on the Observed Reported Communication Ability or ORCA measure. So the positive clinical effect in the CGI, daily and ORCA, are supported by remarkable reports of changes provided by the families of patients treated with GTX-102. The nature of these individual reports align with the CGI domain changes as determined by the physician. Some patients went from being nonverbal, to appropriately using multiple words. While others began to use signs, gestures and augmented communication devices for the first time. Some patients adopted independent capabilities such as using a fork independently for the first time to feed themselves. Others are learning to swim on their own. And others report the ability to follow commands, focus on tasks, respond by name and sleep through the night. In part, due to these reported unprecedented changes, all families have indicated a desire to continue in the study. Overall, these various end points and indications of efficacy are highly complementary and come together to give us confidence that GTX-102 is an active molecule. It is notable that in some patients, the positive changes appear to start in just a few weeks after first treatment with GTX-102. The clinical improvements have also been generally sustained now for 3 months after pausing dosing. For those familiar with Angelman Syndrome, it is well known that progress towards development milestones is slow and plateaus are demonstrated in natural history studies. So the fact that we're able to observe not just any change, but a meaningful and sustained change within weeks to 4 months, is very encouraging. Moving on to the safety results. We have seen a serious adverse event, or SAE, in all the patients of lower extremity weakness with an elevation of protein on the cerebrospinal fluid, or the CSF. The IgG/Albumin ratio is normal, and there is no pleocytosis, meaning there were no inflammatory cells in the CSF. This SAE has been grade 1 or 2 in all patients and led to a reversible inability to walk or bear weight in 2 patients. The SAE began in the first 4 patients after receiving a dose that was approximately 10x higher than the lowest dose. In the fifth patient, the SAE began after receiving a single dose that is about 6x higher than the lowest dose used in the study. The SAE was not observed at any dose lower than that of the second highest dose, beside the fact that indications efficacy started out low as well as the initial lowest dose level used in the study in cohort 1. The dose titration above the lower levels occurred according to a fixed schedule in the study protocol rather than being based on observed efficacy. And all clinical improvement occurred at doses well below the projected effective dose range derived from nonclinical research. GeneTx and Ultragenyx paused dosing per protocol after the first SAE in order to monitor the safety event and observe the ongoing clinical improvements. The patients' physicians began treatment with IVIg and corticosteroids. The most severe aspect of the neurologic findings substantially resolved within a few weeks of their peak symptoms. The SAE has since completely resolved in 4 patients and almost completely resolved in the remaining 1 patient. The time course for resolution of SAE is much faster than the change in the clinical improvements which have been sustained for much longer. Based on MRI evaluations, the lower extremity weaknesses associated with local inflammation at the meninges and nerve roots in the lumbosacral region in the lower back due to exposure of GTX-102 during intrathecal administration, consistent with the location of where the drug is being injected. The CSF protein elevations are similar to what have been reported with other intrathecal antisense oligonucleotides. There has been no indication of inflammation in the brain or weakness in the upper extremities. There have been no other SAEs in the trial to date. Other nonserious adverse events include transient ataxias, fatigue and headache. There have been no reports of patients withdrawing from the study. And as we indicated earlier, so far, the families of all 5 patients have indicated the desire to continue participating in the study. For next steps, the study protocol is being amended to implement changes that are expected to reduce local tissue exposure to GTX-102 at the point of administration during the lumbar puncture and intrathecal injection. Dosing will be lower to a range in which safety was adequate but efficacy was still observed. Dose titration will be based on clinical response as measured by CGI-I-AS and safety on an individual basis. And any titration of dose will occur according to a slower schedule. The administration process will also be modified to minimize the duration of concentration of ASO exposure at the injection site. The companies have provided the FDA with information on the SAEs on a prompt basis as well as high-level information on the efficacy we observed. We plan to submit an amended protocol to the agency shortly for their review. It is anticipated that enrollment and dosing will resume in the next couple of months after discussion and approval by the FDA. Data from patients under the revised dosing regimens are expected in 2021. We will be presenting more detail on these results, and an update on these 5 patients at the FAST Virtual Summit for Angelman Syndrome Research in December of this year. With that, I will hand it back to Emil.

And thank you, Scott, and the rest of the GeneTx team that has been driving this program forward. With your efforts, we have put the first ASO into the clinic for Angelman Syndrome and have now demonstrated the first potentially disease-modifying effect by targeting the underlying disease biology. We also want to thank the patients and their families and the investigator, Dr. Liz Berry-Kravis, for the contribution of the diligence in the clinical study despite the incredible circumstances this year. We believe these data demonstrate that we have an active product with the potential to treat Angelman Syndrome. The SAE we have seen is an important safety issue for us to work through, but the potency and the results assure us of the importance advancing the program to achieve the best outcome for patients. Partially, we believe the safety channels are manageable by adjusting dosing and administration. The GTX-102 program has now quickly become an important piece of Ultragenyx' pipeline due to the meaningful results we are observing and the extent of the unmet need in this relatively larger rare disease population. When combined with our gene therapy program and with other pipeline in progress and the commercial launch of the 3 products in 4 indications, we had our special moment in our history with the potential to improve the life of a patient, with 5 more diseases in development, in addition to the 9 diseases for which our commercial products are approved today. This concludes our prepared remarks. So I will now open the call up to questions. Operator, please provide the instructions for the Q&A.

[Operator Instructions] Our first question is from Maury Raycroft with Jefferies.

Congrats on the efficacy proof of concept. On the safety side, do you know if the inflammation is related to the repeat dosing and development of immunogenicity? Or is it related to the dosing and administration? And I guess, do you know if it's more related to the dosing or the route of administration?

Well, thank you, Maury, for the question and the congratulations. At this time, it's early yet, but this is not likely due to just lumbar puncture itself. This is not something normally associated with lumbar puncture. This is related to the GTX-102 drug and its local action. We do not believe there is an immunological component of this. This is probably a direct toxicity. And antisense oligonucleotides are known to have toxicities of this kind, potentially, but not this particular pattern of clinical finding. So at this point, we think it's related to a local effect of GTX-102.

Got it. And you mentioned a potential to minimize the duration of exposure at the injection side. Is that primarily slowing the course of delivery? And I guess, can you provide some more specifics on that?

Well, it's -- we're hoping to change the administration to improve the degree at which the drug flows toward the brain by tilting the patient and using a flush to help move the drug forward and away from the lower back. The lower back area's where the drug is applied, and we're just trying to reduce the concentration of drug that sits at the bottom of the cord, which will help it move towards the brain. And we think it's a pretty traditional thing. It's been done widely. And we feel pretty comfortable it should help.

Got it. And last quick question, if you can say anything more about changes on some of the exploratory measures in the low versus higher doses. And could we see some of those data at the December update?

We haven't run all the data on the general end points right now, so we don't have them. We will present them at the FAST meeting. So that's what -- you'll have to wait for that. But right now, we feel very comfortable with what we're looking across the board with the data we run and what we're seeing in the patients, that we're seeing efficacy across the domains, even beginning at the lower dose.

Our next question is from Cory Kasimov with JPMorgan.

This is Turner on for Cory. So I'm just hoping you could elaborate on just how much benefit was seen at the lower doses before the lower extremity weakness was observed. Were you able to see improvements in multiple domains? Or was that only really seen at the higher dose levels?

Yes. We saw improvement in multiple domains in the early period that is fine motor changes and kind of language changes. All the changes you're talking about were seen at the lower doses. The challenge is that, at each dose, the patient has got one dose and went on to the next dose. So we didn't have a chance to repeat-dose a patient at the lower doses. We would expect, if you repeat-dose at a lower dose, you would accumulate -- if you're dosing on a monthly basis, you would accumulate drug and drug effect. And that is why we feel comfortable we'll be able to achieve what we need to achieve. And so the dosing effect was across a series of domains. And we feel pretty comfortable that if we can repeat-dose in the low end of the safe range, that we should be able to accumulate enough drug to have a benefit.

Our next question is from Gena Wang with Barclays.

I have a few as well. First, just wondering, Emil, if you can give a little bit more color regarding the actual doses you've used. But just as a reference, I think Spinraza is using 12-milligram per dose. And also, you mentioned a little bit about the CGI improvement, at what dose have you started to see the improvement? And lastly, just wondering regarding the CSF protein level, you said it had elevation. I'm just wondering what kind of protein had the elevation.

Thank you, Gena. We have -- for proprietary reasons, haven't put forth the actual drug concentrations at this time. We will, at some point, but right now, we haven't. What I can say to you is that there are concentrations that are not unexpected within the ASO field, but we haven't decided to put those forward. What we can say and have said is that the GTX-102 molecule is a very potent drug. What -- we have said that, and what I have just said a moment ago, was that we were seeing efficacy in multiple veins at the lower dose. But because we stepped up, we couldn't -- we didn't have a chance to see that dose given repeatedly because they moved up to the next dose level. Is that helpful?

Yes. Yes. And then for the CSF protein?

Oh, the CSF protein, well, the CSF protein is basically -- we said that the ratio of IgG and Albumin was normal, which means it's like serum protein. So it's an indication that there's a little bit of inflammation in the meninges that are leaking some of the serum proteins into CSF. This is a common thing that's been seen in many ASO programs. And what we are seeing here is very similar to those other ones that have been reported in the literature, both in clinical trials and elsewhere.

Okay. And just one last question. When we look at the Spinraza safety profile, they actually don't have this toxicity. Any thoughts -- you did mention it could be specific to the drug, but any other thoughts in terms of the mechanism or chemistry that could be related?

See, the protein piece has been seen across many different types of ASOs. So the elevation of CSF protein has been commonly seen. So I think that's been reported across the board. Spinraza has its own set of different findings. The particular finding of the nerve roots and meninges here causing the weakness is more distinct to this program. I think it's potentially due to the chemistry or it could be due to the nature of these patients, the Angelman patients and some differences that exist. We cannot tell which one of those it is. It was not observed in the toxicology program. So we believe that it's something unique.

Our next question is from Salveen Richter with Goldman Sachs.

This is Andrea on for Salveen. Maybe one for us. If you could just speak a little to the clinical threshold for benefit on the CGI-I-AS score. And then I would love to hear your thoughts on -- or maybe additional color on the baseline status of the patients and how meaningful the plus 2, plus 3 scale improvements are.

Yes. I can -- the CGI scoring system basically sets plus 1 as being minimally improved, but plus 2 is much improved and 3 -- plus 3 is very much improved. In general, when you're looking at trial drugs that do work, you normally would see something around 1 plus. To get to 2 plus or 3 plus is generally more challenging in even other drug programs. In this case, we're looking at individual Angelman domains. And we've given you both scores for the global score, how the investigator feels the patient is doing overall, but also specific scores for different domains. And then each patient had at least 2 domains that were up plus 2 or plus 3 that is much improved or very much improved. The only way to calibrate for you is really refer to the individual patient responses, I think, which were, I think, very distinctive. So we talked about receptive communication. Some patients scored plus 3 or plus 2. All of them had an improvement. In that case, what we're talking about are patients who were nonverbal, who are now using words for the first time, and one of them getting up to 9 words of language. Patients unable to listen and hear their name and respond to their own name are now responding to their name and following instructions. So these are fundamental changes in receptive communication, are extraordinary for families that are interacting with these patients. Fine motor or care issues like being able to feed yourself with a fork are being observed for the first time. That's in the fine motor category. And if you look at that and then certain other things like sleep, patient 5 had a very strong result in sleep. He had been awake 3.5 hours a night for most of his life, with his parents up following him around, and he is now sleeping through the night. So he had a very dramatic effect on sleep. So when we talk about plus 2 and plus 3 in these patients, we're talking about fundamental and critically important changes. These are not subtle things. And this is why the parents are extremely motivated. And if you've read Dr. Berry-Kravis' quote, you can tell her own excitement of what we're observing.

Our next question is from Tazeen Ahmad with Bank of America.

Emil, maybe just one for me. I just wanted to get your thoughts about the observation of ataxia 2 to 6 hours after injection for the patients that are being studied. Is that rate-limiting in any way? Have doctors talked about that particular observation? And as it relates to your earlier comments about being able to distribute drugs to the brain away from the lower back, would that become an issue if patients have to be positioned a certain way?

Thank you. The pattern of having some weakness, possibly ataxia weakness, in the first few hours after intrathecal antisense oligonucleotide has been seen in other programs and other places, it's also seen in nonhuman primates. And so it's something that we've seen across and appears to be a class-specific effect that's local. We don't think that would have any -- that pushing more drug to the brain through the positioning would change, would increase or worsen that. So we're comfortable that should improve the outcome for these patients. But it's a widely known class effect that you observe.

Our next question is from Laura Chico with Wedbush.

I have one on the onset of efficacy that you're seeing here. I guess, how does the onset of activity compare with the preclinical data on your prior expectations? And were you anticipating seeing this rapid of an onset of activity? I guess any color here.

Well, in the animal studies, we had seen very good induction at relatively low doses. But based on those levels, we had projected that they would need to get to the highest dose in this titrating regimen. So the dosing effect in the humans was perhaps more potent than we first saw. We've had data now suggesting that we can get the pharmacokinetic attack the target engagement and the induction of UBE3A production at relatively lower doses with the oligonucleotide. The timing for effect -- remember, the 9 primates are the -- in those studies, don't have the Angelman Syndrome, so therefore, we can't really look at clinical benefit going on in those patients. We can only look at the target engagement. And we've shown that you can get engagement at a relatively low dose and show that, that expression seems substantial and should be sufficient in humans. What we're finding, I think, in our trial is that the level of potency is even greater than we expected and that the speed was faster than we expected. Certainly, inducing the expression of UBE3A, we didn't expect to see clinical changes happening within weeks of a first dose as we see in some patients. I think that's an extraordinary result. And to see -- as many changes we've seen over a period of a few weeks to a few months as we put forth, I think, is really extraordinary and far beyond what we were expecting. We assumed this would take months to maybe a year to see changes in these patients. So this is far faster than you would have expected from any animal work in the past. And that's why we're particularly excited about the effect we're seeing in these patients.

Okay. I appreciate that context. Maybe one last question then. I guess -- and I apologize, I think I'm just confused here. But with the dosing pause, would you anticipate seeing the gains reverse then since they're not receiving drug? And I think I heard that you were seeing clinical changes corresponding with UBE3A protein levels in the CSF, but I just wanted to clarify on that.

Yes. What we said was that in the patients who had benefit were showing -- all the patients were showing benefit. We've seen, in general, a sustained benefit over a 3-month period. Some patients were even continuing to gain ground. So we've seen at least 3 months of benefit, even as the SAE has resolved, their clinical benefits sustained at least for 3 months for some patients -- most patients. With regard to the UBE3A protein, we haven't reported on that. That is information that we would expect to come out later in the year. It's one of the pieces of data we haven't reported on.

Our next question is from Yaron Werber with Cowen.

I mean the efficacy is -- congrats on the efficacy and especially to the GeneTx family. And we know how important this is for you. Just a quick question on -- if you don't mind, number one, just remind us, the chemistry, Emil, it's very safe, Emil, right? So it's very similar to Spinraza, if we remember correctly. Is that correct?

Yes. So chemistry is very similar to Spinraza, yes. It is very similar. The specifics haven't been put out, but the -- it is very similar to Spinraza.

And is the dosing -- can you comment, is it monthly in the study?

In the study, we were dosing once a month and titrating up at each dose. So each patient got one dose and went up to the next, and up the next on a monthly basis.

Yes. And is the clinical benefit -- I mean do you -- is it -- is the benefit -- is the improvement sort of accumulative? Does it get better each month? Or does it happen very quickly?

Well, we observed effects within the first few weeks, and first few weeks to first couple of months, in all the patients. Over time, certainly, the patients continued to gain ground. But the effects were seen in multiple domains really after the first or second dose.

Okay. And in terms of UBE3A, and I know you can't share the data. But if you guys developed a good assay, can you detect it in the CSF? Or is it really intracellular?

Well, it's something we're still working on with regard to the science of UBE3A. Obviously, it's intracellular protein. So its presence in the CSF has to be sourced from there. But at this point in time, we can't really comment on more detail about UBE3A. I will say, though, Yaron, that our original focus on UBE3A was just to figure out if we're dosing enough because we weren't sure if we're going to see anything clinical. But once you see clinical effect, well, then you don't really need the UBE3A as much. If you know what's going on clinically, it changes your whole mindset. So while there was a focus on biomarkers that we thought maybe it would take a year or 2 to see something clinically, when it's working in a matter of weeks, then you have clinical things you can follow and the fact that, that dynamic gives you a tremendous upside in terms of how to manage the program, optimize dosing and design up a study which should receive approval. So I think I'm less concerned about the biomarkers since we kind of know we can see what's happening and we know what we're seeing.

Yes. And I don't know if you can comment, patient 2, 3 and 4, I mean, there is variability in these patients on the gross motor side. And especially when you're talking about lower extremity and potential ambulation, not everybody is ambulatory, obviously. Anything that you can comment about 02, 03 and 04 patients as to what their baseline function was? Were they ambulatory? How strong were they?

Yes. Well, let me point out that the data in the table are at the -- those 3 had their SAE going on at the time. So they were -- and they were having gross motor improvement, by the way. It's just the timing of when that occurred. Now Scott, I don't know if you want to say anything more about patient 2, 3 or 4 in terms of their baseline...

Yes. All the patients that were enrolled in the study, part of the inclusion criteria was that they had to be ambulatory, either independently, with a device or with a handhold from a caregiver. So they all were able to ambulate.

Okay. Okay. If you don't mind, just a couple of more. Did you look at seizure behavior? It's obviously not a part of the scale, but have you looked -- was there any improvement?

We're collecting it. We haven't reported on -- we have reporting on chemistry. We haven't reported as you see on the seizures at this point in time. We'll have that data together for before. So we were not commenting on it yet. But we'll be providing that later in December.

And did you see any platelet effects or anything in the kidney, any kidney changes?

We didn't have any other AEs -- yes, we reported on the AEs we had observed.

Yes. There is no change in renal.

Yes.

Yes. And the final question for me, I promise. I mean is it possible that this is literally localized inflammation at the level just impinging that level of the spinal cord, and that's what it resolves. But I'm trying to get a sense. Is there any kind of broader meningeal or actually spinal sort of nerve inflammation? Or is it just literally localized inflammation and edema that's impinging, and over time, it resolves?

Yes. Yaron, it's very local, and the amount just depends on how big the patient is. So it's very clearly a physical location of where the drug is, depending on the size of the patient. It's all down in the lumbosacral region. It's pretty clearly related to where the drug lands when it's first provided. That's why we feel pretty comfortable that we can -- my answer, we're not seeing inflammation elsewhere as we noted in the spinal cord and the brain or anywhere else. Good?

Thank you so much.

Very good, Yaron. Thank you.

Our next question is from Joseph Schwartz with SVB Leerink.

I just had one. So I think it's really interesting and encouraging that you have such strong and consistent benefits on the communication domain, particularly because these patients have a genetic deletion. So I was wondering if you can characterize that for us, how large were the deletions because it's my understanding that the communication is particularly challenged in patients with large deletions. So were you able to characterize the deletions and provide us with any insight on that?

Sure. So the inclusion criteria required that the patients had a deletion type. I don't know, Scott, if you want to say anything more about the size of deletions. I don't think we have that information.

Yes. The protocol required Class I and II deletions. There's a debate about whether the size of the deletion really matters in terms of communication by -- affected by the size.

Our next question is from Yigal Nochomovitz with Citigroup.

I was also struck by the quality of the results for the communication domain. Looks very impressive. But I was just wondering, that -- the signal that you saw there was that spontaneous acquisition of language over a relatively short period of time, which would be very, very interesting. Or was there any teaching or coaching of words to help some of these patients increase their vocabulary? Or was it all really spontaneous acquisition of language without any additional scaffolding.

Thank you. So the basic protocol, patients were on what they're on. And maybe I can -- I'll ask Scott to finish here. But the things that were occurring appear to be spontaneous, happening within weeks, so it would be highly unlikely to be related to a training effect in that time frame, particularly since as Scott noted, their natural history is they don't really change that much over many years for these patients. Scott, was there anything else you want to speak to with regard to the issue of, yes, training or...

Yes. Yes. I think all these children, between 5 and 16, are in various schools and therapy sessions. So there wasn't anything additional applied. If anything, it was decreased because of COVID. So some of those schoolings were decreased, and so there's just a normal family interaction. So it's quite remarkable to see the changes that were reported.

Our next question is from Jeff Hung with Morgan Stanley.

I might have missed this in your answer to Yaron's question, but was gross motor domain measured for patients 2 to 4 before the time of SAE? And if so, what were they?

I don't know if I had the scores before. I'll ask Scott in a moment to comment. But I know the reports we were getting is that they were improving as well. And then when the SAE came on, they declined, and then they've come back -- some of them now back to their post-baseline improvement. So we were seeing improvement in gross motor in the patients before the SAE. Scott, I don't know. We don't have, I don't think, data yet for the other earlier time points at this point.

Right.

Or at least that we've put out.

They all had to be ambulatory to come in. And we did see improvement in patients before the SAE. As the SAE resolved, they returned back to their post-dosing improvement. And so we'll be glad to share more of that in December.

Okay. And then how should we think about the expected timing of the protocol MEM getting implemented before you're able to resume enrollment?

I think we noted in Scott's text that we're talking about, in the next couple of months, getting us into FDA and moving ahead. We're -- we worked through all the plan, and we will be discussing collaboratively with FDA. They've been very collaborative with us, and I think very helpful in working through the program. And so we'll -- that will be in the next short period, a couple of months, we think. And we hope then to resume dosing.

And sir, I'm not showing any further questions in the queue.

Very good. Thank you very much. Anyways, I think what we -- hopefully you've gotten from the press release today and our call is that GTX-102 is a potent and powerful compound that we're showing exciting interim results. It's still in investigation. There's still much more to do. But the ability to change fundamental aspects of communication behavior, sleep, fine motor function in a matter of weeks to a few months, I think, is extraordinary and far beyond my personal expectations for the program. And the serious adverse event is something we have to manage, but I think, actually, it's extremely -- it's understandable what we're seeing and I think it's something we can manage well, so I feel comfortable we will be able to get through. And I think to have a drug with this level of potency is something you -- don't happen too often in your career, and that certainly, in all my years, I've never seen a drug that improved developmental function in any patient for anything. Most of the time, you're hoping them not to get worse. And to see patients getting better in these fundamental ways and having first ever in their lives, I think, is extraordinary. And we're excited and thankful to the GeneTx team and FAST organization that put this together and put us in the position of making an important difference for Angelman patients. So while we have more to do, we are extremely excited about what we've seen and pleased to be able to be in the -- I mean, to have the opportunity to change the future for Angelman. Josh, can we take this out?

Sure. Thank you. This concludes today's call. If there are additional questions, please contact us by phone or at [email protected]. Thank you for joining us.

Ladies and gentlemen, this concludes today's conference call. You may now disconnect.