Good day, and welcome to the Scholar Rock Conference Call. At this time, all participants are on a listen only mode. After the speaker's presentation, there'll be a question and answer session. To ask a question during the session, you will need to press star then one on your touchtone telephone. If anyone should require assistance during the call, please press star then zero to reach an operator. As a reminder, this call is being recorded. I would now like to turn the call over to Rushmie Nofsinger, Vice President of Investor Relations and Corporate Affairs. You may begin.
Good morning, and thank you for joining us on today's call to review the 24-month extension period results from our TOPAZ phase II clinical trial of patients with type two and type three spinal muscular atrophy or SMA. The webcast slides for this call can be accessed on the Events and Presentation section of the Investor Relations page on the Scholar Rock website. I wanted to note that we'll be making various statements about Scholar Rock's future expectations, plans and prospects that constitute forward-looking statements for the purposes of the safe harbor provisions under the Private Securities Litigation Reform Act of 1995.
Actual results may differ materially from those indicated by any forward-looking statements as a result of various important factors, more fully discussed in the section entitled Risk Factors in our quarterly report on Form 10-Q for the quarter ended March 31st, 2022, as well as other important factors in Scholar Rock's future filings with the Securities and Exchange Commission. Any forward-looking statements represent our views only as of today, and should not be relied upon as representing our views as of any future date. We disclaim any obligation to update any forward-looking statements unless required by law. Next, let's review the agenda for today's call as outlined on slide three. Nagesh Mahanthappa, our Founding President and CEO, will provide opening remarks.
Yung Chyung, our Chief Medical Officer, will review the new data from the TOPAZ trial extension period and provide a brief overview of the ongoing phase III SAPPHIRE trial. Nagesh will be joined by Ted Myles, our Chief Operating Officer and Chief Financial Officer, to provide a business update. We will take questions at the end of the call. Thank you, and I'll now turn the call over to Nagesh.
Thank you, Rushmie. If we could turn to slide four. I would like to just remind everybody the focus of Scholar Rock is on the discovery and development of novel monoclonal antibody therapeutics. Our unique platform it directs cutting-edge antibody discovery technologies towards protein growth factors, making use of cutting-edge structural biology insights. More particularly, we are focused on members of the TGF-beta superfamily. What distinguishes our approach is the fact that we actually target protein growth factors in their precursor or pro forms rather than the mature growth factor. We believe this offers a novel pharmacological profile across multiple members of the TGF-beta superfamily, as exemplified by our clinical stage programs. If we could turn to slide five.
As a quick reminder as to the disease on which we are focused in our current phase III program and the phase II program that we'll be discussing today, is spinal muscular atrophy, or SMA. SMA is a rare neuromuscular disease that causes, from a genetic origin, death of motor neurons. Subsequent to the death of the motor neurons is a lack of control of skeletal muscle and atrophy of those muscles. There are now three approved therapies for the treatment of spinal muscular atrophy, all of which are intended to increase the survival of motor neurons. However, significant deficits remain, and we believe a muscle-targeted therapy has the potential to make a very significant impact on these patients.
In point of fact, Apitegromab has already demonstrated great promise in phase II TOPAZ study when we reported the 12-month data, and today we're excited to talk about the future of this program. Now, if we can turn to slide six. I think many of you are aware that spinal muscular atrophy presents as a, in a spectrum of severity, with type one being the most severe through type two and type three. The focus of Scholar Rock at present is on type two and type three SMA, which from a prevalence perspective represent a vast majority, approximately two-thirds of all SMA patients living today. In the U.S. and Europe, this constitutes approximately 30,000-35,000 patients. Now, beyond the demographics, let me turn to the nature of the unmet need on slide seven.
The Hammersmith Functional Motor Scale Expanded is a validated assessment of motor function in patients with SMA. A maximum score on the HFMSE is 66. This is an evaluation of 33 distinct tasks scored zero, one, or two. The data we're showing you on this slide is representative data from the phase III study of type two and type three SMA patients in the CHERISH trial with Spinraza. These patients, on average, without treatment, show a score in the high 20s. Now, with treatment, you see improvements on the order of four to five points, which is very significant for the patients, but I think you'll see that there's still a long way to go to reach that score of 66. Much opportunity for a muscle-targeted therapy.
Now, if we turn to slide eight, again, just to talk about the efficacy of drugs that are SMN upregulators, such as nusinersen Spinraza or risdiplam Evrysdi. You can see that these drugs do in fact make a significant impact for patients over the initial dosing period. In both cases you see that patients start to plateau. It is here that we believe that there's opportunity to further increase the levels of muscle strength and muscle function in patients with SMA. The data that we'll look at today for the 24-month readouts from the continuation of the TOPAZ study underscore our belief in the potential of this drug and why it is we're so excited to be in the middle of our phase III pivotal SAPPHIRE study as well. With that, let me turn it to our Chief Medical Officer, Dr. Yung Chyung.
Thank you, Nagesh. I want to take a moment to thank the Scholar Rock team for all their hard work and contributions. We are also very impressed by and appreciative of the outstanding effort and contributions from our clinical trial investigators, physical therapists, study coordinators, study site staff, and our CRO colleagues. Most importantly, thank you to the patients and their families for their dedication to the trial despite the challenges of the ongoing COVID-19 pandemic. Let's now direct our attention to the TOPAZ trial, starting with slide nine. In a moment, we will walk through the 24-month analyses and data. Later today, at the annual SMA Research & Clinical Care Meeting, the detailed 24-month TOPAZ results will be presented as a podium presentation by Dr. Thomas Crawford of Johns Hopkins Medicine and the lead principal investigator of the TOPAZ trial.
As an initial overview of the study results, we observed sizable and sustained motor function gains in the non-ambulatory type two and type three SMA population treated with Apitegromab in use with background nusinersen, as measured by the primary efficacy measure of HFMSE. There was also evidence for continued improvement in the Revised Upper Limb Module, a key secondary outcome measure, as well as continued observation of a dose response. In the ambulatory type three population, there was generally stability observed in the Revised Hammersmith Scale measure of motor function for the subgroup of patients receiving Apitegromab in use with background nusinersen, and there were no identified serious safety risks based upon these 24-month analyses. We are pleased with the results of this 24-month TOPAZ readout as they further reinforce our enthusiasm about the therapeutic potential of Apitegromab.
Now let's move to slide 10 to briefly review the TOPAZ trial design. This phase II proof of concept trial consists of three parallel cohorts, each evaluating a distinct subpopulation of patients with type two and type three SMA. All patients were treated with Apitegromab in this trial, and the primary treatment period was 12 months. Two of the cohorts enrolled non-ambulatory patients who were already receiving background nusinersen therapy. One cohort evaluated patients who had previously initiated nusinersen treatment before five years of age, and another cohort evaluated patients who had previously initiated nusinersen treatment at the age of five or older. Within cohort three, patients were randomized to receive either a high dose or low dose of Apitegromab. This study also evaluated ambulatory type three SMA through a separate cohort.
Patients in this cohort, which were treated with either Apitegromab as a monotherapy or in combination with background nusinersen. Going to slide 11. This slide shows the baseline characteristics of the TOPAZ patient population. As a reminder, patients receiving background nusinersen in this trial were well into the chronic maintenance phase of SMN treatment at baseline, receiving on average approximately five doses prior to enrollment, which corresponds to roughly two years of nusinersen. As outlined on slide 12, following the 12-month primary treatment period, patients were offered the option of participating in an extension period to continue receiving Apitegromab treatment for another 12 months. All 57 patients who completed the primary treatment period opted to enroll in the extension, and 55 of these 57 patients completed the second year of treatment. Patients originally assigned to the high dose of Apitegromab stayed on this high dose.
Patients originally assigned to the low dose were all switched to the high dose during year two. The precise timing of the switch varied from patient to patient, as each individual had a different duration of study participation prior to the dose switch being done across the group. As an additional note, there were a small number of individuals in the TOPAZ extension period who underwent scoliosis surgery as part of routine standard of care for their underlying SMA disease. In addition to the main analysis approach, we also conducted a supplemental analysis that took into consideration the potential after effects of scoliosis surgery. Finally, as of the beginning of this month, 54 patients continue to participate in the TOPAZ extension. As a refresher on the primary efficacy measure in TOPAZ of HFMSE, let's advance to slide 13.
The HFMSE is a validated endpoint used in SMA trials, including serving as the primary efficacy endpoint for nusinersen in the phase III CHERISH trial. It encompasses 33 distinct measures of an individual's ability to perform various tasks, including raising a hand to head in a standing position, rolling to one side, standing for three seconds while supported by one hand, or ascending or descending four steps. Each task is scored as zero, one, or two points, in which zero means you cannot perform the task, two means you can, and one means that it can be done either partially or with adaptation. These tasks are important and relevant to individuals living with SMA, which is why we believe a one-point gain has the potential to make a meaningful difference for an individual with SMA, let alone a three-point or even greater increase.
Let's now go to the HFMSE data on slide 14. There were sizable and sustained gains in the HFMSE observed after two years of Apitegromab treatment in patients from the non-ambulatory TOPAZ cohort receiving background nusinersen therapy. The results shown here were based upon an observed case analysis approach using the data available for a given time point. This analysis population includes patients treated with the low dose as well as patients treated with the high dose and does not exclude any patients who missed Apitegromab doses due to COVID-19 site access restrictions. The graph on the left-hand side pulls together the full population of cohort two and cohort three patients. After 12 months of Apitegromab treatment, there was a mean HFMSE increase from baseline of 3.6 points.
After 24 months of Apitegromab treatment, there was a mean HFMSE increase from baseline of 4.0 points. The graph on the right-hand side looks at the exploratory subset of pooled cohort two and cohort three patients who are in the age range of two to 12 years old. Here, after 12 months of Apitegromab treatment, there was a mean HFMSE increase from baseline of 4.6 points. After 24 months of Apitegromab treatment, there was a mean HFMSE increase from baseline of 4.6 points. Together, we believe that these 24-month HFMSE results from the ongoing TOPAZ extension highlight the therapeutic potential of Apitegromab in patients with non-ambulatory type two and type three SMA receiving SMN therapy. We look forward to investigating that potential further through the randomized double-blind placebo-controlled phase III SAPPHIRE trial.
As a reminder, there were a small number of individuals who underwent scoliosis surgery during the TOPAZ extension period as part of routine standard of care for their underlying disease. It can be informative to have a supplemental look at the HFMSE data which takes into consideration the impact of such surgery. Slide 15 provides further background on this topic. Scoliosis is a common complication of SMA leading to surgery in many individuals. In this natural history case series of 17 patients with type two or type three SMA who underwent scoliosis surgery, most patients had subsequent decline in their HFMSE of at least three points. In fact, among the 14 individuals with such a loss, the mean HFMSE change was a 12-point decrease after undergoing scoliosis surgery. With this as background context, please turn to slide 16.
If we exclude data following scoliosis surgery in the TOPAZ extension period, then the mean HFMSE change from baseline after 24 months of treatment was a 4.4-point increase in the full pooled non-ambulatory population. For this analysis for the age two to 12 subgroup within the pooled non-ambulatory cohorts, the mean HFMSE change from baseline after 24 months of treatment was a 5.2-point increase. Advancing to slide 17, let's look at the effect of different doses of Apitegromab upon efficacy. We continue to observe a dose response based upon the mean HFMSE change from baseline through the second year of Apitegromab treatment. This graph displays cohort three data by dose level and use the observed case analysis approach with exclusion of data following scoliosis surgery in the TOPAZ extension.
Here, the high dose of 20 mg per kg numerically outperformed the low dose of 2 mg per kg in terms of mean HFMSE change from baseline across every time point in the two-year treatment period. As patients in the low dose arm switched to the high dose treatment at various time points in the second year, there were signs suggesting that this group may have had further increases in their HFMSE. Turning to slide 18, the PK and target engagement data provide further color in interpreting the dose response. On the left graph, you can see that the 20 mg per kg dose offered high levels of drug exposure relative to the 2 mg per kg dose. As one would expect, the dose switch to the high dose in the originally low dose treated patients led to increases further in the serum drug concentration.
The right graph shows the effect of the two and 20 mg per kg apitegromab doses upon levels of serum latent myostatin, which we use as a marker of target engagement. Both the two and 20 mg per kg doses led to high levels of target engagement as reflected by the greater than 100-fold increases from baseline in the systemically circulating concentrations of latent myostatin after treatment. The 20 mg per kg dose, however, led to higher mean increases from baseline of latent myostatin relative to that from the 2 mg per kg dose. As patients treated with the low dose switched to the high dose, there were further increases. Based on these results, the pattern of dose response seen with the target engagement marker appears consistent with the pattern of dose response observed with the HFMSE results.
Let's now turn our attention to the results of the secondary outcome measure of Revised Upper Limb Module for SMA in TOPAZ. As background on slide 19, the Revised Upper Limb Module, or RULM in short, evaluates motor task performance in the upper limb. This measure evaluates a patient's ability to perform 19 different activities, such as bringing a cup to one's mouth, picking up a coin, opening a Ziploc bag, or drawing a line on a paper, and the maximum achievable score is 37 points. The RULM is validated for SMA and has been used previously by other drug development programs in SMA as an important secondary endpoint. Slide 20 shows the RULM results in TOPAZ based upon the observed case analysis approach. The graph on the left-hand side pulls together the full population of cohort two and cohort three patients.
After 12 months of Apitegromab treatment, there was a mean ROM increase from baseline of 1.3 points, and after 24 months of the Apitegromab treatment, there was a mean ROM increase from baseline of 1.9 points. The graph on the right-hand side looks at the exploratory subset of pooled cohort two and cohort three patients who are in the age range of two to 12 years old. Here, after 12 months of Apitegromab treatment, there was a mean ROM increase from baseline of 1.2 points. After 24 months of Apitegromab treatment, there was a mean ROM increase from baseline of 1.8 points. Slide 21 provides further insights into these results by taking into consideration the impact of scoliosis surgery.
If we exclude RULM data following scoliosis surgery in the TOPAZ extension period, then the mean RULM change from baseline after 24 months of treatment was a 2.3-point increase in the full pooled non-ambulatory population. For this analysis, for the age two to 12 subgroup within the pooled non-ambulatory cohorts, the mean RULM change from baseline after 24 months of treatment was a 2.2-point increase. These RULM results support the potential of Apitegromab in impacting upper limb function, which is of particular importance for individuals with SMA who are non-ambulatory. Let's now look at HFMSE and RULM together in considering the motor function effects of Apitegromab by turning to slide 22. Represented here are scatter plots in which each individual patient's data are represented by a dot.
As the 24-month data on the right-hand side illustrates, there was a correlation between the observed changes in HFMSE and that in the RULM. Notably, the majority of patients experienced improvements from baseline in not just one, but both of the HFMSE and RULM measures after 24 months of treatment. The HFMSE and RULM are two independent but logically related measures of motor function, and the results here provide further support for the therapeutic potential of Apitegromab. Let's now direct our attention to cohort one, evaluating ambulatory type three SMA, as summarized in slide 23. In the subgroup of patients treated with Apitegromab while receiving nusinersen, motor function as measured by the RHS was generally stable with a mean change from baseline of -0.7 points after 24 months.
In the subgroup of patients treated with Apitegromab as monotherapy, the mean RHS change from baseline was -2.8 points after 24 months. Of note, there was a subset of individuals across the full ambulatory type three SMA cohort who had improvements in RHS after 24 months of treatment, as approximately 40% of individuals had at least a one-point increase from baseline, and approximately 20% of individuals had at least a three-point increase from baseline. We find the results from this cohort one analysis to be encouraging and support further exploration of the therapeutic potential of Apitegromab in ambulatory type three SMA. Now let's move to slide 24 to review the safety results from this 24-month TOPAZ analysis, which did not identify any serious safety risks from Apitegromab treatment.
The incidence and severity of adverse events were consistent with the underlying patient population and background therapy, with the five most frequently reported treatment emergent adverse events, or TEAEs, being headache, pyrexia, upper respiratory tract infection, cough, and nasopharyngitis. No deaths or serious unexpected adverse reactions were reported. Adverse events continued to be reported as mostly mild to moderate in severity, as observed in the 12-month analysis. Together, the safety results further support the continued evaluation of apitegromab through our clinical trial program. The next slide 25, summarizes key highlights from this 24-month TOPAZ data readout. In the non-ambulatory type two and type three SMA population treated with apitegromab plus background Nusinersen, sizable and sustained gains in the HFMSE were observed, together with continued increases over time in the RULM. Further evidence of a dose response was observed for apitegromab through the two-year treatment period.
In the ambulatory type three population, there was generally stability in the RHS observed. For the subgroup of patients treated with Apitegromab in use with background nusinersen, as well as subsets of individuals who experience RHS increases after two 2 years of therapy. Collectively, the results from this 24-month TOPAZ readout further strengthen our enthusiasm about the potential for Apitegromab to offer motor function improvements for patients with SMA. We are excited to be continuing the development and investigation of Apitegromab through the ongoing SAPPHIRE trial, the design of which is outlined on slide 26. SAPPHIRE is a randomized, double-blind, placebo-controlled phase III clinical trial that will evaluate the efficacy and safety of Apitegromab. The main efficacy population will be patients aged two to 12 years old with non-ambulatory type two and type three SMA.
Patients will be randomized 1:1:1 to receive for 12 months Apitegromab 20 mg/kg, Apitegromab 10 mg per kg, or placebo by IV infusion every four weeks added on top of background SMN therapy. Patients receiving background nusinersen as well as patients receiving background Risdiplam will both be eligible for enrollment. Slide 27 provides further details on the trial design. For example, at baseline, all patients will be required to be in the chronic maintenance phase of SMN therapy. Randomization will be stratified by both which particular background SMN therapy a patient is on as well as the age at which that therapy had been initiated. The primary efficacy endpoint will be mean HFMSE change from baseline at 12 months.
The trial provides the opportunity for an interim analysis when at least 50% of patients in the main efficacy population have completed 12 months of treatment. Separately from the main efficacy population, an exploratory population will be evaluated, and there will also be an open label extension study for patients to complete the 12-month primary treatment period. To close, there continues to be very high unmet medical need for individuals living with SMA. The Apitegromab development program, including this ongoing SAPPHIRE trial, is aimed at testing whether or not Apitegromab can meaningfully address this important need. We look forward to providing updates in the future on our SMA program. As we turn to slide 28, I'll now hand it back over to Nagesh. Nagesh?
Thank you so much, Yung Chyung. As you can see, tremendous energy and excitement around the TOPAZ 24-month data, which underscores our enthusiasm for the ongoing phase III SAPPHIRE study. Looking at our overarching pipeline, again, we will be continuing TOPAZ. Bulk of the patients in phase II in the 24-month study have in fact rolled over for a third year of treatment. As we've reiterated, SAPPHIRE is ongoing and enrolling. In addition, we are very excited about our anti-TGF-β1 inhibitor of activation, SRK-181. This molecule is currently in phase I proof-of-concept testing in patients with solid tumors, the DRAGON study. As a reminder, this study will start to report out data, initially biomarker data, subsequently, hopefully clinical response data over the course of the latter half of this year.
Then finally, we have in fact retained an exciting core research group who are prosecuting very intriguing and interesting next-generation programs. We believe that we have the opportunity here to build a sustainable pipeline for the long term. In closing for me, I would just like to first of all thank Yung so much for six years of service as he leaves us at the end of June. He has been ingenious, creative, and an amazing leader. Yung, thank you so much. I'd also like to again thank the patients. I'd like to thank their families. I'd like to thank the clinical sites and all the clinical support staff for all they've done to support us as we advance these programs. With that, let me turn it over to Ted to wrap up and read out on very exciting financial news and overall corporate updates.
Thank you very much.
Thanks, Nagesh. Turning to our final slide 29. We are very pleased today to announce the completion of a financing raising $205 million that will fully fund the phase III SAPPHIRE trial. In addition to the clinical advancement of our immuno-oncology program, SRK-181, through Part B of the phase I DRAGON trial. We are thrilled to have such experienced, dedicated, long-term oriented investors supporting the company through this next stage of development. Importantly, this extends our cash runway into 2025. In May, we announced our plans to reduce operating expenses and prioritize these two programs while focusing our discovery work to advance only select preclinical programs that best exemplify the value of our platform.
We are very pleased to be in such a strong financial position as we continue to forge ahead with this streamlined focus on programs that will be key near and long-term value drivers for our company and our patients. That concludes our formal remarks. We can now turn to Q&A. Operator?
As a reminder, to ask a question, please press star then one. If your question has been answered and you'd like to remove yourself from the queue, press the pound key. Our first question comes from Tessa Romero with J.P. Morgan. Your line is open.
Hi, Nagesh and team. Thanks so much for taking our questions and congrats on the update here. Our question is really around in the non-ambulatory patients. Were there any notable differences in the baseline characteristics of the patients that impacted the response kinetics that you've observed here? Whether it's, you know, baseline HFMSE score or time that the patient started SMN Rx or any other factors. Then I had one follow-up.
Sure, I can take that. You know, I think the main one that we observed was in relation to the age at which your background SMN therapy, Nusinersen in this case, had been initiated. You know, we saw relatively large gains in patients who had a background of therapy started earlier in life, which makes sense mechanistically, right? Because you intervene earlier, you have potential to preserve more motor neurons to have a base on which you potentially could build through myostatin blockade. We did look at various other factors such as, for example, prior duration of Nusinersen therapy before enrolling in TOPAZ, as reflected by the number of maintenance dose of Nusinersen.
We did not see any particular correlation between the prior duration of nusinersen therapy with the HF-MSE increases that were observed in the study. I think, you know, we looked at various factors, nothing obvious. Now, there was an exploratory analysis we had done after 12 months on the ambulatory population. Actually, and non-ambulatory, where the presence of significant contracture and scoliosis could have an impact on your Hammersmith scale gains or losses over the course of the study.
Okay. That's helpful. Then one kind of clarifying question for you. I know in the kind of the 12-month updates in the past, you've sort of provided portion of patients that have achieved, you know, one point, three point, five points. Just wondering, was that kind of also stable from the 12 - 24 month time point, if you happen to have looked at that analysis as well? Thanks so much.
The more details of these results, including those type of numbers, will be available at the Cure SMA podium presentation by Dr. Crawford later today. As an overall overview, the large mean increases that were observed through this 24-month analysis do not seem to be driven by a few outliers. On the contrary, there was a broad-based set of improvements across many of patients, just like how we saw in the 12-month analysis.
Okay, great. Thanks so much for taking our questions.
Our next question comes from Do Kim with Piper Sandler. Your line is open.
Hi. Good morning. Thanks for taking my question, and congrats on the strong data update. Question for Yung. When you look at the patients, non-ambulatory patients who started on 20 mg per kg, it looks like their HF-MSE score remained stable during year two. Do you think that the benefit from Apitegromab has peaked? Are patients reaching the maximum score, which it does seem like they should be, or is there damage from the disease that is potentially non-reversible?
Yeah. I think, you know, what we kinda think about as we look at the effects over time for the high dose versus low dose, it appears that a lot of the gains, which we believe are sizable and have the potential to be quite meaningful for patients, happens in year one, and we are thrilled to see that they're sustained and durable through year two. Now, whether or not there is opportunity over further chronic treatment for further gains, TBD, right? We don't know. We've only done this for two years, and we see most of the increases happen in year one and sustained in year two.
Now, in the low-dose arm, we did see that there was potential for further increases, but that makes sense pharmacologically as there's potential for further gains if you haven't fully saturated targeting as you cross over to the high dose. Interestingly, when we look at a secondary outcome measure of the Revised Upper Limb Module, there it seems to be a somewhat different kinetics, where there is improvement or increase through year one, whether you're in the high dose or low dose, and it seems to have these further increases in year two. Raising the question that for the Revised Upper Limb Module, perhaps there's potential for further increases over time. I mean, at least through this two-year time period, there seems to be increases, continuing increases through year two.
As we continue to get more data, learn more insights, test our hypothesis through the ongoing SAPPHIRE trial as well as year three of the TOPAZ extension period, we'll have more insights that'll inform this question.
Great. Thank you for that answer. A question on the patients that went under scoliosis surgery. Maybe you could help us understand what drives that decision for patients to get the surgery. If you were to take those patients out of the 12-month data, how would the remaining patients compare from 12 months - 24 months?
Going to your second part, I don't seem to recall any scoliosis surgeries during the first 12 months of treatment. In any case, the analysis excluding post scoliosis surgery data was relevant for year two as outlined in the slide. Just, you know, taking a step back and thinking about your broader question about what goes into the scoliosis surgery. There are varying degrees of severity of scoliosis as well as the progression of scoliosis. Those are key variables that inform the decision, as well as the impact of scoliosis on a patient's activity, right? It's not a trivial decision to undergo major surgery, but for some patients, it's the investigator or the clinician and the patient and family decide it makes sense because scoliosis can be quite impactful, and has to be addressed.
Those are the factors that go into it. As you point out, it's a complex decision and not a trivial one.
Okay, great. Thanks for taking my questions.
Our next question comes from Marc Frahm with Cowen and Company. Your line is open.
Hi, this is Ernie Rodriguez for Marc Frahm. Just a follow-up to that scoliosis question. For the SAPPHIRE trial, should we expect that population of age two-12 to be patients that are likely to undergo scoliosis surgery? And if that's the case, are you doing anything to account for that?
Our approach is just like we did for TOPAZ, the primary 12-month treatment period. In SAPPHIRE, we are guiding the sites or instructing the sites to not enroll patients who are anticipated to undergo scoliosis surgery or any other major surgery over the next 12 months. Because as you're alluding to, I imagine, there's, you know, confounding potentially, right? From having scoliosis surgery or major surgery during the 12-month period. Step one is making sure to our best of our ability and the site's best of ability to exclude patients who may be more likely to have scoliosis surgery over the 12 months. As we pointed out, even just in TOPAZ, it was only a very small number of patients who underwent scoliosis surgery.
It speaks to just how well the sites did in investigating this. Step two, this is more a TBD thing because there's ongoing discussions with regulators about the statistical analysis approach. There are potential ways to address on the back end as an interim accrual event. It's a little premature to talk about those details just yet because we are still having active ongoing discussions with regulators about the statistical analysis approach.
Got it. That's helpful. Thanks. SAPPHIRE trial also, do you have any enrollment updates? Do you have any idea when you would reach the interim analysis?
In terms of the enrollment, I mean, things are moving along, like, sites are getting up and running. We're starting to bring in patients for screening, dosing, et cetera. We're pleased with the progress to date. In terms of specific guidance on enrollment at this time, I think it's premature to start thinking about when exactly the timing of enrollment. How the dynamic may happen. I mean, you know, just there's always the intrinsic uncertainties of COVID-19. Hopefully, we'll see that it won't be like in past years, but, you know, it's something we have to be open and acknowledge.
We're pleased with the momentum to date, but it's a bit too early to try to predict the timing of when we'll hit certain thresholds in terms of patients.
Yeah, we are confident. We're really thrilled by the financing we completed and announced today and really confident that the financing gets us, you know, through SAPPHIRE data and with room to spare. That was one of the core objectives of not only the refocusing and restructuring that we took on last month, but also this financing.
Yeah, got it. Thank you, and congratulations on the data again.
As a reminder, to ask a question, please press star then one. Our next question comes from Gary Nachman with BMO Capital Markets. Your line is open.
Hi, good morning. This is Dennis on for Gary. Congrats on the positive results. Just a couple quick ones. Could you just remind us about any differences or similarities between the inclusion and exclusion criteria between the phase II and the phase III? Then finally, could you talk about why the decision was made to look at the 10 mg dose for the phase III instead of the 2 mg dose again? Thank you.
One of the key advantages of our TOPAZ trial in terms of the way it was designed was it was a learning trial as much as a proof of concept trial, right? We applied learnings and insights from TOPAZ to inform and optimize the potential for success in the SAPPHIRE trial. Things would include that was the reason why we focused our inclusion, exclusion criteria, study population on the type two non-ambulatory type three population. We're looking at age two to 12. We wanted to ensure the patients were in the chronic maintenance phase and a variety of other measures to really take our learnings from TOPAZ and apply them to SAPPHIRE. In terms of-
Also, of course, we're using the same primary efficacy measure of HFMSE and going with a 12-month time point. In terms of your question about the 10 mg per kg rationale, our prior hypothesis continues to be that 20 mg per kg, we believe, is the potential dose based upon how it performed in our dose-response analysis in the TOPAZ trial. With that said, we do acknowledge that it is possible and plausible that a dose between 2 mg and 20 mg per kg might offer comparable benefit as the 20 mg per kg dose. To test that hypothesis and potential, we are including a 10 mg per kg arm.
Now, to avoid the challenge of multiplicity introduced by that and avoid any having to allocate alpha spend across these two different dose arms, our approach is more of a hierarchical statistical analysis approach, where step one in testing the hypothesis is looking at 20 mg per kg versus placebo. Only if that wins will we then look at the 10 mg per kg arm. If we win with 20, we look at 10, it's comparable to 20, that would be really exciting as upside, right? Because then, you know, for one, it increases the drug supply just by de facto, right? But second, it would allow patients to not have to necessarily receive such a higher dose.
You know, points to interesting down the road potential lifecycle management opportunities about less frequent dosing, et cetera, et cetera.
Great. Thank you so much.
Thank you. This concludes the question and answer session and our conference call. You may now disconnect. Everyone, have a great day.