MeiraGTx Holdings plc (MGTX) Earnings Call Transcript & Summary

Thank you for joining us today as we give an update on our AAV2-hAQP1 program for the treatment of radiation-induced xerostomia. Before we begin, please note that we'll be making forward-looking statements as part of this presentation, which statements are subject to certain risks and uncertainties that may cause actual results, performance or achievements to materially differ from those forecasted. Certain of these risks are described in Slide 2 of today's presentation in our most recent filings with the SEC. I'm Zandy Forbes, the President and CEO of Meira. I'm joined by Dr. Robert Zeldin, our Chief Medical Officer; and by Dr. Michael Brennan, lead investigator on the AQUAx Phase I clinical study. I will now turn it over to Robert.

Thank you. Good morning. Radiation-induced xerostomia is a serious debilitating condition resulting from a reduction in saliva production that occurs when salivary glands are damaged by the ionizing radiation used in radiation therapy. Salivary glands are exquisitely sensitive to damage by ionizing radiation and immediately following radiation treatment for head and neck cancer, almost all patients suffer from reduced salivary gland function and xerostomia. In the 2 years following treatment, there is some reduction in the severity of the initial xerostomia symptoms in many patients. However, 40% to 50% of patients report moderate that is grade 2 or severe that is grade 3 persistent xerostomia, 2 or more years following radiation therapy. These symptoms are life-altering and extremely debilitating with multiple severe sequelae resulting from the lack of oral lubrication and loss of the antimicrobial effects of saliva. These include difficulty eating, chewing and speaking, oral pain, sore throat, uncontrollable dental carries with inability to wear dentures, harmful changes in oral flora and oral burning and these severe sequelae occur in 40% of patients. Current options for the management of radiation-induced xerostomia are few at our limited benefit. Current therapies only treat symptoms and with limited efficacy and poor tolerability, leaving a significant unmet need for patients with Grade 2 or 3 radiation induced xerostomia. Nothing is available to improve salivary gland function, and there are no disease-modifying treatments. Providers generally recommend lifestyle interventions first, for example, extra water consumption followed by topical agents like artificial saliva. Saliva substitutes, however, provide very short-term benefit and are disliked by patients. Greater than 75% of Grade 2 or 3 radiation induced xerostomia patients receive treatment with prescription medications known as sialogogues. These [ muscarinic antagonist ] drugs stimulate the parasympathetic system to increase salivary flow. Pilocarpine is approved for the treatment of radiation induced xerostomia and cevimeline is used off-label. These medications do not work well in patients with limited residual salivary function. Therefore, they are minimally effective in patients with Grade 2/3 radiation induced xerostomia, where the gland structure is damaged and function has been significantly degraded. In addition, they are poorly tolerated with many patients experiencing side effects such as flushing, stomach upset and sweating. As a result, approximately 83% of patients with Grade 2/3 radiation induced xerostomia experienced no response or an inadequate one or do not tolerate these sialogogues and are seeking another treatment option. These patients are candidates for potential AAV2-hAQP1 gene therapy, which is the only known therapy currently in the clinic designed to address the high unmet medical need. There are over 170,000 patients with Grade 2/3 radiation induced xerostomia currently in the U.S. where greater than 2 years post treatment and are potentially suitable for AAV2-hAQP1 treatment, which is a large prevalent population for a gene therapy. There is also a large incident population. In the U.S., there are 54,000 new cases of head and neck cancer per year, and of these, greater than 15,000 each year will have long-term grade 2/3 radiation induced xerostomia. These patients are in the health care system with some form of coverage, having been treated effectively for their head and neck cancer and they see physicians at least once a year to check on their cancer pre-status. While these patients' cancer is in remission, they now have debilitating Grade 2/3 xerostomia with no effective treatment. Our therapeutic approach is to use an AAV vector to deliver a nonpolarized water [ channel]. Human aquaporin 1 into the remaining salivary gland tissue when hAQP1 is expressed in the ductal cells and any remaining acinar cells in the disrupted glands, these cells become permeable to water and water flows down the hydrostatic pressure gradient into the salivary duct and then into the mouth. Our AAV2-hAQP1 vector expresses the human hAQP1 gene delivered using the AAV2 capsid. AAV2 effectively binds and transduces the exposed epithelium, both acinar and ductal cells without penetrating or disrupting the epithelial layer. We deliver a small local dose of AAV2-hAQP1 into the duct of the parotid gland avoiding systemic exposure and minimizing potential safety issues. As salivary gland cells are very slowly dividing, this AAV2-hAQP1 therapy is expected to be a onetime treatment. Now I'd like to hand it to Dr. Mike Brennan, who will provide his clinical perspective as the investigator who has treated many of the participants in our AQUAx study.

Thank you, Robert. I'm Dr. Mike Brennan from Atrium Health Carolinas Medical Center in Charlotte, North Carolina, and I'm the lead investigator for Meira's AQUAx study. It's great to be here for another update. We have now treated 9 patients in this AQUAx study at our site in North Carolina, and the results we are seeing are extremely encouraging. I've been caring for patients with radiation-induced xerostomia for many years. And as Robert has described, they're just simply are not good treatment options for patients with this debilitating condition. The current prescription treatments known as sialogogues have side effects that are often intolerable, and there are no medications that do anything to restore salivary gland function. AAV-hAQP1 seems to be doing just this. The mechanism of action of this gene therapy suggests that this onetime treatment may be having a disease-modifying effect on this severe condition. There are 2 things in particular that are striking about this AQUAx study for me. Number 1 is the rate of positive response and sustained improvement in my patients; and number 2 is the noninvasive nature and simplicity of administration of this potential one-time treatment. I'll start with the procedure, which is remarkably straightforward and noninvasive. We directly insert a small catheter into the opening of the parotid gland in the back of the mouth and then infuse the AAV2 vector through the catheter into the gland. No anesthesia is needed. My patients have tolerated the procedure very well. They experienced minimal discomfort and we had no treatment-related serious adverse events. Of the 9 patients, I have treated with AAV-hAQP1, most reported a positive change within weeks to months of treatment with continued and sustained improvement thereafter, even after 3 years. My patients continue to describe life-changing improvements such as being able to sleep through the night, eating becomes easier and they can get back into social situations, which they had avoided. And patients have reported that they are now able to exercise, which has been quite difficult or impossible due to their dry mouth. Several of my patients are now at least 2 years out from treatment and remarkably have sustained improvement or even complete resolutions of their symptoms. I'm also extremely encouraged by the increase in saliva flow rates that we are seeing. In the context of the debilitating nature of this disorder, any increase in saliva flow, even small amounts may be very meaningful to patients. Therefore, the magnitude of the increases we are seeing is very exciting particularly as increases in saliva flow appear to be associated with meaningful improvements in patient-reported assessments. The size of the improvements we are seeing in the Phase 1 study, both in PROs as well as saliva flow are well above those of the currently approved drugs. This therapy has the potential to result in meaningful clinical benefit for many radiation-induced xerostomia patients. With its simple noninvasive delivery which any ENT specialists and most dentists trained in oral medicine or oral maxillofacial surgery are very familiar with. This could be a transformative one-time treatment for the large patient population who have been in desperate need of a new treatment for more than 2 decades.

Thank you, Dr. Brennan, for your great perspective on the patients that you've treated in this study. MGT016, the AQUAx study is an open-label, multi-center, dose escalation study at 4 sites in the U.S. and Canada in which each patient receives a one-time administration of AAV2-hAQP1 into either one or both their parotid glands. There are 4 escalating dose cohorts with 3 participants per cohort for both unilateral and bilaterally treated participants. All participants have followed for 1 year post treatment and then enrolled in a long-term follow-up study for a total of 5 years. The primary endpoint is safety and the secondary endpoints includes patient-reported measures of xerostomia symptoms using the Global Rate of Change Questionnaire or GRCQ and the Xerostomia Questionnaire or XQ. In addition, whole saliva flow rate was assessed. Enrollment in the unilateral cohorts completed in November 2021. And today, we have full 12-month data for all of those participants. The bilateral cohorts were then enrolled by March 2022. And today, we have full 6-month data for all the bilaterally treated participants. The primary endpoint of this dose-escalating Phase I study was safety and the AAV2-hAQP1 treatment appears very safe and well tolerated and every dose tested with no dose-limiting toxicity or drug-related serious adverse events. With respect to activity, substantial improvements have been observed using both GRCQ and XQ patient-reported outcome measures in unilateral as well as bilateral participants. With substantial responses in both of these validated PROs that are considered transformative by physicians. We are also presenting impressive salivary flow data based on the collection of whole saliva in bilateral participants as well as supporting data from unilateral patients with the cohort of bilaterally treated patients, all of whom entered the study with long-term grade 2/3 radiation-induced xerostomia, achieving a normal level of saliva production by month 6 post treatment. To help interpret the data, I'm first going to give a little background on hyposalivation and xerostomia. Hyposalivation is reduced is saliva production and is based on an objective measure of the actual amount of saliva produced over certain period of time. The person spits into a tube for a number of minutes and the volume of saliva produced per minute is the objective measure of the whole saliva flow. Xerostomia, on the other hand, is a patient-reported subjective sensation or experience of oral dryness. This is assessed using validated patient-reported outcome measures or PROs. The relationship between absolute saliva volume or flow and xerostomia symptoms is not straightforward. While xerostomia is associated with the reduction in saliva flow, there is no direct correlation between the absolute flow rate and the severity of xerostomia or xerostomia score. This is described in the ASCO guidelines shown below. In the Phase 1 AQUAx study, we show improvements in xerostomia symptoms measured by 2 validated PROs, a Global Rate of Change Questionnaire, the GRCQ and the Xerostomia Questionnaire or XQ, as well as increases in absolute saliva production in bilateral and unilateral cohorts. The first measure we looked at was the Global Rate of Change, the GRCQ adapted for xerostomia. In this questionnaire, the patient is asked if they have the experienced the change in their symptoms to which they may reply they are better, worse or the same. If they reply better or worse, they then quantify the degree of change with 7 being the maximum change and very important to the patient and 1 being the minimum. A 2-point change is large enough to be important to the patient and a 2-point overall improvement in the GRCQ compared to placebo is considered clinically meaningful and has been the basis of approval of other drugs such as cevimeline for xerostomia, a change of 3 points on the GRCQ is considered a substantial change that KOLs think is transformative to these patients. With this in mind, data we show in the GRCQ is very encouraging. For the unilateral treated patients shown here, all out to at least 12 months, we show strong durable improvements in the xerostomia severity assessed by GRCQ. 8 out of 12 patients rated their symptoms as better or rated the improvement as 2 or more, reflecting an important change. 4 participants rated the improvement with the highest level of 6 or 7, denoting a very important improvement. Durability was seen in the 3 patients that passed the 2 in year -- 2 and 3-year time point, with patient 1.1, maintaining the maximum 7-point improvement out past 3 years. Importantly, no participant reported any worsening of their xerostomia symptoms. A similar and even more positive story appears with the bilateral cohorts at 6 months. 10 out of 12 participants rated their symptoms as better at 6 months with all rating the improvement as 2 or more and 3 participants giving the highest rating of 6 or 7 denoting a very important improvement. For all participants treated in both bilateral and unilateral groups, 8 out of 24 or 75% reported xerostomia as having improved with a clinically meaningful score of 2 or more. As shown here, the GRCQ responses in the 12 bilateral patients indicated in purple on the graph show greater improvement than unilateral, which is shown in green. With the overall improvement score in the bilateral patients reaching greater than 3 points rapidly by 2 months post treatment and an unprecedented average score of 4 points improvement being seen at 6 months. In the 12 unilateral treated patients, the initial improvement of greater than 2 points was durable and increased over time, exceeding a 3-point score at 12 months. This is very encouraging data, given that a change in score of 2 points on the GRCQ is considered clinically meaningful and a change of 3 or more would be considered a substantial improvement over the standard of care and transformative according to possessions. We saw equally encouraging data using the second validated PRO, the xerostomia Question or XQ. The XQ is a little bit different from the GRCQ. And then they asked about 8 symptoms of xerostomia and is a measure of the overall burden of disease. Patients are asked to rate the severity of each symptom from 0 to 10, with 0 being nonexistent and 10 being most severe for a maximum severity score of 80, an 8-point or 10% change in the XQ severity score is considered clinically meaningful, and a 10-point or more change would be considered transformative and a substantial change. As with the GRCQ scores, we saw very strong improvements, i.e., score decreases in the XQ in both unilateral and bilateral cohorts. In the unilateral cohort, 7 out of 12 participants had an 8-point or greater improvement at 12 months. In the bilateral cohort, 10 out of 12 had an 8-point or greater improvement at 6 months. Overall, 7 out of 24 or 71% of treated participants had an 8-point or greater improvement on the XQ. In the XQ, a decrease in score of 10 points is considered a substantial change. Overall, 50% of unilateral and 81% of bilateral treated participants achieved a substantial improvement in XQ score of greater than a 10-point decline. Substantial clinically meaningful improvements in XQ score was seen in both unilateral and bilateral treated groups with both groups achieving greater than 10 points improvement from baseline. For the unilateral cohort shown in green, improvement was greater than 10 points 6 months after treatment with a 13-point overall improvement at 12 months. For the bilateral cohort, an unprecedented improvement over baseline of a 22-point decline in the XQ Severity Index was achieved at 6 months post treatment, a level that is considered completely transformative by physicians in the field. On a patient-by-patient basis, there was a good concordance between the responses seen on the XQ and those seen in the GRCQ. In conclusion, the data from 2 validated PROs is extremely encouraging with meaningful improvements in both of the PRO scores achieved in bilateral as well as unilateral treated patients. As I mentioned, PROs are a subjective assessment of disease that measure changes in symptoms of xerostomia that are clinically meaningful to the patient. Saliva flow on the other hand is the objective measure of salivary gland function and reflects directly the proposed mechanism of action of hAQP1. The Phase 1 AQUAx study was a dose escalation study with the primary endpoint of safety. And initially, all patients were treated unilaterally in only one of their parotid glands. The safety profile was very clean in the unilateral cohorts and rather than expand the number of unilaterally treated subjects, we decided to treat 4 dose escalation cohorts bilaterally in order to gain some idea of potential activity of AAV2-hAQP1 treatment when both parotid glands are treated. For the bilateral cohort, we systematically measured whole saliva flow from each of the treated patients. We measured whole unstimulated saliva at each assessment visit by having the patients spit into a tube for 3 or 5 minutes, which gave an absolute rate of saliva flow. The Saliva data from the bilaterally treated cohort is shown in this slide. In the bilateral treated patients, we saw a meaningful improvement in absolute saliva production. On the left is the graph showing the average absolute volume of saliva collected for the overall group of bilaterally treated participants at each of the assessment time points. The overall flow rate for the bilateral participant groups improved to a flow rate of 0.4 mL/minute at the 6-month time point with an average percent improvement of around 100%. This degree of improvement is significant for 2 reasons. The unstimulated whole saliva flow rate that is considered normal is a range of 0.3 to 0.4 mL/minute. Thus, this group of bilateral treated patients, all with persistent Grade 2/3 xerostomia prior to treatment achieved the normal rate of saliva production within 6 months post treatment. In addition, a 50% reduction in whole saliva is associated with xerostomia symptoms. Thus, a 100% improvement in flow is a clinically meaningful change that could represent the resolution of xerostomia. We were also able to collect some whole saliva data from the cohorts of unilaterally treated patients. In this group, the data was somewhat compounded as the measurement of whole stimulated saliva using mechanical stimulation was done following extensive manipulation of the mouth and stimulation with citric acid carried out in an attempt to measure saliva from individual glands. This was done immediately prior to measuring the whole stimulated saliva. Despite this, as well as the output of only 1 treated gland contributing to the whole saliva, improvement in whole stimulated saliva was observed in the unilateral-treated cohorts. As shown here on the left, the absolute change in saliva flow improved. And to the right, the percentage improvement over baseline is shown. The Saliva data from both bilateral as well as unilateral treated cohorts is very encouraging as it demonstrates improvement in the objective assessment of saliva production that reflects the proposed mechanism of action of AAV2-hAQP1 treatment. So I've shown a lot of data. In summary, meaningful improvements in both xerostomia symptoms as well as saliva production were demonstrated. Improvements in xerostomia severity scores were seen using 2 validated PROs with response rates and effect size in both the GRCQ and the XQ that are considered clinically meaningful and may be transformative to patient outcomes. In addition, increases in whole saliva production were observed, providing objective evidence supporting the proposed biological activity of AQP1. Across all assessments, greater improvements was observed in bilateral compared to unilaterally treated participants, which makes sense as 2 glands were treated rather than one. The early long-term data in the small number of subjects who reached the 2- and 3-year assessment time points is encouraging, suggesting durability of the post-treatment improvements. With the encouraging data shared today in hand, we plan to initiate a Phase 2 study of AAV-hAQP1 in the first half of 2023. This will be a randomized, double-blind, placebo-controlled study with 2 active doses of AAV-AQP1. The primary endpoint will be the change from baseline to 12 months in whole saliva flow with key secondary endpoints, the change from baseline to 12 months in the GRCQ and in the XQ PROs. We will have full data from the bilaterally treated cohorts in the Phase I AQUAx study in early Q2 2023. We have completed our end-of-phase meeting with the regulatory agencies in Q4 this year, and we have incorporated their feedback into the Phase 2 study design. And we have manufactured clinical material for the Phase 2 study in preparation of that study start early next year. The data shared today suggests AAV-hAQP1 has the potential to be a transformative treatment for Grade 2/3 radiation-induced xerostomia patients who currently have no effective treatment options with the potential to become standard of care for this severe and debilitating condition. Salivary gland cells are slowly dividing and a single administration of AAV-hAQP1 may have a durable effect over many years. It is delivered by our minimally invasive nonsystemic administration and appears extremely safe so far with a large prevalent as well as large annual incident population of patients already in the care of physicians who have treated them for head and neck cancer. This is a large and accessible market with a severe unmet need. The dose delivered is low and the cost of goods also low, allowing flexibility to support reasonable pricing for payors and patients and still achieve a very strong commercial opportunity. With the encouraging clinical data today, supported by our internal manufacturing infrastructure, this is a very interesting market for a gene therapy product. We look forward to moving this program forward and working towards providing access to an effective therapy the many radiation-induced Grade 2/3 xerostomia patients who are currently in need of an effective therapy for their debilitating symptoms.

[Operator Instructions] So the first question will come from Chris Raymond of Piper Sandler.

Just curious on the endpoints. the saliva flow rate in the bilaterally treated patients looks really good. But just kind of curious, the questionnaire I thought was fairly standard measure in this condition. I know you're looking now at this endpoint in your phase to talk about the logic there and not using the patient-reported outcome. And then maybe also a related questionnaire, I think on one of your slides, Zandy, you noted that the PRO scores are not directly correlated to absolute volume of saliva production. Just maybe talk about the interplay, I guess, from those 2 measures.

Okay. Thank you. So the -- as I mentioned, saliva flow is a direct method -- an objective measure and a direct measure of the mechanism of action of the drug which reflects hyposalivation. And the PROs are a measure that's subjective and represent a change in xerostomia, which is a subjective measure. All of those endpoints are important and have been tested in the approval studies for other drugs. Previous drugs have been approved based on the xerostomia scores alone. The reason for that was that saliva flow did not improve significantly. However, xerostomia scores were shown to improve. In our discussions with the FDA, they asked as they do for most drugs that for a primary endpoint, we used an objective measure. It's quite hard to get approval on just a PRO, even though this has been the case, in other drugs for xerostomia, it's really been because the objective measures haven't reached significance. So given this data where we have been able to show improvements in saliva flow, we are taking the advice of the regulatory agencies and putting the objective measures as the primary and then the PROs as key supportive secondary endpoints. Does that answer your question?

Yes, that's perfect. Congrats on the data.

The next question will come from Geulah Livshits at Chardan.

I guess another question on the regulatory part, can you just talk about what it would take for this Phase 2 study to be registration or what additional studies might needed based on your interactions with regulators?

So the next study is a Phase 2 study. And as we've explained, this AAV -- this AQUAx study is a Phase I dose escalation open-label study without control arm. So the Phase 2 will be our first randomized controlled study. And therefore, we can't call it a pivotal study. It isn't a pivotal study. However, we are taking the advice of the regulatory agencies in designing that study, so that if the data is extremely compelling we will, in our end of Phase 2 meeting, discuss with the agency what we need to support a BLA filing. That if it's extremely good, we will ask if this Phase 2 study may be sufficient as a single study to support a BLA, 1 additional pivotal or 2. So without that data, we can't say how -- what this study will end up being, but it is being designed with the elements that are required to support a BLA.

The next question comes from Alec Stranahan at Bank of America.

Congrats on the update. First, maybe you could walk us through from your perspective why some patients responded better than others on the pro-metrics, would you attest this to the effect of the drug, the administration technique, inter-patient variability, subjectivity of the assessment or maybe a mix of these factors? And secondly, maybe a question for Dr. Brennan, what does natural history for patients look like in your experience? Is there a percent of patients that spontaneously resolved or well managed on oral saliva, just trying to think through what we should expect from what placebo are in the randomized study.

Thank you, Alec. So the first question is why does some patients respond and why do others not respond. We don't have large enough patient numbers to really look at exactly why there are differences. What I will say is that, in a sense, but this is an uncontrolled study. It's encouraging to see that some patients don't respond after they've been treated because if every single person responded, that would be strange, but this is highly variable. And as you mentioned, the PRO measures are subjective and the variation between patients on saliva collection is also large. Different people had very different levels of saliva, and that is very differently translated into xerostomia in every patient. So we expect in this disease quite a lot of variability between patients and as well as within patients because of the -- I'm not saying this very well, but saliva is highly variable within any one individual. So it's very difficult to get an individual patient exactly the same at every single measure, let alone 2 separate patients responding exactly the same. Dr. Brennan, unfortunately, is in the clinic, so he can't answer that question. But with respect to radiation-induced grade 2/3 xerostomia, that is something that is quite stable. So in general, we use patients that are 2 or 3 or 4 up to 5 years post treatment for radiation therapy after radiation therapy, the glands stabilize within about 12 to 18 months. And then by 2 years, the glands are fibrosed and actually restored any function that they probably will get by that period of time. So generally, by the time we treat you had stable, low saliva and Grade 2/3 xerostomia. Over time, what tends to happen as with aging normally, the rate of saliva flow decreases, so xerostomia tends to stay Grade 2/3 or even get worse. So in general, this is an indication where you don't get resolution of salivation or xerostomia at the time that we're treating. So does that answer your question?

Yes. That's very helpful.

The next question comes from David Hoang at SMBC.

I had just a couple on the Phase 2 study and the design there. Can you just talk a little bit about how you think about powering the Phase 2 and what's the size of the study -- what size of patient enrollment you may need to achieve statistically significant outcome, and then have you disclosed the doses that you're using for Phase 2?

So we we're going to be having about 40 to 50 patients per arm, and the doses are equivalent to the low dose and just below the highest dose used in the Phase 1 study.

Yes. If I could just have 1 follow-up. I was just looking at the saliva flow trends for the bilateral cohort. They seem to drop slightly a day 100 and then steadily increase at day 180, is there anything to read into that trend or anything we can say about the cadence there?

As I mentioned, saliva flow is highly variable within patients and also between patients. So I think in this small number of patients, we really can't read too much into the specific shape of that graph.

The next question comes from Lisa Walter at RBC. Lisa, I think you are on mute. Okay. We'll move to the next analyst. So the next question will come from Sheldon Fan at Barclays.

This is Sheldon Fan on behalf of Gena Wang. So first, just to clarify, my line broke up a little bit. When you mentioned the 40 to 50 patients, is that across the 2 arms or for each arm?

It's each arm.

Got it. And we have 2 questions. So one is on the saliva collection technique. So you mentioned that there's significant new variability even within the same patient. So to reduce such variability. Is it possible for you to do like repeated measures over a short period of time and take the average? Or when you collect data for the 12-month time point, if the variability is too much, could you do an average like over 3 months, 6 months, 9 months and 12 months to increase their confidence for success? And our second question is on -- when you say if the phase 2 data is compelling you may propose to use it -- to support BLA. So what would be your definition or range of compelling data will if you replicate the Phase 1, the current data, would that be considered as competing by yourself?

Sorry, could you tell me question one again?

Yes, question one is -- with the variability in saliva-collection techniques -- would you do like -- repeat and measure -- each single time point or -- and in the endpoint measure, could it do average over a certain period?

Right. So I mean, both of those ways of looking at saliva are good. We -- based on FDA feedback, we would need to look at a 12-month time point. But yes, it is an interesting way of looking at overall improvement in saliva to look at essentially the area under that curve as patients respond out to 12 months. So both of those are useful ways of looking at the data. With respect to collection, yes, it is variable. And actually, we're currently with Dr. Brennan undertaking a saliva collection analysis where we're looking at untreated patients and looking at multiple times of collection, methods of collection to reduce variability, training of collection. So yes, it is important. And we do use 3 separate time points to get our baseline, and we may use more than 1 collection for a 12-month endpoint. Now one can't just collect saliva repeatedly in a particular period of time. So in half an hour, you can't do a saliva collection at 1 to 5 minutes and then 15 minutes and then 30 minutes because each collection confounds the previous. So we're currently undertaking an analysis of the best way to get the lowest variability in our saliva collection actually, but it's a very important point, specifically, as it's our primary endpoint. And now for the BLA, this Phase 1 study is not a controlled study. It's, therefore, unlikely to support a BLA and you do need some sort of randomization and control, particularly for the FDA in order to support approval.

yes, for the second question. I don't mean that you use the Phase 1 data to support BLA data. Yes. yes, is in the similar magnitude of benefits as the Phase 1? Will that be considered compelling?

Yes. It would. If this was a controlled study, this would be considered transformative by KOLs. So this is extremely compelling data.

Congrats on the data again.

I think we're having some audio issues with Lisa Walter at RBC, but I'm going to go ahead and read her questions for her. So the first question is given the large unmet need could the Phase 2 study be used to support an accelerated approval?

We will look at the Phase 2 data if it is extremely good, we may ask the FDA to consider that in our end of Phase 2 meeting. But given we haven't done the study yet, and this will entirely depend on the -- how good the data is, we can't right now say whether it can support approval or not. If the data in a controlled context looks like the data that we saw today, then yes, we would definitely request accelerated approval based on that Phase 2 study.

So we are component for placebo-treated patients?

So patients on the untreated arm will have the opportunity to be treated following the 12-month or 6-month untreated portion of the study, and it won't be part of the actual Phase 2 study, but it will be in a follow-on study. So it won't be crossover in the statistical analysis plan but it would be available to treat -- untreated patients to be treated.

I'll now turn it back to you for concluding remarks.

I just want to thank everyone for their attention, and that's the end of the call.