Good morning, MeiraGTx program update. At this time, all attendees are in a listen-only mode. A question and answer session will follow the formal presentations. As a reminder, this call is being recorded, and a replay will be made available on the MeiraGTx website following the conclusion of the event. I'd now like to turn the call over to Alexandria Forbes, President and Chief Executive Officer of MeiraGTx. Please go ahead, Zandy.
Thank you for joining us today as we give an update on our AAV-AQP1 program for the treatment of radiation-induced xerostomia. Before we begin, please note that we will 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 two of today's presentation and in our most recent filings with the SEC. I'm Zandy Forbes, the President and CEO of MeiraGTx. I'm joined by Dr. Robert Zeldin, our Chief Medical Officer. Today, we will review the data from the completed Phase 1 AQUAx study. We presented most of this data in our December 2022 update.
Today's dataset now includes the final 12-month data from the 12 bilaterally treated subjects who had not yet reached the 12-month time point in December. We will also discuss some encouraging preliminary biopsy data from the ongoing NIH phase 1 study of AAV AQP1, as well as the recently initiated phase 2 study that is currently enrolling patients, and then we will open the call to questions. I will now turn it over to Robert to give a brief background of grade 2/3 radiation-induced xerostomia or RIX, which is a severely debilitating condition affecting over 30% of all patients successfully treated with radiation for head and neck cancer 2 or more years after radiation treatment and with no available therapies. Robert.
Thank you, Zandy. Good morning. Radiation-induced xerostomia is one of the most frequent complications of treatment for head and neck cancer. It is a serious, debilitating condition resulting from the reduction in saliva production that occurs when salivary glands are damaged by the ionizing radiation used in radiation therapy for head and neck cancers. Salivary glands are extremely 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 a reduction in xerostomia symptoms in many patients. However, approximately 40% of patients report intractable, moderate, or severe grade 2 or grade 3 xerostomia that persists 2 and more years after radiation treatment.
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, difficulty sleeping, inability to exercise, uncontrollable dental caries with inability to wear dentures, and harmful changes in oral flora and oral burning. The current options for the management of radiation-induced xerostomia are few, and importantly, they provide very limited benefit to patients with persistent grade two or three xerostomia. Nothing is available to improve salivary gland function in this patient population, and there are no disease-modifying treatments. Providers generally recommend lifestyle interventions first, followed by topical agents like artificial saliva. Saliva substitutes, however, provide a very short-term benefit and are disliked by patients.
75% or more of grade 2/3 radiation-induced xerostomia patients receive treatment with prescription medications known as sialagogues at some point. These medications are minimally effective in patients with grade 2/3 radiation-induced xerostomia, where the gland structure is damaged and function has been significantly degraded. They are poorly tolerated, with many patients experiencing side effects such as flushing, stomach upset, and sweating. As a result of minimal efficacy with significant side effects, approximately 83% of patients with grade 2/3 radiation-induced xerostomia experience little or no response or do not tolerate these sialagogues and have no effective treatment options for their condition. No drugs have been approved for the treatment of radiation-induced xerostomia in almost 30 years. The last was pilocarpine in 1994.
MeiraGTx's AAV-AQP1 gene therapy is the only known therapy currently in the clinic designed to provide a disease-modifying therapy for this severely affected patient population with no alternative treatments. radiation-induced xerostomia is one of the most frequent complications of treatment for head and neck cancer. In the US, there are currently over 170,000 patients with grade 2 or 3 radiation-induced xerostomia, who are more than two years post-radiation treatment and are potentially suitable for MeiraGTx's AAV-AQP1 treatment. There is also a large incident population, which is unusual for a gene therapy indication and contrasts with treatments for rare inherited diseases, where the incident populations are very small.
In the U.S. alone, there are 54,000 new cases of head and neck cancer per year, and of these, more than 15,000 each year will have long-term persistent grade two/three radiation-induced xerostomia, meaning they would be potential candidates for AAV-AQP1 treatment. Having been treated effectively for their head and neck cancer, these patients are in the healthcare system with some form of insurance coverage, and they see physicians at least once a year to check on their cancer-free status. While these patients' cancer is in remission, they now have debilitating grade two or three xerostomia with no effective treatment options. AAV-AQP1 is delivered locally as a small dose directly into the ducts of the parotid gland. The cost of goods is low, and this large patient population in need of treatment represents a very strong commercial opportunity with no current competition.
In radiation-induced xerostomia, the normal architecture and function of the salivary glands are significantly disrupted or destroyed. While ductal cells remain largely intact, acinar cells are significantly damaged by radiation. Water flow through healthy salivary glands requires a polarized epithelial layer of the water-conducting acinar cells. When acinar cells are destroyed or their polarity is disrupted, water permeability is lost, and the glands can no longer secrete saliva. Our therapeutic approach is to use an AAV vector to deliver the gene encoding the non-polarized water channel, human aquaporin 1, into the remaining salivary gland tissue of the parotid glands. When AQP1 is expressed in the remaining acinar and ductal 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-AQP1 vector expresses the human AQP1 gene delivered using the AAV2 capsid.
AAV2 has been shown to transduce human salivary glands effectively. AAV2 efficiently binds and transduces the exposed epithelium, both acinar and ductal cells, without penetrating or disrupting the epithelial layer. This means that the vector only transduces cells locally within the gland, with minimal entry into the bloodstream and the rest of the body. Later in this presentation, we will show biopsy data confirming the transduction of cells in parotid glands treated with AAV-AQP1 and expression of AQP1 protein. We deliver a small local dose of AAV2-AQP1 into the duct of the parotid gland through the opening of the duct into the mouth, avoiding systemic exposure and minimizing potential safety issues. Salivary gland cells are very slowly dividing, this AAV2-AQP1 therapy is expected to be a durable one-time treatment.
We have demonstrated durability of transduction out to 24 months in biopsies and efficacy out to 3 years in those patients who have reached these time points in our long-term follow-up study. Let me turn it back over to our CEO, Zandi Forbes, to present the data from the completed phase 1 AQUAx study.
Thank you, Robert. The AQUAx study was an open-label, multi-center dose escalation study at four sites in the US and Canada, in which each participant received a one-time administration of AAV2-hAQP1 into either one or both of their parotid glands. There were four escalating dose cohorts, with three participants per cohort for both unilaterally and bilaterally treated participants. All participants were followed for one year post-treatment in the phase 1 AQUAx study and were then enrolled in a long-term follow-up study for a total of five years. The primary endpoint was safety, and the secondary endpoints included: change from baseline to 12 months in 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. Most of these data were presented in our program update in December 2022.
However, today's dataset now includes the 12-month data for the bilateral-treated subjects, which was not yet available in December 2022. The study is now complete, and the data cleaned and database locked. We also now have a few more participants completing assessments at 2 and 3 years post-treatment in the long-term follow-up study, showing durable improvement. The primary endpoint of this dose-escalating Phase 1 study was safety, and the AAV2-hAQP1 treatment appears very safe and well-tolerated at 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 the GRCQ and XQ patient-reported outcome measures in unilaterally and bilaterally treated participants. These responses are considered transformative by physician experts in the field. We also see impressive salivary flow data based on the collection of whole saliva, with increases in absolute saliva production observed in both bilateral and unilateral cohorts.
To help interpret the data, I'm first going to give a little background on hyposalivation and xerostomia. Hyposalivation is a reduction in saliva production and is based on an objective measure of the actual volume of saliva produced over a 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 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 volume of saliva produced and the severity of xerostomia or xerostomia score. This is described in the ASCO guidelines shown below.
In the Phase 1 AQUAx study, improvements in xerostomia symptoms were observed using 2 different patient-reported outcome measures: a Global Rate of Change Questionnaire, or GRCQ, and the Xerostomia Questionnaire, or XQ, as well as increases in whole saliva produced, both bilateral and unilateral cohorts. The first measure we looked at was the Global Rate of Change Questionnaire, the GRCQ, adapted for xerostomia. In this questionnaire, the patient is asked if they have experienced a 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.
Strong, durable improvement in the severity of xerostomia, as measured by the GRCQ, was demonstrated at 12 months and beyond in patients treated unilaterally in the AAV2-AQP1. In the GRCQ PRO, at a 2-point change is large enough to be important to patients, and a 2-point overall improvement compared to placebo is considered clinically meaningful and has been the basis of approval of other drugs for xerostomia, such as cevimeline. A change of 3 points in the GRCQ is considered a substantial change that KOLs think is transformative to these patients. With this in mind, the data we show is very encouraging. For the unilaterally treated participants shown here, we saw strong, durable improvements in xerostomia assessed by GRCQ out to 12 months. 8 out of 12 participants rated their symptoms as better and 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 each of the 3 participants who reached the 3-year time point, as well as an additional participant reaching 2 years, and the 2 responding participants that were assessed at 18 months. An even more positive story appears with the bilateral cohorts, for which we now have 12-month data. 10 of the 12 participants rated their symptoms as better at 12 months, with all rating the improvements as 2 or more, and 5 participants giving the highest rating of 6 or 7, denoting a very important improvement. For all study participants, including bilateral and unilaterally treated combined, 18 of 24, or 75%, reported xerostomia having improved with a clinically meaningful score of 2 or more on the GRCQ.
Importantly, no participants in any cohort reported any worsening of their symptoms. As shown here, the GRCQ responses in the 12 bilateral participants, indicated in purple on the graph, show greater improvement than those of the 12 unilateral participants shown in green. With the overall improvement in the bilateral participants reaching greater than 3 points rapidly by 2 months post-treatment, and an unprecedented average improvement of 4 points by 6 months, which is maintained at 12 months. In the 12 unilaterally 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 two points on the GRCQ is important to patients, and a change of three or more would be considered a substantial improvement over the standard of care and transformative, according to key opinion leaders. Equally encouraging data was seen using the second validated PRO, the Xerostomia Questionnaire, or XQ. The XQ is a little bit different from the GRCQ, as it measures the overall burden of disease. Participants are asked about eight symptoms of xerostomia and 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. In the XQ, an 8-point or 10% change in score is considered clinically meaningful, and a 10-point or more change is considered transformative and a substantial change.
As with the GRCQ scores, we saw very strong improvements in the XQ PRO. That is, the score decreases in both the unilateral and bilateral cohorts. In the unilateral cohort, 7 of 12 participants had an 8-point or greater improvement at 12 months. In the bilateral cohort, 9 of 12 had an 8-point or greater improvement at 12 months. Overall, in the combined bilateral and unilateral cohorts, 16 of 24, or 66% of treated participants, had an 8-point or greater improvement on the XQ at 12 months post-treatment. In the XQ, a decrease of 8 points is considered clinically meaningful, and a decrease in score of 10 points is a substantial change in xerostomia severity. Overall, 50% of unilateral and 75% of bilaterally treated participants reported a substantial improvement in XQ score of at least 10 points at 12 months.
Substantial clinically meaningful improvements in XQ scores were seen in both unilateral and bilateral treated groups, with both groups, on average, achieving greater than 10-point improvement from baseline at 12 months. For the unilateral cohorts, 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, shown in purple, an unprecedented improvement from baseline of over 20 points in the XQ was achieved at 6 months post-treatment and maintained at 12 months, an improvement that is considered completely transformative by physicians in this field. On a patient-by-patient basis, there was good concordance between the responses seen on the XQ and those seen in the GRCQ. In conclusion, the data from 2 PROs is extremely encouraging, with meaningful improvements in both of the PRO scores achieved in bilateral as well as unilateral-treated participants.
Xerostomia is a subjectively defined condition, the severity and clinical impact of which is measured during PROs. In contrast, saliva flow does not directly correlate with clinical measures of xerostomia. However, it is the objective measure of salivary gland function and reflects the proposed mechanism of action of AAV AQP1. Whole saliva volume was measured in the AQUAx study, and improvements were demonstrated in whole saliva flow in both unilateral and bilaterally treated cohorts. For the bilateral cohorts, whole unstimulated saliva flow was measured at each assessment visit by having the participants spit into a tube for three or five minutes, which gave an absolute rate of saliva flow. The saliva data from the bilaterally treated cohorts is shown in this slide. In these participants, 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 0.33 mils per minute at the 12-month time point, with an average percent improvement of 83%, as shown in the graph on the right. This degree of improvement is significant, as unstimulated whole saliva flow rate that is considered a normal range goes from 0.3 to 0.4 mils per minute. Thus, this group of bilateral-treated participants, all with persistent grade 2/3 xerostomia prior to treatment, achieved a rate of saliva production within the normal range rapidly post-treatment and then maintained this level out to the 12-month time point.
In addition, a 50% reduction in whole saliva is considered to be associated with xerostomia symptoms. Therefore, an 83% improvement in whole saliva flow rate is likely to be a clinically meaningful change that could lead to improvement or resolution of xerostomia symptoms. We were also able to collect some whole saliva data from the cohorts of unilaterally treated participants. As discussed in previous updates. In this group, the data was somewhat confounded, as the measurement of whole stimulated saliva using mechanical stimulation was done following extensive manipulations of the mouth and stimulated stimulation with citric acid, carried out in attempt to measure saliva from individual glands, which was done immediately prior to measuring whole stimulated saliva. Despite this, as well as the output, only 1 treated gland contributing to the whole saliva volume, improvement in whole stimulated saliva was still observed in the unilaterally 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 rate of stimulated whole saliva flow that is considered to be hyposalivation is less than 0.5 to 0.7 mils per minute. In the unilaterally treated cohort, the absolute rate of saliva production increased to greater than 0.7 mils per minute, a month following treatment of the single gland, i.e., to above the range that is considered hyposalivation. This level of saliva flow was maintained and increased over time to 12 months. The saliva data from both bilateral as well as unilaterally treated cohorts is very encouraging, as it demonstrates improvement in the objective assessment of saliva production that reflects the proposed mechanism of action of AAV-AQP1 treatment.
The increases, particularly in the bilaterally treated cohorts, appear to improve saliva production to within the normal range in patients who had persistent grade 2, 3 xerostomia for multiple years prior to AAV-AQP1 treatment. We have shown a lot of encouraging data from the Phase 1 AQUAx study, with meaningful improvements in both xerostomia symptoms as well as saliva production demonstrated for bilateral and unilaterally treated participants. Improvement in xerostomia severity scores was seen using two different PROs, with response rates and effect size in both the GRCQ and XQ that are considered clinically meaningful and may be transformative to patient outcomes. In addition, meaningful increases in whole saliva production were observed, providing objective evidence supporting the proposed biological activity of AQP1.
Across all assessments, greater improvements were observed in bilateral compared to unilaterally treated participants. We will be treating all participants in the phase 2 study bilaterally. Early long-term data in the small number of subjects who reached the 2 and 3-year assessment time points is very encouraging, suggesting durability of the post-treatment improvements. We also now have preliminary biopsy data from a subset of participants in the National Institutes of Health phase 1 study, indicating AAV-AQP1 transduction of cells of the parotid gland treated with AAV-AQP1, expression of AQP1 protein, and persistence to at least 24 months post-treatment. In addition to MeiraGTx's AQUAx phase 1 study, a single-site, phase 1 dose escalation study of AAV-AQP1 is ongoing at the National Institutes of Health, using the same batch of drug product as used in the AQUAx phase 1 study.
This is a first-in-man safety study in which all participants are treated unilaterally. That is, in only one parotid gland. The doses used start significantly lower than the doses in the AQUAx phase 1 study, and PRO and whole saliva data are not collected. Biopsies were carried out in a number of participants in this study. While this study is still ongoing, we are able to share some of the preliminary data from those biopsies here today. This is a rather busy slide. From left to right, it shows the doses delivered to each of the biopsied participants in one gland. As 1, the absolute dose per gland. 2, as a dose concentration or titer delivered to each gland after dilution to fill the entire gland, which were of different sizes in different participants.
The visit at which the biopsy was taken is in the next column, and then the last 2 columns show the vector genome copy number normalized to total DNA in the sample, and then the extrapolated vector genome copy number per cell in the sample. Intraductal or core needle biopsies have been obtained from 7 of the 15 participants treated so far in the NIH study. These were taken at extended time points post-treatment, ranging from 12 to 13 months. qPCR analysis of these biopsies provided molecular evidence of AAV-AQP1 transduction and persistence of vector genomes in the parotid gland for at least 2 years post-treatment, as shown in the right-hand columns in this table. There is a trend of increasing vector genomes per cell with increasing viral vector dose. Core biopsies were taken from only 2 participants, AAV-019 and AAV-021.
Tissue from the core needle biopsy from participant AAV-019 was stained using immunohistochemistry. A section is shown here. AQP1 protein expression is shown in white in a group of acinar cells to the left in the slide, which normally expresses only AQP5, which is shown in green. A small patch of white cells further to the right in this slide are non-AQP5-expressing endothelial cells outside the salivary gland epithelium. These cells do not express AQP5 or CK7, which is expressed in parotid epithelium. However, these endothelial cells do normally express AQP1. The levels of expression of AQP1 in transduced parotid acinar cells appear to be similar to the endogenous levels of AQP1 detected in these endothelial cells.
This biopsy data is encouraging, as it demonstrates transduction of parotid cells following introductal delivery of AAV-AQP1, which increases with increasing vector dose and appears to be durable to at least 2 years post-treatment. Expression of AQP1 protein is shown in acinar cells, which normally only express AQP5, indicating that AQP1 vector genome is indeed persistently expressed in the target cells following viral vector delivery. The strong data from the AQUAx study and this preliminary biopsy data from the ongoing NIH Phase 1 study are very encouraging. We have initiated a double-blind, placebo-controlled Phase 2 study of AAV-AQP1 in grade 2/3 RIX patients. The drug product being used in this Phase 2 study was manufactured in-house at the MeiraGTx London facility. This was produced using Meira's proprietary platform process with industry-leading yield and ratio for capsid.
Various aspects of this process have been presented at recent academic meetings, including ESGCT in 2022 and ASTCT in 2023. Importantly, using this process at our own facilities, we were able to cross-reference the CMC sections of our other manufactured products, as well as provide the required comparability package to the FDA. We were very happy that we did not receive any comments, particularly related to CMC, on this IND amendment, and we're able to open the phase 2 study with new Meira manufactured material 30 days after filing. I will now pass it back to Robert.
Thank you, Zandy. As Zandy noted, we are very encouraged by the safety and efficacy data from the Phase 1 AQUAx study and are continuing the development of this potentially transformative treatment for this debilitating condition with our Phase 2 study, AQP1-201, which will also be known as AQUAx2. The Phase 2 study is a double-blind, placebo-controlled study in which a total of 120 participants will be randomized, 1:1:1, to receive treatment with one of two active doses of AAV-AQP1 or diluent administered bilaterally to the parotid glands. The two active doses are 0.4E12 and 1.2E12, and a third higher active dose arm may be incorporated into the blinded design at a future date.
The study's primary efficacy endpoint is the change from baseline to month 12 in xerostomia-specific questionnaire total score. The key secondary endpoints are the change from baseline to month 12 in unstimulated whole saliva flow rate and the safety and tolerability of treatment with AAV-AQP1. The GRCQ, adapted for xerostomia, is again being assessed as a secondary endpoint. After completing this study, participants will be enrolled in a long-term follow-up study for a total of five years, consistent with regulatory agency requirements. We are pleased to report that earlier this month, we initiated screening in the phase 2 study, and the first participant has been treated.
The data shared today suggests that AAV-AQP1 has the potential to be a transformative treatment for patients with persistent grade 2 or 3 radiation-induced xerostomia, 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-AQP1 may have a durable effect over many years. It is delivered via a minimally invasive, non-systemic administration and so far appears extremely safe at every dose tested. With a large prevalent as well as a 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 high unmet medical need.
In addition, it is important to remember that the dose delivered is local and small, and the cost of goods manufactured in-house is very low, allowing flexibility to support reasonable pricing for payers and patients, and still achieve a very strong commercial opportunity. This is an unusually large market for a gene therapy product, with no current competition and a high unmet medical need. With the encouraging clinical data today and the recent initiation of our double-blind, placebo-controlled phase 2 study, we are very pleased to be advancing this exciting program. We look forward to providing access to an effective therapy for the many patients with radiation-induced grade 2 or 3 xerostomia, who are currently in need of an effective therapy for their debilitating symptoms. I will now turn it back to Zandy for the Q&A.
Great. At this time, we'll be conducting our question and answer session. Please hold for a brief moment while we pull for questions. Our first question comes from Chris Raymond from Piper Sandler. Please go ahead, Chris.
Hey, thanks. Can you guys hear me?
Yes.
Yes, we can.
Great.
Hi there.
Hey, congrats on the data, guys. Just a couple of questions on the phase 2. I mean, maybe a 2-part question on that. Just noticing, you know, you're highlighting this XQ PRO as the primary endpoint. I think the last time you guys updated this program, saliva flow was contemplated. So maybe just if you can maybe talk about the decision on that, and maybe, you know, why the XQ PRO and not the GRCQ, and maybe more medically, why not the saliva flow? Was this data from this trial that drove the decision? Was it, you know, regulatory action? Maybe a combination of both. Another question related to that.
I know you've said if this phase 2 trial is positive, you could ask the FDA to consider it for accelerated filing. You know, Zandy, I think you're, you know, you're trying to maybe hold back on expectations on that just because you need to see the data first. Can you maybe talk about what contemplates good enough to file? I mean, is it? I'm assuming it's more than just stat sig benefit. There's probably some measure that's higher, but, you know, any color that you might have on that would be great. Thanks.
Thank you, Chris. I will start with the primary endpoint. This is really driven by our communications with the FDA around this program, as well as the several other programs that we've been discussing with them, and what the FDA requires for a primary endpoint, and what are the key things they need to see for approval. For our xerostomia, our discussions with the FDA, like other programs, really made it clear that they want to see two things, and the two things are: they want to see a clinically meaningful primary endpoint. That has come through very clearly in our discussions around this program and indeed, all other programs. With respect to this xerostomia program, they also requested a objective measure of the activity, the proposed function of the drug.
That objective measure, which they said they needed to see for approval, is not clinically meaningful, i.e., the saliva volume. When we're looking at a phase 2 study, that if it is potentially positive in multiple endpoints, how did we want to order those endpoints? We decided that we should go with the FDA's requirement, which seems to be very important, to use a primary endpoint that is clinically meaningful. For that reason, we use the GRCQ. Sorry, the XQ. The GRCQ is a PRO that reflects the difference in improvements in symptoms, but it isn't specific to xerostomia symptoms. We decided to use something clinically meaningful as a primary, and the most clinically meaningful for this indication is the XQ, because it asks questions specifically about this disorder.
With respect to fulfilling the requirement to show an objective measure of the activity of our treatment, we are having the saliva flow also measured as the key secondary. This leads on to the next question, which is: if this is a positive study, what do we think we need to see in order to take it to the FDA for consideration for expedited approval? We think we have to win on a clinically meaningful change in the XQ, and we also think we have to see a significant change in the saliva flow, which reveals objectively that our treatment has worked. Does that answer all your questions?
it does, yeah. If I can ask maybe a follow-up.
Of course.
I think I heard mentioned in your prepared remarks, potential third higher dose. Did I hear that right?
Yeah. That we just put in there, we haven't determined whether we will do this, but as we noted, this is very safe. We haven't been able to actually see any safety issues, and neither have we seen a clear dose response. The doses that we've used were the highest dose used in the Phase 1 study and the dose below. However, it may be useful to actually have a greater range of doses to show to the agency. The manufactured material was manufactured to the highest known dose, so we're considering, we haven't discussed it with the agency, the possibility of including in the randomized controlled study, an even higher dose. This isn't manufactured yet, neither is it discussed with the FDA, but those would be the reasons for putting that into the randomization.
Got it. Thanks.
Thanks for your questions, Chris. Our next question comes from Geulah Livshits from Chardan. Please go ahead, Gula.
Hi. Morning. Congrats on the update, thanks for taking the questions. I think following on the Xerostomia Questionnaire topic, can you elaborate a little about what's known about the magnitude of placebo effect on the XQ? You know, you talked a lot about the magnitude of benefit here. If you saw a similar degree of benefit in the Phase 2, presumably that's something that you would take forward to the FDA and be excited about.
Yes. You were a little bit muffled, Geulah, but I think you were asking about the XQ effect size.
The XQ effect size, and also what's known about the placebo effect size in this type of questionnaire.
Okay. The effect size, the study is powered to be significant if we see a 7-8-point change in the XQ, i.e., between the active and placebo, i.e., a change that is considered clinically meaningful, that 10%, 8-point change. We saw over a 20-point change. That was versus baseline, right? Without a placebo. We, in this treatment, we have not done a placebo, and it's really unclear that there is a placebo effect in this questionnaire, right? However, we felt that powering the study to show a clinically meaningful degree of benefit when we'd seen a 20-point change versus baseline, gave us a good chance of hitting that primary endpoint, and also probably showing a greater change, which would be considered transformative and extremely meaningful. That's how we powered the study.
Yeah. Great. Thanks.
Thanks for the questions, Geulah. Our next question comes from Alec Stranahan from Bank of America. Please go ahead, Alec.
Okay, great. Hey, guys. Congrats on the data, as well, and thanks for taking our questions. Just a couple from us. Encouraging to see the durable expression data from the NIH study. Are biopsies for aquaporin 1 expression a part of the phase 2? If not, from a regulatory perspective, given precedents, do you think the biopsy data from the NIH study should be enough to support durable expression of the transgene? I've got a follow-up.
Biopsies are not required in any study. It would be extremely hard to enroll a study where you have debilitated, you have salivary glands that aren't functioning properly, and you absolutely require a biopsy. In none of the studies, a biopsy is required. Biopsies were optional in our phase 1 study, and we don't have biopsies. They weren't opted for. At the NIH, where it's a much more academic center and a much longer running study, they were able to have people who agreed to biopsy. Biopsies are not required by the FDA for xerostomia, and they could not require this intervention into damaged salivary glands. The NIH study is continuing. It's got several more years to go, but we are able to use that data to support our studies going forward.
Okay, that makes sense. Correct me if I'm wrong, but I recall seeing from your slides that you're preparing a global commercial supply, supporting a BLA filing in 2024. Is this sort of the earliest, sort of on the earlier end that you could expect to see maybe a top-line readout from the study? You know, obviously appreciating that you just dosed your first patient.
Sorry, that was on the manufacturing slide. It wasn't related to xerostomia. We are manufacturing commercial material for our RPGR BLA, which is in 2024. Our manufacturing infrastructure and know-how, and regulatory interactions are fit for commercialization based on that RPGR timeline.
Okay. Thanks for the clarification. And one more quick one, if I may, just thinking about the potential market opportunity here. Is the 15K incidents you cited sort of the right addressable population we should be thinking about? I know, it may be a bit early for discussions with payers, but do you have a sense from your market research, what kind of appetite there would be for a gene therapy option that would presumably be more expensive than the limited other options available? Thank you.
Number one, the market. The 170,000 patients and the 15,000 patients per year are grade 2, 3 xerostomia, who are 2 or more years post-radiation treatment. That group is exactly the target population. That is the group that are seeing their physicians annually, they have healthcare coverage, and they are in need of a treatment. These are grade 2, 3, therefore, the other treatments actually don't work. Those numbers are the patients that are in care that could be addressed with this treatment. With respect to, is this an acceptable option? There are no other options, and we have a lot of interest from patients and physicians.
I've mentioned before that Sloan Kettering had a great interest in this, not the dental unit, but the head and neck cancer unit, because this is a major problem for the patients that they see annually, that they've cured of head and neck cancer. It's the number one complaint of patients who have been essentially cured. There is a lot of interest in any treatment for this really unpleasant condition. Now, with respect to pricing compared to other drugs, this is a very small dose, locally delivered, with a cost of goods in the hundreds of dollars, right? It is a gene therapy that may be durable for 5 or 10 years, with our ability to price it at the cost of what you might charge for a drug, right?
Such as $5,000 or $10,000 a year for 10 or 5 years. When we looked at this market and we looked at pricing, and we priced what a drug that was effective would cost, when you charge that sort of amount for this gene therapy, which is in the $50,000-$100,000 a year for 10 years, right? A one-time treatment. This is a very good market, a very accessible patient population. We have had a broad study done by L.E.K. globally on this drug, and what we found is when our physicians and payers were polled about whether they would use and pay for this treatment, indeed, the price that was acceptable in the U.S. was at least as high as what we had modeled, and in Europe and other countries, it was about what we had modeled.
We do think that this is a drug that we don't have to charge $ millions of dollars for. We can charge in the $ tens of thousands, between $50,000 and $100,000 for a 1-time, 5-10 year durable treatment, and it's a very strong market with a large incident population.
Got it. Thanks again.
Thanks for the question, Alec. Our final question comes from Luca Issi from RBC. Please go ahead, Luca.
Oh, great. Can you guys hear me okay?
Yes, we can.
Yes.
Fantastic. I have 2 quick questions. One, maybe on business development. How are you thinking about business development here? Is this a program that you're willing to partner? If so, who will be an ideal partner here, and how are you thinking about potential deal structure? Again, any thoughts there are much appreciated. Maybe if I can circle back on the regulatory question earlier. Is it fair to assume that you essentially need to hit on all 3 endpoints, essentially the Xerostomia Questionnaire, the McMaster, and the whole saliva flow, to really make a strong case with the FDA? Do you think you have a shot of potentially getting accelerated approval if you only hit the primary endpoint in the phase 2, which is the Xerostomia Questionnaire? Any call there, much appreciated. Thank you, guys.
I'll take your second question first. Like, what will we do if we only win on the primary? I, you know, I don't think it's particularly helpful to speculate on what data will be like and what we would or wouldn't do. I think we'd have to look at the strength of the data, and we'd have to look at all of the endpoints, and when we have that data in hand, we would take it to the FDA and try and gain their approval. If we did only win on the primary, would we have discussions with the FDA about early approval? Yes, we would. This is a really severe condition.
There are no other treatments, and a transformative change of the type that we've seen in our phase 1 uncontrolled study would be a meaningful benefit to these patients that have nothing else. While we feel that the strongest package would be clinical meaningfulness and objective improvement, we also feel that there is a huge need and a good reason for looking at something where there was a significant benefit of a clinically meaningful size in the primary endpoint. Your first question, I didn't really hear well, what was it?
Partnering.
Just, how are you thinking about business development? Is that the program-?
Oh, partnering.
Potentially partnering.
You know, we have multiple programs that have significant interest from different pharma and biotech companies, and they run from interest in individual programs to extremely broad collaborations, and they cover all of our programs, all of our infrastructure, all of our technology, from manufacturing to gene regulation, Parkinson's, xerostomia, and this is one area that we are considering partnering. I think this is a particular area that we could keep ourselves and actually commercialize ourselves because it's a really targeted population that we have increasingly good relationships with.
Got it. Thanks so much.
Thank you for the questions, Luca. This concludes today's program update. You may now disconnect.