Astellas Pharma Inc. (4503) Earnings Call Transcript & Summary

[Interpreted] Good morning. Thank you very much for joining Astellas Pharma's IZERVAY online meeting today out of your very busy schedule. I'm delighted to serve as emcee today. I'm Ikeda, Chief Communications and IR Officer. Thank you very much for your time. Today, GATHER2 study's 24-month data presented at the AAO, American Academy of Ophthalmology, will be explained by our clinical development person-in-charge. Today's participants: Iveric Bio's Senior Vice President and Chief Development Officer, Dhaval Desai; Iveric Bio's Vice President, Product Strategy and Innovation, Erin Henry; Vice President, Head of Cell and Gene Therapy Development, Carolyn Sasse. Today, we provide simultaneous interpreting between Japanese and English, including Q&A. We cannot guarantee the accuracy of simultaneous translation. On the Zoom menu screen, please select the language of your preference. If you select original, you can listen to the original sound without going through simultaneous interpretation. Today, we are going to explain based on the explanatory meeting materials posted on our website. This material or presentation by representatives for the company under answers and statements in the Q&A session includes forward-looking statements based on assumptions and beliefs in light of the information currently available to management and subject to significant risks and uncertainties. Actual results may differ materially depending on a number of factors. They contain information on pharmaceuticals, including compounds under development, but this information is not intended to make any representations or advertisements nor provide medical advice of any kind. We'd now like to go into the presentation. Dhaval, please start your presentation.

Hi, everyone. My name is Dhaval Desai, and I am the Chief Development Officer at Iveric Bio, an Astellas Company. Next slide, please. Today, my colleague, Erin Henry, and I will be providing updates on IZERVAY and recapping the GATHER2 year 2 data that was presented yesterday at the American Academy of Ophthalmology. Next slide, please. I will start with an update on our presentation at AAO and a brief background on the GATHER2 clinical trial. Next slide, please. We presented the IZERVAY 2-year results for the first time yesterday at the AAO Annual Meeting. The reaction among attendees was highly positive, and we have already conducted a number of interviews with key media. Next slide, please. To summarize the major findings, after 2 years of treatment, IZERVAY dosed monthly and every other month had a similar effect on reducing the growth of geographic atrophy, or GA, versus sham. Compared to the first year, the treatment effect more than doubled over 2 years for IZERVAY treated monthly or every other month compared to sham. IZERVAY continued to be well tolerated. After 2 years of treatment, there was one case of nonserious intraocular inflammation, one case of culture-positive endophthalmitis and no cases of ischemic optic neuropathy or retinal vasculitis. In the second year of treatment, the incidence of choroidal neovascularization, or CNV, was similar between the sham group and IZERVAY dosed every other month. Over the same time period, there was only a slightly increased incidence of CNV between the pooled IZERVAY treatment groups versus sham. Next slide, please. As a quick background, survey is a pegylated RNA aptamer designed to be a specific inhibitor of complement C5. Inhibition of C5 slows inflammation and cell death associated with the development and progression of GA. By inhibiting this terminal-most effector, IZERVAY may preserve beneficial upstream areas in the complement system, including the anti-inflammatory benefit of C3a. Next slide, please. As a reminder, IZERVAY is the first treatment for GA to achieve a statistically significant reduction in GA lesion versus sham over 12 months across 2 pivotal Phase III studies. These reductions observed in GA growth are consistent with the broader landscape of complement inhibition for the treatment of GA. Furthermore, these results validate IZERVAY's status as the only Breakthrough Therapy for GA and the expedited approval IZERVAY received from the FDA. Next slide, please. Now to take a moment on the design of GATHER2, which is an international, randomized, sham-controlled study. As shown on the prior slide, in year 1, the study met the primary endpoint of a statistically significant reduction in the mean rate of geographic atrophy growth from baseline to month 12 compared to sham. After the first year of treatment, patients treated with IZERVAY were rerandomized to continue with monthly treatment or receive every other month until month 24. Sham patients continued to receive monthly sham out to month 24. In year 2, we were excited to explore if reducing the dose intensity to every other month resulted in a meaningful treatment effect as well as to better understand the long-term safety profile at this dosing regimen compared to sham. As we've already stated in the summary, we're pleased that the findings support both effectiveness and a well-tolerated safety profile with IZERVAY dosed every other month in year 2. As a background for the statistical design for GATHER2 in year 2, to control for multiplicity, testing for statistical significance was conducted sequentially on the study's prespecified outcomes. The first test was reduction on GA growth for IZERVAY monthly versus sham. The second test was reduction in the rate of persistent vision loss for the pooled IZERVAY groups versus sham. And the third test was a reduction in GA for every other month IZERVAY versus sham. If a result was not statistically significant, we stopped formal testing. p-values were still calculated but would be considered nominal. And with that, I'm going to turn the presentation over to my colleague, Erin Henry.

Thank you, Dhaval. Hello, everyone. My name is Erin Henry, Vice President of Product Strategy and Innovation at Iveric Bio, an Astellas company. Next slide, please. Pictured here are the results for the primary efficacy outcome in year 2 reduction in GA growth for monthly and every other month IZERVAY versus sham. As Dhaval just mentioned, the monthly treatment arm achieved statistical significance, and the every other month treatment arm had a nominal p-value of 0.0015. We believe both IZERVAY dosing arms represent robust reductions in GA growth versus sham irrespective of the sequential statistical testing. And as we've seen, nominal p-values are common in this therapeutic space and are considered meaningful to physicians. As I will discuss on the next slide, when we examine the difference in millimeter-squared reduction after 2 years of treatment, we are seeing a trend of year-over-year improvement in efficacy and impact on GA lesions compared to year 1. Next slide, please. Here is another way to look at the increased treatment effect over time for both IZERVAY monthly and every other month versus sham. This graph clearly illustrates how for both IZERVAY monthly and every other month groups the treatment effects more than doubled over 2 years compared to 1 year. Next slide, please. The prespecified objective demonstrating that IZERVAY reduced the rate of greater than or equal to 15-letter persistent vision loss compared to sham over 2 years was not statistically significant. The mean change in best corrected visual acuity and low-luminance best corrected visual acuity from baseline between IZERVAY and sham was similar at 2 years. We are continuing to explore persistent vision loss across several sensitivity analyses and look forward to presenting more data in the future. Next slide, please. In terms of top line safety, the overall treatment-emergent adverse events, or TEAES, were similar and consistent with year 1. For ocular treatment-emergent adverse events, there was an incident of 64% versus 48.2% in IZERVAY versus sham study eyes, respectively. Serious ocular treatment-emergent adverse events in the study eye were the same between groups, less than 2%. Treatment-emergent adverse events leading to study drug discontinuation were less than 2% and 0% in the IZERVAY and sham group, respectively. Next slide, please. Serious ocular adverse events in the study eye were less than 2% over 2 years. Focusing on the year 2 results, you can see that there were 2 serious ocular adverse events reported in the pooled IZERVAY groups, including one case a culture-positive endophthalmitis and one case of subluxated intraocular lens in the IZERVAY monthly group. Next slide, please. In GATHER2, if a diagnosis of choroidal neovascularization was confirmed, the patient was provided with study-supplied aflibercept or ranibizumab and remained in the study. Of the 26 total choroidal neovascularization cases over 2 years in the pooled IZERVAY dosing groups, 2 were considered serious. And of the 20 total choroidal neovascularization cases in the sham arm over 2 years, 1 was considered serious. In year 2, as highlighted in the center box, the incidence of choroidal neovascularization was similar for sham and the IZERVAY every other month group. Over 2 years, we're only seeing a slight increase in the incidence of choroidal neovascularization in the pooled IZERVAY dosing groups versus sham. Next slide, please. Importantly, there were no cases of ischemic optic neuropathy or retinal vasculitis over 2 years. In year 2, there was one case of nonserious intraocular inflammation reported as trace vitreous cells and one case of culture-positive endophthalmitis. Overall, these 2-year safety data are critical because they provide evidence that IZERVAY is not associated with inflammatory side effects. Ocular inflammation has been a concern with complement inhibitors in geographic atrophy. But after 2 years of treatment, we're seeing no evidence to support a concern with IZERVAY. Next slide, please. To summarize, we're excited that in the second year of GATHER2, IZERVAY showed a consistent impact on reducing GA growth in both the monthly and every other month dosing arms compared to sham. And importantly, we saw a treatment effect that more than doubled over 2 years compared to 1 year. IZERVAY continued to be well tolerated with no new safety signals and similar rates of choroidal neovascularization in every other month IZERVAY versus sham in year 2. In totality, we believe this is great news for patients and retina specialists and will build confidence in the use of IZERVAY for geographic atrophy. I will now turn the presentation back to Dhaval. Next slide, please.

Thank you, Erin. After completing 2 years of the GATHER2 study, patients had an option to enroll in an open-label extension, which will enable us to capture long-term safety data. In terms of our U.S. regulatory progress, we anticipate completing our filing with the FDA in early 2024, which is Q4 fiscal year 2023 for Astellas. We will be pursuing label changes to remove the restriction on treatment duration and provide an option for every other month dose. The marketing authorization application for IZERVAY was accepted by the European Medicines Agency on August 17, 2023. Next slide, please. And with that, I will begin the question-and-answer portion of today's call.

Thank you, Dhaval. [Interpreted] Thank you very much. This is all from us. [Operator Instructions] The first question, Citigroup Securities, Yamaguchi-san, please.

[Interpreted] Can you hear me?

[Interpreted] Yes, we can hear you.

Good data. A couple of questions, if I may. The first question is that every other month is down by 19%. Every month is down by 14% [ computation ], which is great data. But every other month reduction is higher than every month, which I'm not quite sure I understand mechanism of these situations. Can you tell me why every other month is more efficacious than every month? That's first question.

Thank you for your question. And I'll ask Erin to take that question.

Thank you. So what we're seeing over the 2 years is the rerandomized population of patients, and we believe that both monthly and every other month dosing showed a meaningful reduction in GA growth relative to sham. The differences between these 2 arms, we believe, are most likely due to disease heterogeneity and not due to meaningful differences between monthly dosing and every other month dosing.

Okay. The second question is that you showed me the 15-letter clinical evidence on Page 14 and it looks pretty good up until 12 months, 14 months, but it's getting closer to the difference between IZERVAY and sham. And hazard ratio is 90% at the moment and there's no significant difference. For clinical purposes, is it okay to -- it's better to have clinical difference, but it's not really the target to have this statistical significance in the future or not really if you show the difference and numerical difference is good enough. How do you think about this clinical evidence?

Yes. So based on the year 1 results, we had actually looked to see whether or not we would get a statistically significant finding of this from year 2, as was mentioned in the statistical design. We are doing more work on this data set and reviewing each patient individually to be -- to further understand what happened over the course of the 2-year period, and we're committed to presenting that data once we've completed our review.

Did you get the 12 months data already announced or not really?

Yes. The 12-month data was presented at a number of meetings, most recently at the ARVO meeting.

[Interpreted] Next, Morgan Stanley MUFG Securities, Mr. Muraoka, please.

[Interpreted] Muraoka from Morgan Stanley. Can you hear me?

[Interpreted] Yes, we can hear you.

[Interpreted] I also have a question, which is similar to the previous one. First of all, congratulations on the wonderful data. Regarding the vision loss data, there was no significant difference for 24 months. For your future marketing penetration competition, what about the possibility of a negative impact, including your discussions with FDA? I hope you can respond to my question.

Thank you for the question. And as I mentioned previously, we continue to evaluate this data to understand what happened over the period of 2 years. Certainly, at 12 months, the data look like the curves are separating. If you look at the sensitivity analysis that were presented at the AAO meeting, the curves for 10, 20, 25 letters do look to have some separation. And so we'll do further analysis on this data, certainly will be submitted to the FDA and EMA, and we'll see what the discussions turn into. But we continue to work on this data, and we will continue to present it as we learn more.

[Interpreted] Regarding the penetration, what's the current impact on the penetration of the product in the market?

I don't think we can make a comment on what the penetration of the vision data is. Up to date, we have not had vision data for any complement inhibitor in geographic atrophy. What we do believe is that over time these will separate as patients lose valuable real estate in terms of visual acuity. And so it's impossible to say what the impact of this data will be. We continue to commit ourselves to understanding what this data is and share it with the clinical community as soon as we understand it better.

[Interpreted] Another question. It's not about the presentation today, but at AAO there was a physician survey for complement therapy or complement inhibitors. The slide was reported in the media: professionals, 17% -- pros, 17%; 83%, cons. Pros and cons, 17% and 83%, according to the information I received. I think it's an extreme response. It may not be reliable, in my view. But regarding this physician survey, how do you perceive this physician survey? And how this will affect the future penetration of IZERVAY in your opinion, I'd like to hear your view.

Yes. Thank you for the question. I think a couple of things that you have to understand about any of these surveys, they were probably done a handful of months ago. And if you would remember, a handful of months ago, we were right in the middle of unveiling of a lot of safety findings from another compound in this class and so that certainly potentially has the ability to color opinions of physicians. What I will tell you is that we believe that the consistent safety profile that we saw in year 2 combined with the efficacy seen with monthly and every other month dosing is really going to provide both the clinical community and their patients something to think about. And so I think we have to take those results with a little bit of a grain of salt, understanding that they were probably done during a highly sensitive time in the retina community. And now we have 2-year results from the GATHER2 study, which really kind of hold up an efficacy profile that is similar for every other month and monthly and a safety profile that is really well tolerated with no cases of ischemic optic neuropathy, no cases of vasculitis and a low case of intraocular inflammation.

Dhaval, if I may add one additional comment. The percentages that were reported were in the retina subspecialty day debate session that happened a day before we had an opportunity to present the GATHER2 2-year results. I'd say this is a new field and people are still very much trying to understand the data. But I think being able to provide our results, I'd be curious how that may have changed people's perspective. And of course, there isn't another opportunity for that survey, at least not in this meeting.

[Interpreted] Next, Daiwa Securities, Hashiguchi-san, please.

[Interpreted] Hashiguchi from Daiwa Securities. So in this AAO, another complement inhibitor 36-month data was also presented. Based upon such presentation, the specialists, now what kind of comment do they say about the selection of the options of the treatment? It's been showed a while after the presentation of other product and your product clinical trial data. But what kind of view do specialists have for the differentiation of usage of the drug? For this kind of patient, this drug will be used; for that kind of patient, another drug will be used. How do they think? If you know any information about that, we are very happy to hear the actual field voice.

Absolutely. Our results were just presented yesterday morning. We've heard generally positive results. People were very interested to see the details of the results, to begin to digest the results. We heard a lot of positive responses on the outcomes of the IZERVAY every other month dosing group compared to sham. I think there had been some questions about what that would look like. I've also heard a lot of positive comments on the safety results over 2 years. The exceptionally low number of adverse events of special interest. The intraocular inflammation rate, the lack of ischemic optic neuropathy, the single case of endophthalmitis are all things that, I think, practitioners are feeling better about seeing that additional follow-up. So it's still early days, and I would say that we look forward to continuing to get more insights from doctors in the community. But that's the preliminary feedback that I can share here.

[Interpreted] Next, UBS Securities, Ms. Haruta, please.

[Interpreted] Haruta from UBS Securities. Statistical testing in the study, it was done sequentially. So this was done at the timing of after 12 months. Every other month dosing, there's a mention of a nominal p-value. Because of the nature of the testing, you explained or you stopped when there was no statistical significance. So until what timing this nominal p-value? Could you elaborate on that, please?

I think the question is asking, if you could please confirm when do we stop -- at what time point did we stop the testing for the every other month. Is that correct?

[Interpreted] Yes. For every other month, yes, I'd like to ask you about the timing. And regarding the 24-month data, is it 24 months or after 12 months? I'd like to confirm.

Yes. Thank you. So the statistical testing that was done for year 2 was done at the end of year 2. So all patients that had completed -- or all patients that were in that 24-month cohort when the last patient lasted, it happened at month 24, that is when the analysis was done for every other month in terms of the efficacy and the nominal p-value.

[Interpreted] Understood. So that is a p-value as of month 24.

24, correct.

[Interpreted] Understood. Second question, CNV rate, that is not really high in the study. But looking at the real world, dry AMD VEGF IVT and GA, dry AMD [ IVD ], I think those are utilized in real world. With these regards, how do you view the situation?

Asking -- looking at the difference between the CNV rates between IZERVAY and sham, how are we looking at the difference between the 2? Could you please confirm the question?

[Interpreted] Sorry, the way asking is a bit complicated. I'm so sorry. So CNV rate was not really high in this study. But in real world, for wet AMD treatment that is ongoing and I think for GA as well, the treatment will be done. So using for both, what will be the points needed to be concerned if both drugs are to be used?

Erin, can I pass that one to you?

Yes. Absolutely. So in this population, if patients were to develop choroidal neovascularization during the course of the GATHER2 study, they were able to receive anti-VEGF, either aflibercept or ranibizumab, and remain on their study dose. So while we don't have many patients in total that received both IZERVAY and anti-VEGF, you can see here we only had 26, they did have the opportunity to receive both drug -- both the study drug and the anti-VEGF. In this small population, we did not find that to be a problem or an issue. There were no concerns based on what we've seen in the small number of patients. When you think about real world, we know that there are many patients with neovascular AMD that are treated regularly with anti-VEGF. Geographic atrophy is the other advanced form of age-related macular degeneration, and up until now, we haven't had treatment options. So we imagine that clinicians will use this data to figure out the right patients to treat with IZERVAY. And they will manage them accordingly if they were to have this small, but real risk of conversion to choroidal neovascularization with an anti-VEGF agent that they think is most appropriate.

[Interpreted] Next, Sanford C. Bernstein, Ms. Sogi, please.

I have a few questions about the data first. So at Page 12, I've been always wondering whether -- why you are only showing the 12-month data and 24-month data while Apellis' SYFOVRE had a more actually granular data. That's my first question.

So can you help us understand what you're referring to in terms of granular data?

Oh, I'm sorry, more of the data point. That's what I meant.

Right. So a couple of things as it relates to showing the 12- and 24-month data. The first thing that you understand about geographic atrophy is this is a chronic disease. And that once a patient starts a treatment, they are on it, essentially, for the rest of their lives. And so there's not a decision point where at 6 months or at 18 months that we're going to say, look, we're going to stop treating you. And so the data that we're showing you at 24 months basically shows you that with IZERVAY, what you see, and you can see clearly from the lines, is that there's an early separation of those curves that starts at 6 months, continues through 12 and is expanding through 18 and 24. And so that is what we believe that clinicians and their patients will ultimately find the most useful in terms of making treatment decisions for treating geographic atrophy.

Right. And the next is how to look at this Page 13. First of all, when you look at -- for both the every month and every other month, the baseline to month 12, so I assume that these are coming from the same one single arm. So I'm having a little bit hard time understanding why the number is different, 0.31 versus 0.41. And the next one is the difference in mean rate for baseline to 24 months. So every other month, it doesn't mean that the growth rate is almost the same as the sham.

Yes, Erin, you answered this one previously. So maybe I'll just kick it back to you to answer this one as well.

Absolutely. So what this bar graph is demonstrating is that in the first year for both what we're calling the monthly arm here and the every other month, you see the difference between the sham arm with respect to the difference between monthly and sham arm then the every other month and sham arm, which in the first year, everyone is receiving monthly dosing. While we saw that in these rerandomized populations that baseline characteristics remained relatively balanced, there are slight differences in year 1 when everyone is dosed monthly. We believe this is most likely due to heterogeneity of the disease. I think what's the important point is regardless of that 1-year difference, when you look from baseline to 2 years, that's the difference in the monthly arm that continues on monthly through the second year and the treatment effect over that 2 years is 0.81. That's an absolute difference between the sham arm and the monthly arm. That's more than a doubling from 1 year to 2 year. So the difference from 12 to 24 is the difference between this baseline to 12 and baseline to 24, so 0.5 millimeter squared. And then when we look at the every other month arm, again, similarly, when we look from baseline to 12, it's 0.41 millimeter squared. That's the difference between the every other month arm and sham. And then when we look at baseline to 24 months, it's 1.04 millimeter squared. So again, more than a doubling. If you look at the difference, that's about 0.6 millimeters squared. So regardless of whether or not they stayed on monthly dosing or they moved to every other month dosing in the second year, we see a similar increased treatment effect in that second year. And so that over 2 years, you're seeing this absolute difference of 0.81 millimeter squared for the monthly arm and 1.04 millimeter squared for the every other month arm. We think these are both meaningful reductions in GA growth relative to the sham arm.

Thank you very much for clarification. It's very clear. And then -- so it looks like, interestingly, the every other month, the over 24 months -- of course, the first 12 month was patients were receiving every month treatment. But every other month seem to be slightly better. And so I'd like to see if there's any of the hypothesis why the every other month seems to be even slightly better than every other month (sic) [ every month ]. And also, I assume that based on the how this trial has been designed, the actual label will be that the patients can receive every other month treatment after the completion of 12-month treatment. Is that correct?

Erin, can I ask you to take that one as well?

Sure. So you're correct in that we see slightly bigger delta in the every other month arm relative to sham over 2 years. Again, there's nothing that we have seen in terms of the baseline characteristics of the rerandomized population that gives us a reason why this arm would perform a little bit better. We think that geographic atrophy is a heterogeneous disease, and so I think both of these demonstrate meaningful reductions relative to the sham arms. And I think it adds to our knowledge that moving from monthly dosing in the first year to every other month dosing in the second year still provided this meaningful treatment reduction with p-values that was 0.0015. In terms of submission to FDA and other health authorities, we will submit the totality of these 2-year results. And we will have that conversation with the health authorities about what they believe is appropriate in terms of potential updates to the label.

One final question. We understand that from the clinical trial, you show a really robust safety data. But at the same time, I think the issue of the emerging, the concern around the adverse event is about those very rare adverse events that won't be able to be probably detected in the clinical trial with a limited population. And so what is your plan moving forward to ease this type of adverse event?

Thanks for the question. And so just to clarify, to date, there's only been one case of retinal vasculitis that has been reported in a patient that does not have GA, but has Stargardt's disease. In terms of our plan, Astellas is committed to transparently reporting safety data, and what we find in both our clinical trials as well as in our post-marketing setting will be transparently communicated to the retina community over the course of the coming years.

[Interpreted] Next, Mizuho Securities, Mr. Tsuzuki, please.

[Interpreted] Tsuzuki from Mizuho Securities. Can you hear me?

[Interpreted] Yes, we can hear you.

[Interpreted] I have one question. GATHER2, I'm looking at Page 9, GATHER2 data. If I look at data at 12 months, [ 17.2% ] reduction for GA growth. Regarding this data, if you look at Page 12, 24 months monthly dosing, 14% reduction. For you, 24 months, original reduction of 17.7% at 12 months. You could have been expecting a higher value, a higher reduction or is this what you expected? You think you could have expected a higher reduction here? Any comment on your side?

Yes. Thank you for the question. And so a couple of points as it relates to the statistical analysis and the year 1 results versus the year 2 results. So remember that in year 1 of GATHER2, all patients, all 225 patients, were on monthly dosing and treated as one singular group. If you go to the year 2 results for GATHER2, the difference is that 225 patients has now been split into 2 separate groups and the analysis goes all the way back to baseline. And so the numbers that you saw in year 1 cannot be used to put the year 2 numbers in reference because the entire analysis has changed. What is more relevant is to look at the difference in absolute lesion size. And what you see with the absolute lesion size is that the number that you see at year 1 in the reduction with monthly dosing more than doubles whether you use monthly or every other month dosing out to month 24. And that is the data that treating clinicians will see when they are treating patients in their office, when they're looking at their fundus autofluorescence images. And so that's what we believe is the most appropriate and relevant number, not necessarily percentage reduction that has been changed due to a statistical analysis and how you treat the data.

[Interpreted] There are some others who are raising their hand, but we are running over. So we'd like to close this meeting here. Regarding the questions we could not handle, IR team can receive your questions. So if any, please contact us. Thank you very much for joining from early in the morning. Thank you very much. We'd like to close this meeting here. Thank you very much. [Portions of this transcript that are marked [Interpreted] were spoken by an interpreter present on the live call.]