Eisai Co., Ltd. (4523) Earnings Call Transcript & Summary

Good afternoon. We now start explanation meeting for Recanemab Phase III Clarity AD study top line results, which was announced at 8:30 this morning. Thank you for joining this meeting today. I will facilitate this meeting. My name is Sasaki from Corporate Communications. This meeting has a hybrid format with participants in this room and those connected via telephone. And as a countermeasure against COVID-19, we ask the participants in this room to wear masks. Thank you for your cooperation. Those in the room here, you had the press release announced today in presentation slides distributed on the table. Please confirm that. And those who are connected via telephone, you can see the presentation slides posted on our website. And we have simultaneous interpretation of English and Japanese: channel 1 is Japanese; English, channel #2. Let me introduce the presenter today, CEO Haruo Naito; global AD Officer, Ivan Chan; Neurology Chief Discovery Officer, Teiji Kimura are also with us to respond to the Q&A session. Let's move to the presentation. We have sufficient distance for disease control and the infection control. I hope you understand that Naito will remove his mask. Naito?

Please allow me to be seated while I make this presentation. As we have announced this morning with the press release, Clarity AD study top line results were reported, and on this press conference, I directly would like to talk to you on the top line results as well as I share with you some ideas on the study results. Could I have the first slide? Let me start with the discovery of lecanemab, origin of lecanemab as shown on the right -- left. On the amyloid beta precursor protein, APP, there was the Arctic mutations found out in 2001 by as shown in the note, was found out by Professor Lars Lannfelt. Actually, in the Northern Sweden, there was the family of AD patient. And this mutation occurred on the amyloid beta 22. So since closer to the Arctic, this mutation was named as Arctic mutations. So for those people with AD, the autopsy was made and found out that there are no blocks and in fact, there are a large number of A protofibrils in those brain. And this molecule, the A protofibril is the soluble edema having the very significant neurotoxicity. So against this Arctic mutation, there is an idea that the antibody therapeutics would be developed. So in 2005, the mouse antibody BioArctic, founded by Professor Lannfelt, started to produce the antibody. And also, we had the research cooperation with this company. And the humanized antibody was formed in 2007. So this was the very first amyloid beta protofibril antibody. Because of this region, this has a very high affinity to protofibril. If you look at the right side, this red -- this orange bar represents the amyloid beta having the 1 to 42 [indiscernible]. Right now, there are 4 antibodies called A, D, M, T. As shown the recognition sites, [indiscernible] are different. Recanemab, in this case, as shown in red color, A-beta is in [indiscernible] state, it recognizes 1 to 16. But when the aggregates and forms protofibrils, the active location expands and 21 to 29 are also recognized. As a result, protofibrils are easier to be recognized, leading to high selectivity. Next, I may show you the history of the lecanemab clinical development. In 2010 in the U.S., the Phase I study was initiated. And then as shown in the middle part, in 2012, the major global Phase II study was initiated. And this study is called 201 study. And in this study, in order to get the Japanese in the study as shown on the right, Phase I study, a little bit late, was initiated in Japan. And this 201 study, actually, played a very important role leading to the success of the Phase III. I believe, as shown here, the 854 early AD patients were enrolled in this large Phase II study. Of course, this was the placebo controlled or double-blinded study. And in this study, as you may recall, very sophisticated statistical analysis was used. Bayesian statistics were used to make the fine-tuned analysis. As shown on this bullet point, in relation to placebo group, there were 5 dose groups of lecanemab, 5 doses. And also, this was the double-blinded study, meaning that this 201 study is really significant in the clinical development. And out of these 5 doses, the clinically effective dose, 10-milligram per kilogram biweekly lecanemab was identified. So this dose selection led the great success to the Clarity AD study. And of course, we run the Clarity AD study initiated in March 2019, enrolling early AD patients, so 1,795 patients. So as I mentioned, the optimum dose, 10-milligram per kilogram biweekly dosing were given to this population. And this slide shows the Clarity AD study design. Clarity AD is the largest global placebo controlled, double-blind, parallel group trial in AD. On the left, you can see the patient population or the eligibility criteria of this population. Total registration was given to 1,795 people and the population was the MCI due to AD or mild AD, and these 2 are called as the early AD. And also, the patients have to have the amyloid pathology confirmed in the brain, and also, MMSE score between 22 to 30 at screening and the objective evaluation indicative of episodic memory impairment screening was needed. And these population were randomized 1:1 ratio to either lecanemab 10-milligram per kilogram biweekly dose. And here, another benefit of the lecanemab is shown in this dosing. This benefit is the -- it can be given from the intial dose, the effective dose, without titration. But for the other antibody therapeutics, 3 to 9 months titration period was needed. During the time, the effective dose cannot be dosed, and therefore, the onset of the action is delayed. Conversely, for lecanemab, first dosing was the effective dose. Therefore, the onset of action was much earlier, quite fast. That's benefit. And also primary endpoint as shown on the right is the change in CDR-SB from the baseline at 18 months. And this shows the endpoints of the Clarity AD. Primary endpoint was the change of CDR-SB from the baseline clinical dementating sum of boxes. As you may know, this quantifies the severity of the symptoms of AD, and therefore, it is widely used in the clinical studies of AD. And also, FDA and other regulatory agencies accept this CDR-SB as the primary endpoints. So the memory, orientation, judgment and problem solving, community infills, home and hobbies and personal care. For these 6 items, the questionnaire is given. And in the center, there are some key secondary endpoints, again, change from baseline at 18 months, amyloid PET centiloid. This is a quantification of the amyloid in the brain and the ADAS-cog14 is widely used to assess the AD. And the third is at comps is the composite score developed by Eisai. And for early AD patients, the general improvement of the overall conditions are reflected. And number 4 is the ADCS MCI-ADL. And as shown here, this is the ADL assessment instruments. And there are 24 items of the questions to the patients' family members and caregivers. Unlike the selection of clothing, domestic works such as cleaning, family activities such as shopping is evaluated from these 24 items of questions. And as for the safety, ARIA-E and H. As you well know, this is the AD amyloid associated imaging of normalities ARIA. So those are the adverse events of amyloid targeted therapies. And mostly, it goes down over time. So this is the transient edema or [indiscernible] is the ARIA-E. And also, the small hemorrhagic spots in the marine on the surface are called as ARIA-H. Many of the ARIA are asymptomatic, but there are some symptoms such as headache, confusion, dizziness, changes in vision and nausea. Here is the Clarity AD top line results. Highly statistical significant was demonstrated and we met primary endpoint. In terms of reduction of clinical decline at month 18 from baseline, CDR-SB against placebo, 27% was the reduced clinical decline p value of 0.00005. I have been in this industry for a long time, but I have never seen p value like this in the past. This is really highly statistically significant result. And as I showed before, for important key secondary endpoint, in all key secondary end points, they were all met with highly statistically significant result, p value of less than 0.01 for all those endpoints and safety ARIA-E 12.5%, symptomatic E was 2.8%, ARIA-H 17.0%, symptomatic 0.7%. From the results of 201, we can expect this range, and so this was in line at least our expected range. For detailed results, at the end of November, in San Francisco, there would be a CCAD meeting, we will present at, and we will publish the findings in a peer-reviewed medical journals. From here on, I would like to express some of the, what I think are important points. The clinical decline of CDR-SB reduced 27% at 18 months compared to placebo, and score changes in the treatment difference showed 0.45 difference. We consider this as clinically meaningful results. The second bullet, the clinical decline on CDR-SB was reduced from as early as 6 months after initiation of treatment and has been sustained. The third bullet point, the effect of CDR-SB expanded over time on therapy, indicating a disease modifying effect. The cause of the disease is removed, and also, the removal of aggregated A-beta in the brain was strongly confirmed at an early stage in Clarity AD and the ADAS-cog14 in key secondary endpoint, and that is cognitive function valuation. And the -- this effect was also observed at the early stage. The clinical decline of ADCS MCI-ADL was strongly reduced, which is evaluated by caregivers and family members for improvement in daily living. This suggests a possibility for significant improvement in the QOL of the people living with AD and caregivers. Earlier incidence profile, as I mentioned before, was within expectations and the -- that from 201 in symptomatic ARIA rate was low. So we have a very robust efficacy and safety results. And the reason for this is mentioned at the bottom. Protofibril high selectivity, which is the cause of neurotoxicity, and titration is not necessary in dosage and administration, therefore, we can expect very strong effect from early stage. Now going forward, upcoming regulatory events are shown here. As you know, we have filed U.S. accelerated approval already. And PDUFA action date is expected January 6, 2023. The significance of requesting accelerated approval, let me express my opinion on that. As soon as possible, this lecanemab should be delivered to the people with AD, as soon as possible. They are waiting. Of course, there is an issue of reimbursement, but with accelerated approval, we are able to deliver this product to the people with AD. Eisai and our focus is AD and dementia, and we want to deliver this product as soon as possible to the population with AD. That is our strong aspiration. And in accelerated approval process, preclinical and clinical up to 201 study and CMC module datas are already submitted to FDA. Those reviews are ongoing, we hope. And because of that, for full approval, we hope the review period relatively would be shorter. That is our expectation. So those 2 reasons, the significance of pursuing accelerated approval. And in the U.S. traditional approval or full approval should be made within fiscal year 2022, that means until March 31st next year. And in Japan, submission should happen around the same timing. In Japan, as shown here, from March this year under the priority assessment consultation system, we have been discussing with PMDA preclinical, clinical and CMC data portions were already submitted. And therefore, EU submission, we want to achieve that around the same time. So we aim for full approval in Japan, U.S. and Europe. We want to complete submissions within FY 2022, and full approval, we hope to achieve by calendar year 2023 in those regions. Next, other than Clarity AD study, there are some new treatment options that we have developed, and I'd like to share some of them. One of them is AHEAD 3-45. Before MCI, there is a stage preclinical AD. That's the population for this study. U.S. Academia Consortium, ACTC, is our partner in this collaboration work. This is a Phase III clinical trial study for registration. There are 2 Phase A3 trail, A45 trial. And for A3, this is earlier for clinical AD, that means normal cognitive function for those people and borderline amyloid accumulation in the brain. That is the population for this trial. For A45 preclinical AD cognitive function normal, however, brain amyloid accumulation positive, that's the population for this trial. The second one is development of maintenance dosing regimen. In Phase II study 201 in open-label extension, OLE, that's a long-term extension study. And this study is ongoing, which has been reported to you already. In the core study of 18 months and after the 18 months of dosing, as shown here, once every 4 weeks and once every 12 weeks dosing regimen is explored and evaluated. This sub-study is ongoing. Depending on the result of the study, after full dose for 18 months for maintenance, with dose reduction, you can have the maintenance treatment acid regimen. That is what we are evaluating. The third one is subcutaneous formulation development. In Clarity AD study, in the part of full LE that's also long extension study, a sub study of subcutaneous administration, including auto injection is ongoing. So the AD population can have lecanemab at home or at institutions. That is the type of formulation we want to develop. If successful, then simpler, convenient and for longer-term treatment can be possible. The fourth one is clinical trial in China. Global version of Clarity AD is used for submission. And if Chinese cohort is required, if there is a request like that, then we have the completed enrollment of 111 patients from China and the enrollment has been completed and the study is ongoing. We could use this for submission in China. And the last one is DIAN-TU Tau NexGen, mainly by University of Washington and the Academia Network, they have this DIAN-TU Tau NexGen trial. This is to evaluate tau therapy. Our E2814 is actually selected. And in the protocol, as the bullet mentions, as anti-amyloid agent, lecanemab was selected as the background A-beta agent. So that data from this study can be available for lecanemab. And at the bottom, it says we aim for early and longer-term contribution to the people living with AD. And this is my last slide. My appreciation and the termination aspiration is expressed. First of all, those with AD, their families, caregivers and the health care professionals, my heartfelt appreciation to your support. Without your effort, it has not been possible. But with your efforts and understanding, we are able to complete the study successfully. As looking back, COVID-19, globally started to be pandemic and the peak period of this study coincided with the pandemic peak. And this study, to be completed according to the plan, was thanks to those efforts of those mentioned here. I would like to express my gratitude to all of those people. And Clarity AD success could be a great advancement in AD treatment. And also going further, it can put energy into development of therapies and diagnostics. As I look back 1991, Professor John Hardy from University Collage of London, first mentioned A-beta hypothesis that was announced. Since then, various A-beta verification and testing have been performed. And after 30 years now, for the first time, anti-protofibril, antibody lecanemab can remove brain A-beta. And with that, Alzheimer's clinical conditions are improved, and that has been demonstrated very firmly. That means A-beta proteinopathy therapy possibilities are open. We can have that possibility, and that is not to the world. And at the same time, other abnormal protein accumulation can be caused by [ pathology ] tau accumulation for Parkinson's disease or DNV alpha-synuclein. Those therapies may benefit from this because there is now high hope for possible therapies. And also, in terms of diagnostics, P-E-T, PET, and CSF, those are 2 major diagnostic techniques. And going forward, how broadly we can have diagnostics, that's important. And at low cost, we should have access to those diagnostics, and we need further efforts. Furthermore, blood-based biomarker, or BBB, like A-beta 42/40 ratio and p-Tau, those technologies are being established. Convenient and low-cost new diagnostics are being developed, and we believe it will accelerate. And this success of the study can bring energy to the development. And there will be less concern about AD on the population and lower burden of family caregiving, including family, the caregiving and recover productivity in society, there would be positive impact on the society. Success of the Clarity AD achieved one big milestone in opinion, but this is not the end of our job and mission. Going forward, we want to bring lecanemab to those people who wait for this. We want to do that as soon as possible. And for that end, we will put our full efforts to have the approval and deliver this drug to the people waiting for it. Thank you very much.