Good afternoon. We now start explanation meeting for the lecanemab phase III Clarity AD study top line results, which was announced at 8:30 A.M. 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 with telephone. 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 have the press release announced today and presentation slides distributed on the table. Please confirm that. Those who are connected via telephone, you can see the presentation slides posted on our website. We have simultaneous interpretation of English and Japanese. Channel one is Japanese. English, channel number two. Let me introduce the presenter today, CEO Haruo Naito.
Global AD Officer Ivan Cheung, 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 infection control. I hope you understand that Naito will remove his mask.
Please allow me to be seated while I make this presentation. As we have announced this morning with a press release, Clarity AD study top-line results were reported. On this press conference, I directly would like to talk to you on the top-line result, as well as, I share with you some ideas on the study result. 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 a family of familial AD patient. This mutation occurred on the amyloid beta 22.
Since closer to the Arctic, this mutation was named as Arctic mutations. For those people with AD, the autopsy was made and found out that there were no plaques, and instead there are a large number of the protofibrils in those brain. This molecule, the protofibril, is the soluble oligomer having the very significant neurotoxicity. Against this, Arctic mutation, there is idea that the antibody therapeutics would be developed. In 2005, a mouse antibody BioArctic, founded by Professor Lannfelt, started to produce the antibody. Also we had the research cooperation with this company, and the humanized antibody was formed in 2007. This was the very first amyloid beta protofibril antibody.
Because of this origin, this has a very high affinity to protofibril. If you look at the right side, this orange bar represents the amyloid beta having the one to 42 amino acid. Right now there are four antibodies are called AD-MT. As shown, the recognition sites, epitopes are different. Lecanemab, in this case as shown in red color, when Aβ is in the monomer state, it recognizes one to 16. When AB aggregates and forms protofibrils, the epitope location expands and 21 - 29 are also recognized. As a result, protofibrils are easier to be recognized, leading to high selectivity. Next, let me show you the history of the lecanemab clinical development. In 2010 in U.S., the phase I study was initiated.
As shown in the middle part, in 2012, the major global phase II study was initiated. This study is called 201 Study. 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. 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 double-blinded study. 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 five dose groups of lecanemab. Five doses. This was the double-blind study, meaning that this Study 201 study is really significant in the clinical development. Out of these five doses, the clinically effective dose, 10 mg/kg bi-weekly regimen was identified. This dose selection led the great success to the Clarity AD study. Of course, we ran the Clarity AD study initiated in March 2019, enrolling early AD patients, so 1,795 patients. As I mentioned, the optimum dose, 10 mg/kg bi-weekly dosing were given to this population. This slide shows the Clarity AD study design.
Clarity AD is the largest and 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. These two are called as the early AD. The patients have to have the amyloid pathology confirmed in the brain, and also MMSE score between 22-30 at screening. The objective evaluation indicative of episodic memory impairment at screening was needed. These population were randomized 1:1 ratio to either lecanemab 10 mg/kg bi-weekly dose arm. Here, another benefit of the lecanemab is shown in this dosing.
This benefit is. It can be given from the initial dose, the effective dose, without titration. For the other antibody therapeutics, three to nine 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 the benefit. Primary endpoint as shown on the right is the change in CDR-SB from the baseline at 18 months. This shows the endpoints of the Clarity AD. Primary endpoint was the change of CDR-SB from the baseline. Clinical Dementia Rating - Sum of Boxes , as you may know. This quantifies the severity of the symptoms of AD.
Therefore, it is widely used in the clinical studies of AD.
Also FDA and other regulatory agencies accept this, CDR-SB as the primary endpoints. The memory, orientation, judgment and problem-solving. Community affairs, home and hobbies, and personal care. For these six items, the questionnaire is given. 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. The ADAS-Cog14 is widely used to assess the AD. The third outcome is the composite score developed by Eisai. For early AD patients, the general improvement of the overall conditions are reflected. Number four is the ADCS MCI-ADL. As shown here, this is the ADL assessment instrument. There are 24 items of the questions to the patient's family members and caregivers.
Like, the selection of clothing, domestic work such as cleaning, familiar activities such as shopping is evaluated from these, 24 items of questions. As for the safety, ARIA-E and H. As you may well know, this is the amyloid-related imaging abnormalities, ARIA. So those are the adverse events of amyloid-targeted therapies. Mostly, it goes down over time. This is the transient edema or effusion, the ARIA-E. Also, the small hemorrhagic spots in the brain on the surface are called 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 statistically 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 and the R&D job for a long time, but I have never seen p- value like this in the past. This is really highly statistically significant result. As I've shown before, for important key secondary endpoint. In all key secondary endpoints, they were all met with highly statistically significant result. P- value of less than 0.01 for all those endpoints. Safety ARIA-E 12.5%, symptomatic incidence 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 with our expected range.
For detailed results, at the end of November in San Francisco, there would be a seated meeting. We will present that, and we will publish the findings in the 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 a clinically meaningful results. The second bullet, the clinical decline on CDR-SB was reduced from as early as six months after initiation of treatment and has been sustained. The third bullet point, the effect on 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 Aβ 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 evaluation. This effect was also observed at an 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. ARIA incidence profile, as I mentioned before, was within expectations and that from 201 and symptomatic ARIA rate was low. So we have a very robust efficacy and safety result. 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. 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 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.
In accelerated approval process, preclinical and clinical up to 201 Study and CMC module data are already submitted to FDA. Those reviews are ongoing, we hope. Because of that, for full approval, we hope the review period relatively would be shorter. That is our expectation. Those two reasons are the significance of pursuing accelerated approval. In U.S., traditional approval or full approval should be made within fiscal year 2022. That means until March 31st next year. 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. Therefore, EU submission, we want to achieve that around the same time. 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 priority 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 of preclinical AD. That's the population for this study. Alzheimer's Clinical Trials Consortium, ACTC, is our partner in this collaboration work. This is our phase III pivotal study for registration. There are two parts, A3 Trial, A45 Trial. For A3, this is earlier preclinical 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. This study is ongoing, which has been reported to you already. The core study of 18 months and after the 18 months of dosing, as shown here, once every four 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 as regimen. That is what we are evaluating. The third one is subcutaneous formulation development. In Clarity AD study, in the part of OLE, that's also a long extension study. A sub-study of subcutaneous administration, including auto-injection, is ongoing.
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. If Chinese cohort is required, if there's a request like that, then we have the completed enrollment of 111 patients from China. The enrollment has been completed, and the study is ongoing. We could use this for submission in China. The last one is DIAN-TU Tau NexGen, mainly by Washington University and the academic network. They have this DIAN-TU Tau NexGen trial. This is to evaluate tau therapy. Our E2814 is actually selected.
In the protocol, as the bullet mentions, anti-amyloid agent, lecanemab was selected as the background Aβ agent. That data from this study can be available for lecanemab. At the bottom it says, "We aim for early and longer term contribution to the people living with AD." This is my last slide. My appreciation and determination, aspiration is expressed. First of all, those with AD, their families, caregivers, and healthcare professionals, my heartfelt appreciation to your support. Without your effort, it has not been possible. With your effort and understanding, we are able to complete this study successfully. Looking back, COVID-19 globally started to be pandemic and the peak period of this study coincided with the pandemic peak.
The 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. Clarity AD success could be a great advancement in AD treatment. Going forward, further, it can pour energy into development of therapies and diagnostics. As I look back, 1991, Professor John Hardy from University College London first mentioned Aβ hypothesis that was announced. Since then, various Aβ verification and testing have been performed. After 30 years, now for the first time, anti-protofibril antibody lecanemab can remove brain Aβ. With that, Alzheimer's clinical conditions are improved, and that has been demonstrated very firmly. That means Aβ proteopathy therapy possibilities are open. We can have that possibility and that is known to the world.
At the same time, other abnormal protein accumulation can be caused by tauopathy or tau accumulation or Parkinson's disease or DLB, α-synucleinopathy. Those therapies may benefit from this because there is now high hope for possible therapies. Also in terms of diagnostics, PET and CSF, those are two major diagnostic techniques. Going forward, how broadly we can have diagnostics, that's important. At low cost, we should have access to those diagnostics, and we need further efforts. Furthermore, blood-based biomarker, or BBB, like Aβ42/40 ratio and p-tau, those technologies are being established. Convenient and low cost new diagnostics are being developed, and we believe it will accelerate. This success of the study can bring energy to the development.
There will be less concern about AD on the population and lower burden of family caregiving and recover productivity in our society. There would be positive impact on the society. Success of the Clarity AD achieved one big milestone, in our 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 effort to have approval and deliver the drug to the people waiting for it. Thank you very much.