Eli Lilly and Company (LLY) 2023 AAIC Lilly Alzheimer's Disease Update Conference (Transcript)

Eli Lilly and Company (NYSE:LLY) 2023 AAIC Lilly Alzheimer’s Disease Update Conference July 17, 2023 1:00 PM ET

Company Participants

Lauren Zierke - Executive Director of IR

Daniel Skovronsky - Chief Scientific and Medical Officer

Anne White - President, Lilly Neuroscience

Mark Mintun - Group Vice President of Neuroscience Research and Development; President, Avid Radiopharmaceuticals

John Sims - Head of Clinical Development for Donanemab

Conference Call Participants

Tim Anderson - Wolfe Research

Alec Stranahan - Bank of America

Chris Schott - JPMorgan

Terence Flynn - Morgan Stanley

Seamus Fernandez - Guggenheim

Evan Seigerman - BMO

Colin Bristow - UBS

Umer Raffat - Evercore

Robyn Karnauskas - Truist

Kerry Holford - Berenberg

Andrew Baum - Citi

Louise Chen - Cantor

Trung Huynh - Credit Suisse

Ladies and gentlemen, thank you for standing by, and welcome to the 2023 AAIC Lilly Alzheimer's Disease Update Conference Call. At this time, all participants are on a listen-only mode. Later we will be conducting a question-and-answer session and instructions will be given at that time. [Operator Instructions]

I would now like to turn the conference over to your host Lauren Zierke, Executive Director of Investor Relations. Please go ahead.

Lauren Zierke

Thanks Tom. Good evening from the Alzheimer's Association International Conference in Amsterdam. Thank you for joining us for Eli Lilly and Company's 2023 Alzheimer's Disease Update. I'm Lauren Zierke, Executive Director Investor Relations.

Joining me on today's call are Dr. Dan Skovronsky, Chief Scientific and Medical Officer; Anne White, President of Lilly Neuroscience; Dr. Mark Mintun, Group Vice President of Neuroscience Research and Development and President of Avid Radiopharmaceuticals; and Dr. John Sims, Head of Clinical Development for Donanemab.

During this conference call we anticipate making projections and forward-looking statements based on our current expectations. Our actual results could differ materially due to several factors including those listed on Slide 3. Additional information concerning factors that could cause actual results to differ materially is contained in our latest Form 10-K and subsequent filings with the Securities and Exchange Commission. The information we provide about our products and pipeline is for the benefit of the investment community. It is not intended to be promotional and is not sufficient for prescribing decisions.

Now I will turn the call over to Dan to provide some introductory remarks.

Daniel Skovronsky

Thanks, Lauren and thanks to everyone for joining us today.

It's certainly an exciting time in Alzheimer's disease research. Congratulations and thank you to scientists across academia and industry for bringing us to this point of progress. Lilly has long been a leader in elucidating Alzheimer's disease pathology and in the research and development of potential diagnostics and disease modifying medicines to address this devastating disease. This has allowed us to pursue unique trial designs with highly potent medicines.

Following Donanemab's TRAILBLAZER-ALZ study in 2021 which was the first study to demonstrate a statistically significant slowing of cognitive and functional decline in patients with early symptomatic Alzheimer's disease, we are now delighted to discuss the results from TRAILBLAZER-ALZ 2 which is the first replication of positive clinical trial results in treating Alzheimer's disease and showed the largest and most meaningful clinical benefit to date.

On Slide 4, we highlight some of the most telling indicators of clinical meaningfulness all presented using the Clinical Dementia Rating Scale or CDR. To provide context for these data, Alzheimer's disease is the only leading cause of death in which until quite recently we haven't seen meaningful treatment improvements.

As a result, we do need to spend some time to overcome the natural skepticism resulting from decades of failure. When we showed Donanemab's Phase 3 data, we saw this manifest into questions related to the clinical meaningfulness of 0.67 of improvement on the CDR scale. As a reminder and TRAILBLAZER-ALZ 2, the maximum benefit a 100% efficacious drug could have shown was 1.88 improvement over 18 months since this is the decline seen in the placebo group. In the context of 1.88, 0.67 is highly meaningful. As we previously noted, this translates to 36% slowing of disease.

Another way to think about 0.67 is how this equates to time savings. A gated and pre-specified analysis showed 7.5 months of time savings out of a total opportunity of 18 months. Again, this is very meaningful to patients.

Additionally, we can look at responder analysis at the individual patient level. In one responder analysis we showed that approximately 50% of patients on donanemab had no disease progression as measured by CDR Sum of Boxes over one year.

In another gated pre-specified analysis, we used to cut point of two full points on the CDR Sum of Boxes scale for most patients or one point for MCI patients to define responders. We found a significant difference in responders favoring donanemab with a highly statistically significant hazard ratio of 0.60.

Similarly, we looked at progression on the CDR global scale in which each event represents progression to the next clinical stage of disease. These are large steps in progression. For example for mild cognitive impairment to mild AD or mild AD to moderate AD. Here we saw 39% reduction in progression, equating to a hazard ratio of 0.61, which was highly statistically significant.

Of course, we are used to measuring similar progression-free survival or PFS numbers in oncology, even though in oncology PFS is pure radiographic measure. Let me point out that Alzheimer's improvement in disease progression as much higher clinical relevance, since it's based purely on a clinical outcome and progression on CDR global clinical scale is the gold standard for clinical meaningfulness in Alzheimer's disease.

Finally and maybe most importantly, we see the curves separating over-time. So while we already saw meaningful effects in 18 months, these data potentially indicate even larger time savings could accrue to patients in the real world. So we're excited about what donanemab treatment can potentially do for patients subject to regulatory approvals across the globe.

I recognize many of you have already had a chance to review our JAMA publication and AAIC Presentation earlier today. Rather than recapitulate those disclosures, we're going to use our time on this call to provide additional context for the study, as well as highlight some new analysis that may not have been fully discussed in those venues but which may inform future Alzheimer's disease treatment.

The topline conclusions from these analyses on Slide 5, which I'll cover briefly. First, efficacy analysis. TRAILBLAZER-ALZ 2 is a large study, which followed more than 1,700 participants and that allows us to look at some pretty interesting pre-specified additional analysis that are still quite large. In fact, nearly all of the additional analyses we'll talk about are more highly powered, then our entire TRAILBLAZER-ALZ Phase 2 study. Mark will show those in detail, but at a high-level whether we cut the population by age, by baseline cognitive performance on MMSE, by physician assessed clinical-stage or by pathological burden, we see that donanemab treatment showed the strongest benefit in-patients who were treated earliest as we would have predicted.

These results have three important implications. First, they may help treating physicians understand the need for earlier detection and treatment. While donanemab showed efficacy in the full population, it's likely that patients who are younger by which we mean under the age of 75, who have a less severe clinical-stage or who have lower levels of tau could have the greatest opportunity for efficacy benefit.

In some of these additional analyses, we saw 50% to 60% slowing of disease progression. We expect this observation will help drive increased urgency for earlier detection of cognitive impairment and diagnosis of AD. Since we saw benefits across the entire population of participants regardless of tau level, we believe confirming amyloid pathology, consistent with the labeling for other approved amyloid targeting therapies is sufficient to identify patients for treatment should donanemab be approved. Still we recognize some physicians may use tau scans to gain additional information and we're working to make those more widely available.

The second implication of these data are that they allow better contextualization of treatment magnitudes across different clinical trial designs. For example, Mark will show an analysis of participants for TRAILBLAZER-ALZ 2, who would have met the primary enrollment criteria for other contemporary Phase 3 designs which is clinical criteria, rather than pathological staging to identify participants to enroll. Again, we'll see that such an approach bias towards earlier-stage patients which can yield larger treatment effects.

The final and perhaps most important implication of these results is that they increased confidence that amyloid targeting therapies could be successful in delaying or even potentially preventing Alzheimer's disease when used in pre-symptomatic patients, that's an ambitious goal. And I'll give an update later on our progress in our TRAILBLAZER-ALZ 3 AD prevention trial .

In addition to these efficacy analyses, Mark will show additional analyses around safety, which I think can help understand how to predict risk of serious ARIA in different patients, and again, can help us understand why different trials or different populations could show different results in the rate of overall ARIA.

TRAILBLAZER-ALZ 2 intentionally enrolled a population with broader ARIA risk factors than other trials with the goal of understanding ARIA risk in various subgroups. These new data, along with FDA's labeling information for lecanemab could enable physicians and patients to have an even more well informed conversation about the benefits and risks of these medicines.

Finally, we'll show some new analyses that address an important question around our novel limited duration dosing. One question many investors have asked us, is what happens to participants after they stop taking donanemab. Mark will show that even in participants who cleared plaque quickly and ceased therapy, their curves continue to separate from placebo over-time even when they are off-drug. We're excited about this aspect of our therapeutic regimen and feel even more confident that we've made the right choice in stopping therapy once a PET scan shows plaque have been cleared.

Patient convenience is a big factor for all medications and especially for people with Alzheimer's disease. Even though the once a month infusion of donanemab could be more manageable than other more frequent infusion regimens, knowing that most participants were able to complete therapy at one year in our trial suggest limited dosing maybe a potential option.

Before we get into all that data, let me turn it over to Anne, who will talk about efforts to improve the ecosystem, especially with respect to diagnostics and give you some views on how we're seeing the commercial opportunity for donanemab assuming regulatory approval.

Anne White

Well, thanks Dan

Moving to Slide six, Alzheimer's disease remains one of the most significant unmet medical needs in society. The Alzheimer's Association project annual healthcare costs in the U.S. for this disease could exceed $1 trillion by 2050. Our recent analysis estimates the U.S. prevalence of people with early symptomatic Alzheimer's disease and the presumed presence of amyloid plaque is approximately 6 million to 7.5 million people. Lilly estimates only 20% to 30% of those Americans are clinically diagnosed today but so many people are not diagnosed or are underdiagnosed until they reach the later stages of diseases underscores the need for education and diagnosis and treatment.

Even if disease-modifying medicines become available, we believe improvement in diagnosis rates will take time. In addition, we believe the number of people likely to be treated with amyloid targeted therapies will initially be significantly lower than the number of diagnosed. Greater diagnosis and treatment will require Lilly and others to work to build awareness of all diagnostic pathways and remove constraints in the current healthcare system.

We remain focused on supporting physicians, patients and their loved ones through the complex Alzheimer's disease journey from initial symptoms to a formal diagnosis and onto treatment. These efforts include creating awareness about the importance of timely detection of symptoms often in the primary-care setting and reducing the stigma surrounding the disease. Today, it can take more than two years on average to diagnose after the first symptoms are detected.

Ensuring health care professionals who routinely incorporate cognitive and functional assessment tools and diagnostics in their clinical practice at the first side of disease to accurately diagnose and identify patients who could potentially benefit from treatment.

Advocating for and assuring broad and simple access without barriers to diagnostic and ensuring awareness of the need for monitoring patients for safety and to determine when people could potentially stop therapy due to plaque clearance. We have significant work to do in each of these areas, but I'll focus my comments today on diagnosis.

While we believe the potential to significantly delay and eventually to prevent Alzheimer's disease, lies in early diagnosis and treatment. Today, there's often no diagnosis or an incorrect or very late one. There are many tools physicians can use to confirm neuropathology to inform an Alzheimer's diagnosis and identify appropriate patients for treatment. We expect a variety of biomarker-driven diagnostics such as PET imaging, CSF and emerging blood-based diagnostics will all be important options for physicians to confirm amyloid pathology.

While largely still in development, we think blood-based biomarkers have the potential to significantly broaden availability of diagnostic testing, and we remain committed to this effort. Our internal and partnered efforts to support the Alzheimer's diagnostic ecosystem in the U.S. include Amyvid, an amyloid PET tracer approved in 2012; TAUVID, a tau PET tracer approved in 2020; p-tau217, a blood-based biomarker being developed at Lilly. We're planning on making this available as a laboratory developed test or LDT later this year; and p-tau181, another blood-based biomarker being developed in collaboration with Roche Diagnostics.

Awareness and broad access to both diagnostic tools and treatments are critical to change the trajectory of this disease. We believe the centers for Medicare and Medicaid Services, or CMS, should reconsider the current national coverage determination and permanently provide coverage and access without barrier for this class of medicines upon FDA approval.

People with Alzheimer's disease already face significant hurdles in their journey from detection to diagnosis to treatment, and we should [technical difficulty] additional barriers. We believe the Phase 3 TRAILBLAZER-ALZ 2 trial results answer the questions that CMS has posed in its coverage with evidence development or CED pathway. We believe this data meets the high level of evidence criteria set forth by CMS for reconsideration.

As Dan mentioned earlier, we have shown this data is clinically meaningful, and we plan to publish additional data in the future that directly answers the questions that CMS has posed in their CED. We also intend to initiate real-world studies to help establish the impact of donanemab on long-term outcomes. The aim of this work is to compare amyloid-positive early symptomatic AD paid through with donanemab plus supportive care to patients receiving supportive care alone. The primary outcome of these studies focuses on changes in dependence level.

We remain concerned that mandating patient enrollment in registries even simplified ones will continue to pose unnecessary barriers and runs counter CMS' promise of broad coverage without barriers to all Medicare beneficiaries. We believe this could exacerbate existing racial and rural health disparities as we've seen before in CED registry. Still, we acknowledge the current position of CMS and nonetheless, we remain confident in the opportunity for donanemab launch, assuming FDA approval.

When thinking about the launch trajectory, it's important to remember that it will take several years for the health care ecosystem to develop to better support the timely identification, accurate diagnosis, treatment and ongoing management of patients with early symptomatic Alzheimer's disease.

Now let me turn the call over to Dr. Mark Mintun to provide additional insight into the results of the TRAILBLAZER-ALZ 2 study.

Mark Mintun

Thanks, Anne.

Turning to Slide 8. Let me first briefly touch on key attributes of the TRAILBLAZER-ALZ 2 study design. Participant screening required proof of positive amyloid pathology in either low, medium or high tau pathology. We focused on the low medium tau participants to demonstrate confirmation of our Phase 2 population. Note that once a participant on the donanemab arm met a predefined level of amyloid clearance, they were switched to placebo.

On Slides 9 and 10, you can see important baseline characteristics for TRAILBLAZER-ALZ 2. The proportion of ApoE4 carriers was well balanced across arms, and baseline clinical and biomarker measures were also well balanced. Donanemab in this study was - been studied in a broad patient population, which included common comorbid conditions and concomitant medications.

On Slide 11, it is notable that when compared to other contemporary AD Phase 3 clinical trials, both the low medium tau and the combined population from the TRAILBLAZER-ALZ 2 had more advanced disease based on key baseline clinical and neuropathological characteristics, including MMSE, CDR Sum of Boxes, age and amyloid level. We think this is an important consideration when assessing study results.

Moving to Slide 13, you see a summary of adverse events in the combined population. And then in Slide 14, we see a more detailed breakout of ARIA rates in the study. Like all amyloid-targeting therapies that remove plaque and as acknowledged by the FDA with the box warning in the Leqembi traditional approval label, a key risk associated with treatment is ARIA.

In the combined population, ARIA-E and ARIA-H were present in 24% and 31% of participants, respectively. The incidence of a serious adverse event related to ARIA was 1.6%, including three participants whose death occurred after incidence of serious ARIA. The death included two ApoE4 heterozygous carriers and one noncarrier. None were prescribed anticoagulant or antiplatelet medication.

One case had retreatment after resolution of severe ARIA-E which was accompanied by severe ARIA microhemorrhages and ARIA-H and one had superficial siderosis at baseline. Careful monitoring and observation of patients can reduce the risk and impact of ARIA through real-world data generation as well as studies such as TRAILBLAZER-ALZ 6, we're committed to better understanding ARIA, a risk that must be monitored across this class of therapies.

In TRAILBLAZER-ALZ 6, we aim to improve our understanding of the patient characteristic and dosing dynamic that may affect this risk, such as a pause in dosing if patients with high risk of ARIA can be identified earlier. We anticipate these study results will serve to inform physician treatment decisions.

On Slide 15, we have noted key ARIA safety considerations. On the left, we see ARIA rates based on ApoE4 carrier status. In TRAILBLAZER-ALZ 2, we saw ARIA-E events in 16% of non-carriers, 23% of heterozygous carriers, and 41% in homozygous carriers. Additionally, participants with at least one serious ARIA-E event included 12 ApoE4 carriers and one noncarrier. The data suggests people who are ApoE4 homozygous do have a higher risk of ARIA-E than non-carriers or heterozygos carriers, similar to what we have seen in other trials.

Next, evaluated the frequency of ARIA-E for participants grouped into terciles by amyloid level at baseline. As I mentioned earlier, when compared to other contemporary Phase 3 AD clinical trials, the population across donanemab studies had more advanced disease based on key baseline characteristics, including amyloid level. This analysis shows increased incidence of ARIA-E based on amyloid level at baseline, particularly for participants in the highest tercile. We think this is important to consider in the context of other clinical trials, which enrolled different populations.

Finally, it is worth noting that TRAILBLAZER-ALZ 2 in other trials evaluating donanemab included eligibility criteria, allowing for superficial siderosis at baseline. Superficial siderosis is a condition that results from chronic global great bleeding in the brain and is not uncommon in Alzheimer's disease patients.

Participants with superficial siderosis at baseline had higher frequency of ARIA events, including ARIA-E compared to those without. Thus, all of these factors, ApoE genotype, amyloid burden and superficial siderosis may impact rates of ARIA following treatment.

Shifting now to efficacy on Slide 17, we see 35% slowing of decline for the low medium tau population as measured by the primary endpoint of iADRS, or Integrated Alzheimer's Disease Rating Scale. We also see 36% slowing of decline as measured by CDR Sum of Boxes, the strongest results seen to date in an Alzheimer's trial. For both endpoints, the treatment effect increased relative to placebo over the course of the trial even after the majority of participants completed active therapy.

In Slide 18, we show the iADRS and CDR Sum of Boxes for the combined population, which includes both the low, medium and high tau participants. Results showed 22% and 29% slowing of decline as measured by iADRS and CDR Sum of Boxes, respectively, both of which were statistically significant improvements.

With this data, we believe all amyloid-positive, early symptomatic Alzheimer's disease patients should be considered for treatment with donanemab regardless of tau status. As Dan mentioned earlier, additional analyses we've generated shows patients can receive the most benefit from donanemab when they are diagnosed and treated as early as possible. I will now discuss five analyses from the TRAILBLAZER-ALZ 2 that inform this conclusion. Results were consistent across CDR Sum of Boxes and iADRS, but we'll be sure to highlight the CDR Sum of Boxes results since investors are more familiar with this scale

First, as shown on Slide 19, we simply evaluated participants in the study based on a prespecified age in the low medium tau population. For participants under the age of 75, donanemab slowed declined by 48% on the iADRS scale, which is an improvement of 13 percentage points compared to the entire low medium tau group. When measured with CDR Sum of Boxes, there was a 45% slowing of decline in those under 75, an improvement of 9 percentage points compared to all ages.

On Slide 20, we look at participants with MCI or mild cognitive impairment, in the low medium tau population. In TRAILBLAZER-ALZ 2, these participants are at the earliest stage of the disease as measured by the MMSE score.

Now while we acknowledge this is a smaller subset of the population with a wider confidence interval, this analysis showed a 60% slowing of decline on the iADRS compared to 35% in the full low medium tau group. This analysis also showed a 46% slowing of decline as measured by the CDR Sum of Boxes.

Moving to Slide 21, we show slowing of decline as measured by CDR Sum of Boxes for a typical population that would be enrolled in other contemporary clinical trials. While the TRAILBLAZER-ALZ 2 trial included MMSE scores between 20 and 28 at screening and no restriction for CDR global score, the analysis shown here represents efficacy for a population that is less progressed based on MMSE scores between 22 and 30 and a CDR global score of 1 or less. These criteria - with this criteria, we observed 38% slowing of decline in the CDR Sum of Boxes as compared to 22% for the remaining population.

Looking at these graphs side-by-side, one can almost imagine the progression of a typical AD patient through the earlier stages of the disease on the left and into the more advanced symptoms on the right. The potential benefits of donanemab can be seen in both populations, but are obviously more impactful when initiated early.

On Slide 22, we've analyzed the low medium tau combined - and the high tau populations based on the PET imaging where you see greater benefits of disease slowing with lower levels of tau as measured by CDR Sum of Boxes. The low medium tau participants had an average of 36% slowing while high tau participants averaged 21% slowing. It's important to note that the high tau group still sees improvement of a similar numerical magnitude on the CDR Sum of Boxes. Although as expected, this lesser percentage impact - this is a lesser percentage impact in a more quickly declining population.

In our final analysis on Slide 23, we've divided the combined population into terciles by our blood-based biomarker, P-tau217 rather than brain tau PET. For both the iADRS and the CDR Sum of Boxes endpoints, we see increased efficacy as we look at lower turns of P-tau217.

In the lowest tau tercile, we see 36% slowing of disease as measured by iADRS and 46% slowing when measured by CDR Sum of Boxes. On the other end of the spectrum, participants in the highest tau tercile had 21% and 26% slowing of decline, when measured by iADRS and CDR Sum of Boxes, respectively.

As we have shared, we believe that a wide range of patients with early AD will benefit from donanemab. These data and participants in the earlier stages of the disease reinforces our belief that earlier treatment provides the most potential for benefit and reinforces the need of urgency in detection and diagnosis of the disease to have the greatest impact for patients. This data also increases our confidence in the success of the ongoing TRAILBLAZER-ALZ 3 study in presymptomatic Alzheimer's disease.

Also notable in the additional analysis is the efficacy by ApoE4 genotype. We did see increased efficacy in non-carriers and heterozygous carriers as compared to homozygous. However, we are encouraged to still see benefit in homozygous e4e4 participants and believe this supports use in those patients as well.

Moving to Slide 24. We show that the level of significant amyloid plaque clearance in participants treated with donanemab. In the low medium tau population, 80% reach amyloid clearance by 76 weeks and in the combined population, 76% reached amyloid clearance at the same time point.

Recall that baseline amyloid plaque levels in TRAILBLAZER-ALZ 2 were significantly higher in participants enrolled - than participants enrolled in other contemporary clinical trials. For both populations and TRAILBLAZER-ALZ 2, about half completed their course of treatment at one year and about 70% at 18 months.

With the TRAILBLAZER-ALZ 2 data, we continue to believe that limited duration dosing is a possibility once a patient's amyloid plaque is considered cleared. Model data from multiple donanemab trials suggest that in participants who completed their course of therapy after achieving amyloid plaque clearance following six months of treatment, we observed an average reaccumulation of only 2.8 centiloids in the 12 months following treatment cessation.

As we look to answer the question of whether treatment benefits will continue to grow even after patients finished dosing, we have seen supportive evidence as shown now on Slide 25. Here, you see analysis of the roughly 50% of participants who completed the treatment regimen by achieving amyloid clearance at the six or 12 month scans and thereafter switched to placebo.

While these data cannot perfectly answer the question due to factors, including post-randomization events and not perfectly controlled across arms, we are pleased to see that these participants continue to separate from the placebo population even while they are off active therapy. We believe limited duration dosing, along with the convenience of once-monthly infusion could represent a lower burden of treatment for patients and bring significant value to the health care system.

In summary, we are very excited about the Phase 3 results for donanemab, which demonstrated clinically meaningful benefit across patients with early symptomatic Alzheimer's disease. We are also thrilled to see the very strong results and participants earlier in their disease progression, offering potentially even more hope for patients identified at that stage. We remain committed to further studying and understanding ARIA and are confident data from both our TRAILBLAZER-ALZ 2 and our TRAILBLAZER-ALZ 6 studies will provide further insight for physicians on managing patient safety. Additionally, these results give us confidence that limited-duration dosing is a possibility for many patients.

Now let me turn the call over to Dan to discuss our broader clinical efforts in Alzheimer's disease and neurodegeneration.

Daniel Skovronsky

Thanks, Mark.

As we look to the future and focus our efforts on earlier diagnosis, we're excited to explore the possibility of delaying or even potentially preventing symptomatic disease. In the donanemab TRAILBLAZER-ALZ 3 study, we're enrolling participants with evidence of amyloid pathology but who are still cognitively unimpaired. We identified these participants using our plasma P-tau217 blood-based biomarker.

Based on what we've seen to date in donanemab clinical studies, we have increasing confidence in the opportunity to further slow Alzheimer's disease in TRAILBLAZER-ALZ 3. And since these participants will have less amyloid pathology than participants in TRAILBLAZER-ALZ 2, we expect to observe less ARIA in this setting.

We're using the event-based CDR global score progression as the primary endpoint in the study. This is the endpoint, which demonstrated robust results with a hazard ratio of 0.61 in the TRAILBLAZER-ALZ 2 study. And our expectation is even increased potential in this earlier TRAILBLAZER-ALZ 3 population. This trial is enrolling well, but of course, as an event-based study, we expect it will take several years to reach the events necessary to complete the study.

Lilly again has been leading research and development efforts in Alzheimer's for decades, and I'm proud to show on Slide 28 that our neuroscience efforts, including those targeting neurodegeneration, continue to expand. First, our submission of donanemab for traditional approval was completed in Q2, with regulatory action expected by the end of this year. We expect regulatory submissions in other key markets, including Japan, EU, U.K. and China, will be completed during the second half of this year.

Also in Phase 3 for early Alzheimer's disease is remternetug, which targets amyloid in the same way as donanemab and offers the potential for subcutaneous dosing. We've initiated the remternetug Phase 3 program, which includes TRAILRUNNER-ALZ 1, a randomized double-blind placebo-controlled study to evaluate safety and plaque-lowering effects of remternetug in amyloid-positive participants with early symptomatic AD.

Participants received remternetug or placebo administered via subcutaneous injection or IV infusion. Our overall Phase 3 program will also include Phase 3 studies with clinical outcome endpoints similar to donanemab TRAILBLAZER-ALZ 2 study. We anticipate disclosing more details including the overall Phase 3 study design, as well as expected completion time lines in the future.

Earlier in the pipeline, we continue to evaluate agents targeting tau, like our O-GlcNAcase inhibitor, which is currently in Phase 2. We're also investing in clinical programs for diseases such as Parkinson's and frontotemporal dementia through gene therapy, both of which are progressing well in patients.

In summary, we're at an inflection point in Alzheimer's disease research and treatment, where we've shown the potential to meaningfully slow this devastating disease that impacts millions of people as well as their loved ones. We're particularly encouraged by the data showing the impact we can make for people when we identify and treat the disease in its earliest stages. We still have significant work to do to strengthen the health care ecosystem for Alzheimer's and ensure these medicines reach people with this disease, but we're committed to tackling this challenge.

Our recent successes have further energized Lilly's R&D team, and I'm excited by what I'm seeing in our labs and in our early clinical trials. And I look forward to what we can yet do for patients that need us.

This concludes our prepared remarks. Now I'll turn the call over to Lauren to moderate the Q&A session.

Lauren Zierke

Thanks, Dan. [Operator Instructions] Tom, please provide the instructions for the Q&A session, and then we're ready for our first caller.

Question-and-Answer Session

Operator

[Operator Instructions] And our first question today is coming from Tim Anderson from Wolfe Research. Tim, your line is live. Please go ahead.

Tim Anderson

Great. Thanks so much. I know it's more of a commercial question, but it's focused on kind of safety and there's a lot of focus on how donanemab compares to lucanumab. Side by side Leqembi looks better. I'm not sure anyone would disagree with that. But of course, the big trade-off is that donanemab offers finite dosing. So how do you think this is going to kind of play out in the commercial marketplace in terms of how docs and patients are going to choose between one product versus the other. So how is Lilly kind of viewing market share apportioning between you and your competitor over the years? Thank you.

Daniel Skovronsky

Thanks Tim, this is Dan here. Maybe I'll just start with the question on safety and then Anne can talk about the commercial implications here. So I think it was Slide 15, we showed some safety considerations around ARIA. And I think maybe I do disagree with your conclusion here that we can make comparative assessments about the safety of these two drugs, given the differences in populations.

So as Mark said, we allowed patients with superficial siderosis in our trials, look at the right side there, the difference between patients who had that and who didn't have that, whereas other drugs haven't allowed that in their trials. Same thing with amyloid levels, we had much higher levels of amyloid in our trial than other contemporary studies. We didn't have any patients who were negative by amyloid PET scan in contrast to some others. And we know amyloid is a risk factor for ARIA.

So it's a little hard to back those things out and come up with sort of an apples-to-apples comparison. Probably the only real way to do that is a head-to-head trial. We did that with aducanumab. We can consider doing that with aducanumab if there's significant confusion in the field. But I'd be pretty optimistic about what a trial like that would show for both safety and efficacy based on the data we saw.

Having said that, I don't think the biggest challenge right now is like competition with lucanumab, it's building a market opportunity so that patients can benefit from either of these drugs, which I think have a great potential for patients

And maybe with that, I'll turn it over to Anne.

Anne White

Yes, I just want to echo what Dan said. I think we've said this before that we don't really think of this in terms of being a class where we need to compete over market share. We're building a new class of medicines on behalf of people disease. We're working to drive increased awareness, earlier diagnosis, especially with the data that we shared with you today and access to these treatments. And that's what we all should be focused on.

There are a lot that need our help. And obviously, you can imagine that we're thrilled with the data that we shared today on our opportunity potential to help them. So I would imagine both companies, it's really the focus for us. It's going to be on market building, disease led education, and help [technical difficulty] determine how to diagnose patients.

I do want to emphasize, as you said, we do think that limited-duration dosing, and I would say we feel even more confident about that with the data that we saw today. We do think that offers incredible value both for patients suffering from this disease, but also for the health care system. So we do feel really good about the potential benefits of the limited-duration dosing offer, especially after sharing the data we issued today.

Tim Anderson

Thank you.

Lauren Zierke

Thank you, Tim. Next caller?

Operator

Your next question is coming from Geoff Meacham from Bank of America. Geoff, your line is live. Please go ahead.

Alec Stranahan

Hi. This is Alec Stranahan on for Geoff Meacham. Thank you for taking my questions. And congrats on the data. So at several of the symposiums, AD Alzheimer's as a chronic disease is brought up. How do you think this could change the treatment paradigm? Another major theme was the challenge of ARIA detection using the available imaging techniques and the difficulties for prescribers to decide the next steps for treatment. Can you talk a little bit about what Lilly is doing to develop - what Lilly is developing to help overcome this? Thank you.

Lauren Zierke

We'll start off with Dan.

Daniel Skovronsky

Yes. I think the first question, which is viewing Alzheimer's as a chronic disease. And then Mark will talk maybe a little bit about what we're doing to further understand how to detect and manage ARIA. Yes, of course, Alzheimer's is a chronic disease, and plaques are probably an early initiating factor in the disease, that’s why we're trying to remove them completely as quickly as we can and as many patients as we can. I think we've achieved a new bar for that in this trial.

And then, of course, for us, the next step is going earlier. I think in the earlier population, we might be able to stop this disease for most patients with amyloid-lowering drugs. I think in symptomatic patients, including sort of the - maybe the more affected half of the population in this trial, you can just see that we're going to need additional therapies. If you want to get to patients at that level of disease, we're going to need anti-amyloid therapies and then someday anti-tau therapies, and we're, of course, working on those. Mark, ARIA?

Mark Mintun

Yes. So you bring up an interesting point, which is there's two levels in MRI that we might, could be able to do better. One is at the very beginning and trying to characterize the patient and trying to predict their risk of ARIA once being put on donanemab, one of the important parts of TRAILBLAZER-ALZ 6, it's a trial that is investigating additional types of MRI sequences to better understand whether we can identify those patients at high risk of ARIA and better characterize the risk.

The other aspect you sort of brought up is that is it possible to be able to detect ARIA that in an earlier level, be able to pause dosing. What's the best way of pausing doses? How long? And that's also being investigated in the TRAILBLAZER-ALZ 6 study.

So we are looking at both those aspects of novel and new MRI sequences that might be able to predict patients at risk and also how to better detect it in the middle of treatment. But we also see that now with approval of Leqembi and what we hope is the approval of this drug by the end of the year, we will see a much more interest in trying to be able to define patients at risk, whether it's with new blood tests that come out or whether there's new sequences and how to evaluate those patients easier and quicker. We see this as now a kickoff of a very rapidly evolving field, where we will probably be learning almost on a yearly basis, major steps in being able to take care of patients and being able to prevent and mitigate this.

Lauren Zierke

Thanks Anne, and Mark. Next question?

Operator

Your next question is coming from Chris Schott from JPMorgan. Chris, your line is live. Please go ahead.

ChrisSchott

Great. Thank you so much for the questions, and congrats on the data. Just two from me. First, just with regards to your potential FDA label and finite duration of dosing. How do you expect that will be handled in label? So do you think that there'll be specifically finite dosing is a possibility called out in the label? Or is it going to be really left for physicians to determine? And then my second question was just a bigger picture one, just kind of continuing the theme of the questions here. I'm just trying to get my hands around how long you think it's going to take before this market really ramps. It seems like there's still a number of questions to address here, how to detect ARIA, how to better identify patients. Just practically, how do you see physicians dealing with this as the drug launches next year? Is this going to be just go in lower-risk patients? And easier way into it, does it go broad? Just help me a little bit of just how you're envisioning this first maybe a year or two before we maybe have data from TRAILBLAZER-ALZ 6, et cetera. Thanks so much.

Lauren Zierke

Thanks, Chris. We'll let Dan address your first question on the FDA label, and then we'll shift to Anne to answer your question on market ramping.

Daniel Skovronsky

Yes. Thanks, Chris. We probably have to be careful speculating too much about FDA label while we're under review here. But look, I think for most drugs, you would have a description of your dosing regimen used in your clinical trial section of the label. That's pretty typical. I think in the dosing section of the label, it's rare to talk about like how long dosing should continue for or for the FDA to mandate that you have to stay on drug, you have to come off drug. I pretty sure like even for drug like Leqembi, it's pretty silent on that topic.

So physicians all probably, over time, generate their own treatment guidelines for both drugs, which could be similar to what was used in clinical trials or could be different. And you can imagine scenarios where even both drugs are used for fixed or limited duration set. That wouldn't surprise me based on the data I've seen. Anne?

Anne White

Yes. So I think as I shared, we do think it will take several years to improve the detection, the diagnostic and treatment ecosystem to let these medicines reach their full potential. So as I shared, I think there should be limited expectations in first few years, but the mid-and long-term opportunity here is significant given the huge unmet need.

But the fact is we are building a new class of medicines here. And so that's going to take some time. Physicians, as you said, I think they're going to need to get their own experience. They're probably going to start with a few patients and get some of that experience.

Obviously, I think the most important first step we have is to have such a meaningful - clinically meaningful effect. And so that was the important first step in the journey. One thing I can share though, if it's any indication of patients' desire to access these medicines, the enrollment and the demand to participate in our clinical trials for donanemab is very high.

Now however, as I said, there's still quite a bit of work to do to ensure that the ecosystem can meet that demand. So while the demand is there from the patients, I think as you're hearing from us, there's certainly work to be done to make sure that we can help all the patients that potentially could be helped the disease. And I think it's physicians, I think, are going to start flow and then get that experience and grow.

I think it's important though, as you think about which patients that we do, as we shared the data today, we saw benefit across the patients that we studied. So I don't think that out of the gate, physicians are going to restrict by any of the different criteria on the patients themselves other than early symptomatic Alzheimer's disease with amyloid pathology. But I do think that they'll start slowly get their own experience. I think as Dan described too and make their treatment positions based on that experience.

Lauren Zierke

Thanks, Dan and Anne. Ready for the next question.

Operator

The next question is coming from Terence Flynn from Morgan Stanley. Terence, your line is live. Please go ahead.

Terence Flynn

Great. Thanks so much for taking the questions. Maybe a two-parter for me. Just wondering how you think tau will most likely be handled on a potential donanemab label. And for you, just wondering any proxy we should think about for market build? Again, I've heard your comments now a couple of times here in terms of the time it's going to take to build this market. But as you look back historically, is there any analog market you can think of that you'd point us to? Thank you.

Lauren Zierke

Thanks, Terence. We'll go to Mark first on your question on tau in the label, and then we'll move to Anne on your question for market proxies.

Mark Mintun

Yes. So - and I'm assuming you mean tau PET and obviously, tau PET was an important part in the - I think, in the development of Alzheimer's disease drugs in general because we can use it to identify the amount of pathology. We see it as incredibly useful research and development tool.

As we look forward though, from the data we have now, we are seeing efficacy and benefits directionally in all of our measures in the high-tau group. So it's a big question. And it's - and what we are looking at is that the tau PET could well inform clinicians and patients and families in certain situations, but it does not look like something that we would see would be mandated.

We see too much other ways of identifying groups. As we went through, you can look at different ways of specifying by age and by MMSE and by tau. So we look at this as something of which it will be a valuable adjunct in certain patients for fully evaluating the potential benefits, but not a necessary part, and we would not sit here and predict that it would end up in the label. Anne, do you want to...

Anne White

Yes. So on your question around proxies, there really is not [technical difficulty], I think, a disease state like this. So we've discussed that as well. Obviously, a large number of patients exist out there. But as I mentioned, very few of them are even diagnosed today. Now the first step, obviously, as I said, is a medicine that drives diagnosis. So there's been such a stigma and really not answers to offer patients that I think there's been that reluctance by physicians. But now they have something [technical difficulty] for these patients with the approval of these medicines.

So I think that, that will help change the trajectory. I wish I could give you a great proxy. I don't really think that there is one. I think this is going to be one where it is going to start slow as physicians get their experience. But as we've shared today, and particularly as we have the potential to move into the earlier stages of disease where there could be even more patients, there is incredible opportunity in the future. But we'll keep thinking about it. We can - as we have insights and ideas on what the proxies may be, we can share those with you. But I think we're in a new place here with the number of patients we can help, but the work that needs to be assessed, identify these patients.

And really, even if many of these patients present themselves as a primary care or family doctor. And so there's an effort there to just help them diagnose this versus normal aging. That's like the first step in a fairly complex journey from there getting into neurologists or others to get treated. There's quite a journey in front of the patients. But that's what I think we can do well is help develop this ecosystem in partnership with the health care system that over time will change that trajectory, but we do think it will take some time.

Lauren Zierke

Thanks, Mark and Anne. Next caller please.

Operator

Certainly. The next question is coming from Seamus Fernandez from Guggenheim. Seamus, your line is live. Please go ahead.

Seamus Fernandez

Great. Thanks guys. And congrats on the data. So just a couple of things here. As we look at the ApoE4 carrier status, that does look like it is a helpful guide. And then you kind of layer on top of that the superficial siderosis. To me, this looks like an opportunity for a relatively effective REMS for FDA to put in place. Can you just help us understand if that's part of the current applicant or something that you would anticipate being part of this analysis? And is superficial siderosis another layer to that potential REMS that you would recommend to physicians? And then just the second question is really on remternetug. In terms of the opportunity to see development advancing there, it seems like there would be an opportunity for a potential accelerated approval purely on the basis of amyloid imaging. When might we see those type of data? And am I thinking about that as the opportunity for remternetug appropriately? Thanks.

Lauren Zierke

Thanks, Seamus. So your first question related to potential REMS, we'll start that off with Dan. And for your second question on remternetug and potential approval timing, we'll take that one for Mark.

Daniel Skovronsky

Okay. Thanks, Seamus. It's a good question here. REMS isn't something we've considered all. I don't think that's going to be required here. But I think you've raised a good point about e4 status and superficial siderosis being two important things. And I think to use this class of drugs, doctors need to know a couple of things about their patient. And we've tried to highlight in our paper presentation in this call, like what are the important things doctors need to know.

I think from an efficacy standpoint, it's about the stage of disease. So that can be measured with MMSE or CDR, the pathologic stage is helpful. Frankly, I think we would have guessed pathologic stage would have been even more important than clinical stage, but it looks like they both work really well in assessing efficacy. Age is really important in assessing efficacy as well.

So what about safety side, you pointed out. E4 status, that's really important. And then everything else is basically what you see on the MRI, superficial siderosis. We didn't mention it, but of course, the microhemorrhages are an important risk factor for ARIA and then baseline amyloid status from the PET scan.

So then how does that all fit together? I think it means that doctors are neurologists and tier attritions are going to have their work to do. They're going to have to have conversations with patients and families and say, okay, given your age, given your cognitive status or your pathologic burden if we know it, here's what we can expect around efficacy. And then given your genotype and your MRI, here's what we can expect around safety. Sometimes that will make it an easy call, if it's a great patient, sometimes it may be more complicated and more aggression from the doctor and the patient will come into play. So that's how I see it playing out rather than a regulatory REMS or anything like that.

Mark, do you want to talk about remternetug and next steps there?

Mark Mintun

Yes. So remternetug, obviously, we're excited about this and particularly, we're noting sort of the ability for it to be used in the subcutaneous formulation. You mentioned accelerated approval. I think it's - you're not the first person to mention that. That sounds like a really - it is a really interesting idea. But we also - and we see the potential for that, but we also see how - that we don't know exactly what the future of this regulatory landscape is going to be. We see things evolving from this point forward. And of course, accelerated approval is - it does require not only the evidence of amyloid removal, as judged by the recent accelerated approval, but also the safety database and also an evidence of novelty and something different from existing therapies that are approved.

So while it's absolutely something that we are actively considering and thinking about and watching, at this point, we can't say exactly when - exactly how we're going to commit to that. And also, unfortunately, I have to say that we are not able - we're going to be able to inform time lines a little bit in the future, but at the moment, we're not able to review the time lines for the remternetug Phase 3 development program.

Daniel Skovronsky

Yes. Maybe to put a finer point on what Mark said, Seamus. I mean I think in some sense, the CMS decisions around unwillingness to pay for drugs approved under accelerated approval is going to take that pathway off the table for most sponsors of drugs and Alzheimer's, which is really unfortunate. That's depriving patients of future therapies. So we're sorry to see that.

Lauren Zierke

Thanks. Next caller please.

Operator

The next question is coming from Evan Seigerman from BMO. Evan, your line is live. Please go ahead.

Evan Seigerman

Hi, guys. Thank you so much for taking the question. Really congrats on the data. So with data indicating that patients post-amyloid negativity to continue to show improved slowing of their decline versus placebo, how do you envision kind of the patient provider conversation on stopping therapy and then potentially redosing? And do you anticipate patients will be reexamined for amyloid formation to be redosed? Thank you.

Lauren Zierke

Thanks, Evan. For your question on staffing and potentially redosing, we'll go to John.

John Sims

Yes. Thanks, Evan. So clearly, we haven't answered those questions on redosing. That's an area that we're currently actively studying. We have discussed about the - our understanding now of the reaccumulation which we described is about 2.8 centiloid, which is a little less than the natural reaccumulation rate that occurs.

And so at the level that we're reducing amyloid, if that rate continues, we certainly don't anticipate any need to redose if that were an option or an area that we want to develop until five years for an average patient or something like that.

So I think we've got some time to kind of figure out that. I think the conversation is hard to know here, right? I think patients want to know, I think, what their amyloid level did, just like almost all treatments. So how do my cholesterol respond, how do my hypertension go? So I think that's another area where I think we also need to see some evolution is on the biomarkers. And particularly, we know how to use PET scans for that.

But we also want to see some evolution for some of the blood-based biomarkers that we hope might be able to evolve and give us some similar answers. We're still not there yet for that, but we'll certainly be working that will be one area that we'll be working on vigorously because that's certainly a more tractable and scalable solution here for monitoring work to become a solution for a retreatment in the future.

Lauren Zierke

Thanks John. Next caller please.

Operator

The next question is coming from Colin Bristow from UBS. Colin, your line is live. Please go ahead.

Colin Bristow

Hi, good afternoon. And congrats on the data. So I guess given the strong data you showed in the MCI patients in TRAILBLAZER-ALZ 2 and then I guess what you highlighted around baseline amyloid versus ARIA risk, it feels like the donanemab is arguably better suited earlier in the disease course. And given the long duration of TRAILBLAZER-ALZ 3, how should we think about interim looks and/or the potential to stop early? And then just on donanemab, just given the potential for amyloid negativity to drive treatment duration, how are you thinking about pricing models when this hit the market? Thank you.

Daniel Skovronsky

Okay. I'll take the TRAILBLAZER-ALZ 3 question, and then Anne can take the pricing question. So you're right. We maybe painstakingly showed a number of analyses, all concordant on the idea that the earlier you treat, the bigger impact you can have on disease progression, which gives us confidence that TRAILBLAZER 3 should be successful. We've structured this as an event-driven study, and we can - we have powered it for certain effect size, which we could be more optimistic about now.

Having said that, we never - we usually have an opportunity across our therapeutic areas in our Phase 3 trials for including interim analyses but we try to never comment on specifics of what or when that might look like because we don't want to unblind the study by then having to disclose things prematurely.

Anne White

Thanks for the question on price. Unfortunately, we can't comment on price just yet, but it is our approach at Lilly, as you know, to price our medicines according to the value that they bring. And as I mentioned before, I think the opportunity for limited duration dosing patients complete their course of treatment once they reach that predefined the low plaque offers quite a bit of value. It also offers the value of the once-monthly infusions, so I think we're enthusiastic about the value that it brings, but too premature to comment on price just yet.

Lauren Zierke

Thanks, Dan and Anne. Next question please.

Operator

The next question is coming from Umer Raffat from Evercore. Umer, your line is live. Please go ahead.

Umer Raffat

Hi, guys. Thanks for taking my question. Dan, so obviously, the median time on the trial was 47 weeks. And on an absolute basis, the effect size was expanding as we go from sort of the week 52 to week 76, that extra time when maybe most patients were not on the drug. But on a percentage basis, the percentage efficacy delta, effect size does seem like it's closer to 50% by week 52 but then it kind of shrinks towards more like mid-30s by week 76, and I'm talking the low to mid taus and iADRS and CDR Sum of Boxes. So my question is, how do you think about effect size evolution as patients go beyond the drug on a percentage basis, but also what are the implications of that heading into remternetug Phase 3 because you don't necessarily get off the drug in that trial?

Lauren Zierke

Thanks, Umer. We'll go to Dan for your question.

Daniel Skovronsky

Yes. Thanks, Umer. Great question. I understand it well. I'd just point out though, that the 47 weeks is the median duration of therapy for the patients who actually came off therapy. The median duration of the whole trial is a bit longer than that. So that's for the patients in that subgroup analysis.

But you're right, even the patients who came off drug at - with a median duration of 47 weeks continue to expand out from placebo over time, which is encouraging. And I think once you've removed the amyloid plaque, you can continue to accrue the benefits from that removal over time. So that's good news. And I think that will bode well for TRAILBLAZER 3, where, as you point out, there's a very limited duration of treatment and then a long follow-up.

Your question on the percentages though is a bit more complicated. I think early in a trial like this, you can actually have 100% slowing of disease progression or even more. I don't think that suggests that you've got maximal efficacy achieved at 12 weeks even though we can see some analysis close to 100%, probably in the MCI patients, you can even see that at that time point, it's more than 100%. They're better than they were at the start of the trial.

I don't interpret that as the maximal drug effect. I think this is just a consequence of insidiously progressive disease, that early on, the drug effect as a percentage of a small number, it looks big. And then as the study goes on, the placebo prorations progress more and more. And now you have a treatment effect, which may be divided by a larger decline and comes out of a smaller percent. So that doesn't surprise me or worry me in any way. I think that's just typical for Alzheimer's drug.

Lauren Zierke

Thanks Dan. Next caller please.

Operator

The next question is coming from Robyn Karnauskas from Truist. Robyn, your line is live. Please go ahead.

Robyn Karnauskas

Thanks for taking my questions. I guess, first, on the homozygous patients, it looks like they were a higher risk. I know you've mentioned we see efficacy across all populations. But how do you see doctors incorporating decision-making initially with these drugs into the homozygous patients? And my second question is just you brought up ALZ 6 still a ways away, there's an OLE extension timing to. Are the time lines still on track for '25? When can we see the next update that could help doctors inform potentially how to better identify the ARIA patients and how to treat patients with MRI? Thanks.

Daniel Skovronsky

Okay. I'll start with the e4 question, and then John can take the TRAILBLAZER 6 timing question. I think that's what it was, right? So the - on the e4s, you raised a good point. Clearly, there's a different level of risk here. I think the efficacy looks very consistent. But the e4 homozygous people who are e4 homozygous, I should say, have a higher risk of ARIA.

So I think with those individuals, it probably comes down to physician and patient discussion, if they're younger, if they don't have superficial siderosis, if they have less amyloid, if they don't have microhemorrhages, it's probably a pretty easy decision to treat them. If they start to look like a patient who could have less efficacy because they're older and more severely affected the time they come for treatment or they look like a higher risk patient because in addition to being e4 homozygous, they have superficial siderosis and microhemorrhages, that might be a more difficult conversation and decision for the physician.

But it's I think, really important to now have this data, which in general, I think, will be helpful. When ARIA in the past was sort of a black box for doctors and they had no idea what the risk would be, I think that could be a little more scary and hard to deal with than now when we start to understand which patients might be at higher risk and which are at lower risk.

John Sims

Yes. Thanks for the question. So for TRAILBLAZER 6, the screening is going very well. We anticipate that to be fully enrolled sometime this year. And you recall that primary outcome for that actually is at a six-month look. So six months from that time that we close enrollment, we'll hopefully be getting an answer soon on that.

And I think the other question was on the open label or the blind extension. I'm not sure if you're mixing those two up or being very precise on that. So we have an open-label safety addendum that we've talked about. There's 1,000 people that we enrolled is that all on dona. We hope to have the last patient visit for that here late in the third quarter.

And then for the extension study, if you were referring to that, which is blinded and ongoing, that last patient enters that when we closed the double-blind period, and so that goes on for another 18 months from April.

Lauren Zierke

Thanks Dan, John. Next question please.

Operator

The next question is coming from Kerry Holford from Berenberg. Kerry, your line is live. Please go ahead.

Kerry Holford

Thank you. Just one really remaining for me and most of them have been answered already, but just interested to get more detail on your views regarding the diagnostics approach for the disease. So perhaps you'll take a update on your approach, your collaboration with Roche. And then more conceptually, when we might ultimately be able to routinely rely on a blood-based biomarkers to diagnose this disease more broadly. Thank you.

Lauren Zierke

Thanks, Kerry. So on your question on diagnostics, we'll go to Mark.

Mark Mintun

Yes. So it's a really good question, and I think it's one of the things we're incredibly hopeful for in the - basically within the next year. There are multiple different efforts going on. In fact, many of them are being presented at this meeting today, tomorrow and of different academic and also companies that are presenting data on blood test.

Now many of them involve the P-tau217. We have published extensively on P-tau217 from a research capacity, and we are working hard to develop and scale that so that we can launch that as a test available later this year. We believe that other groups, however, are also making a lot of progress in P-tau217 and we're looking forward to evaluating that data as it's presented here and continues to be published.

We believe several are coming over the next six months. So we think that will be a major change. Many of those companies have indicated plans of also making their tests available in the very near future, if not already. So P-tau217 has the potential both in the data we've seen in our hands, in other people's hands and as well as the ability to scale it has a test of revolutionizing the way we diagnose patients because a positive P-tau217 even though the word tau is in the name, is incredibly correlated with a positive amyloid PET scan or a positive CSF for amyloid. So we believe that with these tests, there will be a dramatic ability to faster and more easily evaluate.

As you pointed out, we also have a collaboration with Roche to develop a P-tau181 test. That also has - could have incredible value not only because of its ability to potentially rule out Alzheimer's disease and make the - and move the patient more quickly into further diagnostic depending on whether it's in or out, but also because of the extensive footprint of Roche diagnostic equipment around the world.

And so we see them as a fantastic partner in this, and we're working very hard for - to help them and move that forward in that development. But those are the major things that I think are going to happen. And I believe that as Dan pointed out, it is slow for people to change how they think about Alzheimer's disease, but well validated and P-tau217 tests and P-tau181 test with good clinical data published, we think would go a long way to more speeding up that change in the market.

Lauren Zierke

Thanks Mark. Next caller please.

Operator

The next question is coming from Andrew Baum from Citi. Andrew, your line is live. Please go ahead.

Andrew Baum

Thank you. First question for Anne. You've spoken about the need to build the market and logistics and so on. But separately, could you talk to managing the launch into a real-world patient population if the initial experience or news flow for physicians and patients is negative because they have been hemorrhagic leads or symptomatic ARIA, obviously, that's not going to help the long-term goal. So to what extent is really educating physicians to avoid patients who have had neurovascular in cell or antithrombotics, just because of the impact it may have on the perception of the risk benefit of the drug? That's the first question.

The second question is for Dan on remternetug. I know that you're running the Phase 3 trial, and this will probably answer the question. But from where you sit right now, given what you know about the molecule, do you anticipate remternetug will be dosed in the same way, i.e., fixed dose? Or do you believe that instead, it's going to be chronic dosing? Thank you.

Lauren Zierke

Thanks, Andrew. We'll go first to Anne on your question on, and then we'll go to Dan for your question on remternetug dosing.

Anne White

Well, I think you asked a very good question, which is there is quite a bit of education to do here for this patient population for physicians treating that. Certainly, in our trials, we've learned quite a bit. And we've seen that with good training and good support, physicians really can do this well. So I think that you'll see us continue those efforts around education. And I think others will also be - this will be an area where other votes will be listed as well as other companies and other efficacy groups and others contribute to the education that we have on how to manage patients, how patients can be treated safely.

And that's certainly why we did TRAILBLAZER-ALZ 6 is also to inform the space because we're committed, I think, to continuing to provide answers. And as I said, we'll continue to do, as we always do, with new areas to do real evidence studies of our own, and we certainly share that data as we go as well.

But I have a lot of confidence that I think together with others in the field, we can educate well in this space and help inform the risks and I think along as these patients get treated. And as I think as John mentioned, we have a lot more data that's coming as well that will help inform the field.

So I think we feel good that with that continued data, we have the support that we need to help educate how to treat these patients, how to manage safety, certainly how to manage ARIA, and you'll see us continue to commit to educating the field about that with additional data.

Daniel Skovronsky

Okay. Thanks, Andrew, for the question on remternetug dosing. I really like that question. From where I sit today, I think remternetug is going to be limited-duration dosing. In fact, my prediction is all amyloid-lowering drugs will eventually get to limited-duration dosing. It just makes a ton of sense. And the data we showed today, I think, make that case stronger than before.

In different therapeutic areas, sometimes the base assumption is dosed for the rest of your life, and then people have to do work to prove that you don't need to do that. In other therapeutic areas, the base assumption is like dose until you've solved that every problem you're trying to solve and don't continue dosing. I think what we see right now is a moment where Alzheimer's is changing from scenario A to scenario B, thanks to our data. But we'll sit tight and we'll find out. So thanks.

Lauren Zierke

Thanks. Next caller.

Operator

The next question is coming from Louise Chen from Cantor. Louise, your line is live. Please go ahead.

Louise Chen

Hi. Thanks for taking my questions here. So I wanted to ask you how you size the initial market opportunity for donanemab based on the patient population study to your clinical trials thus far? And then second question I had for you was how do you plan to build out your Alzheimer's franchise around donanemab and stay ahead of potential competition? What are some of the next big steps that we should be focused on? Thank you.

Anne White

So thanks, Louise. Great question. So we've spent a lot of time working on sizing this market because, obviously, as I mentioned, there's a certain level of underdiagnosis here. And so we - I think we've been the meeting where we're continuing to inform the size of the market, the rate of diagnosis, the incidence rate as well.

So as I mentioned in my [technical difficulty] we think that the presence of early symptomatic Alzheimer's disease with amyloid plaque is probably between 6 million and 7.5 million people here in the U.S. As I said, only about 20% to 30% of them get diagnosed today. So that's the job in front of us is how do we change that trajectory quite a bit. And as you - certainly, MCI and mild Alzheimer's have different rates of diagnosis today, too. We need to drive earlier diagnosis in MCI, which is certainly underdiagnosed today. So I think that you'll see us continue to do that.

On the building the franchise, I mean, we're incredibly excited that we have additional molecules coming. I mean remternetug is in Phase 3, and then as Mark shared and Dan shared today, we have molecules in Phase 2 on tau, and we have a robust portfolio prior to that. So I think what I'm most excited about is that the results that we've seen today, the results from others should give a lot of confidence about investing in this field. We've got answers now to build on for the future.

And so you'll see Lilly remain very committed to this space. I'm so proud that we stayed committed as we have over three decades. It certainly is paying off in the results that we see today and share today. And I think it only gives us renewed confidence about investing in this space in the future. These people need our help, we'll continue to move forward. I think as Dan said, moving forward into how we can actually work towards prevention of this disease would be the goal that we all have. And so we'll build on the results today to move forward in that space.

Lauren Zierke

Thanks Anne. Next caller please.

Operator

The final question today is coming from Trung Huynh from Credit Suisse. Trung, your line is live. Please go ahead.

Trung Huynh

Hi, guys. Trung Huynh from Credit Suisse. Thanks for fitting me in. Just two from me. So firstly, in three of the editorials in JAMA today, they were quite critical on the patient diversity of the trial. If you have a look at some of the subgroup data in the black population and next the benefit favored the placebo groups on some of those endpoints. We do know that confidence intervals were wide because of the lower patient numbers. But with diversity in clinical trials increasingly important to FDA, when they look at this data, is there any risk the generalization of the overall data in these populations when it comes to the review?

And then my second question is, can you just update where we are with the donanemab manufacturing? Any FDA site inspections if you've had the capacity as we ramp for that potential approval? Thank you.

Lauren Zierke

Thanks, John. We'll go to Dan for both of your questions.

Daniel Skovronsky

Yes. Thanks. Two good questions, Trung. Thank you. So first of all, on diversity, I think we acknowledge John did a good job commenting on this during the presentation, that we wish we had more diverse patients in this clinical trial. It's really hard to do in Alzheimer's disease for a variety of reasons, particularly in the time frame that we were enrolling the study, which was impacted by the pandemic, et cetera.

Subsequent to that, we've actually done a number of other studies, which have done much better in enrolling minority group members in the United States, particularly. And so we actually do have a larger database. Of course, that's a safety database among these individuals which is part of our submission to the FDA. So I feel good about that and don't see any particular risk there, although, of course, we're always trying to improve. And every - we could just plot out minority group participation in each of the clinical trials we've done in Alzheimer's disease. Each one gets better than the last.

In terms of manufacturing, I think we're in good shape here. In some sense, we benefited from the application for accelerated approval, where we were able to discuss those topics and have those sections, the application reviewed with the FDA. So we feel confident about that. Thanks.

Daniel Skovronsky

Great. I think that was the last question. So maybe I'll just wrap up here by saying we're excited with the opportunity ahead of us here with donanemab, encouraged by the potential that we see for even more future innovation in Alzheimer's and other neurodegenerative diseases.

Having been in this field personally for decades now, I know that patients have been waiting for this progress, and we just feel honored to have the potential to bring donanemab to them. We can't close without saying that we're so thankful to the patients, to their care partners and the many investigators who participated in this study and the many people around the world who have partnered with us on this journey.

And thanks again for all of you for your participation in today's call and your interest in Eli Lilly. Feel free to follow up with the Investor Relations team if you have questions we've not addressed. Enjoy the rest of your day.

Operator

Thank you, ladies and gentlemen. This does conclude our conference call for today. This conference will be made available for replay beginning at 4:00 p.m. today running through July 31 at midnight. You may access the replay at any time by dialing (800) 332-6854 and entering the access code 295801. International dialers can dial (973) 528-0005. Again those numbers are (800) 332-6854 and (973) 528-0005 with the access code of 295801

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