Daniel M. Skovronsky
Senior Vice President and Chief Scientific and Medical Officer at Eli Lilly and Company
Thanks, Anat. 2021 has clearly been a productive year for R&D at Lilly, with continued strong progress in our pipeline and more potential catalysts on the way. Before I get into the broader portfolio update, I'll spend a few minutes highlighting several updates for our late-stage pipeline. I'll start with donanemab. In Q2, the first amyloid-long agent for the treatment of Alzheimer's disease was approved under the FDA's accelerated approval pathway, based on plaque lowering, which we believe reflects a shift in policy and sets a new path for Alzheimer's drug approval in the U.S.
Lilly has long been an advocate for using biomarkers for amyloid plaque and neurofibrillary tangles to identify patients for treatment and to monitor their response to therapy. We were pleased to see the FDA's conclusion that improvements in brain pathology are appropriate surrogates for clinical efficacy of Alzheimer's drugs. Based on data we've seen to-date, we believe donanemab clears plaque faster and deeper than previously seen with other therapies and achieved complete plaque clearance in a majority of patients in TRAILBLAZER-ALZ after only limited duration of dosing. On the basis of the clinical evidence for donanemab, we were pleased to have received breakthrough therapy designation from the FDA.
At the Alzheimer's Association's International Conference last week, we shared additional important analyses from donanemab TRAILBLAZER-ALZ. Briefly, I'll highlight several findings. First, we shared detailed exploratory statistical analyses comparing a variety of methods beyond MMRM and DPM, as summarized on slide 14. We were pleased to see that these new analyses showed consistency of effects on primary and secondary outcomes across all statistical methods. Notably, all of the new analyses conducted showed good separation of treatment from placebo, with statistical significance achieved for most endpoints at nearly all relevant time points measured. The robustness of the treatment efficacy across analytical methods increases our confidence in the potential clinical benefit of donanemab.
While all statistical methods evaluated showed similar results, we note that the Bayesian disease progression model, DPM, closely reflected the raw observed data, with the smallest standard error of any method. These results reinforce our hypothesis that DPM is a preferred analytical method for Alzheimer's trials. Additionally, we shared new data showing a relationship of amyloid plaque reduction and slowing of cognitive decline, as shown on slide 15. To our knowledge, this is the first time such results have been available. When we initially reported the results of TRAILBLAZER-ALZ, we commented that, at a group level, patients treated with donanemab showed both statistically better plaque reduction and statistically better slowing of cognitive decline at 18 months.
But patient-level correlations between degree of plaque reduction and magnitude of slowing of cognitive decline were not significant. Now, using a more sophisticated PK PET ADRS exploratory analysis that uses all of the available time-course data, we showed a highly significant relationship between degree of amyloid plaque reduction and slowing of cognitive decline with P less than 0.001. The Conrado model, shown here, was published in 2014 and is the results of efforts from the Coalition Against Major Diseases, CAMD, which collected placebo data from 15 randomized trials, including almost 4,500 participants.
We introduced a treatment arm and incorporated percent amyloid plaque removal into this model to generate these results, and we believe this is important support for the use of amyloid plaque reduction as a surrogate for clinical efficacy. Notably, these data suggest the full clearance of amyloid plaque is required for highest efficacy, as model results predict that patients achieving 100% clearance of amyloid plaque could have more than 40% slowing of disease progression. Moving to slide 16, we show an exploratory analysis looking at the effect of donanemab's plaque clearance on development of tau pathology.
Tau pathology is an exciting biomarker, since measures of Alzheimer's disease tau, unlike measures of amyloid plaque, have been correlated with clinical measures of cognitive and functional decline, as noted here. Importantly, we had previously shown that donanemab-treated patients had slower accumulation of regional brain tau pathology than placebo-treated patients. This is an important finding because the amount of brain tau pathology is an excellent predictor of subsequent cognitive decline, a finding we observed with solanezumab in Expedition 3 and reproduced, once again, in TRAILBLAZER-ALZ. Now, we've extended these results to show that the donanemab-treated patients who achieved complete clearance of amyloid plaque by six months had the most marked slowing of tau spread with nearly complete abrogation of progression in the frontal lobe.
This reinforces our hypothesis that both deep and rapid amyloid plaque clearance are required for optimal drug efficacy. With this new data we presented last week, we have now linked degree of amyloid plaque reduction with degree of clinical benefit as well as degree of amyloid plaque reduction with degree of benefit on brain tau pathology which is itself linked to clinical benefit. As displayed on slide 17, we have just recently obtained data with our plasma tau biomarker, phospho-tau217. These new data demonstrate that amyloid plaque clearance with donanemab also resulted in reversal of the typical increases of phosphorylated tau seen in the blood, with decreases from baseline of more than 24% and a change from the untreated arm with a P value of less than 0.0001.
This highly significant effect was seen as early as three months following initiation of treatment and could reflect a combination of less tau spread in the brain as well as less neuronal damage, which could account for tau leakage into the periphery. You can see on the right side of the slide that the effect on plasma tau is also correlated to degree of plaque reduction, with nearly every patient on treatment who achieved substantial plaque clearance showing flat or declining plasma phospho-tau. We are delighted to see the potential utility of P-tau217 not just for diagnosing disease but also for monitoring treatment efficacy.
We believe this could be another important contribution to the Alzheimer's field. Finally, on slide 18, the significant relationship between plasma P-tau217 reduction and the slowing of cognitive decline is shown. This additional biomarker for efficacy links the donanemab mechanism of amyloid plaque clearance with positive effects on both clinical outcomes and tau pathology. These data suggest that patients who achieved a 30% decrease in P-tau217 from baseline showed more than 40% slowing of disease progression.
The three main findings I just discussed, one, the consistency of clinical benefit across statistical methods; two, the correlation of plaque lowering to clinical benefits, the patients who achieved the greatest plaque clearance having the greatest opportunity for benefit; and three, the correlation between achieving complete plaque clearance and beneficial effects on tau pathologies seen in the brain and measured in the periphery, which themselves are predictors for a clinical benefit, strongly support the efficacy of donanemab and give us confidence that the remarkable levels of amyloid plaque clearance achieved by donanemab could translate into a meaningful breakthrough for patients.
Moving to slide 19; accordingly, we've announced that we plan to submit to the FDA under the accelerated approval pathway before the end of this year based on data from completed studies, supplemented by additional safety data from the ongoing TRAILBLAZER-ALZ 2 study. We remain focused on enrolling TRAILBLAZER 2 with the aim to replicate the positive results of TRAILBLAZER 1. Replication is important to overcome skepticism in the field. We hope that TRAILBLAZER-ALZ 2 will generate important confirmatory data for patients, physicians and payers and help us understand how to make sure the right patient gets the right duration of therapy at the right stage of disease.
We are pleased to announce today that we have closed screening for TRAILBLAZER-ALZ 2 with an adequate number of subjects now in the trial's screening process to fully enroll the study. Given that conducting and processing imaging studies used during screening takes several weeks to complete, we expect that the final subject to complete screening procedures and receive their first dose of donanemab or placebo by the end of the third quarter, and the study will complete 18 months later. Given this progress in enrollment, we are confident that we will achieve the number and duration of drug exposures needed to appropriately characterize the safety profile of donanemab, allowing for regulatory submission by the end of this year.
Discussions with the FDA are consistent with our prior statement supporting a submission before the end of 2021. I also want to provide a few comments on how we believe the National Coverage Determination opened for monoclonal antibody therapies targeting amyloid by the Centers for Medicare and Medicaid Services may impact Lilly and donanemab. We believe this NCD is a clear opportunity to focus treatment on the patients most likely to benefit from amyloid-plaque-reducing therapies. This would align with our goals, which have long been to use advanced diagnostic tools to identify the right patients that can benefit the most from amyloid-reducing therapies.
We're particularly encouraged that our progress with the plasma P-tau217 assay could open up broader access to diagnostic tools. Still, despite the advances in diagnostics and the promise of donanemab, we acknowledge the current skepticism in the national discussion, and we hope that each drug will be evaluated by payers and prescribers based on its own data. This could be particularly important given the data I've shared today, which suggests that the degree of donanemab's amyloid plaque clearance relates to clinical benefit. In summary, we look forward to submitting donanemab to the FDA later this year with the potential to bring a robust amyloid plaque clearing agent with limited treatment duration to market for early symptomatic Alzheimer's patients in 2022 with potential replicated clinical efficacy results expected in 2023.
Transitioning now to Verzenio; on the last earnings call, we commented that FDA had asked to see an overall survival trend in favor of Verzenio in the monarchE trial in adjuvant breast cancer. We also noted that the OS data set is quite immature in the overall population which makes interpretation challenging. We have now provided to the FDA additional data from the monarchE study, and we were encouraged to see continued strengthening of the primary endpoint of Invasive Disease Free Survival, IDFS, as well as consistent benefit in the key secondary endpoint of Distant Recurrence Free Survival, DRFS.
Of note, with this continued follow-up, we can now confirm this benefit extends beyond the two-year Verzenio treatment period. We look forward to disclosing this new analysis at a medical meeting this fall. Our discussions with the FDA have focused on the pre-specified subpopulation of patients with high Ki-67 index, a marker of increased cell proliferation. These patients have more aggressive disease and higher risk of relapse and, thus, are more mature for overall survival analysis. This group, which makes up approximately half of the monarchE population are demonstrating an overall survival trend that favors the treatment arm.
And based on FDA feedback, we expected initial approval in adjuvant breast cancer in this population before the end of the year, in line with the current review cycle. Importantly, since the IDFS and DRFS hazard ratios favoring Verzenio are similar in patients with high and low Ki-67 index, we expect that the OS trend first seen in the Ki-67 high population will in time be replicated in the broader study population. We hope to expand the label to the entire enrolled population in the future once we see more overall survival events in the broader population. To-date, regulators outside the U.S. have not raised the same questions on overall survival.
Finally, moving to Olumiant, we shared in July that the FDA will not meet the PDUFA action date for the supplemental new drug application for atopic dermatitis. This delay is related to the FDA's ongoing assessment of JAK inhibitors. Patient safety is critical to Lilly, and we continue to further evaluate baricitinib's safety provide with ongoing randomized and observational safety studies. We're confident that the efficacy and safety data for baricitinib support a favorable benefit-risk profile for the treatment of atopic dermatitis, and we look forward to continuing to work with the FDA during the remainder of the review process. We do not have additional information on timing or specific action date from the FDA, but we see potential for regulatory action for atopic dermatitis in the U.S. later this year.
We're committed to bringing Olumiant to market in the U.S. to help meet the needs of people living with atopic determine tie is the. Slide 20 shows select pipeline opportunities as of July 30, and slide 21 shows potential key events for the year. There have been several additional major developments since our last earnings call, and I'll cover these by therapeutic area. In May, we shared the positive results for tirzepatide in SURPASS 4 and announced that the SURPASS program met regulatory submission requirements for evaluating cardiovascular risk and confirmed our intention to submit a registration package for tirzepatide in Type 2 diabetes to global regulatory authorities by the end of 2021.
At ADA in June, tirzepatide was a large focus as we shared detailed data for the first four studies from the tirzepatide SURPASS program for the treatment of Type 2 diabetes. These results support our belief that tirzepatide may represent a substantial improvement in the treatment of patients with Type 2 diabetes with early and unsurpassed improvements in A1C and body weight reduction across doses. We remain on track for global regulatory submissions before the end of this year. We are also excited about tirzepatide's opportunity across multiple indications including cardiovascular outcomes, obesity, NASH and heart failure.
In Q2 we initiated SUMMIT, our planned Phase 3 study for tirzepatide in heart failure. In July, we achieved an important milestone with Jardiance, as the first and only medicine to achieve a primary endpoint for heart failure with preserved ejection fraction, or HFpEF. The EMPEROR-preserved Phase 3 trial met its primary endpoint and demonstrated significant risk reduction with Jardiance for the composite of cardiovascular death or hospitalization for heart failure in adults with HFpEF. This is a significant breakthrough for patients and we're proud of what we've achieved here in partnership with Boehringer Ingelheim.
We look forward to presenting detailed results from this study at the European Society of Cardiology on August 27 and we expect to submit this indication to regulators later this year. We also received approval in the EU for Jardiance HFrEF in June and expect regulatory action in the U.S. and Japan later this year for this indication. Additionally, we've advanced our GGG tri-agonist into Phase 2 for diabetes based on the promising data we shared at ADA, which supports the potential for differentiated efficacy from tirzepatide with respect to bodyweight while maintaining glycemic control. We also started two Phase 1 studies for diabetes and cardiovascular disease.
Lastly, we removed one of our oral GIP/GLP Phase 1 molecules from our pipeline. In Oncology we also continued to make important progress. Starting with Verzenio, we've initiated two Phase 3 studies since our last update. As planned, we've initiated an adjuvant study for HR+ HER2 breast cancer. And we are announcing today that a result -- as a result of a favorable blinded interim analysis for our Phase 2 trial in metastatic castration-resistant prostate cancer, we've also initiated the Phase 3 portion of this adaptive study. This action was based on a recommendation from the Independent Data Monitoring Committee or IDMC.
The IDMC reviewed interim efficacy and safety data and concluded that the results met the pre-specified expansion criteria based on radiographic progression-free survival and recommended advancing the study to the registrational Phase 3 stage. While Lilly remains blinded to the study, we are obviously very pleased with this development and have already begun dosing patients in the Phase 3 portion of this trial. Given that the expansion to Phase 3 includes the cohort of patients who were in the Phase 2 study, these data remain blinded, and we will not be disclosing these at medical meeting. On the development front in oncology, we also made progress with pirtobrutinib and our Oral SERD.
We've initiated the Phase 3 study for pirtobrutinib in relapsed refractory MCL monotherapy, executing on our commitment to a robust Phase 3 program for this molecule. Regarding Oral SERD, we announced our plans to begin a Phase 3 study later in 2021 based on the Phase 1 results we shared at ASCO in June that showed an efficacy and safety profile in line with our expectations. In addition, we've now achieved the first human dose for our next generation KRAS G12C inhibitor. Lastly in oncology we announced that the FDA has accepted our submission of Sintilimab for non-small cell lung cancer.
This submission is an encouraging start for our collaborative efforts with Innovent to make Sintilimab available in countries beyond China. In neurodegeneration, in addition to the donanemab news I just shared, we anticipate a Phase 2 readout for zagotenemab later this year and note that our GBA1 Gene Therapy asset from Prevail started a Phase 2 study in Type 2 Gaucher disease. For immunology we do not have additional significant updates in Q2, but we're looking forward to the Phase 3 readouts of lebrikizumab in atopic dermatitis and baricitinib for Lupus later this year.
We also submitted baricitinib for alopecia areata in Japan. Lastly, we're moving our COVID-19 antibody therapy LY-CoV1404 now known as BEBTELOVIMAB into Phase 2 to address viral variants as part of our ongoing commitment to help combat COVID-19 if needed. To recap, Q2 was another positive quarter for R&D at Lilly, and we're excited about a number of further readouts and important milestones coming later this year, reflecting continued advances on behalf of patients suffering from disease.
Now, I'll turn the call back over to Dave for some closing remarks.
