Daniel M. Skovronsky
Senior Vice President and Chief Scientific and Medical Officer at Eli Lilly and Company
Thanks, Anat. Like 2020 before, 2021 continues to be a very productive year for R&D at Lilly. Before I get into the broader portfolio update, I'll highlight several updates from our late-stage pipeline. Starting with tirzepatide. We shared detailed results from tirzepatide's SURPASS-4 study at EASD this quarter. SURPASS-4 is the largest and longest SURPASS trial completed to date and we were encouraged by the continued hemoglobin A1C and weight control which participants experienced even past the initial 52-week treatment period and continuing up to two years.
Looking at Slide 14. This shows the change from baseline in hemoglobin A1C over time during the study. A1C reduction plateaued by roughly 24 weeks and was maintained at 52 weeks and thereafter to 104 weeks across all three tirzepatide doses, while in the insulin glargine comparator arm, A1C began to increase after 52 weeks. Durability of A1C control is a challenge for type 2 diabetes treatments. While the 104-week data isn't a definitive answer as to whether tirzepatide could potentially offer even longer term durable blood glucose control, these data certainly are encouraging.
Moving to Slide 15. As you can see, weight loss plateaued at approximately 52 weeks and was maintained thereafter such that at two years, weight difference at the highest dose was approximately 15% compared to insulin glargine. We've seen in previous incretin therapy trials conducted with GLP-1s, a further increased impact on weight reduction in participants with obesity without type 2 diabetes compared to studies in participants who do have type 2 diabetes, such as this one. It will be interesting to see if this trend also extends to the dual agonism of tirzepatide, which has demonstrated weight reductions in type 2 diabetes trials beyond what has been shown by GLP-1s to date. We clearly are excited about the weight loss potential here and we believe the data to date bode well for upcoming readouts in obesity, starting with SURMOUNT-1, which reads out next year.
Tirzepatide represents a new class of medicines and we're focused on continuing our significant investment for patients with type 2 diabetes, obesity and related metabolic disorders who may benefit from tirzepatide.
Moving to Slide 16. Today, we announced the U.S. submission for tirzepatide in type 2 diabetes and that we used a Priority Review Voucher with the intention of bringing this investigational treatment to patients as quickly as possible. We are delighted at the continued progress for this novel dual agonist incretin, and hope to obtain approval in the U.S. by the middle of next year.
Moving to donanemab. We have several important updates for this program. First, in the U.S., we initiated a rolling BLA submission to the FDA for accelerated approval in early Alzheimer's disease. We intend to complete the submission in the next few months and expect regulatory action in the second half of 2022. We've also completed the original planned enrollment of 1,500 participants for TRAILBLAZER-ALZ 2. And based on the pre-specified 18-month primary endpoint, expect to have topline results by the middle of 2023. We've added a separate single-arm addendum for safety exposures to TRAILBLAZER-ALZ 2, which has already enrolled more than 300 patients and is continuing to enroll rapidly. This addendum will provide us with additional safety data to support the rolling submission.
Moving to TRAILBLAZER-ALZ 3. This is a prevention study for cognitively-unimpaired individuals who already have Alzheimer's brain pathology but don't yet have clinical symptoms. We're excited to report that we have already initiated screening. This pioneering trial has multiple novel elements to reduce research subject burden, including the use of our phospho tau217 blood assay currently in development to help detect Alzheimer's disease pathology in the patient screening process, video call technology for assessing cognitive function in the subjects' home and a large network of infusion centers that allows subjects to select the site most convenient to them in a decentralized clinical trial paradigm.
We also announced today our plans to conduct a head-to-head Phase 3 study comparing donanemab to aducanumab to assess superiority of brain amyloid plaque clearance in early symptomatic Alzheimer's disease. The co-primary endpoints will evaluate complete amyloid plaque clearance as measured by Florbetapir F18 PET scan and will assess superiority on brain amyloid plaque clearance in the total population, and also the intermediate tau sub-population. This study, TRAILBLAZER-ALZ 4, is expected to begin enrollment this year and we expect to share primary endpoint data in the second half of 2022.
We're encouraged with the progress we've made with donanemab and with its potential to positively impact patients with high unmet medical need. We have, of course, followed progress in the Alzheimer's disease landscape since our last call and are watching closely as CMS's National Coverage Determination process plays out. We're committed to facing the challenges of effectively communicating donanemab's clinical data and value proposition and to ensuring that the diagnostic in patient management ecosystems are adequately well prepared.
Given the current environment, we think it's reasonable to have modest expectations for the scale of patient impact for anti-amyloid therapies available under Accelerated Approval prior to the readout of their definitive Phase 3 data. Assuming potential Accelerated Approval for donanemab in the second half of 2022, our expected TRAILBLAZER-ALZ 2 Phase 3 readout by mid 2023 would follow quickly, meaning the window of Accelerated Approval without definitive Phase 3 data is likely to be brief. Assuming positive Phase 3 results, we should be confident in the mid- and long-term opportunity for donanemab if approved.
Moving on to Verzenio. In line with the expectations I outlined last quarter, we were pleased with Verzenio's recent FDA approval as the first and only CDK4/6 inhibitor in combination with endocrine therapy for adult patients with HR+, HER2-, node positive, early breast cancer who are at high risk of recurrence with a Ki-67 index of greater than or equal to 20% as detected by an FDA-approved test. This approval in the adjuvant setting represents the first new addition to endocrine therapy in adjuvant treatment of HR+, HER2- breast cancer in nearly two decades. We are delighted to bring this important new treatment option to patients.
Also, we recently shared updated data from the entire monarchE study at the ESMO Virtual Plenary Meeting and co-published these data in the Annals of Oncology. These data, which reflect additional follow-up since our last public presentation, highlights the robustness of the effect size we're seeing for Verzenio in the adjuvant setting. Notably, with a median follow-up of 27 months, we were pleased to see both IDFS and DRFS benefit extend beyond the two-year study treatment period. These data are not only important for patients, but also to help dispel concerns that the curves would come back together over time. We're clearly observing -- we've clearly observed continued separation of the curves, if not expanding separation.
Since the adjuvant approval two weeks ago, there have been questions regarding why the FDA approval applied only to a subset of the study population. As previously communicated, overall survival was a secondary outcome measure for the monarchE study and an important component of the FDA's review. While we do not typically publish immature overall survival data, we feel it's valuable to address these important questions about the difference between the enrolled study population and the approved indication. As a result, while the overall survival data remain immature, we do plan to publish the OS data from the additional follow-up analysis with cut off of April 1, 2021 in a medical journal in the coming days. These data will show what we have observed thus far for overall survival trends in the ITT population compared to the approved population. We'll continue to follow patients in the ITT population for more mature overall survival data. If a positive OS trend emerges in the ITT population, we plan to work with regulators to expand our adjuvant indication.
Importantly, the collective results from Verzenio's clinical development program have demonstrated a differentiated CDK4/6 inhibitor profile and we look forward to continued investment in Verzenio for breast and prostate cancer and are excited about the opportunity to serve more patients.
Slide 17 shows select pipeline opportunities as of October 22 and Slide 18 shows potential key events for the year. There have been several important developments since our last earnings call and I'll cover these by therapeutic area.
In oncology, in addition to the exciting news for Verzenio, we continue our investment in pirtobrutinib's Phase 3 program with an additional study starting in chronic lymphocytic leukemia, including fixed duration pirtobrutinib plus venetoclax and rituximab in relapsed or refractory patients. We plan to start a study in first-line treatment compared to bendamustine plus rituximab before year-end. We prioritized this first line study, rather than the head-to-head study evaluating superiority compared to ibrutinib as we think this first-line study could provide a faster pathway to bring pirtobrutinib to patients in the first-line setting. We expect the head-to-head ibrutinib CLL study to start in the first half of 2022. We look forward to sharing updated data set from the Phase 1/2 BRUIN study at a medical meeting later this year. We plan to provide a regulatory update for pirtobrutinib at our Investor Day in December.
Imlunestrant, our oral SERD also moved into Phase 3 with the start of its monotherapy study compared to exemestane or fulvestrant.
Finally, we also publicly identified and presented pre-clinical characterization for two new agents at the Molecular Targets meeting this month: LOXO-783, which is a highly mutant-selective allosteric PI3K alpha inhibitor; and LOXO-435, which is a highly isoform-selective FGFR3 inhibitor. We look forward to filing INDs for both programs in 2022 and subsequently moving them into the clinic.
In diabetes, in addition to the tirzepatide update, we obtained U.S. approval for Jardiance in HFrEF, presented detailed results from the EMPEROR-Preserved study at the European Society of Cardiology and submitted for HFpEF in the U.S. and Europe. We're excited about the opportunity Jardiance has to improve outcomes for patients across type 2 diabetes, heart failure and chronic kidney disease. We also started Phase 2 studies for our GLP-1 non-peptide agonist in collaboration with Chugai in type 2 diabetes and in obesity, and look forward to sharing some Phase 1 data from this molecule in December.
In immunology, we were delighted to have multiple positive Phase 3 readouts for lebrikizumab in atopic dermatitis, and look forward to the readout of the maintenance data from the ADVOCATE-1 and 2 studies in the first half of next year, ahead of global submissions expected by the end of 2022. We're pleased with our progress in immunology this year with positive Phase 3 readouts for mirikizumab and lebrikizumab, and look forward to sharing more about our next generation of early-phase immunology assets in December.
In neurodegeneration, our anti-tau antibody zagotenemab recently concluded its Phase 2 study in early symptomatic Alzheimer's. Zagotenemab failed to meet the primary endpoint and was unable to modulate tau spread in the brain. The placebo population progressed as expected. While this negative outcome was disappointing and we're discontinuing development for zagotenemab, we remain committed to tau as a high conviction target in Alzheimer's disease and plan to continue studying tau biology, including inhibition of tau aggregation with a small molecule OGA inhibitor, currently in the clinic.
In the pain therapeutic area, in collaboration with Pfizer, we discontinued the global clinical development program for tanezumab following receipt of a Complete Response Letter from the FDA for tanezumab in osteoarthritis pain and a negative opinion adopted by the CHMP.
And finally, the FDA expanded the Emergency Use Authorization for bamlanivimab and etesevimab administered together to include post-exposure prophylaxis in certain individuals for the prevention of SARS-CoV-2 infection.
To recap, Q3 was another positive quarter for R&D at Lilly, continuing the positive momentum we've seen with a steady stream of significant pipeline advancements over the last couple of years as we move closer towards our goal of delivering more first or best-in-class treatment options to patients in areas of unmet need.
Now, I'll turn the call back to Dave for some closing remarks.
