Daniel M. Skovronsky
Executive Vice President; Chief Scientific Officer and President, Lilly Research Laboratories; Presi at Eli Lilly and Company
Thanks, Lucas. Lilly R&D had another productive quarter. Let me begin by sharing some late-phase updates, including some exciting Phase 3 data that we shared at recent medical congresses.
Starting with neuroscience. Yesterday, at the clinical trials in Alzheimer's Disease Conference, we were pleased to share positive results from our Phase 3 TRAILBLAZER-ALZ 6 trial, which evaluated different dosing regimens for initiation of donanemab treatments to understand their effect on ARIA-E. In this trial, we tested a modified titration, which shifted one vial of donanemab from the first infusion to the third, as shown on Slide 14. We designed this modified titration to achieve identical total dose of donanemab administered in the first three months as does our standard dosing regimen, but we hypothesized that the smoother increase in dose could result in less ARIA.
We are pleased to see in this trial that indeed by pharmacokinetic analysis, we achieved equivalent cumulative exposure between the modified titration and the standard dosing regimen. And as a result, we achieved similar levels of amyloid plaque removal and phospho-tau217 reduction. Importantly, we also confirmed our hypothesis on ARIA and showed that the modified titration reduced the incidence of ARIA-E to 14% compared with 24% for those receiving the standard dosing regimen. As well, lower frequency of symptomatic ARIA-E, lower radiographic severity of all categories of ARIA-E and lower ARIA-E in ApoE4 genotype carriers was observed using the modified titration as compared to the standard dosing regimen. We plan to submit a supplemental DLA to the FDA in the coming weeks for this modified titration.
Our efforts on remternetug continued to progress and we are starting a Phase 3 efficacy study of remternetug focused on the pre-clinical phase of the disease, similar to our ongoing TRAILBLAZER-ALZ 3 trial for donanemab, where we are trying to reduce the risk of progression to symptomatic Alzheimer's disease. In this upcoming Phase 3 registrational trial called TRAILRUNNER 3, we are evaluating a fixed duration of monthly subcutaneous administration of remternetug offering what we see as a potentially convenient option for this earlier patient population. We'll share more details about the study design of TRAILRUNNER 3 tomorrow at CTAD.
Turning to Cardiometabolic Health. Last month we shared data from our remaining Phase 3 studies for our weekly basal insulin called insulin efsitora alfa. As a reminder, the efsitora Phase 3 consists of five global registration studies, four of which are in adults with type 2 diabetes and one is in adults with type 1 diabetes. We are pleased that each study met its primary endpoint of non-inferior A1c reduction versus insulin glargine or insulin degludec, which are the most frequently used daily basal insulins.
In the studies evaluating efsitora in people with type 2 diabetes, the results demonstrated that efsitora achieved meaningful A1c reduction with relatively low hypoglycemia rates. We were particularly excited with the results for QWINT-1 in which efsitora was administered via six doses using a single-use autoinjector. In this 52-week study in people with type 2 diabetes, efsitora lowered participants A1c by 1.31% compared to 1.27% for insulin glargine. This impressive A1c reduction was achieved in low hypoglycemia rates.
Actually, efsitora had approximately 40% lower rates of severe or clinically significant hypoglycemia than the daily insulin glargine. These data highlight the power of an easier-to-use dose form of a weekly insulin for people who are just initiating baseline insulin therapy for the first time. We look forward to discussing the results from the QWINT Phase 3 program with global regulatory agencies. It has also been a productive quarter for our late phase incretin programs.
First, as shown on Slide 15, we shared positive 176-week data from the SURMOUNT-1 Phase 3 study of tirzepatide in adults with pre-diabetes and obesity are overweight, which demonstrated a remarkable 94% reduction in the risk of developing type 2 diabetes. This is the longest duration tirzepatide data to date, and we are highly encouraged to see that patients on the 15 milligram dose achieved sustained weight loss of nearly 23%, driven more than three-year treatment period and that this weight-loss was accompanied by a significant reduction in risk of developing diabetes.
We look forward to sharing the detailed results next week at Obesity Week. These results add to compelling data showing the benefit of the combined pharmacology of dual GIP and GLP-1 receptor agonism in several obesity-related complications, including type 2 diabetes, metabolic dysfunction associated steatohepatitis or MASH, moderate-to-severe obstructive sleep apnea and heart failure.
We are working quickly to bring tirzepatide to more adults living with obesity and its complications, and we are pleased to share that we expect US regulatory action for tirzepatide in adults with obesity and obstructive sleep apnea yet this year and that we will submit for US approval to tirzepatide in adults with obesity and heart failure with preserved ejection fraction before the end of this year.
Another avenue to advance patient care is the maintenance of body weight reductions. We are conducting two Phase 3b weight loss maintenance trials. The first is SURMOUNT-MAINTAIN, which compares either tirzepatide 5 milligrams or tirzepatide maximum tolerated dose to placebo. The second is ATTAIN-MAINTAIN, which evaluates our oral GLP-1 Orforglipron versus placebo after tirzepatide or semaglutide in participants who complete SURMOUNT-5, the 3b head-to-head study of tirzepatide versus semaglutide. We look forward to sharing the top line data readout for SURMOUNT-5 later this year.
Next, in oncology. The Phase 3 EMBER-3 study evaluating our oral SERD, imlunestrant, in patients with second line ER-positive HER2-negative metastatic breast cancer was positive. The study evaluated three-arms, imlunestrant as a monotherapy, investigator's choice of endocrine therapy monotherapy and imlunestrant in combination with abemaciclib. Based on the results from this trial, we expect to submit an NDA to the FDA by year-end, and we look forward to sharing detailed results at an upcoming medical meeting.
The Phase 3 portion of the olomorasib first-line KRAS G12C lung cancer study is now underway. The first Phase 3 trial for this class of medicines in newly-diagnosed locally advanced or metastatic lung cancer regardless of PD-L1 expression. This comes after recently defining the dose of the medicine in combination with standard-of-care regimens in consultation with the FDA under Project Optimus. We continue to believe we could have a leading agent in this class and look forward to execution of the late stage program.
Finally, in immunology, we're excited by the recent US FDA approval of lebrikizumab as Ebglyss for adults and children 12 years and older with monitor severe atopic dermatitis. Ebglyss provides a new first-line biologic treatment that targets a main cause of eczema inflammation that offers significant early skin clearance and itch relief with convenient once-monthly maintenance dosing following the initial phase of treatment.
We recently shared compelling long-term data showing that lebrikizumab provides sustained disease control for up to three years in more than 80% of patients with moderate-to-severe atopic dermatitis who responded to Ebglyss treatment at 16 weeks. We have also initiated two Phase 3 studies of lebrikizumab in adults with perennial allergic rhinitis and chronic rhinitis/sinusitis [Phonetic] with nasal polyps.
As we continue to expand our immunology portfolio to help more patients, we're conducting two Phase 3 studies evaluating ixekizumab and tirzepatide together in patients with obesity or overweight in either psoriatic arthritis or moderate-to-severe plaque psoriasis. Obesity is associated with an increased risk of developing autoimmune diseases and can negatively impact disease outcomes. Taltz has already demonstrated strong efficacy in treating psoriatic arthritis and plaque psoriasis. And we are excited to see the potential for additional benefits for patients when combined with a significant and sustained weight loss offered by Zepbound.
Slide 16 shows select pipeline opportunities as of October 28, and Slide 17 shows potential key events for the year. I've already covered our late-phase progress so now I'll quickly cover updates for the early phase pipeline. Starting again with neuroscience. We recently initiated a Phase 2 study of an epiregulin antibody in chronic neuropathic pain associated with distal sensory polyneuropathy. We had previously shown this molecule in Phase 1 of the pipeline as an undisclosed mechanism in pain.
We also have begun Phase 1 studies on two new neurodegeneration assets, an alpha-synuclein-directed siRNA and a tau-directed siRNA. Earlier this morning at CTAD, we disclosed detailed results from our Phase 2 study of ceperognastat, our oral O-GlcNAcase anti-tau agent. While neither dose slowed clinical decline in early symptomatic Alzheimer's disease, biomarker data suggests potential impacts on tau pathology, brain volume and neuroinflammation. Safety follow-ups for the study are ongoing.
Turning to Cardiometabolic Health. In the coming days, we will initiate a Phase 2 study of eloralintide, our long-acting amylin receptor agonist for chronic weight management in combination with tirzepatide in patients with type 2 diabetes and the Phase 2 study of bimagrumab alone or in combination with tirzepatide for chronic weight management and participants without type 2 diabetes. We will also be advancing volenrelaxin our long-acting relaxin molecule into Phase 2 in adults with chronic kidney disease. We removed the Phase 1 APOC3 siRNA asset in cardiovascular disease as it did not meet our bar for continuing clinical development.
In oncology, 2024 continues to be a very productive year for new clinical starts. Since the last call, we advanced three new molecules into Phase 1 studies. Our oral SMARCA2 or BRM inhibitor, our KRAS G12D inhibitor, and our pan-KRAS inhibitor. These three initiations bring to total new clinical starts in oncology in 2024 to seven, exceeding the goal we shared earlier this year to put at least five new potential medicines in the clinic. And we've done that across three different modalities, emblematic of our strategy to utilize therapeutic modality diversification to combat treatment resistance and improve patient outcomes. We expect this new slate of clinical programs will set us up for an exciting 2025 as we look to see which programs deliver differentiated and important early clinical data sets for patients.
Finally, in early stage immunology, we're also excited to initiate several new Phase 2 studies. First, we moved DC-853, an oral IL-17 inhibitor from the DICE Therapeutics acquisition into Phase 2 in adults with moderate-to-severe plaque psoriasis. And we removed DC-806 in the pipeline in favor of 853, which is a more potent molecule.
Second, we are initiating a Phase 2 study combining eltrekibart and mirikizumab in adults with moderately to severely active ulcerative colitis. In addition, we are terminating the Phase 2b study of peresolimab in rheumatoid arthritis due to the overall benefit risk profile of the molecule in this study.
Finally, after welcoming our Morphic colleagues to Lilly in August, our pipeline now reflects the oral alpha-4-beta-7 integrin inhibitor, MORF-057 in Phase 2 for moderate-to-severe ulcerative colitis and moderate-to-severe Crohn's disease. Q3 was an exceptionally productive quarter for Lilly R&D, and we're pleased with our important progress we're making for patients across all of our therapeutic areas.
Now I'll turn the call back to Dave for closing remarks.
