Daniel M. Skovronsky
Executive Vice President, Chief Scientific and Medical Officer, and President, Lilly Research Labora at Eli Lilly and Company
Thanks, Anat. It's been a productive and busy few months for Lilly R&D. Since our last earnings call, we've had a few major readouts across our therapeutic areas, and we've announced several business development transactions. Let me start with the data that we shared in June at the American Diabetes Association. We presented over 40 abstracts across our portfolio and shared data during two ADA-sponsored symposia.
The first was for the Phase 3 results from the SURMOUNT-2 study of tirzepatide in adults with obesity or overweight in type 2 diabetes, which was simultaneously published in the New England Journal of Medicine. And the second symposium was for the results from two Phase 2 trials of retatrutide, our GIP/GLP glucagon tri-agonist in adults with obesity and overweight as well as in people with type 2 diabetes. The retatrutide results in obesity and type 2 diabetes were simultaneously published in New England Journal of Medicine and Lancet, respectively.
We also shared an oral presentation on our Phase 2 trial results for orforglipron, our once-daily, non-peptide oral GLP-1 in adults with obesity or overweight. These results were simultaneously published in New England Journal. We also presented results from a Phase 2 trial of orforglipron in patients with type 2 diabetes, and these were published in the Lancet. Clearly, we're proud of all of this data in diabetes and obesity portfolio.
Since we discussed the top line data for SURMOUNT-2 tirzepatide trial during our last earnings call, I'll focus my updates today on the Phase 2 data shared for orforglipron and retatrutide, starting with orforglipron on Slide 14. The orforglipron presentation highlighted safety and efficacy data across six dose arms in our Phase 2 study in obesity. With an overall mean body weight at baseline of 109 kilograms, orforglipron demonstrated an average of up to 14.7% body weight reduction at 36 weeks.
At the second highest dose tested in the study, 75% of participants reached a weight reduction goal of 10% or more. We also shared data showing a dose-dependent decrease in systolic blood pressure and an overall improvement in lipid levels. The most common adverse events were GI-related and generally occurred earlier in the trial during the titration phase and were mostly mild to moderate. While we've not yet shared the dosing details for our Phase 3 studies, these Phase 2 results have informed our approach on dose escalation.
We also presented data at ADA from a similar Phase 2 study of orforglipron in people with type 2 diabetes, the results of which are highlighted on Slide 15. Orforglipron demonstrated a mean reduction in hemoglobin A1c at 26 weeks of up to 2.1%, and over 90% of participants on the highest three doses achieved A1c levels less than 7%. We initiated Phase 3 trials for orforglipron in both obesity and type 2 diabetes in the second quarter, and we look forward to those results in 2025.
For retatrutide, the full results of two Phase 2 trials were presented during an ADA-sponsored symposium, which discussed efficacy and safety in adults with obesity or overweight with at least one weight-related comorbidity as well as in people with type 2 diabetes. There's also a segment of the symposium focused on liver fat and NASH-related biomarker data in patients with nonalcoholic fatty liver disease, which showed relative liver fat reduction of over 80% at 24 weeks for the [Indecipherable].
Slide 16 highlights key results from the obesity Phase 2 trial in which retatrutide met the primary end point at 24 weeks, demonstrating mean weight reduction up to 17.5%. The safety profile of retatrutide was similar to other incretin-based therapies. In a secondary end point of weight reduction at 48 weeks, participants treated with the highest dose of retatrutide demonstrated a mean rate -- weight reduction up to 24.2% or almost 58 pounds on average.
If confirmed in registrational trials, we believe that magnitude of mean weight reduction would represent a new high watermark for weight loss from a pharmacologic agent at this time point. It's also worth noting that the Phase 2 retatrutide trial in obesity was well balanced between genders with females representing just under half of all participants in the trial. This was intentional and is atypical for incretin clinical trials in obesity, which often have a higher proportion of female participants, a subgroup that typically experiences greater weight loss than males.
Indeed, in the retatrutide Phase 2 obesity trial, the mean change in body weight for female participants at the highest dose was 28.5%. Given these encouraging results, we moved rapidly to initiate the Triumph Phase 3 program, which will evaluate the safety and efficacy of retatrutide for chronic weight management, obstructive sleep apnea and knee osteoarthritis in people with overweight and obesity. These four Phase 3 trials will each run between 68 and 80 weeks. The trajectory of weight loss seen in the Phase 2 study reinforces our belief that retatrutide can potentially represent a further improvement and additional option for patients seeking pharmacological treatment for obesity and its complications.
While retatrutide's Phase 2 results in obesity garnered much attention at ADA, the Phase 2 results in patients with type 2 diabetes are also very encouraging with participants receiving retatrutide achieving a hemoglobin A1c reduction of up to 2% on average in addition to meaningful levels of weight loss. I'm pleased to share that we plan to advance retatrutide into Phase 3 for type 2 diabetes.
Moving to tirzepatide on Slide 17. We were delighted to announce in late July that SURMOUNT-3 and SURMOUNT-4 trials of tirzepatide in obesity met all primary and key secondary objectives. In key secondary objectives for both these studies, participants achieved similar mean weight reduction, 26.6% in SURMOUNT-3 and 26.0% in SURMOUNT-4. While these two trials were not required for our chronic weight management submission to the FDA, they provide important additional information regarding the role tirzepatide plays in maintaining or adding to the weight loss achieved with either intensive lifestyle intervention or pharmacotherapy in adults living with obesity or overweight.
SURMOUNT-3 evaluated tirzepatide following an intensive lifestyle modification program and demonstrated that even in people who have a weight loss response to lifestyle intervention, tirzepatide provides significant additional weight loss. SURMOUNT-4 was a randomized withdrawal study in which all participants received tirzepatide for a 36-week lead-in period, at which point, half the participants were switched to placebo and the other half continued treatment with tirzepatide. This study demonstrated that those participants who continued on tirzepatide experienced continued weight loss, while those who switched to placebo started to regain weight.
These data reinforce our understanding that obesity is a complex chronic disease for which multiple treatment approaches, including lifestyle modification and effective medications, are needed. We believe tirzepatide is well positioned to be one such treatment option. Accordingly, we submitted an application for tirzepatide for chronic weight management to the FDA during Q2. The FDA granted this application priority review designation, and we anticipate FDA action by year-end.
Slide 18 shows select pipeline opportunities as of August 4, and Slide 19 shows potential key events for the year. I've covered the major updates in diabetes, including the advancement of orforglipron and retatrutide into Phase 3 since our learning -- last earnings call.
Turning then to our neuroscience portfolio. Three weeks ago with the AIC meeting in Amsterdam and simultaneously published in JAMA, we were excited to share the detailed results from the TRAILBLAZER-ALZ 2 study, highlighting donanemab's robust efficacy profile across a number of new analyses that reinforce our belief in the medicine's ability to meaningfully slow the progression of Alzheimer's disease, especially in patients earlier in disease progression. We cover the results in some detail during our AIC investor call so I won't cover that again, except to note that we submitted donanemab to the FDA and to the EMA for approval, and we look forward to FDA action before the end of this year.
Shifting to oncology. Launch progress continues with Jaypirca and mantle cell lymphoma, and we are pleased to have the detailed chronic lymphocytic leukemia results from the BRUIN Phase 1/2 trial published in New England Journal in early July. Following the discussion with the FDA, we've now submitted an application for accelerated approval for Jaypirca in CLL patients previously treated with both a covalent BTK inhibitor and venetoclax based on the results from the BRUIN Phase 1/2 study. We expect FDA action by year-end.
Also during the quarter, we completed the regulatory submission in Japan for pirtobrutinib for patients with MCL. We continue to study pirtobrutinib in multiple Phase 3 trials and look forward to the results from the BRUIN 321 trial in CLL, which we now expect to see before the end of this year, and it has been added to our key events slide.
In other oncology developments, at ASCO in June, we presented new data from the Verzenio monarchE trial in high-risk early breast cancer. For the first time, we showed data demonstrating the efficacy of the medicine in this setting is not compromised when patients undergo dose reductions. We believe that the ability to manage Verzenio's side effects while preserving efficacy could be very important to ensuring that patients complete their two years of therapy. This is an emerging part of Verzenio's differentiation in this class.
We're also very excited about last week's announcement regarding the randomized trial of Retevmo in treatment-naive RET fusion-positive lung cancer. As we communicated in the press release, this randomized trial was declared successful on its primary end point of progression-free survival, the first time any targeted therapy in lung cancer has ever shown superiority to a PD-1 plus chemotherapy regimen. While we remain disappointed by the low levels of genomic profiling done at the time of lung cancer diagnosis, we're hopeful that these data will continue to advance the practice of genomic-driven medicine. We look forward to sharing the full results of the study at an upcoming medical meeting.
In our earlier-stage oncology portfolio, the combination experiment of our KRAS G12C inhibitor with pembrolizumab continues to mature nicely. And we're now working to initiate Phase 3 trials in first-line G12C-mutated lung cancer in the next six to nine months.
More broadly, we're excited to see the overall progress of our oncology portfolio. In addition to last week's Retevmo announcement, we expect another seven randomized trial readouts in four to six new first-in-human trials across small molecules and biologics in oncology over the next 12 months. With the acquisition of Loxo Oncology four years ago, we catalyzed a change in the strategy and direction of oncology at Lilly, and we're seeing the fruits of these efforts.
Finally, in immunology, we have several updates related to mirikizumab. A Digestive Disease Week in May, we presented new analyses from the Phase 3 LUCENT-1 and LUCENT-2 studies, demonstrating that remission of key symptoms of ulcerative colitis, including biourgency, was associated with significant improvement in the quality-of-life assessment in adults with UC. In Q2, we launched mirikizumab marketed as Onvia in Japan as a treatment for adults with moderately to severe active UC. In late May, we received approval for Onvio in the EU and have subsequently launched Onvio in Germany and planned additional launches in the EU later this year.
In the US, we've resubmitted our application to the FDA. We now expect regulatory action by the end of this year. For lebrikizumab, our IL-13 monoclonal antibody under regulatory review for atopic dermatitis, we presented a new secondary analysis at the Revolutionizing Atopic Dermatitis Conference in May. This post hoc analysis demonstrated improvement or clearance of face or hand dermatitis in adult and adolescent patients treated with lebrikizumab. These are parts of the body that are highly visible and for which dermatitis can be particularly burdensome and stigmatizing. We expect regulatory action for lebrikizumab in both the US and EU later this year. Together with Almirall, our development and commercialization partner in Europe, we look forward to potentially bringing this important medicine to patients who suffer from this chronic disease.
Looking earlier in our immunology pipeline, we're pleased in May to have the detailed results from our Phase 2a study of parasolimab in rheumatoid arthritis published in the New England Journal. These data were first presented as a late-breaking abstract at the American College of Rheumatology Annual Meeting in late 2022 and represent the first clinical evidence that's stimulating endogenous PD-1 inhibitory pathway could be an effective approach to treat rheumatologic disease.
As you can see, Q2 was another productive quarter for Lilly R&D with important progress in each of our therapeutic areas. Now, I'll turn the call back to Dave for closing remarks.
