Client Id: 77 NOVEMBER 25, 2019 / 6:00AM, NOVN.VX - Novartis AG to Acquire The Medicines Company for USD 9.7 Billion Call difference on the primary endpoint in the pooled analysis with a highly significant p-value. And when you look at it, greater than 90% achieved the threshold of less than 70 milligrams, as stated in the guidelines, so really showing that the medicine can deliver versus the cardiovascular guidelines. And greater than 50% LDL lowering in 87% of patients, so again, very, very compelling. So when you go to Slide 15. When you look at the safety of this medicine, we were very compelled by the outstanding safety profile consistently shown across the range of studies even going back to Phase I and Phase II. When you look at the general safety across the study, it's comparable to placebo across all of the relevant MedDra groups, and so I think this was already quite positive. And then when you looked at the prespecified exploratory CV endpoint, there's been some focus in the investor community on this point. We would like to highlight when you look at the prespecified exploratory endpoint across composite CV events, you can see that in ORION-10, there were 58 events versus 79 events in placebo, so you can see a compelling reduction there already even though this was only for safety and not an endpoint that was really to be looked at from an efficacy standpoint. And you can see a similar result in ORION-11. And when you look at the composites in cardiovascular death or fatal, non-fatal MI and stroke, you see a very favorable profile overall. Again, important to note the studies were not designed to look at efficacy, but I think you can already start to see a compelling effect on cardiovascular CVRR in these 2 studies. Now if you move to Slide 16. One of the elements of this class historically has been a focus on liver signals, and I wanted to just spend a moment to explain the history of that and why we believe this has been addressed by the design of this molecule. Historically, the view and some of the issues with the class related to RNA interference, interfering with non-target RNAs in liver, so off-target RNA effects. And then the other element of the story was that given the dose given in the patient, the RNA splicing enzyme complex was overwhelmed by the medicine. And this led to other RNAs that needed to be spliced or shut down not to be appropriately regulated. What the inclisiran now brings to the table is a very uniquely designed molecule. The RNA sequence is highly specific and very designed not to trigger any off-target events. And also the dose, given the GalNAc conjugation, has allowed for a much lower dose of the medicine to be given, which then allows the normal functioning of the RNA splicing mechanisms within the cell. So a very compelling mechanistic rationale for why. As you can see in the clinical data, we don't see any liver signals versus placebo. And this is the case for patients now followed out beyond 3 years who received multiple doses over time. Mechanistically, there is no reason to believe that additional exposure would increase risk to the liver given the overall PK of the medicine. So we feel very good about the liver, TD muscle and platelet profile of the medicine. Now moving to Slide 17. Now of course, the ORION-4 outcome study will be critical to the longer-term outlook of the medicine. And we feel very confident in how The Medicines Company has designed this critical CV MACE and CV mortality study. Now just in terms of the protocol, it involves patients over 55 years of age with prior MI, stroke or PAD. These are high-risk patients with LDL over 100 milligrams on standard of care so not well managed under the current treatment. The sample size is 15,000 patients and, as I said, 6,000 patients enrolled, plan for full enrollment at the end of next year; standard composite MACE endpoint powered for a 25% reduction with relevant secondary endpoints in cardiovascular death, MI or CV death. Now the way The Medicines Company has designed the study was informed by the Cholesterol Treatment Trialists Collaboration look at prior trials in this space. And one of the most interesting trends you see is as you follow patients longer with these kinds of therapies, you see effect sizes on the primary endpoint improve. So as you can see on the x-axis here, you see reductions in LDL-cholesterol millimolar per liter. The inclisiran assay would be around 1.3. And a follow-up, it is planned of median of 5 years, which is not even on the chart. But as you can see, as you follow longer, you get to higher and higher reductions in CVRR. This gives us confidence that we can reach the target we hope of above 20% but the potential upside of reaching 20 --above 25% and potentially as high as 30%. That's been modeled, if you look at Slide 18, in more detail by The Medicines Company. We believe this is a relevant upside. When you use the Phase II and III data and you model it out, you can see that based on the LDL-lowering effects seen both in ORION-10 and 11 of 56%, a time average reduction of 54%. The computed 5-year relative risk reduction would get you to a 30 --31% to 32% relative risk reduction. When you extend that modeling out to ORION-4, you would get to an estimate of 5 years of a potential 30% reduction in CVRR. We've modeled the base case of reaching 20%, but we believe that with the design of the study, the potential exists to get to as high as 30%, which would provide a compelling case to payers around the world for the use of this medicine. 5 THOMSON REUTERS STREETEVENTS | www.streetevents.com | Contact Us ©2019 Thomson Reuters. All rights reserved. Republication or redistribution of Thomson Reuters content, including by framing or similar means, is prohibited without the prior written consent of Thomson Reuters. 'Thomson Reuters' and the Thomson Reuters logo are registered trademarks of Thomson Reuters and its affiliated companies.
