Novartis AG Investor update

Good evening, and welcome to our conference call on remibrutinib in MS. I'll first read our safe harbor statement. The information presented today contains forward-looking statements that involve known and unknown risks, uncertainties, and other factors. These may cause actual results to be materially different from any future results, performance, or achievements expressed or implied by such statements. For a description of some of these factors, please refer to the company's Form 20-F and its most recent quarterly results, Form 6-K, that respectively were filed with and furnished to the U.S. Securities and Exchange Commission. Before we get started, I would also like to remind our analysts to please limit yourselves to one question at a time, and we'll cycle through the queue as needed. With that, I'll pass it over to Nazem.

Thank you, Inish. Good evening, everyone. My name is Nazem Atassi. I'm Global Head of Neuroscience Development Unit at Novartis. We are calling from MSToronto2026. I'm delighted to be here in the room with Victor Bultó from Novartis, President U.S. for Novartis, and Professor Heinz Wiendl, Professor Director of Department of Neurology and Neurophysiology at University of Freiburg. Next slide. The agenda. I'll start by giving an introduction about remibrutinib, and then Dr. Wiendl will walk us through the results of the REMODEL-1 and -2 trial. After that, Victor will go over the commercial opportunity in MS and beyond for remibrutinib. Next slide. Novartis has a long legacy in multiple sclerosis. This is a history that transformed MS care over the past two decades. Starting with Extavia, Gilenya, Mayzent, and Kesimpta.

Today we have remibrutinib results presented at MSToronto2026 and with simultaneous publication at The Lancet. Remibrutinib is the next chapter in the MS legacy for Novartis and the focus of today's presentation. Slide number 7. Remibrutinib is a BTKI inhibitor with a pipeline-in-a-pill potential. As you can see on the slide, it is in multiple indications, including approved indications such as chronic spontaneous urticaria and chronic inducible urticaria in the U.S. In addition to RMS and SPMS, RMS is the focus of today's discussion, in addition to a number of late-phase development in immunology and dermatology. Next slide 8. The promise of BTK inhibition is in addressing both the relapses and the disability progression without chronic B-cell depletion. Remibrutinib has dual mechanism of action. It targets B-cell in the periphery with adaptive immunity to reduce acute inflammation and relapses.

It also targets microglia with innate immunity in the CNS to reduce chronic neurodegeneration and disability progression. Remibrutinib is very different than B-cell depleters, such as anti-CD20s. As opposed to anti-CD20s, it modulates B-cells without depleting them. It also targets not only B-cells, but also microglia in the CNS. It is a covalent binder with short half-life, which allows for fast start or stop if needed. It has, as you will see, a safety profile that is favorable. Next slide. Slide number 9. Remibrutinib is unique. It was designed to deliver the potential of BTK inhibition. It is a covalent, irreversible binder for sustained inhibition of BTK beyond the PK exposure. It is also CNS penetrant, reaching levels above microglial IC50 in the CNS. It is highly selective compared to other BTKI inhibitors. It allows for near-complete BTK occupancy and high potency versus other BTK inhibitors tested in vitro.

It has optimal PK and PD with short half-life, and as you can see in the middle, it has distinct chemistry compared to other BTKIs. Slide number 10. This is published data showing remibrutinib selectivity as highly selective compound tested in vitro, leading to fewer off-target effects and a differentiated benefit risk profile. As you can see, compared to other BTKIs, it achieves 100% BTK inhibition without off-target effects on other kinases. Next slide. Slide 11. As I mentioned, remibrutinib is approved in other indications. We have extensive clinical data that reinforces its proven and robust favorable safety profile. The comprehensive evidence of favorable safety profile includes not only the remibrutinib trial data that you will see today, but also includes more than 4,500 participants across 40 different studies, with dosages up to 600 milligrams, that took this drug.

There is no liver safety signal, including no Hy's Law cases in any of these programs or patients. In the CSU REMIX I and II Phase III trials, the safety profile of remibrutinib was comparable to placebo. That includes adverse events, infections. Liver enzyme abnormalities were less than 2% in each of the arms, the placebo arm and in the treatment arm. In terms of discontinuation rates, low discontinuation rate to less than 3% in both arms. We also have more than 10,000 patients that were treated with remibrutinib for CSU commercially, with no liver safety signals reported. That translated to two FDA approvals for remibrutinib with a clean label. No black box warning, no contraindication, and no requirement for routine lab monitoring. With that, I will turn it over to Dr. Wiendl to walk us through REMODEL I and II results in RMS.

Dr. Wiendl. Yeah. Thanks, Nelson.

My name is Heinz Wiendl. I am a neurologist participating in the REMODEL steering committee, and I am presenting the data that has been released in full transparency today. This is the trial design, and this is a trial design that is rather classical. Remibrutinib is tested against teriflunomide as an active comparator. Remibrutinib is given in the MS indication with twice a day 100 milligrams. Teriflunomide is given with 40 milligrams. The trial has been done in a double-blind, double-dummy fashion, so that means patients had to take three pills. The trial design was an event-driven trial design. That means that participants were actually in variable duration within the trial, and the trial endpoints were powered on events.

The inclusion was the diagnosis of relapsing MS, and patients had to have signs of activity based on either relapses or the presence of gadolinium-enhancing lesions on MRI. This is the list of the pre-specified endpoints. This trial was basically designed to show a superiority of remibrutinib against teriflunomide based on relapses. So reduction of relapses calculated by the annualized relapse rate. We know in contemporary trials in multiple sclerosis that the number of relapses, in general, but particularly also on the comparator arms, is going lower and lower, which makes the key secondary endpoint, such as MRI, even more relevant. Why is that? MRI is 10 times more sensitive than relapses, clinical relapses. That means a very objective measure of what a drug is doing in regard to suppressing focal lesion development or gadolinium-enhancing lesion development can be objectively measured on MRI.

The disability progression is then the next secondary endpoint, and in difference to the shown endpoint on the left side, I am on slide number 14, they have been done not independently in the both trials. There were two trials. One was REMODEL-1 and the other REMODEL-2. It was done on pooled trials to increase the likelihood of the number of events. I will explain later what the difference is between the 3-month confirmed disability progression, which is CDP, and the 6-month confirmed disability progression. Then there is a combination endpoint, which is called NEDA, no evidence of disease activity, and then there is a biological marker of neural degeneration, which is neurofilament light. There is then another endpoint which is secondary, which we will show is progression independent of relapse activity over 6 months. And of course, safety and tolerability, very importantly, as endpoints in addition.

Slide number 15 shows you the baseline characteristics. To run you through this graph and the table, first of all, you have to note that the balance between REMODEL-1 and REMODEL-2 looks very good. That means there is no major differences in age or sex ratio or in time since diagnosis, et cetera. This is a typical trial in relapsing MS population with rather mild affection of those patients, which you can see as measured by the expanded disability status scale, and what you also can see on the basis of the previous relapses. So it is not atypical to see this number of relapses and a rather mild affection of the EDSS score, which goes from 0 to 10, but it is a very typical relapsing MS population nowadays. On average, those patients had approximately 6 years since first MS symptoms and approximately 4 years since diagnosis.

This is in slide number 16 that shows you our primary endpoint. Remibrutinib demonstrated a strong relapse control, translating to approximately one relapse every 13 years. The independent analysis show in REMODEL-1, a 35% relative reduction of relapse rates, and in REMODEL-2, it is 31.2%. If you translate that, how often a relapse then occurs is, as written in the title, approximately one relapse every 13 year, which is a quite robust disease control. Next slide shows you the MRI outcome measures. I was mentioning already that they have to be looked at with equal attention despite being secondary outcomes because they are more sensitive to changes and therefore also to differences between the two arms. Here, remibrutinib reduced new enlarging T2 lesions on an annualized rate by 65.3% or 70.3% in the two trials.

When you look at contrast-enhancing lesions, you are seeing a reduction of 66% and 66% in both trials. When you look at the absolute numbers, you will realize there is virtually no more gadolinium-enhancing lesions, so it is 0.08 or 0.07. All in all, this is a very significant reduction on MRI. Why am I emphasizing this? We have seen now a couple of BTK inhibitors, and the first ones we have seen, they basically did not really have a superior effect on MRI efficacy parameters in contrast to teriflunomide. When you look at also comparative data from fenebrutinib, which is another compound that has been tested in relapsing MS population, these reductions are in the same ballpark region, suppressing new T2 lesions and gadolinium-enhancing lesions. When you look at the MRI, this is a quite impressive effect. Next slide. This is now the combined analysis of the disability endpoint.