Immune Maintenance and Scientific & Clinical Evidence with KESIMPTA®

[Voice Over]

The speakers have been paid by Novartis Pharmaceuticals Corporation (NPC) to conduct this presentation.

[Dr Berger]

Dr. Boster, I wanna chat with you about the potential to maintain components of the immune function for our patients with MS, and the safety data for KESIMPTA, which is indicated for the treatment of relapsing forms of MS, including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease in adults. I'd like to chat about the warnings and precautions, which include infections, injection-related reactions, reduction in immunoglobulins, and fetal risk. The most common adverse reactions with incidences greater than 10% include upper respiratory tract infection, headache, injection-related reactions, and local injection site reactions. Please see additional Important Safety Information throughout this presentation and accompanying full Prescribing Information

[Dr Boster]

That's an important topic for clinicians, and many of our patients. But let's first talk about the proposed mechanism of action of KESIMPTA. While the precise mechanism in which KESIMPTA exerts its therapeutic effect is unknown, KESIMPTA is thought to work by binding to CD20, a self-service antigen present on pre-B and mature B lymphocytes, resulting in B cell depletion.

[Dr Boster]

• That's an important point, because pre-clinical studies show that subcutaneous delivery of KESIMPTA preferentially targets B cells in the lymph nodes, and is thought to spare B cells in the spleen. This targeted delivery may help maintain components of immune function in KESIMPTA patients. We, of course, also have considerable clinical data for KESIMPTA, including up to five years for KESIMPTA compared to Teriflunomide

[Dr Berger]

Yes, you are absolutely correct. Both in the clinical trials compared to teriflunomide, and in my own clinical experience, the frequency with which we see breakthrough disease, that is relapse or new lesions on MRIs, is lower than teriflunomide. Today, I have more than 125 patients on KESIMPTA, and when starting them on this drug in inform my patients of the efficacy data in an attempt to reassure them that they're on a high efficacy therapy with KESIMPTA. I typically don't get into the specific numbers, but if they ask, I will give them the high level overview, and maybe mention the 58% relative reduction in annualized relapse rate versus teriflunomide, or one of the other trial end points, depending on what is the patient's primary concern.

[Dr Boster]

Wow. With 125 patients treated with KESIMPTA, it's clear you have a lot of clinical experience with the drug. And it's great to hear that your patients' experience with KESIMPTA aligns with the data of the Phase 3 clinical trials. Similarly, what I'm seeing in my practice aligns with your experience and the Phase 3 clinical trial data. It's my goal to put patients on the most effective drug that they're comfortable taking. Now, I crafted that sentence very carefully, because finding the right drug requires a risk-benefit assessment. While we're assessing efficacy, it's also important to consider safety, including more or less serious adverse reactions.

[Dr Boster]

I'm curious, Dr. Berger, how does the concept of safety tie into your clinical decisions when selecting an MS treatment?

[Dr Berger]

Well, I completely agree with you that striking a balance between efficacy and safety is key, because safety is of critical importance. So, I advise my patients that there's a risk of infections associated with KESIMPTA, but that the risk, and the risk of serious infections, is comparable to teriflunomide, at 51.6% versus 52.7%, and 2.5% versus 1.8%, respectively, in the pivotal trials and in my clinical experience. Also, similar to the Phase 3 clinical trials that found treatment discontinuation rate due to adverse events for KESIMPTA at 5.7%, I've seen comparably low rates of treatment discontinuations due to adverse events. The Phase 3 data consisted of collecting data for three years, but we do have extension data up to five years.

[Dr Boster]

Speaking of, how have the extension study and its 5-year safety data evolved how you think about KESIMPTA?

[Dr Berger]

We continue to see relatively comparable rates of infection at 51.58% in the pivotal trials, and 67.75% in the extension analysis. Similarly, the rate of serious infections was 2.54% and 5.38%, respectively. The risk for malignancies did not increase over time in the overall population. What I also find interesting is the low rate of discontinuation due to adverse events at 7.1% in the extension study.

[Dr Boster]

Yeah. Through the extension phase we're not seeing new safety signals. That's very important to me, because we don't treat patients for just three years. So having a sense of the behavior of the therapy over an extended period of time is important. It's always very reassuring to me, and my patients.

[Dr Berger]

In your view, what does the safety data for KESIMPTA tell us about the potential for maintenance of immune function on therapy?

[Dr Boster]

So when we're trying to help someone with an autoimmune disease, we often need to alter their immune response. However, we have an immune system for a reason. When you alter the immune response, it comes at a degree of risk, including risk of infection. Clinicians should take that into consideration when selecting treatment options, and educate patients to be vigilant of any infection. As we mentioned earlier, KESIMPTA results in depletion of B cells. If you suppress B cells, you potentially see IG levels decline, which some have thought to potentially increase the risk of infection as a result.

[Dr Boster]

So how do you approach monitoring Ig levels in patients treated with KESIMPTA in your practice, and how do these results impact your approach to treatment?

[Dr Berger]

I monitor the level of immunoglobulins at the beginning, during, and after discontinuation of treatment with KESIMPTA, until B cell repletion. Consider discontinuing KESIMPTA if a patient develops a serious opportunistic infection, or recurrent infections if immunoglobulin levels indicate immune compromise. KESIMPTA has the potential for an increased risk of infections, including serious bacterial, fungal, and new or reactivated viral infections. Some of these infections have been fatal in patients treated with other anti-CD20 antibodies. I delay KESIMPTA administration in patients with an active infection until the infection is resolved. With these recommendations in mind, I find it important to remember that I'm not treating labs. I'm treating patients. So monitoring their well-being overall is my top priority.

[Dr Boster]

How does the IG data we have for KESIMPTA relate to what you see in your practice?

[Dr Berger]

In the extension study, the mean IgG levels remain stable over five years in patients treated with KESIMPTA, while the mean IgM levels declined, but remained above the lower limit of normal. Although I don't monitor mean Ig levels as frequently in my practice, I'd say these data are pretty comparable to my experience.

[Dr Boster]

Yeah. To the extent that the patients were followed in the extension study, which is 5 years, the data look reassuring. In alignment with the 5-year data, I'm seeing similar IgG/IgM levels and severe infection rates with my patients treated with KESIMPTA. Do you have any relevant examples from your practice related to potential Ig level variability, and what, if any, association did you find to risk of infection?

[Dr Berger]

I can think of a very recent and relevant example that arose during the COVID-19 pandemic. There was a concern that individuals treated with B-cell-depleting therapies, like KESIMPTA, may not generate enough immunoglobulins and might be more likely to contract COVID or display serious symptoms of COVID infection. But I haven't seen an increase in serious COVID-19 outcomes in my patients treated with KESIMPTA, which aligns with the data on COVID-19 outcomes from the extension study.

[Dr Boster]

Yeah. I think that it's a very poignant example. It seems like everyone is more worried about infections since COVID-19 and how patients might tolerate their MS treatments, but when my patients have contracted COVID-19, they seem to be mostly mild to moderate severity, similar to what we might expect to see in the general population. In addition to these safety concerns, patients also want to know what their experience of taking KESIMPTA is going to be like.

[Dr Boster]

So, what are you seeing in practice with your patients receiving KESIMPTA with regards to tolerability and injection-related reactions?

[Dr Berger]

Similar to the clinical trial data, which showed that the incidence of injection-related reactions was highest with the first injection at 14.4% and decreasing with subsequent injections, at 4.4% with the second and <3% with the third injection, I do not as frequently see injection reactions beyond the first injection in my patients treated with KESIMPTA. I think that helps tremendously. I mean, it eliminates many phone calls from patients concerned about an injection-related reaction experienced after self-administration. One of the great things is that it's not necessary to premedicate patients, I will typically forewarn them that they may have some reaction at the time of the initial injection, and that they may want to have some acetaminophen for symptomatic treatment if

injection-related reactions occur.

[Dr Boster]

Now, there's one more aspect about KESIMPTA that I'd like to discuss with you before we wrap up our chat. How are your patients faring with adherence to KESIMPTA?

[Dr Berger]

Well, what I'd say is the following,The real-world data on persistence to KESIMPTA is reassuring. However, from my own experience, I might even expect more patients to persist with KESIMPTA. The two real-world, retrospective, cohort studies demonstrated that 75% of patients taking KESIMPTA remained on treatment at 1 year vs 43% of those on platform injectables, and 82% of patients taking KESIMPTA remained on treatment at 1 year vs 68% of those on orals.

[Dr Boster]

Yes, and I think asking some patients to inject themselves poses a potential challenge, even as a once-monthly injection. Prescribers should be mindful of the persistence data, particularly in patients for whom they're concerned about adherence and staying on a monthly regimen.

[Dr Berger]

Dr Boster, what are your final thoughts on the safety data we've discussed today, including the Ig levels in patients treated with KESIMPTA for up to five years?

[Dr Boster]

Well, the ALITHIOS extension analysis is important because it provides further understanding of KESIMPTA beyond the initial clinical trials. So, when the extension phase demonstrates no new safety signals, stable IgG levels, and IgM levels declining but remaining above the lower limit of normal it helps to provide insight into the behavior of KESIMPTA over an extended period of time.

[Dr Berger]

Let's not forget that there are efficacy and safety data showing a proven ability to significantly reduce the risk of disease relapse and demonstrated similar safety compared to teriflunomide. Add to that the fact that after an initial dosing of 20 mg at weeks 0, 1, and 2, KESIMPTA is administered at home once monthly starting at week 4, and, well, I think you have a potential trifecta for clinicians. Please continue watching to hear the full Important Safety Information.

Narrator

Important Safety Information

Infections

• Delay KESIMPTA administration in patients with an active infection until the infection is resolved. Vaccination with live-attenuated or live vaccines is not recommended during treatment with KESIMPTA and after discontinuation, until B-cell repletion

Injection-Related Reactions

• Management for injection-related reactions depends on the type and severity of the reaction

Reduction in Immunoglobulins

• Monitor the level of immunoglobulins at the beginning, during, and after discontinuation of treatment with KESIMPTA until B-cell repletion. Consider discontinuing KESIMPTA if a patient develops a serious opportunistic infection or recurrent infections if immunoglobulin levels indicate immune compromise

Fetal Risk

• May cause fetal harm based on animal data. Advise females of reproductive potential of the potential risk to a fetus and to use an effective method of contraception during treatment and for at least 6 months after stopping the last dose