Journey to KESIMPTA® (ofatumumab): KESIMPTA Pivotal and Long-Term Data

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Over 150 years ago, a French neurologist named the debilitating disease he'd been observing and treating, "sclérose en plaque disseminée"

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Today, this illness is called multiple sclerosis, or MS, a disease often distinguished by clearly defined relapses that profoundly affect patients' lives and that is further complicated by ongoing MS activity patients may not be aware of

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While relapsing MS, or RMS, has not changed over time, our understanding and approach to managing the disease has

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Over 20 therapeutic options, with varying mechanisms of action and clinical endpoints studied, exist. But even with such progress, we continue to ask new questions, such as… What steps can we take to bring a new product to market in RMS with a unique set of attributes?

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And that's where our journey begins

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KESIMPTA is indicated for the treatment of relapsing forms of multiple sclerosis, or MS, to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults. KESIMPTA is contraindicated in patients with active hepatitis B virus (HBV) infection, or history of hypersensitivity to ofatumumab, or life-threatening injection-related reaction to KESIMPTA. Hypersensitivity reactions have included anaphylaxis and angioedema. Warnings and precautions include infections, injection-related reactions and hypersensitivity reactions, reduction in immunoglobulins, and fetal risk. Most common adverse reactions (incidence greater than 10%) are upper respiratory tract infection, injection-related reactions, headache, and local injection-site reactions. Please see additional Important Safety Information by watching this entire video and by referring to the adjacent panel and accompanying full Prescribing Information, including Medication Guide. And continue watching at the end of this video to hear full Important Safety Information for KESIMPTA

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Early Phase 2 studies of ofatumumab in RMS indicated that SC, once-monthly dosing of KESIMPTA could deliver robust efficacy with a tolerable safety profile. But would we see the same outcomes in larger, randomized, Phase 3 studies?

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The 20 mg ofatumumab dose that was identified through Phase 2 studies was ultimately evaluated in Phase 3 studies, ASCLEPIOS I and II. These studies determined the efficacy and safety of SC ofatumumab vs oral teriflunomide in 1882 patients with RMS

[Dr Coyle]

Using the 20 mg subcutaneous dose in this trial may have been striking to some. But it made sense to me because investigators did extensive clinical research in Phase 2 studies to identify it as the optimal ofatumumab dose. Beyond the dose assessed in the study, the dosing frequency and mode of delivery for ofatumumab were also quite different from other approved therapies at that time. For these reasons, there was a lot of intrigue in the RMS community surrounding the outcome of these trials

[Dr Norman Putzki]

In the randomized ASCLEPIOS I and II studies, Novartis chose to assess the efficacy and safety of ofatumumab vs teriflunomide, an oral therapy. Why teriflunomide? Our rationale was simple. To demonstrate to the RMS community that ofatumumab offered improved efficacy while maintaining safety and tolerability, we needed to compare our experimental product to an established treatment already known for these attributes. With this in mind, we ultimately chose teriflunomide as the most relevant comparator for our studies

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The ASCLEPIOS I and II studies were conducted from October 2016 to March 2018 in over 350 sites in 37 countries around the world

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As part of the ASCLEPIOS I and II trials, patients were randomized 1:1 to receive either SC ofatumumab 20 mg at Days 1, 7, and 14, followed by 20 mg every 4 weeks, or oral teriflunomide once daily

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In both ASCLEPIOS I and II, baseline characteristics were similar across treatment arms. Overall, patients included in the study had a mean age of about 38 years, and more than half of the patients were women

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Approximately 40% of patients treated with ofatumumab in ASCLEPIOS I and II were treatment naïve. More than 80% of the patients were either treatment naïve or previously treated with commonly used first-line therapies such as interferon or dimethyl fumarate

[Dr Berkovich]

The percentage of patients from the ASCLEPIOS trials who were either treatment naïve or treated with only one prior DMT is worth noting, because it aligns so well with the types of patients with RMS that clinicians like myself see in practice daily

[Dr Shin]

The ASCLEPIOS studies were important, in part because they presented the RMS community with the opportunity to see firsthand the efficacy and safety of a B-cell therapy in many patients still in the early stages of their disease

[Voice Over Narrator]

The efficacy of ofatumumab was shown to be superior to teriflunomide in these randomized double-blind trials. In particular, KESIMPTA significantly reduced relapses by 51% in ASCLEPIOS I and by 58% in ASCLEPIOS II, compared to teriflunomide

[Dr Berkovich]

With teriflunomide already viewed as an efficacious disease-modifying therapy in RMS, seeing KESIMPTA demonstrate greater efficacy beyond teriflunomide was impressive

[Dee Stoneman]

It was amazing to see how significantly ofatumumab reduced annualized relapse rates vs teriflunomide. Achieving a target of just 1 relapse every 10 years is remarkable

[Dr Hauser]

It was also remarkable to see an up to 98% reduction in gadolinium-positive T1 lesions in patients on KESIMPTA compared to their baseline scans, representing near-complete suppression of focal inflammation in people with RMS.16 Then, and still today, these results for KESIMPTA represent an impressive outcome in modern medicine.

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Beyond efficacy, the pivotal Phase 3 studies for KESIMPTA demonstrated a safety profile comparable to teriflunomide. The proportion of patients with adverse events was similar in the KESIMPTA and teriflunomide groups, at 83.6 percent versus 84.2 percent, respectively

[Dr Berkovich]

KESIMPTA offers a demonstrated safety profile comparable to teriflunomide, an oral therapy.9 The most common adverse reactions occurring in greater than 10% of patients treated with KESIMPTA and more frequently than in patients treated with teriflunomide were upper respiratory tract infections, headache, injection-related reactions, and local injection-site reactions. The overall rate of infections and serious infections in patients treated with KESIMPTA was similar to that with teriflunomide

[Dr Shin]

The safety and tolerability profile established in these KESIMPTA pivotal trials were reassuring to both clinicians and patients, offering high efficacy paired with a demonstrated safety profile for treating RMS

[Dee Stonemason]

It's important to place the pivotal trials data for ofatumumab in context of our goals for this product. Demonstrable efficacy? Check. Demonstrated safety and tolerability profiles? Check.16 ASCLEPIOS I and II represented a culmination of the research efforts of Novartis, and the positive outcomes were so satisfying to see

[Voice Over Narrator]

Expanding upon the powerful efficacy and established safety profile seen in ASCLEPIOS I and II, we now have 6 years of efficacy and safety data for ofatumumab from the ALITHIOS open-label extension trial. It continues to show results, with an ARR of 0.06 in patients who switched from teriflunomide to ofatumumab.11 This equates to a 74% risk reduction in ARR in patients who switched from teriflunomide to ofatumumab

[Dr Hauser]

We also saw that starting KESIMPTA earlier reduces the risk of disability progression, as highlighted by the 6-year CDP data for KESIMPTA

[Dr Coyle]

Open-label extension data are so important, because you want to have the documentation that your disease-modifying therapy continues to work over time. In particular, the long-term clinical disease progression data were impressive. These results really seem to reflect the importance of starting on KESIMPTA from the beginning

[Dr Hauser]

In the ALITHIOS trials, no unexpected safety signals were identified over 6 years, and the most common adverse events were comparable with those previously reported. With any high efficacy therapy, clinicians and patients alike sometimes have concerns about side effects. That's why the open-label extension data from ALITHIOS are so important.

[Dr Norman Putzki]

NEDA (no evidence of disease activity), a composite measure composed of 3 clinical end points, was emerging as a new goal in RMS treatment23 right during the clinical development of ofatumumab. Patients who achieve NEDA-3 experience no 6-month confirmed disability worsening, no confirmed MS relapse, no Gd+ T1 lesions, no new or enlarging T2 lesions, and no discontinuation from the study drug due to either lack of efficacy or death.21 Therefore, we at Novartis thought it was important to include NEDA as a post-hoc analysis in ASCLEPIOS I and II

[Dr Shin]

In reviewing the 6-year data from ALITHIOS, I was most impressed with the fact that more than 90% of patients achieved NEDA-3 by year 6, whether they start treatment with KESIMPTA or switch from teriflunomide to KESIMPTA

[Dr Coyle]

Within the relapsing MS community, these NEDA-3 outcomes, albeit a post hoc analysis, were impressive and gave us a clearer picture of what could be achieved with a high efficacy therapy such as ofatumumab

[Voice Over Narrator]

These studies demonstrated the powerful efficacy and established safety profile of ofatumumab in patients with RMS

[Dr Norman Putzki]

ASCLEPIOS I and II validated the 2 key learnings from our Phase 2 and modeling studies: a 20 mg subcutaneous dose of ofatumumab administered once monthly could prove efficacious for patients with RMS, and this precise 20 mg SC dose could provide tolerability as well. The ALITHIOS extension trial confirmed our pivotal findings, demonstrating that KESIMPTA maintains its positive benefit-risk profile and offers the potential for long-term disease control in RMS patients

[Dee Stoneman]

The commitment of Novartis to RMS was apparent throughout these clinical programs, which allowed us the ability to collaborate with physicians and patients alike for a number of years and bear witness to the clinical activity of KESIMPTA in enrolled patients. Imagine our delight at the results of ASCLEPIOS I and II, and the still-developing results from ALITHIOS. Seeing our clinical development goals for ofatumumab come to life through these clinical programs and the impact it's had on RMS patients during the trials has been a true pleasure to witness. We recognize that there is still much work to be done and intend to continue our efforts in this area for the long term. Please continue watching this video to hear the full Important Safety Information for KESIMPTA

[Voice Over Narrator]

Thanks for your attention, and please continue watching to hear the full Important Safety Information.

Important Safety Information

Contraindications: KESIMPTA is contraindicated in patients with active hepatitis B virus infection, or a history of hypersensitivity to ofatumumab, or life-threatening injection-related reaction to KESIMPTA. Hypersensitivity reactions have included anaphylaxis and angioedema

Infections: Serious, including life-threatening or fatal, infections have been observed during and following completion of treatment with anti-CD20 B-cell depleting therapies. 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 and Hypersensitivity 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 the last dose

Please see additional Important Safety Information and full Prescribing Information, including Medication Guide, by watching this entire video and by referring to the adjacent panel of this video