Journey to KESIMPTA® (ofatumumab): Early Advancements of ofatumumab in Relapsing Multiple Sclerosis

[Voice Over Narrator]

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

[Voice Over Narrator]

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

[Voice Over Narrator]

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

[Voice Over Narrator]

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?

[Voice Over Narrator]

And that's where our journey begins

[Voice Over Narrator]

Patients are often diagnosed with RMS during the prime of their lives, between the ages of 20 and 40 years. Some are pursuing higher education. Others are embarking on their careers. Still others are starting or growing their families. Life has really just begun for them. Imagine how frightening it must be for these patients to then suddenly experience the distressing first signs of RMS and face the harsh reality of living with a potentially debilitating condition

[Dr Shin]

An RMS diagnosis can be an anxious time for patients. The sudden onset of symptoms, which may be indicative of relapses and/or MRI activity—such as vision changes, muscle weakness, or stiffness—is challenging for patients

[Stephanie Ribbie]

Let's take a moment to put ourselves in the shoes of Caylee. She was a dedicated athlete who played volleyball competitively throughout her college career, and in 2021, she received the shocking news that she had been diagnosed with RMS. Caylee first sought medical attention after experiencing blurred vision in her right eye during her senior year. And upon further evaluation, she received a definitive diagnosis of RMS. Though Caylee attempted to push through her diagnosis and continued playing volleyball, eventually, a relapse indicated that her RMS was advancing, forcing her volleyball career to come to an end. Caylee was young, healthy, and excited to graduate when she got an unexpected diagnosis that she just wasn't prepared for.

[Dr Berkovich]

It's often my responsibility as a clinician to navigate difficult conversations with patients who have recently been diagnosed with relapsing MS. I can say, it never gets easier. However, in today's world, patients feel reassured when presented with a variety of therapies that can help manage their condition. But for many patients with RMS, the need for treatment options that go beyond slowing progression remains critical. We need options that allow people living with RMS to seamlessly incorporate treatment into their active lives.

[Dr Norman Putzki]

Overall, accelerating RMS research has always been a passion at Novartis, because patients are our priority. Patients drive not only our continued development in pursuit of effective therapies for the treatment of RMS but also our significant investments in clinical trials. We aimed to introduce a new treatment in the RMS space that would offer a long-term solution for patients. An option that, combined with powerful efficacy and a proven safety profile, allowed patients the flexibility and convenience of self-administration at home.

[Stephanie Ribbie]

Because of patients like Caylee, Novartis set out to develop a new treatment option for patients with RMS

[Voice Over Narrator]

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

[Dr Norman Putzki]

In the rapidly evolving field of RMS treatment, Novartis aimed to develop a drug that possessed not only proven efficacy in patient outcomes commonly assessed in clinical trials, like annualized relapse rate and MRI activity, but also a favorable safety profile.Prior clinical research and development at Novartis contributed to the advancements in the treatment of RMS, but the idea of adding to the treatment armamentarium a therapy that could be self-administered by patients at home was of keen interest to us.Ultimately, we hoped that ofatumumab would translate into an at-home, self-administered B-cell therapy

[Dr Hauser]

KESIMPTA, or ofatumumab, is the first and only fully human anti-CD20 antibody that is self-administered using 20 mg once-monthly subcutaneous injections. The precise mechanism by which ofatumumab exerts its therapeutic effects in multiple sclerosis is unknown.6 Similar to other B-cell therapies, ofatumumab has a high binding affinity to CD20. Ofatumumab binds selectively to the extracellular loop of CD20, eliciting complement-mediated B-cell lysis

[Voice Over Narrator]

In discovering how ofatumumab is thought to work, what were the early developmental goals of Novartis for ofatumumab?Ofatumumab was previously approved in other disease states, administered at a high IV dose. Based on learnings from those disease states, Novartis sought to explore the potential use of ofatumumab in RMS, first as an IV infusion, then as a subcutaneous injection at lower doses

[Dee Stoneman]

Through meticulous clinical research in Phase 2 and modeling studies, we aspired to identify the ideal dose, frequency, and route of administration for ofatumumab in RMS. This provided hope of a new RMS treatment option that could offer patients the flexibility to safely self-administer their treatment from home or anywhere else

[Dr Hauser]

In the first Phase 2 study to explore the safety and efficacy of IV ofatumumab, patients with RMS were randomized to receive ofatumumab or placebo, with ofatumumab IV doses of 100 mg, 300 mg, or 700 mg administered 2 weeks apart over two 24-week treatment periods

[Dr Shin]

In the study, ofatumumab showed a notable reduction in inflammatory activity when compared with placebo, providing early yet valuable insights on the potential effectiveness of ofatumumab in RMS

[Dr Coyle]

The safety outcomes for this trial were favorable overall. No unexpected safety signals were identified for ofatumumab in the study. About 96% of patients experienced any AE while 92% of patients experienced drug-related AEs. One patient experienced a severe AE, and 2 patients experienced an AE greater than or equal to Grade 3. Infusion-related reactions (IRRs) were common with ofatumumab, occurring in 89% of patients on the first day of infusion but not observed on the second day

[Dr Berkovich]

Thinking back, results from this study generated significant excitement about ofatumumab in the RMS community. It was intriguing to see early demonstration of the drug's potential efficacy and safety profile in these patients, especially considering the cross-over design of this trial

[Dr Norman Putzki]

While we at Novartis were elated to see early evidence of the efficacy and safety profile of IV ofatumumab,9 the real challenge was to find the lowest effective dose we could use to maintain this initial activity. "How could we give patients the flexibility of self-administration from home or anywhere else?"

[Voice Over Narrator]

To examine the possibility that efficacy could also be attained subcutaneously, subcutaneous ofatumumab was investigated in RMS in the Phase 2b, placebo-controlled MIRROR study at doses ranging from 3 mg to 60 mg every 12 weeks, or 60 mg every 4 weeks

[Dr Berkovich]

The MIRROR study's evaluation of a subcutaneous route of ofatumumab administration presented significant potential for patients, setting up the development of an alternative option that patients could use to administer their RMS treatment independently

[Dr Shin]

Across doses, the subcutaneous ofatumumab study showed that we could achieve an effective response in patients with RMS with this therapy

[Dr Shin]

The injection-related reactions, regardless of dose, decreased over time upon further exposure, with most being mild to moderate and resolving after the first dose. This reinforced that a lower dose of ofatumumab, administered subcutaneously, could be utilized without compromising efficacy

[Dr Norman Putzki]

The MIRROR study confirmed that ofatumumab had the potential to deliver efficacy at a much lower dose. Based on the results of the MIRROR trial, modeling studies were performed to define the most optimal dose of ofatumumab. These studies then showed that efficacy could be achieved and maintained using a subcutaneous, once-monthly 20 mg dose of ofatumumab

[Dr Norman Putzki]

We were pleased to see the modeling work aligned with our predictions. It was encouraging to confirm the 20 mg dose in these studies. The results exceeded our expectations, which was something that doesn't happen very often in drug development

[Voice Over Narrator]

In order to further validate and confirm that the chosen 20 mg therapeutic dose of ofatumumab for patients with RMS provided optimal characteristics vs other doses, a pharmacokinetic–pharmacodynamic (PKPD) model of B-cell counts vs ofatumumab concentration was developed using pooled studies in RMS. The results of the simulations determined that the monthly 20 mg subcutaneous dose was associated with a rapid and near complete B-cell depletion

[Dr Coyle]

The data from the PKPD modeling study suggests that body weight does not significantly affect the efficacy of ofatumumab, further validating the 20 mg dose as optimal.9 This finding is crucial as it demonstrates that, regardless of a patient's weight, ofatumumab achieves consistent levels of B-cell depletion

[Voice Over Narrator]

But research into ofatumumab didn't stop there. Because subcutaneous ofatumumab held promise as a flexible treatment for at-home administration, it was also important to understand how to create an easy administration experience for patients

[Dr Hauser]

Another Phase 2 study, APLIOS, was conducted to assess the efficacy of ofatumumab when administered using a pre-filled syringe, or PFS, vs an autoinjector pen. The APLIOS trial demonstrated the bioequivalence of 20 mg ofatumumab administered with a PFS vs the autoinjector pen, intended for commercial use

[Dr Hauser]

Results from this study were significant, because they further crystallized the likelihood of a simple at-home delivery system that many patients could use, irrespective of where they live, their access to transportation, or their lifestyle. The ability to administer treatment using an autoinjector pen could become a key deciding factor for patients when choosing an RMS treatment

[Stephanie Ribbie]

This additional element of convenience created a new and unique choice for patients, enabling them to potentially take their treatment from the comfort of their own homes

[Voice Over Narrator]

The Phase 2 ofatumumab trials culminated in the further development of a once-monthly administration of 20 mg subcutaneous ofatumumab

[Dee Stoneman]

After integrating insights from the Phase 2 studies, Novartis developed the once-monthly 20 mg dose of ofatumumab, delivered subcutaneously in just 0.4 mL per administration, to be tested in the Phase 3 trials. This is a very small volume, yet it delivered results while helping to manage patients' RMS with once-monthly at-home dosing

[Dr Norman Putzki]

The clinical research conducted at Novartis demonstrated that a low-dose subcutaneous formulation administered every 4 weeks put us on the path to realizing our goal of a clinically proven and flexible treatment option, with a favorable safety profile, for patients with RMS. Thanks to these early studies, we demonstrated that a lower dose of ofatumumab could provide efficacy, tolerability, and a flexibility of self-administration. We were also excited to use these data to explore a more convenient at-home administration method, comparing the ease of administration between an autoinjector pen vs a pre-filled syringe in the APLIOS study. This early clinical research laid the groundwork for Novartis to take a significant step forward in their commitment to enhancing the treatment experience for patients with RMS, bringing them a renewed hope

[Voiceover]

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