Myth or Not? NEDA-3 may only be useful in the clinical trial setting

[Barry Hendin]

Welcome to "Myth or Not?". We'll be discussing some of the common misconceptions regarding KESIMPTA

I'm your host, Dr. Barry Hendin

Joining me today is Dr. Sharon Stoll

[Sharon Stoll]

Hi Dr. Hendin

It's great to be here today

[Barry Hendin]

Today, we'll be discussing a common myth

NEDA-3 may only be useful in a clinical trial setting

I’ve been involved as an investigator in many clinical trials, so I’ve come to understand NEDA-3 pretty well

But I’ve heard this sentiment from my colleagues who are also in the trenches treating patients day to day with MS and wanted to get your perspective

But before Sharon answers that, let’s make sure that everyone is aware of some key information about KESIMPTA

[Narrator]

KESIMPTA is indicated for the treatment of relapsing forms of multiple sclerosis (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, Liver Injury, and Fetal Risk. Most common adverse events (greater than 10%) are upper respiratory tract infection, injection-related reactions, headache, and local injection-site reactions

[Barry Hendin]

So, Sharon, what do you think about NEDA-3 as a clinical endpoint in the context of KESIMPTA?

[Sharon Stoll]

I’d love to jump ahead to the NEDA-3 data. But remember, it’s a composite end point,2 so we really should look at the individual components from the pivotal trial first

ASCLEPIOS I and II were 2 identical, randomized, active-controlled, double-blind Phase 3 studies in patients with RMS

Patients were randomized to KESIMPTA® (20 mg every 4 weeks) or oral teriflunomide (14 mg daily) for up to 30 months

Treatment duration was variable based on end of study criteria. Maximum duration 120 weeks, median duration 85 weeks

The primary end point of ASCLEPIOS I and II was reduction in annualized relapse rate, and KESIMPTA reduced relapses by a significant amount—51% and 58%, respectively, compared to teriflunomide

And when we consider MRI activity, KESIMPTA significantly reduced gadolinium-enhancing T1 lesions by up to 98% and new or enlarging T2 lesions by up to 85%

Plus, a pooled analysis showed it reduced the risk of confirmed disability progression by 34% in 3 months and 32% in 6 months

In my opinion, choosing a relapsing MS therapy, including KESIMPTA, means looking at all of these end points and having a real conversation with my patients to find something that fits their needs

[Barry Hendin]

So now we’ve covered all of the components of NEDA-3 from the pivotal trial for KESIMPTA. Let’s move on to the extension study, ALITHIOS

ALITHIOS was an open-label, umbrella extension, Phase 3b, single-arm study evaluating the long-term (up to 7 years) data of KESIMPTA in patients with relapsing MS

The primary objective was safety and tolerability, with a secondary objective of efficacy

The study enrolled patients from the ASCLEPIOS I and II, APLIOS, and APOLITOS trials

[Sharon Stoll]

One thing I like about the ALITHIOS study design here is that we have both patients that switched to KESIMPTA from teriflunomide and patients who started and remained on KESIMPTA.9 Having both data sets gives me more context when considering treatments for different populations

[Barry Hendin]

In ALITHIOS, the primary objective, of course, was safety, so I don’t want to overlook the safety data for KESIMPTA. KESIMPTA has an established safety profile, with over 7 years of data

[Sharon Stoll]

You’re right, Barry, it's one thing to see results in a year or 2, but knowing that a treatment has a safety profile over several years makes a big difference to some

And it's a good reminder that, even though we're talking about NEDA and efficacy, safety is always paramount

Before we dive into that safety data from the ALITHIOS trial, it’s important to remember the safety from the core ASCLEPIOS trials

The rate of serious infections in the KESIMPTA group was 2.5% vs 1.8% for teriflunomide

While there was no deaths in the KESIMPTA arm, there was 1 death in the teriflunomide arm, which was attributed to aortic dissection

And now looking at the ALITHIOS trial, the rate of serious infections was 6.2% for the overall population and the recently diagnosed treatment-naïve, or RDTN, subgroup

And in the overall safety population, the proportion of patients with adverse events leading to discontinuation was 7.7%

What else stood out to you, Barry?

[Barry Hendin]

Well, there were a total of 12 deaths in the overall population and 7 in the RDTN subgroup

In the overall and treatment-naïve population there were 8 and 2 events of IgG decrease, respectively

The mean IgG levels remained above the lower limit of normal, which was 5.65 g/L, in 96.8% of patients at all assessments

For the IgM decrease there were 284 events and 79 events, respectively

The mean IgM levels decreased but remained above the lower limit of normal, which is 0.4 g/L, and were above the lower limit of normal at all assessments in 64.5% of participants

The proportion of participants with Ig-related adverse events leading to interruption or discontinuation of KESIMPTA due to low IgG was 0.2% and 0.2%, respectively, and for low IgM it was 10.4% and 3.6%, respectively

Of course, we have to remember that ALITHIOS wasn't powered to draw definitive conclusions

Alright, Sharon, now that we’ve set the stage around NEDA-3 and KESIMPTA, let’s get back to the heart of the question

[Sharon Stoll]

Definitely

When thinking about our myth that “it’s only useful in the trial setting”, this has not been the case in my practice

I appreciate that we have multiple measures now to assess patients; whereas in the past, I was mainly concerned with just relapses or lesion data, we've learned that progression can be looked at as well

Relapsing MS is more than just what happens on imaging, we also should account for what’s going on beneath the surface

When I’m with a patient, I find it very useful to explain and show them the different ways we measure their progress

I’ll show my MS patient their MRIs over time or walk them through other exams we do in clinic

I find it helpful for the patient to understand the objective measures that I’m looking at when assessing for progression and I find it helpful to show them how they are doing now compared to how they have done in the past

Also, it’s helpful to have data for KESIMPTA in first line and when switching to KESIMPTA

The analysis included all randomized patients who received KESIMPTA in the ALITHIOS extension study, following the intent-to-treat principle

However, patients who discontinued early for reasons other than lack of efficacy or death—and had achieved NEDA-3 prior to discontinuation—were excluded to ensure accurate representation of treatment outcomes

It is important to keep in mind that this analysis considers patients without evidence of disease activity, and patients classified as NEDA-3 might have had incomplete data

In the ASCLEPIOS core phase from year 1-2, patients on KESIMPTA showed a higher rate of achieving NEDA-3 compared to those on teriflunomide

Re-baselining for year 2, meaning months 12 to 24, was done at month 12 to adjust for impact of disease activity prior to treatment initiation through T2 lesions, and continuing through the first year of treatment

This re-baselining enables a more accurate measure of disease activity in year

80% of patients taking KESIMPTA achieved NEDA-3 during year 2, vs 35% of patients switching from teriflunomide to KESIMPTA

Switching from teriflunomide to KESIMPTA during years 2-3 resulted in an increase in NEDA-3

[Barry Hendin]

And I see that treatment with KESIMPTA showed a high proportion of patients achieving NEDA-3 over time in both the continuous KESIMPTA group and also in the switch group

And 95% of patients in the overall population taking KESIMPTA achieved NEDA-3 in year 7

But what about those treatment-naïve patients? I’m curious about how NEDA-3 performed in those patients

[Sharon Stoll]

In ASCLEPIOS from years 1-2 recently diagnosed treatment-naïve patients on KESIMPTA showed a higher rate of achieving NEDA-3 compared to those on teriflunomide

89% of patients taking KESIMPTA achieved that NEDA-3 during year 2, vs 36% of patients switching from teriflunomide to KESIMPTA

Similar to the NEDA-3 data in the overall study population, a switch from teriflunomide to KESIMPTA during the years 2-3 in recently diagnosed, treatment-naïve patients resulted in an increase in NEDA-3

KESIMPTA treatment achieved NEDA-3 over time in both the continuous KESIMPTA group and the switch group

Approximately 96% in the KESIMPTA group and 93% in the switch group

However, despite our observations of the data we of course have to keep in mind that the analysis was not sufficiently powered and, therefore, no conclusions should be drawn

[Sharon Stoll]

9 out of every 10 recently diagnosed, treatment-naïve patients who started on KESIMPTA achieved NEDA-3 in year 2 which comes to about 89.4%

And in year 7, 95%

[Barry Hendin]

So, let’s circle back to the original statement that: “NEDA-3 may only be useful in a clinical trial setting”

Sharon, what do you think about that statement?

[Sharon Stoll]

From my perspective, we use a lot of measures in practice

And in a way, we do use NEDA-3 outside of the trial setting

Most of the time, it’s not just a single value like in the trials but more of a composite of those end points and patient presentation

This actually brings to mind a patient who was recently referred to me

By their account, everything seemed fine

But when I reviewed their old MRIs and compared it to their new MRI, I noticed a new lesion

The patient was aware that there were new lesions on prior images, but the focus had always been on managing their relapses

With this patient I’ve taken a comprehensive approach—assessing relapses, MRI findings, and disease progression

That’s why I believe it’s essential to evaluate all of the components of NEDA to truly understand how a patient is responding to treatment

I think it’s clear to say… we can consider this myth debunked

[Barry Hendin]

I hope we don’t get in any trouble for doing that

And, to any listeners who might want to see what else your peers are saying about KESIMPTA, check out the links to the digital education lab

[Narrator]

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

Liver Injury

Clinically significant liver injury has occurred. Obtain serum aminotransferases, alkaline phosphatase, and bilirubin levels before initiating KESIMPTA, and during treatment as clinically indicated. Discontinue KESIMPTA in patients with evidence of liver injury in the absence of an alternative etiology

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