Myth or Not? Is it ever too early to start adult patients with RMS on KESIMPTA?

[Barry Hendi]

Welcome to "Myth or Not?," where we discuss some of the common misconceptions regarding KESIMPTA

I'm your host, Dr Barry Hendin and joining me today is Dr Gabriel Pardo

[Gabriel Pardo]

Hi, Dr Hendin

Happy to be here with you

[Barry Hendin]

I would really like to discuss the recently released 7-year data, but I think a good place to start is if we step back and consider whether it might be too early to start adult patients with relapsing MS on KESIMPTA

What do you think if you'd heard one of your peers say that?

[Gabriel Pardo]

Well, "too early" is really the heart of that statement

I would want to consider the patient's need for treatment along with the safety and efficacy of treatments when deciding what to start and when to start

But our perception of high-efficacy therapies has evolved, especially as more data have become available and with that, so too have my treatment decisions

[Barry Hendin]

So, how does the data factor into these conversations?

But before we answer, let's discuss some of the important safety information

[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

[Gabriel Pardo]

Going back to your question, Barry

How does the data factor into these conversations?

Let's start with the pivotal trials

ASCLEPIOS I and II were 2 identical, randomized, active-controlled, double-blind Phase 3 studies in patients with relapsing MS, approximately 40% of whom were naïve to DMT treatment for MS

Patients were randomized to KESIMPTA 20 mg every 4 weeks or oral teriflunomide for up to 30 months

The primary end point of ASCLEPIOS I and II was the annualized relapse rate over the treatment period, which demonstrated that KESIMPTA significantly reduced relapses by 51% in ASCLEPIOS I and 58% in ASCLEPIOS II compared to the active comparator, teriflunomide

While ASCLEPIOS I and II are a necessary first step in approval, I have to acknowledge that those data are significant

KESIMPTA reduced the number of gadolinium-enhancing T1 lesions, with relative reductions of up to 98%, and the number of new or enlarging T2 lesions, with relative reductions of up to 85%, in both studies

That tells us a lot about what's happening with the inflammatory activity of the disease

Then, the pooled analysis showed that KESIMPTA significantly reduced the risk of 3 and 6 month confirmed disability progression by 34% and 32%, respectively, compared to teriflunomide

[Barry Hendin]

Now that we've covered the pivotal data, I want to discuss the recently diagnosed treatment-naïve subgroup who will be the focus of our conversation today

A post hoc analysis of the data from our pivotal studies, ASCLEPIOS I and II, assessed the benefit-risk profile of KESIMPTA vs teriflunomide in 615 treatment-naïve participants who were within 0.1 to 2.9 years from diagnosis

Annualized relapse rate reduction in patients on KESIMPTA was 0.09, a 50% relative reduction compared to patients treated with teriflunomide

[Barry Hendin]

Additionally, MRI lesion activity was also reduced in the recently diagnosed treatment-naïve patients treated with KESIMPTA vs teriflunomide

The mean number of gadolinium-enhancing T1 lesions per scan was 0.02 in patients treated with KESIMPTA, a 95% relative reduction compared to patients treated with teriflunomide

KESIMPTA also resulted in an 82% relative reduction in new or enlarging T2 lesions vs teriflunomide

But please keep in mind that this post hoc study is not sufficiently powered and, therefore, no conclusions can be drawn on these studies that assessed treatment-naïve patients

[Gabriel Pardo]

As physicians, we look to evaluate the longevity of clinical outcomes and assess if there are any new safety signals discovered during the extension studies

For that, we have the 7-year data for KESIMPTA coming out of ECTRIMS

Barry, I spent a lot of my time as an investigator on the safety data for KESIMPTA

I understand how helpful long-term safety outcomes are when evaluating treatment options for patients

Let's first describe the ALITHIOS extension study so we can understand how we are getting to the long-term results

ALITHIOS is an open-label, umbrella extension, Phase 3b, single-arm study evaluating long-term, up to 7 years now, safety, tolerability, and effectiveness of KESIMPTA in patients with relapsing multiple sclerosis

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

Patients who started on KESIMPTA continued KESIMPTA, and patients who started teriflunomide were switched to treatment with KESIMPTA

[Barry Hendin]

I think the ALITHIOS study is valuable to consider because I want to understand how patients have been managed over the long term for a long-term disease

With that in mind, it's essential to also remember the safety data from the core ASCLEPIOS trials

The rate of serious infections in the KESIMPTA cohort was 1.9% vs 0.7% for teriflunomide

And there were no deaths in either arm

In ALITHIOS, safety was actually the primary end point, with efficacy as a secondary objective

We saw that in recently diagnosed treatment-naïve patients, adverse events leading to discontinuation was 9.5%

Ig levels are always something I key in on when looking at the safety of B-cell therapies

Gabriel, would you walk us through those results for KESIMPTA?

[Gabriel Pardo]

Sure, mean IgG levels remained stable up to 7 years on treatment; mean IgM levels decreased but then stabilized and remained above the lower limit of normal

There were 2 and 79 events of IgG and IgM decrease, respectively

IgG and IgM levels were above lower limit of normal at all assessments for 97.6% and 62.4% of participants, respectively

The proportion of participants with Ig-related adverse events leading to ofatumumab interruption or discontinuation due to low IgG was 0 and 0.2% and for low IgM was 9.7% and 4.2%

In my practice, I continually monitor Ig levels to assess for any safety concerns

Here, we have results for 7 years

Overall, we can say that KESIMPTA has an established safety profile, demonstrated over 7 years

No new safety signals were identified in the ALITHIOS extension study

However, safety signals have been identified through post-marketing studies for anti-CD20s approved for the treatment of multiple sclerosis, including KESIMPTA

And one should always refer to the full Prescribing Information and Important Safety Information

As a reminder, ALITHIOS was an open-label study and not sufficiently powered, and as you mentioned before, no conclusions can be drawn

[Barry Hendin]

Thank you, Gabriel

The 7-year safety data really speak to the long-term analysis that my patients often ask about when they want to know the reported safety profile of any medication they will be taking for a long time

With this 7-year ALITHIOS data we can see that KESIMPTA continues to be observed for safety risks

[Gabriel Pardo]

Alright, I know this is the portion of our discussion we have been waiting for

To make an informed decision on when to start high-efficacy therapy for a newly diagnosed patient, I think it's helpful we understand long-term outcomes

[Barry Hendin]

And if I may interject for a second, I want to say that I don't think it's ever too early to start a patient with relapsing MS on treatment

And therefore, by that logic, I don't think it's ever too early to start the appropriate patient on KESIMPTA, a high-efficacy therapy

As I like to say, "Time is brain"

So having long-term data is certainly something that provides that extended data set for us as clinicians to refer to

[Gabriel Pardo]

I agree, Barry

So with that, let's talk about the 7-year efficacy results with KESIMPTA

Over a period of up to 7 years, first-line continuous vs later initiation of KESIMPTA was associated with a 72.5% reduction in the cumulative number of relapses

Patients who remained on KESIMPTA maintained a low annualized relapse rate over years 1 through 7

Annualized relapse rate was low at 7 years for the first-line continuous KESIMPTA, with a value of 0.04

[Barry Hendin]

And next, I think we should discuss what I think is one of the core biomarkers that we have for assessing relapsing MS disease activity, MRI lesion activity

There was a nearly complete suppression of gadolinium-enhancing T1 lesion activity in the core phase for KESIMPTA vs teriflunomide with a 96.5% reduction

Then, there was an 84.8% reduction with the continuous KESIMPTA group in the extension phase and a 98.5% reduction in the teriflunomide-to-KESIMPTA group after switching

There was reduction in new or enlarging T2 lesions in the core phase, 85.8% for KESIMPTA vs teriflunomide, which was also shown with the continuous KESIMPTA group, at 86.9%, in the extension phase

This reduction was also observed in the teriflunomide-to-KESIMPTA group after switching

Gabriel, what else does the 7-year data show us?

[Gabriel Pardo]

At 7 years, over 8 of 10 recently diagnosed treatment-naïve participants receiving first-line continuous KESIMPTA were free from 6-month confirmed disability progression

[Barry Hendin]

I want to pause on that for a second because I think there is a numerically larger gap around 7% between the continuous KESIMPTA and the switch group in the percentage of patients free from 6-month confirmed disability progression for the treatment-naïve population, compared to the less than 4% gap that we saw in the overall population

As a provider, I really like to focus on the CDP data along with the annualized relapse rate because disability conversations are so important when I have shared decision-making discussions with my patients

Because in an ideal world, we would just treat an MS relapse and be done with it

But the reality is, in a progressive disease like MS, patients can accumulate disability

And, for patients, one of the many goals we set when managing relapsing MS is to address that progression to the best of our ability

[Gabriel Pardo]

Now, I know my patients well, and they want even more information

So, what do we have that might show more than just a single measure?

For that, let's look at NEDA-3

Re-baselining for year 2, that is months 12 to 24 on treatment, was conducted at month 12 to adjust for impact of disease activity prior to treatment initiation and continuing through the first year of treatment

This re-baselining allows for an accurate measurement of disease activity in year 2

All patients from the pivotal trial, full-analysis set population and who received KESIMPTA in the ALITHIOS extension study were included in the intent-to-treat principle

The outcomes presented here are the proportion of study patients within a treatment group who met the NEDA-3 criteria vs those who did not

The proportion of patients meeting NEDA-3 criteria was analyzed cross-sectionally in year 1 time intervals across 7 years

At year 1, NEDA-3 was achieved by 47.9% of patients on continuous KESIMPTA and 24.9% of patients on teriflunomide switching to KESIMPTA

At year 2, NEDA-3 was achieved by 89.4% of patients on continuous KESIMPTA and 35.8% of patients on teriflunomide switching to KESIMPTA

At year 4, NEDA-3 was achieved by 92.7% of patients on continuous KESIMPTA and 86.5% of patients who switched to KESIMPTA from teriflunomide

Limitations of this study include a potential for attrition bias and the open-label nature of the extension study

Keep in mind, no conclusions can be drawn

[Gabriel Pardo]

NEDA-3 at year 7 was observed in more than 9 out of 10 treatment-naïve patients

What I really like about NEDA-3 is that it is a composite analysis of the things that we can measure

It's all there in one single measure

[Gabriel Pardo]

Well, Barry, we covered a lot of important data

Now, I'm an optimist, so the data have not been a surprise, it was really the expectation based on my experience in practice

[Barry Hendin]

Those are fair points

Well, we have covered a lot of information about the myth that it might be too early to start adult patients with relapsing MS on KESIMPTA

What do you think, Gabriel?

[Gabriel Pardo]

If patients have questions about starting KESIMPTA early, we have data that we can share with them

[Barry Hendin]

Just a final thought, beyond the data we also consider what the patients are saying to us

Of course, the data's key, but it's also helpful if we listen to what they're experiencing when making a joint decision to start a high-efficacy therapy like KESIMPTA

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 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