Myth or Not? Can high-efficacy therapy also have a demonstrated safety and tolerability profile?

[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

And joining me is Dr. Donald Negroski

So, Don, let’s have a look at our first statement

It is possible for a high efficacy relapsing MS therapy to have a demonstrated safety profile

What are your thoughts?

Actually, before we start, and in case anyone is not familiar with 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

[Donald Negroski]

So, is it possible for a high efficacy RMS therapy to have demonstrated safety profile?

Let’s take a look at an example of a high efficacy treatment: KESIMPTA.

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

Patients were randomized to KESIMPTA or oral teriflunomide for up to 30 months

In ASCLEPIOS I and II, we saw that KESIMPTA offered powerful efficacy, as evidenced by reduction in annualized relapse rate, MRI lesion activity, and confirmed disability progression vs teriflunomide

The primary end point, annualized relapse rate showed a reduction of up to 58%

For MRI lesion activity, KESIMPTA significantly reduced the number of gad-enhancing T1 lesions, with relative reductions up to 98%, and the number of new or enlarging T2 lesions saw relative reductions up to 85% in both studies

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

I think understanding these data points is critical so we can evaluate the full benefit-to-risk profile

[Barry Hendin]

I agree! So, what safety components of KESIMPTA do you look for first?

[Donald Negroski]

When I think about whether or not KESIMPTA has a demonstrated safety profile, I first turn to the pivotal trials before diving into the 7-year safety data

I also focus on data with the lens of what I think my patients care about most often. And most frequently, it’s what they might expect from adverse reactions

So, the most common adverse reactions, with incidence greater than 10% in patients taking KESIMPTA, were upper respiratory tract infections, injection-related reactions, headache, and local injection-site reactions

As you can see in the ASCLEPIOS chart pictured, the adverse events were comparable to teriflunomide

[Barry Hendin]

Picking that apart a little, we find that the overall rate of infections and serious infections in patients treated with KESIMPTA was similar to that of teriflunomide

So, the pooled data from both clinical trials show that treatment discontinuation rates due to adverse events were similar between KESIMPTA, at 5.7%, and teriflunomide, at 5.2%

The most common cause of discontinuation in patients treated with KESIMPTA was low IgM at 3.3%, defined in the trial protocols as an IgM at 10% below the lower limit of normal

[Donald Negroski]

In summary, the data from the pivotal trials showed that KESIMPTA has a demonstrated safety profile comparable to teriflunomide, an oral therapy

And remembering that’s all while demonstrating powerful efficacy

[Barry Hendin]

OK. Don, we’ve established what the safety of KESIMPTA looked like in the pivotal trials, but I want to shift our focus to our next statement, and that’s something that’s far more nuanced, and it’s about tolerability

I like to think about treatment from the patient’s perspective, and I know that patients want to understand long-term safety data

I think they also want to understand tolerability

They want to make sure that the treatment fits into their lifestyle

So, I’d like to hear your thoughts about the second statement

Tolerability may not be a factor to consider in your joint decision-making process

What are your thoughts?

[Donald Negroski]

So Barry, I like that you separated tolerability into its own topic. I do think it makes more sense, when I can speak to them as two separate entities, as it sounds like tolerability might be overlooked in the process

So, let’s look at the tolerability data for KESIMPTA

First, and I think that this is so important for my patients to understand, the incidence of systemic injection-related reaction was the highest with the first injection at 14.4%, and decreased with subsequent administrations: 4.4% with the second and <3% with the third administration

Remember, though, that 99.8% of injection-related reactions were mild to moderate

The most frequent reported symptoms, 2% or greater, included fever, headache, myalgia, chills, and fatigue

[Barry Hendin]

Also, another consideration is that KESIMPTA is the only B-cell therapy that does not require premedication since there was only limited benefit of premedication with corticosteroids, antihistamines, or acetaminophen observed in the relapsing MS clinical studies

Don, we think down the road for our patients, what they may expect years later. That’s why it’s also important to expand discussions into the long-term results as well

[Donald Negroski]

So, how about 7 years later?

Because that’s what we currently have with KESIMPTA from the ALITHIOS extension study

For some quick background, ALITHIOS is an open-label, umbrella extension, Phase 3b, single-arm study evaluating long-term (up to 7 years) safety, tolerability, and effectiveness of KESIMPTA in patients with RMS

The primary objective in ALITHIOS was safety and tolerability, while the secondary objective was efficacy

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

In the treatment arms, patients who started on KESIMPTA continued KESIMPTA, and patients who started on teriflunomide were switched to treatment with KESIMPTA

So, what did ALITHIOS show? As a reminder, we already covered the core safety data which is shown on the screen here

Serious infections occurred in 6.2% of the overall population, while there were 12 deaths

The proportion of patients with adverse events leading to discontinuation was 7.7%

8 patients from overall population had IgG decrease

284 patients from overall population had IgM decrease after 7 years

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

Mean IgM levels decrease but remained above lower limit of normal, at 0.4 g/L, and were greater than lower limit of normal at all assessments in 64.5% of patients

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

Keep in mind, ALITHIOS was not powered, and no clinical conclusions should be drawn

[Barry Hendin]

What stood out to me from the extension study was that there were no new safety signals in the ALITHIOS trial. But I do want to point out that there have been safety signals in the post-marketing cases since the approval of KESIMPTA

And that’s why we, as physicians, really need to see long-term observation in this long-term disease

Alright! So, Don, in deciding what is a myth or not, we looked at 2 statements

Statement number 1: “It’s possible for a high-efficacy relapsing MS therapy to have a demonstrated safety profile”

I think we got to the bottom of that one. And I really like this card, so if it’s OK with you, I’m going to keep it

But for the second one, “Tolerability may not be a factor to consider in your joint decision-making process”

I have strong opinions about this one, but I don’t know if you’d like to do the honors

[Donald Negroski]

Well, Barry, I think we can consider this one debunked

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