11/10/23, 6:54 PM
`
`Short-Term Dosing Regimen Gives Cladribine an Advantage in MS
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`Short-Term Dosing Regimen Gives Cladribine
`an Advantage in MS
`July 1, 2020
`Matt Hoffman
`
`Article
`
`Kottil Rammohan, MD, director of the MS Division and Multiple Sclerosis Center
`of Excellence at the University of Miami, discussed the EMD Serono agent’s history
`and advantages for the patient community.
`
`Kottil Rammohan,
`MD, professor of
`clinical neurology,
`and director, MS
`Division and
`Multiple Sclerosis
`Center of
`Excellence,
`University of
`Miami
`
`Kottil Rammohan, MD
`
`In mid-2019, cladribine (Mavenclad; EMD Serono) was
`approved as an oral therapy for the treatment of relapsing
`multiple sclerosis (MS), as well as active secondary progressive
`MS. The synthetic agent targets lymphocytes and selectively
`suppresses the immune system, with the goal of depleting
`those lymphocytes in order to “reset” the system.
`
`It was approved based on the data from a trial including more
`than 1300 patients with relapsing forms of MS, ultimately
`showing a significant decrease in the number of relapses
`experienced by patients who had ≥1 relapse in the previous
`year, compared to placebo. Its unique dosing regimen has
`offered patients a more convenient method of medication
`administration, and up to 10 years of data from its clinical
`development program, consisting of the CLARITY
`(NCT00213135), CLARITY-EXT (NCT00641537), ORACLE-MS
`(NCT00725985), and PREMIERE (NCT01013350) studies.
`
`To find out more about how cladribine got to this point and
`what it offers the MS patient community, NeurologyLive spoke
`
`https://www.neurologylive.com/view/shortcommitment-dosing-regimen-gives-cladribine-an-advantage-in-ms
`
`Merck 2042
`Hopewell v Merck
`IPR2023-00480
`
`1/5
`
`

`

`11/10/23, 6:54 PM
`
`Short-Term Dosing Regimen Gives Cladribine an Advantage in MS
`with Kottil Rammohan, MD, professor of clinical neurology, and
`director, MS Division and Multiple Sclerosis Center of
`Excellence, University of Miami.
`
`NeurologyLive: Could you provide a brief overview of
`how cladribine got to this point through its
`development?
`Kottil Rammohan, MD: It was after the discovery of the cause
`for the bubble babies who are born immunodeficient. And
`when those children were studied, what was found was they
`were perfectly normal in every way, except they had no
`lymphocytes. The lymphocytes were severely, severely
`depleted. Then the enzyme that was the basis of that
`abnormality was discovered to be adenosine deaminase—
`ADA—and adenosine deaminase deficiency led to the
`severe lymphopenia that was seen in these patients.
`
`That gave the idea for Ernie Bueller and his colleagues at
`Scripps to potentially utilize this as a mechanism to deplete
`lymphocytes—they were looking mainly for hematological and
`oncological reasons to do it—and what they did was to
`put a chlorine molecule on deoxyadenosine and that literally
`recreated the ADA deficiency that was seen in these children.
`The molecule had the ability to be toxic to lymphocytes, and
`the beauty of it was that you could adjust the dose and control
`the lymphopenia. That was the beginning of cladribine, and
`cladribine became the drug of choice for hairy cell leukemia, a
`type of leukemia in which it was extremely effective, and then
`people started looking at the lymphocyte as a target for a
`variety of autoimmune disorders, including multiple sclerosis.
`The story goes that Ernie Bueller’s sister, who had multiple
`sclerosis, was treated by Jack Sipe from Scripps. It was an IV
`formulation—nobody knew the dose to use at the
`time—so a very large dose was used. But it clearly was
`effective in controlling progression of MS, and that led to a
`whole series of trials of the IV formulation until the tablet was
`discovered.
`
`The tablet is about 40% efficient compared to the IV
`formulation. The dose is 60% more, so the comparable dose
`tablet will achieve the same thing as the IV formulation. So, it
`was very convenient. The drug has a very short half-life, but in
`the time that is it is in the body, it goes after the lymphocytes,
`so the effect of the drug is long-lasting. Even though the half-
`life is only a few hours, the drug has a lasting effect on
`producing lymphocyte depletion.
`
`Could you provide a brief overview of the CLARITY
`study and its extension?
`The trial in MS was designed and the and that trial was going
`to be the first pill for multiple sclerosis because you look at the
`landscape of MS treatment at the time that the CLARITY trial
`was launched, you will notice that the treatments we had were
`the interferons—3 interferons—and Copaxone. We had
`nothing but the injectables, and the FDA gave it fast track of
`getting approval early.
`
`The trial was completed, and in this trial, there were 2 doses of
`cladribine that were used: 3.5 mg/kg and 5.25 mg/kg. Both of
`these doses were tested, and the 2-year trial was completed,
`and—fortunately, or unfortunately—there was no
`
`https://www.neurologylive.com/view/shortcommitment-dosing-regimen-gives-cladribine-an-advantage-in-ms
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`11/10/23, 6:54 PM
`
`Short-Term Dosing Regimen Gives Cladribine an Advantage in MS
`extension planned, so a lot of the people who completed the
`core trial were without any other additional treatment, which
`turned out to be actually a useful piece of information. When
`the core part of the trial was completed, a lot of patients
`finished their trial and there was no extension to go into. But
`nobody started another disease-modifying therapy because
`they were doing really well. That's how we really found out that
`the effect of the drug is long-lasting. It had a durability of
`effect that was unexpected.
`
`The other good thing about the CLARITY extension was that
`for the first time—we had never done it before—we
`randomized patients who are on treatment with cladribine to
`either stay on treatment with cladribine or to go on a placebo.
`That was to find out how long can one go without retreatment.
`What became clear, with both the lapse in going into the
`extension immediately and also about the extension, was this
`drug has a durability of effect that was unexpected. What that
`tells us is that this is not a drug that is going after activated
`lymphocyte, it is it takes resting lymphocytes and activated
`lymphocytes and it gets the memory cells. The memory B cells
`and T cells are depleted, so when new cells are repopulated by
`the bone marrow, they are not autoreactive cells, they are
`normal cells. You have eliminated the autoreactive cells for at
`least a brief period of time—we don't really know how
`long that period of time is.
`
`When the drug was approved, it was approved to be given 5
`days a week in the first week, and then 4 weeks later they get
`the next 5 days, and then nothing for a year. Then the 2 cycles
`are repeated a year later, and that's it. That's the
`recommendation, that we do not give more than the 2 cycles.
`When we do the 2 cycles, the patients go through
`lymphopenia, and then they recover from the lymphopenia.
`What looked like something that was unacceptable at the time
`that this trial was done is now readily acceptable because there
`are other drugs that cause even more lymphopenia than what
`this drug does. The Grade III, Grade IV lymphopenia is only 1%
`of the patients—most patients go through Grade I and Grade
`II, which is totally acceptable. We never really found any
`dreadful infectious complications because of the lymphopenia.
`No cases of PML occurred with this drug. Although, it is
`important to monitor for it in the long haul and the post-
`marketing scenario.
`
`Has any of the recent data that’s been presented on
`cladribine stood out to you?
`One of the posters at ACTRIMS 2020, in particular, about this
`study was a post hoc analysis of that group that went after the
`trial on cladribine versus placebo. We have now 4 years. The
`first 2 years were the core part of the study, the next 2 years
`was the extension. In the extension, you had patients who were
`initially on cladribine that's now randomized to placebo, or
`initially on cladribine who are remaining on cladribine. When
`you look at the annualized relapse rate or exacerbation-free
`patients, it was about 70% to 80% of patients. That number
`was the same whether you retreated them in year 3 or year 4
`versus whether you just put them on placebo afterward.
`Essentially, what it's telling us is 2 years of treatment is
`adequate, and 3.5 mg/kg is adequate compared to 5.25 mg/kg
`because the 5.25 mg/kg did not offer any benefits more than
`
`https://www.neurologylive.com/view/shortcommitment-dosing-regimen-gives-cladribine-an-advantage-in-ms
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`3/5
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`11/10/23, 6:54 PM
`
`Short-Term Dosing Regimen Gives Cladribine an Advantage in MS
`the 3.5 mg/kg, and the lymphopenia was even more severe in
`the 5.25 mg/kg group compared to the 3.5 mg/kg group.
`
`This is a drug that is novel. And it's novel not only because it's
`an oral formulation, but it's a new concept in the treatment of
`MS. That concept is that we do not need to keep giving a
`disease-modifying agent through the lifetime of the patient
`because every treatment that we use today is literally, once you
`start, you don't stop. They keep going on the drug. But this is 1
`drug that you give for 2 years, just like Lemtrada. You give it for
`2 years, and it resets the immune system—if that's what you
`want to call it. The autoreactive cells are no longer at sufficient
`numbers to cause issues, and what is recommended that we do
`is basically just follow the patients year after year after year,
`clinically and by MRI. It's possible that some patients may
`breakthrough and reactivate the disease, at which point either
`you will re-treat. If that's what you're going to do, you're in
`unchartered waters because there is really no data on re-
`treatment at year 3 or year 4.
`
`What is the impact of this dosing regimen being the
`way it is?
`It's huge. I mean, from a patient standpoint, once they invest in
`the initial 5 days, and then the second 5 days, their
`commitment for a year is over. A year later, you commit
`yourself for another 5 days and another 5 days, and that's the
`end of the treatment. To be able to do that and not to have to
`worry about, “Did I miss my drug? Did I take it?” You can go on
`vacation. You can leave your home for 6 months or even a year
`and you don't have any problems. That convenience for them
`is really, really big.
`
`I have patients from the Bahamas and the Caribbean and the
`islands, and they don't have large medical care over there. They
`come to the University of Miami and we are the sort of a hub
`for medical care for those patients. They used to come once a
`month to get their Tysabri or every 6 months for their service.
`A number of them have moved onto cladribine and are very,
`very happy. When they take the tablet, they literally feel
`nothing. I mean, it's like taking an aspirin pill. You don't have
`any side effects—no nausea, vomiting, hair loss, nothing
`because it doesn't have an effect in the doses that we
`administer on any other organ other than the lymphoid
`system.
`
`Once that commitment is over, their life is theirs, and it's such a
`relief. They were spending a significant amount of time, effort,
`and money to come to Miami to receive their care. And it's not
`just that population—I think any patient anywhere has the
`benefit of a short commitment to the treatment and a long-
`lasting possibility to offer relief. If you look at NEDA, no
`evidence of disease activity, it's pretty impressive how many
`patients—almost half the patients—who go on
`the drug are in the NEDA state at 2 years. Very few drugs can
`claim that. That's another attractive thing about this drug. It
`improves patient quality of life enormously.
`
`Transcript edited for clarity.
`
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`11/10/23, 6:54 PM
`
`Short-Term Dosing Regimen Gives Cladribine an Advantage in MS
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