Sipping siponimod and other SIPs

S

Go grab a cup of tea

There are a group of drugs used in MS called Sphingosine-1-phosphate receptor modulators. These are known as “the imods”. Here, mod means modulator” and “i” means immune so the immune modulators have been shortened to “imod”. Some people get paid a load of cash to come up with drug names and they have come up with interesting ones like fingo, sipon, ozan and pones. This has given us fingolimod (Gilenya), siponimod (Mayzent), ozanimod (Zeposia) and ponesimod (Ponvory).

How do you choose which one to take?

What’s the difference?

In some ways not alot…. but are you paying for the cardboard (packaging) and they are doing the same thing or are there real differences?

They are all sphingosine-1-phosphate one receptor modulators and so they block egress (moving out) of lymphocytes from lymph glands. Thereby they inhibit inflammatory MS lesions accumulating in the brain and are, thus, useful for blocking relapsing MS.

Sphingosine-1-phopshate (S1P) is a lipid (fat) molecule that is a major regulator of the vascular and immune systems. S1P regulates angiogenesis, vascular stability, and permeability. In the immune system, it is now recognized as a major regulator of trafficking of T- and B-cells. It is a “cellular catnip” and the chemical scent attracts white blood cells towards it like a whirlpool pulling water and stuff floating in the water down a plughole and out into the drain/sewer (blood system).

Space-filling model of the sphingosine-1-phosphate anion
Sphingosine 1 Phosphate

Which one to take, thankfully, It is not my job to make those decisions. You can do this with the help of your neurologist.

However – hopefully – this enlightens you a little bit:

The imods create cellular-anosmia (loss of sense of smell) and remove the cellular nose so it can’t sense the catnip, so white blood cells can’t migrate towards sphingosine-1-phopshate. In other words the sphingosine-1-phosphate receptor is removed off the cell surface. Therefore, white blood cells stay in the lymph glands and don’t get into the blood, and if they are not in the blood they can’t get to the brain, and if they can’t get into the brain they can’t cause MS. Contrast this with natalizumab, which traps cells in the blood (rather than lymph nodes) so they can’t get in the brain.

There are differences between the different imod drugs, and this is based on (a) what they bind to (b) duration of action of the drug and (c) their breakdown and activity of the break down products.

There are five receptors to which Sphingosine-1-phophate binds and the different imods bind to different combinations of receptors.

Distribution of S1P receptors in the brain

Fingolimod binds to S1P1, S1P3, S1P4, S1P5. Siponimod and ozanimod bind to S1P1 & S1P5. Ponesimod binds to S1P1 (only weakly to others). This is probably going to give the drugs a different biological function and could influence the side effect profile.

In terms of blocking relapsing MS, S1P1 is important. It is involved in white blood cells escaping the lymph glands and getting white blood cells into the brain.

It is also probably involved in the cause of one of the side effects on first use, which is a heart arrhythmia, is found with all of the imods used in MS. This was thought originally to be caused by S1P3 which also present on blood vessels.

S1P1 is also expressed by blood vessels and astrocytes, and S1P5 is expressed notably by oligodendrocytes and so it could be involved in myelination.

Fingolimod is the “Grandad” of the S1Ps and was the first pill for MS. Therefore, more people have taken this agent and, hence, we know a lot more about this drug than the others. We have some knowledge about Siponimod, whereas ozanimod and ponesimod are the new kids on the block. For them, this may be a good thing because during the COVID-19 pandemic mud has been thrown at MS drugs and some of it may stick to fingolimod.

Early in the COVID-19 pandemic, when lymphocytes where thought to be the problem of severe disease, fingolimod was touted as a treatment for SARS-CoV-2, but now can be viewed as a COVID-19 vaccine “problem-child”, along with anti-CD20 depleting antibodies. People on fingolimod not only make a poor anti-vaccine antibody response, but also a poor T cell response.

What does this mean for COVID-19 infection and vaccination?

We know that vaccine antibody responses can be inhibited with the other imods as well, but the question is whether fingolimod inhibits the vaccine responses more than siponimod, ozanimod and ponesimod. The data have not properly surfaced yet. Is this because of lack of data, or is it a case of without any mud, it can’t stick?

From an immune perspective, based on messenger RNA sequencing, it looks like the innate immune arm expresses S1P4 possibly suggesting fingolimod could do something more than siponimod, ozanimod and ponesimod. Does this lead to inhibition, and if it does would it affect the response to infections by monocyctes and neutrophils? And could it influence the generation of an immune response?

It looks like the adaptive immune arm expresses S1P1 and S1P4, Natural Killer cells have S1P1, S1P4 and S1P5 so are siponimod, ozanimod, ponesimod and potentially fingolimod going to be that different or does the S1P4 add to a more inhibited immune response with fingolimod than the other three? Time will tell…

It seems that they all have the potential to enter the CNS but some may be pumped out to some extent by Drug pumps such as ABCG2.

There are other differences and this relates to their activity and duration of activity.

Fingolimod is a prodrug in that it has to be activated before it can bind to the S1P receptors, ozanimod can bind to the S1P receptors but, importantly, it is metabolised (broken down) into other molecules that are also active on S1P1 receptors. How this occurs is relevant as we will see later.

When fingolimod is broken down this is happening slowly and takes about 6-9 days for half of the drug to disappear, whereas for siponimod and ponesimod it takes about a day and a half. So if something goes wrong, like you catch COVID-19 and you want to stop the drug it means that for fingolimod it will take much longer to be cleared from your body so it is active for some time, whereas with fingolimod it may take weeks to months for the white blood cells to return to the blood stream; this can take about a week with ponesimod. Ozanimod is an interesting one since it disappears pretty quickly, so some people swapped over from fingolimod to ozanimod in the pandemic perhaps ready in case you need to stop or switch the drug. However, ozanimod is metabolised in chemicals that are also active on S1P receptors, though half of it disappears over about 11 days, so like fingolimod it is cleared functionally from the body very slowly.

All relevant information is in the label summary of medical product characteristics (links below)

Which one can I take?

In Europe, the situation is made easier by the regulatory labels, but in the USA the choice is going to be more complex – why?

In Europe

Fingolimod is indicated as single disease modifying therapy in highly active relapsing remitting multiple
sclerosis for the following groups of adult patients and paediatric patients aged 10 years and older:

  • Patients with highly active disease despite a full and adequate course of treatment with at least
    one disease modifying therapy
    or
  • Patients with rapidly evolving severe relapsing remitting multiple sclerosis defined by 2 or more
    disabling relapses in one year, and with 1 or more Gadolinium enhancing lesions on brain MRI
    or a significant increase in T2 lesion load as compared to a previous recent MRI.

Siponimod is indicated for the treatment of adult patients with secondary progressive multiple sclerosis
(SPMS) with active disease evidenced by relapses or imaging features of inflammatory activity

Ozanimod is indicated for the treatment of adult patients with relapsing remitting multiple sclerosis
(RRMS) with active disease as defined by clinical or imaging features.

Ponesimod is indicated for the treatment of adult patients with relapsing forms of multiple sclerosis
(RMS) with active disease defined by clinical or imaging features.

There is no scientific logic why availability is different, but historially fingolimod (approved around 2010) was more expensive (people may argue it had more side effects) than the platform (Beta interferon, and glatiramer acetate) and it was given a greater hurdle to get access to it so disease had to be “highly active” as opposed to “active” so use was more restricted to people with more agressive MS or it could be used second line after failure of a platform agent. It was also shown to work in children (approved in 2018). It was approved for relapsing MS.

Siponimod was introduced later (approved 2020), and it was approved for active (lesions or relapses) secondary progressive MS. So, one is used for relapsing MS and one for secondary progressive MS. By the time ozanimod got approval in 2021 the regulators could see there was essentially no biological difference between relapsing MS and relapsing secondary progressive MS. Ponesimod came later and was also approved in 2021 and was given the same degree of usage as ozanimod.

In USA (info from drug label at FDA website)

Fingolimod is a sphingosine 1-phosphate receptor modulator 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 patients 10 years of age and older

Siponimod “is a sphingosine 1-phosphate receptor modulator 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”

Ozanimod “is a sphingosine 1-phosphate receptor modulator 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”.

Ponesimod “is a sphingosine 1-phosphate receptor modulator 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”

So in the USA if you are an adult you have the choice of four different drugs that can be used from the first sign of clinical demyelination through to secondary progressive MS.

Who would have thought that an issue for siponimod was a “Sip”. Is that how it got its name?

Clearly I have no idea how siponimod got its name but, first abit of science:

Cytochrome p450 (CYPS) are a superfamily of protein-based enzymes. CYPs would be pronounced “sips” and CYP would be pronounced “sip”

Human CYPs are primarily membrane-associated proteins located either in the inner membrane of mitochondria (cell powerhouses) or in the endoplasmic reticulum (protein factory) of cells. CYPs metabolize thousands of chemicals. Some CYPs metabolize only one (or a very few) targets, while others may metabolize multiple targets (substrates). Cytochrome P450 enzymes are present in most tissues of the body and there 57 human genes coding for the various cytochrome P450 enzymes, as well as for hormone synthesis and breakdown.

For the Science Geeks: CYPs are, in general, the terminal oxidase enzymes in electron transfer chains, broadly categorized as P450-containing systems. The term “P450” is derived from the spectrophotometric peak at the wavelength of the absorption maximum of the enzyme (450 nm) when it is in the reduced state and complexed with carbon monoxide. Most CYPs require a protein partner to deliver one or more electrons to reduce the iron (and eventually molecular oxygen).

So the first sip we have to think about is 2C9, a CYP not a robot off star wars

Siponimod, a potent, selective sphingosine 1-phosphate receptor subtypes 1 and 5 (S1P1,5) receptor modulator, is eliminated primarily through cytochrome P450 (CYP) 2C9

The gene for CYP2C9 has more than 50 variants, some of which change enzyme activity. The wild-type version (i.e. the most common version) of the gene is called CYP2C9*1. There is a specific polymorphism that has significance for drug metabolism called CYP2C9*3. The CYP2C9*3 variant has significantly decreased enzyme activity.

Because every person has two versions of each gene (one inherited from your mother and one from your father), you may have two copies of the *1 variant, two copies of the *3 variant, or one copy of each. The CYP2C9*3 polymorphism is relatively common in people of European descent . If you have two copies of the *3 variant you are morely to have higher levels of drug than two copies of the *1 variant. This can effect your response to pot (cannabis) but also your effect to siponimod. Therefore before you are given siponimod this is checked. If you are a *1/*1 , *1,2 or *2,*2 you are given one dose if you are *1/*3 or *2/*3 you are given half a dose and if you are *3/*3 the drug is not given

What does this mean for MS drugs, and are any of the imods targeted by CYPs?

The answer is yep they are all targeted by CYPs, but are any broken down by CYP3A4 and CYP2D6 meaning that you should avoid paxlovid and try getting access to one of the other anti-virals if you get COVID-19?

We know that CYP2C9 is good at degrading Siponimod but there are others and a main one is CYP3C4 (Siponimod SpMC EU).

Fingolimod is degraded by CYP4F2. Other enzymes like CYP3A4 may also contribute to its metabolism, notably in the case of strong induction of CYP3A4, which would decrease fingolimod. Caution should be exercised with substances that may inhibit CYP3A4 (Fingolimod SpMC EU)

Ozanimod is degraded by CYP3C4 and other, major, metabolites are degraded by CYP2C8 and an enzyme called monoamino oxidase and CYP2C8 (Ozanimod SpMC EU). Because of this people on ozanimod are advised about eating certain foods due to the “cheese effect“. Certain cheeses and other foods contain a substance called tyramine that can control blood pressure. Tyramine is degraded by monoamino oxidase and so inhibitors of monoamino oxidase like ozanimod could precipitate hypertension (High blood pressure) in the presence of tyramine .

Ponesimod multiple, distinct enzyme systems, including multiple CYP450 enzymes including CYP2J2, CYP3A4, CYP3A5,
CYP4F3A, and CYP4F12.

Grapefruits are a fruit to be avoided…..Why?

Grapefruit - Wikipedia

In my opinion…….because they taste like SH1.

They are too sour, Yuck! However, a slice of a red one complements a G & T…

Naturally occurring compounds in Grapefruits inhibits certain CYP activity, notably CYP3A4, and this affects metabolism of certain medications, leading to increased bioavailability and, thus, the strong possibility of overdosing

Because of this risk, avoiding grapefruit juice and fresh grapefruits entirely while on drugs is usually advised. Check to see if your drugs are affected.

The imods and anti-COVID-19 anti-virals

If you are daft/unlucky enough to catch COVID-19, one question you may ask yourself:

(a) “Should I have gone out to dinner into that crowded restaurant using the tube?”…..No only kidding, but it did happen, didn’t it Christine!

(b) Was I right to get a COVID-19 vaccination?…..to which the answer is a clear “yes”.

These have helped people stay out of hospital either through preventing infection or protecting people when they do get infected. Even if you are on a sphingosine-1-phophate inhibitor, which we know blocks SARS-CoV-2 vaccine responses, it looks like there is still vaccine-induced protection and more people taking siponimod who haven’t been vaccinated do worse. (Q: Where’s the data? A: At the next MS meeting!)

(c) Can I have an anti-viral COVID-19 drug? This is the point of my whole post today…

Antivirals for COVID-19

There are:

(a) Antibodies (Casirivimab/imdevimab if not infected with omicron and sotrovimab )

(b) Anti-viral drugs (Remdesivir, Molnupiravir and Paxlovid)

Paxlovid is a pill which is a combination of two drugs nirmatrelvir and ritonavir. Nirmatrelvir is the main anti-viral that was developed by modification of the earlier clinical candidate lufotrelvir, which is also a viral protease inhibitor, but it needs to be administered intravenously, limiting its use to a hospital setting. Ritonavir is also viral protease inhibitor but importantly it is a CYP blocker. Typically, it is used to inhibit the enzyme that metabolizes other protease inhibitors, notably this inhibits CYP3A4 and CYP2D6. This is important as nirmatrelvir is broken down by CYP3A4. However, this also means that paxlovid will augment the action of a number of drugs, and would be dangerous if it the drug has the potential to be toxic.

Therefore, there is a long list of drugs (click here ) which are a red flag and means that you will be adviced to avoid paxlovid if you are taking them. Some of these drugs are used in the control of MS symptoms, such as anticonvulsants and some statins such as simvastatin which may be relevant to those in the STAT2 trials

However, with regard to the imods.

Fingolimod read the label (US)/ summary of product characteristics (EU) However “population pharmacokinetic evaluations indicate that CYP3A inhibitors and CYP3A inducers have no effect or only a weak effect on the pharmacokinetics of fingolimod and fingolimod phosphate. Fingolimod and fingolimod phosphate had little or no activity on CYP2D6, CYP3A4 at concentrations up to 3 orders of magnitude of therapeutic concentrations.

Siponimod read the label/summary of product characteristics “USA . CYP2C8 and CYP3A4 inhibitors is not recommended” Siponimod is inhibited by about 79% by CYP2C8 about 18.5% by CYP3A4 and one study found no increase with a CYP3A4 inhibitor

Ozanimod read the label/summary product characteristics.. Approximately 94% of circulating total active drug exposure is represented by ozanimod (6%), CC112273 (73%), and CC1084037 (15%), in human. No clinically significant differences in the pharmacokinetics of ozanimod and its major active metabolites CC112273 and CC1084037 were observed when co-administered with itraconazole (strong CYP3A inhibitor). Itraconazole increased ozanimod levels by approximately 13% suggesting a minor role of CYP3A

Ponesimod read the label/summary product characteristics, whilst there is a warning about strong inducers of CYP3A4, inhibitors are not mentioned and the label states at the “recommended dose of 20 mg once-daily, ponesimod and its metabolite M13 do not show any clinically relevant drug-drug interaction potential for CYP” and although multiple CYP are involved in metabolisms these are “without major contribution by any single enzyme”

Remember all of these drugs have been tested at higher doses during the development phase and treatment with paxlovid is for 5 days

COI: Multiple

Disclaimer: This post represents the views of the author and does not represent those of any institution and are here for educational purposes and not considered to be medical advice

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MouseDoctor

8 comments

  • Would it be safe to take paxlovid if you immediately stopped Siponimod after covid dx? Thank you for breaking down this information!

  • Regarding antivirals generally and Ms.

    It is useful knowing about paxlovid and drug interactions but what worries me is that neither my GP knows nothing
    about the PCR priority test which people with MS have received and what their involvement should be if you test positive but hear nothing back from the NHS in 24-hours.
    The letter I received clearly states that if you do not hear from the NHS you must contact either 119 or your GP so the chance of someone picking up that you should not have paxlòvid due to your current medication is zero
    What is your understanding of the process?

    • In some places this works but you know as much as me on htis…..I am not sure if you should not have paxlovid…but maybe somebody in the know will let me know that what the warning means is it AND or OR

  • Woah! That’s a lot of reading and links, must have taken some putting together, thanks for posting. All we ever need to know about the imods and we see they clearly get in the brain despite dogma saying moa is via S1P1 lymph nodes.

    Since (sometime post 2010 fingolimod) FDA have taken a common sense pragmatic approach to licensing where a licence for RRMS automatically extends to CIS and active SPMS. Saves a heap lot of time and effort jumping through hoops. Wish EMA would do same and hope MHRA catch on quick. They could take it one stage further and include active PPMS 🙂.

    Did not know:
    1. Predicted pharmacokinetic interactions are tested post licensing in healthy volunteers (siponimod link).
    2. Ozanimod is an MAOI. Best stay clear of the LemS1P 😉

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