Interferon types, Old and New, what are the options?

[EPguy]

In some recent threads this has come up in context of the PEG shortage and there is some confusion.

For those interested here are some thoughts on MPN interferon versions.

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There are a many different types of IFNs, with various Greek letters and type classes.

For MPNs only two among these many have historically been used: Type 1, IFN α -2a and Type 1, IFN α -2b.

In the early days these were used as is, under brands IntronA (IFN α -2b) and Roferon (IFN α -2a). These required frequent dosing, even daily in some cases and the early IFN data we have often discussed were partly based on these.

About 25 years ago Pegasys was introduced, and was used mostly for Hep C infections. This new formula was "pegylated" meaning a separate molecule was added to create Type 1, IFN α -2a + Peg. This is where the abbreviation "PEG" comes from. Peg prevents fast clearance of the IFN so it can be dosed less frequently, weekly or even monthly. This allows lower peak IFN levels in the body and thus better tolerance.

More recently Besremi became available, intended to be an improvement on Pegasys. The pegylation is designed differently and they used a slightly different IFN: Type 1, IFN α -2b + Peg. Note the "2b" in Bes vs 2a in Pegasys. I've posted long ago on this small difference, with unknown implications.

The image here for Besremi shows the old IFN in green, attached to the Peg in blue. So Roferon and Intron A were essentially just the green portion.

One member posting recently has used the early IFN for a long time, and found PEG to be less tolerable. Another member in a thread today had a request denied for Besremi to replace PEG, with Bes asserted to be an "old" medicine. So some Drs should read this post.

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Intron A is no longer made, but Roferon is. With out-of-the-box thinking maybe Roferon could be a temporary stand in for Pegasys during the production pause. It would require more frequent dosing and care on the dose:

Here is a mention of Roferon, for MPNs, so there should be a reference dosing schedule. It's much lower cost than Bes so maybe easier to get approved for off-label use (ET).

"Interferon alfa (Intron® A, BESREMi® [alfa-2b], and Roferon®-A [alfa-2a]), and sustained-release preparations of these called Peg-Intron and Pegasys® [peginterferon alfa-2a])". (Peg-Intron, like IntronA, is out of production)

lls.org/myeloproliferative-...

This may not be not be practical or reasonable, but could be worth a discussion esp if other options are problematic.

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As side note, one of the other IFN types, brand name Plegridy, Type 1IFN-β, is sometimes used for MS. It is also pegylated. It was sort of random that IFNα was selected for MPNs, and there has been some suggestion that IFN-β might have provided milder profile. I've posted long ago on this. Their patents covering MS are expired or will soon, maybe they will consider an MPN trial to get a fresh patent but I wouldn't count on it.

[RedCardRob]

That clears a lot of things up indeed. You are a star.

Cheers

[MPort]

Thank you so much for this info. It will help in the coming weeks when we have run out. It will give us information for discussion. Much appreciated.

[George1976]

Great info. Thanks.

I remember you had trouble with interferons. Did you try both and did you have the same reaction to both?

[EPguy in reply to George1976]

"Trouble" is a nice soft description, and unfortunately it remains present tense. My post Last Dose has the details. My guess is having that reaction twice would be fatal, which does fix all that ails. I was told never re-challenge. I was on Bes.

There's actually 4 options among these, Roferon, PEG, Bes, and Plegrity. Among these, the least frightening if I did ever rechallenge would be Plegridy. (Beta rather than alpha) Its label has signif less severe autoimmune warnings and no black box, suggesting a mild history in its decades of use. But getting an Rx for MPN is not going to happen. This report has conjecture from a well known lead author on using Plegrity for MPN, but the only way this could be tried right now is with a pt that has both MS and MPN.

ncbi.nlm.nih.gov/pmc/articl...

[George1976 in reply to EPguy]

Thanks. My last dose of Peg caused fairly intense burning in my upper abdomin and lower legs. I’d love to know why. This was after 4.5 years of it. The first 3.5 years were pretty good. And I was considering the possibility of trying Besremi. HU is keeping my platelets down pretty well now but i have a very sick feeling in my head most days that I did not have on Peg.

[EPguy in reply to George1976]

While IFN hazards are more likely to show in the 1st year or so, as you experienced it can happen at any point in the therapy. Re-reading your posts your conclusion is the IFN most likely triggered some sort of autoimmune (A-I). A-I's can be affected by a long list of traumas, as in my case and maybe yours the IFN tipped it over.

You also are finding the frustrating parts of A-I, often so hard to get a Dx to even start treating it. Did you get all the A-I tests I listed in my post about that?

On the MPN side, have you checked any of the CALR trials? This is one example with many locations:

clinicaltrials.gov/study/NC...

There's also the cell trials that look to curative solutions.

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I know the trials site too well as I scan for B-cell A-I trials that aren't Lupus.

[George1976 in reply to EPguy]

Thanks for bouncing ideas with me.

What were those AI tests again?

I know I keep beating this old drum like a dead horse. In my case some doctors have suggested COVID played a role in my neuropathy since this started in 2020 when the good times on Peg were coming to an end. But they have no idea why I feel so sick. Having so many good years on Peg makes me wonder sometimes if maybe Besremi could be different enough from Peg to help my blood without the side effects and maybe theres something else in interferons that dampens some other aspect of my blood disease that is not currently known but might be making me feel so sick. Because I also have anti-mag antibodies that keep going up since 2020 too which is usually associated with a b-cell problem but my BMB and other tests for things like myeloma or lymphoma have been negative. Rituximab is often effective for those.

Besides weakness, whatever I have also makes me feel like I'm recovering from a concussion almost all day everyday for the past 3 years, basically since stopping Peg and having that really bad neuropathic reaction to it.

Recently I was given IVIG in hopes it would help my neuropathy but that only seemed to amplify my sick head and even make the neuropathy a bit worse. I've seen Peg listed as a possible treatment for anti-mag but I already had a really bad experience with it. Things that are supposed to be good for the immune system seem to make me feel worse and sometimes a lot worse like vitamin D and B12. So now I'm wondering what IVIG and Peg might have in common that could rev up the immune system and then what could I take or do to block that action.

[EPguy in reply to George1976]

Here is the post with the tests I got. Other members have posted some additional in other threads. Note the "Neuropathy Profile". There are lots more as one gets to more obscure things, but this is a good start.

healthunlocked.com/mpnvoice...

In my Sjogrens forum there are discussions of Covid and A-I. Since Covid there has been a marked increase in A-I prevalence. It has overlap with Long Covid but these are distinct entities. Here is one article on the issue:

"Autoimmunity: Infection with the SARS-CoV-2 virus may trigger autoimmune disease. Elevated levels of autoantibodies, which are believed to play a role in other autoimmune conditions, such as lupus (SLE), rheumatoid arthritis, or Sjögren’s syndrome, have been noted in some patients with Long COVID."

yalemedicine.org/news/the-l...

It seems you got Covid in 2020, I got the version still fresh from Wuhan in early 2020. Earlier in the pandemic had higher risk of L-covid, but the risk remains for the latest variants.

Is anti Mag a B cell mediated A-I? A quick search I don't find this connection. But this report I read briefly points to a subset of anti Mag pts having a B cell profile with "excellent response to anti-CD20 therapy".

neurology.org/doi/10.1212/W...

You note Rituximab (Rituxan) This therapy is used for some A-I's and is a B-cell depleter. Could be worth a deeper Dr discussion. Suggest you look for the many B-cell driven A-I diseases beyond the hematological ones your Drs checked.

As noted above A-I's can be triggered by almost any trauma and present very quickly, even just days. This is unlike MPN which develops slowly maybe from toxin exposures etc. Could be your Covid set you up like my flu vax did, and the IFN tipped it.

Interesting you note IFN as a proposed therapy for your A-I, it was proposed ~10-20 years ago for Sjo. But I'm with you, for us it's a bad idea. Some A-I's are specifically IFN driven and several therapies in use or trials are IFN inhibitors. Adding more seems not wise.

Maybe Bes would work better, but both are IFN-alpha-2 and my case shows Bes can have teeth just like PEG. Maybe Plegridy is a safer option for A-I pts, (see my very recent posts) but you'll need to catch MS to try, best not to have that option.

Shame IVIG didn't work out. Hope your Drs can narrow it down with that negative result.

You say Vit D and B12 make trouble. Are your vitamin tests ok? I strongly suggest to get B6 and all the others tested if you have not. B6 hides in many supplements and is a neurotoxin when well over limit. I was 400+ % over, it takes up to 6 months to clear from the nervous system.

[George1976 in reply to EPguy]

Many thanks for the detailed reply. I will review those links.

You mention early COVID, while happily using peg weekly and controlling my ET perfectly I was exposed to COVID in San Francisco in Feb 2020. Got sick as a dog but did not get tested for 8 months. Test showed no COVID antibodies.

Is anti Mag a B cell mediated A-I? I don’t think it is but it often comes along with a monoclonal gammopathy (MGUS) which is a b-cell cancer like myeloma. People with it usually have an MGUS or develop one within a few years. nature.com/articles/s41598-...

Since I do have a blood cancer I’ve convinced myself that there is probably a link between the anti mag and my MPN that the doctors don’t know about yet. So far the closest I got was this old study that found people with MPNs who also have nonmyelomatous paraprotein pubmed.ncbi.nlm.nih.gov/394...

For about a year I thought I had lupus because many rheumatologic tests were pointing to it like speckled pattern, mid body pattern, anti cardio lipid IGM high but it was eventually all considered inconclusive. Seems rituximab is used for some of this too but IVIG is still preferred by my neurologist for now. also had Lyme about 15 years ago which was supposedly successfully treated but I still test positive for one of the IGM markers, p23.

B12 and D were normal. Will have to get B6 tested.

[EPguy in reply to George1976]

My covid was similar jan-feb 2020. When you and I had it there were no tests available for the public. I also tested neg in Apr 2020. I had a mild medium case, Hubby almost died but is A-I free. But you and I were likely set up for higher A-I risk from this. Lyme is another A-I trigger/inducer. The PEG clearly didn't help here.

I see paraprotein is an old marker that still has relevance. But not much actionable since 1986 is the latest info.

You likely had ANA test if speckled was in the results. ANA is relatively unspecific to which A-I. Lupus has one advantage among the A-Is with many potentially curative cell therapies under trial, from zero two years ago to handfuls now. If Lupus was even a consideration you could have B-cell A-I lurking and you do want to get the more complete A-I panels. Ruling out Evil Sjogren's is another goal.

[George1976 in reply to EPguy]

thanks. I had several of those done already with mixed results. If it’s just blood for testing should be easy for me to do some more.

Did a rheumatologist do this for you?

[EPguy in reply to George1976]

Mix results is too often the muddy A-I story. The Sjogren's forum is filled with these frustrations.

My GP ordered most of them, Rheum ordered a bunch more, and Neuro also did some. A-I pts can employ Drs from a whole med org.

[Aldebaran25]

thanks! post saved

[light]

Thanks ofr this info.

[Poppy6060]

Thank you so much for information I will bring all this up at hospital Poppy

[PhysAssist]

Hi EPguy,

Excellent as always! Thank you...

For those thinking that it may be 'too early' or told that they do not need treatment beside aspirin and/or phlebotomy because they are considered 'low risk' [in their current phase of the disease process] there is this:

"Advantages of early treatment

Early treatment of MPNs can result in better outcomes for patients in terms of lowering the risk of thrombotic events and delaying disease progression. Research has shown that JAK2 V617F+ cells can be present decades before the development of MPNs as a result of a single mutated HSC growing exponentially and competitively over years. In addition to addressing cell counts of patients with MPNs, interferons can have positive effects on the driver mutation-bearing stem and progenitor cell pool, thus effectively reducing VAF. Higher JAK2 V617F VAF correlates with negative clinical outcomes and a higher incidence rate of MF. It is important to note that although the early reduction of JAK2 V617F may result in better clinical outcomes, it is not currently part of treatment guidelines.

From this source:

ncbi.nlm.nih.gov/pmc/articl...

[EPguy in reply to PhysAssist]

The current problem is many pts are on one of those valid early treatments (PEG) but cannot stay on as PEG vanishes. I suggested Roferon as a last chance way to stay on IFN if all other options are not viable.

[PhysAssist]

This [UK ] website suggests that the Pegasys shortfall isn't so much from low PEG availability, but from business/licensing issues:

bloodcancer.org.uk/news/int...

"The shortage has come about because the license to make the drug has passed from one pharmaceutical company to another, and there are delays while the new company sets up its manufacturing processes."

It's always something- and no doubt when it returns to being available, it'll be at higher price-point 'due to demand vs availability ' issues.

They do mention a year as the prospective time frame of this occurring, but who really knows?

Maybe Besremi will be the long-term solution for UK patients sooner because of this.

Hopefully, it will not trigger a follow-on shortage of Besremi.

🤞😱😭😰😖

[EPguy in reply to PhysAssist]

The pain point is getting the new mfg line approved for quality and safety. It's like starting with a whole new drug from the gov't regulator aspect. Besremi had delays to market for these reasons. Even more the inspectors had to visit Taiwan at the height of the pandemic with an extra special entry visa. Peg won't have that issue at least.

Agree on the PEG price, if it gets EU/UK approval for MPN they will up the price. but it could bring down the Bes price with a new competitor.

I wish Plegridy would go for MPN trials.