Open Norway: Plasma cell aimed treatment with daratumumab in ME/CFS - Haukeland University Hospital

[Utsikt]

The reason could be something as boring as a condition of grant,

I don’t understand how this would work, because why would those that provide the grant care about if something gets patented, unless they own a share of the patent?

or that their institution requires researchers to do it as a matter of course.

Turns out that’s what has happened here:

Haukeland University Hospital, through its Technology Transfer Office, Vestlandets Innovasjonsselskap AS, holds a pending patent application related to plasma cell-targeting treatments for ME/CFS, WO2021038097A1: method for the treatment of chronic fatigue syndrome using an inhibitory or cytotoxic agent against plasma cells. OF and OM are listed as inventors on these applications.

There is actually a law in Norway about this specifically that gives the employer a right to patent any work related inventions by the employees.

The explicit reasoning by their employer for patenting in general is to generate income:

Innovasjon ved Haukeland universitetssjukehus

Innovasjon i helsetenesta handlar om å utvikle og forbetre tenester gjennom nye metodar, betre organisering og smartare pasientflyt. For å møte endringar i sjukdomsbilete, demografi og teknologi, satsar Haukeland universitetssjukehus på forsking og tenesteinnovasjon. Målet er tryggare, meir...

www.helse-bergen.no

 

[Kitty]

I don’t understand how this would work, because why would those that provide the grant care about if something gets patented, unless they own a share of the patent?

The question may have been answered anyway, but it could well be to prevent commercial interests making large profits from treatments developed using philanthropic or charitable funding that was given with the aim of improving sick people's lives.

That's an unlikely scenario in this case, but it's not difficult to imagine a situation where a really major discovery is made by a small team struggling by on a patchwork of grants and support-in-kind.

It's comparable to a script commissioned from a young playwright for a tour of local primary schools, which gets picked up by Disney for a film. I had to draft the contract with that possibility in mind, even though it's vanishingly unlikely to happen.

 

[ryanc97]

proteasome is the cell’s garbage disposal. PIs are particularly good at killing cancerous plasma cells since the process of making immunoglobulins is intensive, and if a cell can’t turn over those proteins fast enough they will build up and cause the cell to die (at least that’s the current thinking of why they work).

I think the idea here is that using a proteasome inhibitor would confirm whether any potential beneficial effect from Dara comes from targetting CD38 on plasma cells specifically or from blocking CD38’s other enzymatic functions.

Fluge did mention temporary improvement from two patients on Bortezomib in the paper.

Problem is from my research it seems proteasome inhibitors may be less effective than directly attacking CD38 as apparently the LLPCs can somehow resist it (they are hard to kill)

 

[Jonathan Edwards]

what would you expect the time profile to look like if JAK kinase blockade works? Are we sure the trials are set up to detect any effects if they are there? I think I remember you talking about other drugs flunking in trials for many years because the people trialing them didn’t know how to use them properly.

Difficult to be sure but I would guess within 6 weeks. The trial design problems related to the complex issues of B cell repopulation with ritux and the problems with lupus outcome measures specifically.

 

[Jonathan Edwards]

I think I've asked this question before, but would Isatuximab be a good alternative for dara non-responders?

Quite possibly. Others have made relevant comments.

 

[Jonathan Edwards]

What about CD38 CAR-T cell therapy? Hypothetically speaking.

CAR-T has a lot of disadvantages. It is something to consider if there is no other way to maintain remissions long term.

 

[Jonathan Edwards]

Say the Norwegian team got their £2 million for this trial and it showed a response that does look convincing. Do you think there'd be a reasonable chance of getting a UK replication study?

If the Norwegians gt a positive result from a goof blinded study I think we are more or less home and dry. Getting replication for licensing may take a few years but being a drug with a license for other things means that it can be used off-label as many people did with rituximab before the license came through. A formal replication study is likely to be a multinational recruiting drug company sponsored phase 3. It is conceivable that drug companies will not get involved and then there will need to be another academic study. I think that could occur in the UK. If the Norwegian study is convincing it would be hard to turn down.

 

[hotblack]

So I stand corrected: there might be a way to use patents to ensure other patents based on the original patents are not being used to generate money.

That was the misunderstanding I thought it was important to correct, so people reading this don’t jump to conclusions. This all off a bit of a side topic and speculation, we just don’t know the reasons for Fluge and Mella making this patent claim. It may be useful to, but we don’t.

The points I were raising were just the realities of how the patent system is used. We may not agree with it or like it or even think it’s logical but they happen. It is the agreed method of proving you’ve invented something and it has many flaws. I’ve seen patents made just because a company encourages people and rewards them for patents, even if the patents are largely useless and don’t make money. Some treat them like badges of honour or conditions for bonuses.

The reason could be something as boring as a condition of grant, or that their institution requires researchers to do it as a matter of course.

The question may have been answered anyway, but it could well be to prevent commercial interests making large profits from treatments developed using philanthropic or charitable funding that was given with the aim of improving sick people's lives.

Exactly.

 

[Sasha]

If the Norwegians gt a positive result from a goof blinded study I think we are more or less home and dry. Getting replication for licensing may take a few years but being a drug with a license for other things means that it can be used off-label as many people did with rituximab before the license came through. A formal replication study is likely to be a multinational recruiting drug company sponsored phase 3. It is conceivable that drug companies will not get involved and then there will need to be another academic study. I think that could occur in the UK. If the Norwegian study is convincing it would be hard to turn down.

So if the Norwegians get a positive result from this trial we could be getting it off-label at the end of the trial? So if it works, is the only thing slowing us down the speed at which this trial gets carried out? In which case, the extent to which we are not all hands on deck fundraising is astonishing, if this is looking really promising.

What's the best-case scenario in terms of speed?

 

[Kitty]

So if the Norwegians get a positive result from this trial we could be getting it off-label at the end of the trial?

I'm not sure how likely that would be? I doubt it's something a GP would prescribe, and hospital clinics have long waiting times. Maybe it would need an academic centre to get interested initially and develop a protocol?

 

[Sasha]

I'm not sure how likely that would be? I doubt it's something a GP would prescribe, and hospital clinics have long waiting times. Maybe it would need an academic centre to get interested initially and develop a protocol?

This is a good point. We don't have physician-led centres ready to leap into action. If this dara trial was positive, would that lead immediately to the setting up of such centres, and if so, how immediate would that be? Would we be stuck waiting in our beds another six months, a year, two years? Or would be get referred to specialists who are used to using dara? If so, who would that be? Immunologists? Oncologists?

Do we need to be doing something now to enable swift roll-out?

 

[Kitty]

Best thing might be getting licensed so that NICE would look at it? I suspect it makes life a lot easier if they recommend it.

That wouldn't be especially quick, but then again some of us might want to see the results of a larger trial before we took the risk. (I would, anyway.)

 

[Trish]

Aren't we getting ahead of ourselves? I thought this was a phase 2 trial. We need to wait for the results of at least one full scale double blind controlled trial before we start talking about roll out. Remember how long it took for the series of trials of rituximab.

 

[EndME]

Aren't we getting ahead of ourselves? I thought this was a phase 2 trial. We need to wait for the results of at least one full scale double blind controlled trial before we start talking about roll out. Remember how long it took for the series of trials of rituximab.

Yes, I agree. I'm guessing there will be an interim analysis at some time point?

 

[V.R.T.]

Best thing might be getting licensed so that NICE would look at it? I suspect it makes life a lot easier if they recommend it.

That wouldn't be especially quick, but then again some of us might want to see the results of a larger trial before we took the risk. (I would, anyway.)

Some of us cant afford to wait that long though. If there's an off label drug that might improve my condition with results from a well run phase 2 and there's a decent chance I might be a responder, I'm going to try it. There's a very big risk I don't make it til the results of a subsequent phase 3 study. I'm far from alone in that. And my partner, who is moderate, has to care for me. I can't put that burden on her for any longer than absolutely necessary.

We have people stuck in between life and death in hospitals and dark rooms. People trapped in dangerous living situations. Those people can't wait either.

If the daratumumab pilot responder ratios bore out (obviously its just a sample of ten but for arguments sake) you're talking about 50-60% of pwME responding. And the sooner we have an effective treatment the sooner rank and file doctors start to believe in ME/CFS, which will improve things for everyone.

So if off label prescription is an option we need to prepare for that possibility as best we can, so it is done promptly and safely rather than by Habets-esque cowboys. Maybe that means working to establish an academic centre in the meantime - we've heard that the winds might be changing on that front soon anyway.

Perhaps at first daratumumab might be given by oncologists like F&M? I think the protocol is already laid out in the trial is it not? And they would be most familiar with how to give the drug.

 

[hotblack]

One of the documents attached to the english fund-raising page talks a lot about the mechanism and goal being reduction of autoantibodies, my understanding was this was not the case and it’s some other mechanism involving B cells/plasma cells, potentially antibodies but more autoimmune adjacent. Is it helpful to have the autoantibody/autoimmune label thrown in here?

 

[Sasha]

Aren't we getting ahead of ourselves? I thought this was a phase 2 trial.

Quite possibly! I haven't read stuff properly and am very confused about what stage we're at and what needs to happen next.

We need to wait for the results of at least one full scale double blind controlled trial before we start talking about roll out. Remember how long it took for the series of trials of rituximab.

OTOH, we don't want to be waiting for the end of a definitive trial to start making roll-out possible, if there are things we need to do to make that happen. For example, PwME have been campaigning for years to get physician-led services and we don't have them. If that's what we'd need for a dara roll-out (or a roll-out of any effective drug), we may need to start serious, joined-up campaigning now. I think we need to think strategically.

 

[OrganicChilli]

I agree with @V.R.T.. It would be ridiculous to wait 10 years when it's been on the market for so long and the risks are well-managed within cancer patients.

The NHS only uses dara as a fourth-line treatment in multiple myeloma because they have other (cheaper) options. Given the BPS influence I can imagine they would be very reluctant to prescribe it for ME/CFS unless the biosimilar is much cheaper.

 

[V.R.T.]

For example, PwME have been campaigning for years to get physician-led services and we don't have them. If that's what we'd need for a dara roll-out (or a roll-out of any effective drug), we may need to start serious, joined-up campaigning now. I think we need to think strategically.

I agree. I think perhaps the time is about right to push hard for this. If JE is right and more studies come out in the next little while, especially if they point to possible drug targets as he mentioned, we will have more evidence and more of a reason for establishing this kind if service even without factoring in daratumumab.

And then there is somewhere for any trials that need doing be that a dara phase 3 or a pilot/phase 2 of some hypothetical other drug, and any off label prescriptions to be administered.

 

[EndME]

OTOH, we don't want to be waiting for the end of a definitive trial to start making roll-out possible, if there are things we need to do to make that happen. For example, PwME have been campaigning for years to get physician-led services and we don't have them. If that's what we'd need for a dara roll-out (or a roll-out of any effective drug), we may need to start serious, joined-up campaigning now. I think we need to think strategically.

There's currently quite a few ME/CFS clinical trials. The Charite regularly runs trials, @Mebfeb has an ongoing trial, Simmaron is doing some stuff and others are active as well. I don't think one has to worry about things not working out if there is actually positive data. Currently people are running trials whilst being in the dark, I'm pretty sure they'll all happily turn on the lights if they could. Patient recruitment will always be a problem but I'm not sure if there is much one can do about that right now or at least not on the basis of anything that is dependent on Fluge and Mella's work.

I guess "physican led services" is a UK-centric viewpoint (or what would the Charite considered to be)? I thought the problem was that it's hard to get one genuinely interested person invested to run an ME/CFS-clinic and possibly that might take a positive phase 2 trial or other genuinely useful data? At least I don't think that any of that discussion should be dependent on Daratumumab and I don't think one can get anyone smart invested on the basis of the current Daratumumab data.

In short: if you try to get people interested on the basis of the Daratumumab data you'll likely get the wrong kind of people.