The EVOLUTION phase 3 clinical trials showed evobrutinib did not meet its primary endpoint of annualised relapse rate for up to 156 weeks compared to oral teriflunomide. Why?
Please read the Sormani et al. 2013, meta-analysis correlating the reduction in Gd-enhancing lesions in phase 2 trials and the subsequent reduction in the annualised relapse rate (ARR) in Ph3. For comparison, the reduction in GdEs observed in the evobrutinib Ph2b trial for the 75 mg b.i.d. arm (i.e., the dose originally chosen for Ph3) was 56%. Going back into the archives, the teriflunomide Ph2b trial (O’Connor, 2006) showed a 61% reduction in combined unique active lesions or (similar values for GdE reduction). Accordingly, the Sormani analysis predicted qualitatively the EVOLUTION RMS Ph3 ARR values.
Thank you for sharing this. Interesting that BTK trials set against teriflunomide are unintentionally promoting the antiviral and new disability parameters. Based on your previous posts on IRT therapy, and since teriflunomide is antiviral and not as immunosuppressive as other DMTs, it's my DMT choice for continued therapy after I complete my second year of Cladribine/Mavenclad in 2024--unless we have better options or a cure. ;)
" I have little doubt that teriflunomide after induction with a depletion therapy (alemtuzumab, mitoxantrone, cladribine, AHSCT or anti-CD20) will revolutionise the management and outcome of pwMS."
Thank you prof G, when I see new email from you it really lightens up my day. Would you consider switching to Teriflunomide from Ocrelizumab, if immunoglobuline levels are very low and the patient has frequent infections (UTIs, pneumonia)?
Hi Belma, I went back on interferon beta 1a (Avonex). Because of my age and the constant UTIs and colonized bacteria, I think she was afraid of a suppressant. But at least she put me on something! I’m using this bitter cranberry capsule with no additives called Utiva made in Canada. I’m having great results with with bladder emptying. Hope you are doing as well as you can. I share your frustrations. Best to you..🌷
Dec 7, 2023·edited Dec 7, 2023Liked by Gavin Giovannoni
Hello Italien- I'm curious on the Utiva. My bladder doesn't empty for a number of reasons which they are not sure on. Part of it is MS and part of it is being an older guy. I don't get UTIs but bladder control is partly random. I get "frequency" but it never empties, I'm left usually with something like 300 cc's. Would be great if it would empty out all the way. Without having to share too much detail, how did it work for you?? Could you tell the Utiva was "doing its thing" right away?
Congrats on the Avonex, I guess. I stopped Betaseron after 23 years (no rebound or anything), but wouldn't want to go back- it is so "normal" not to have to do shots. Love it!
Hi Tom, I stopped Avonex after neid and 21 years. Thrilled to get rid of the needle fatigue also! 5 years later, I went downhill quickly, particularly with bladder and bowel. As a woman, 300 is about all my now damaged bladder holds, so I was constantly peeing out 100 ml at a time with never ending UTIs, leaving the rest in. Cathing made UTIs worse. More and ugly varied bacteria. (My old uro wanted me on Flomax, but I have sulfa allergy. She kept yelling that the sulfa was “safe” in it. Package insert claims otherwise. I was otherwise. I roll my eyes..) So new uro said get on this bitter cranberry supplement, one a day, and it works for a lot of people. I’d just had another huge infection and I’m tired of cathing. Within 2 days, I was emptying my bladder almost fully and getting at least 6 hours of sleep. (Be still my heart! Not for good, of course..) I have been a supplement skeptic, however, it’s worked for me so far. Btw, I don’t see a lot of us in the era of the Betaseron lottery. Here in the U.S., my spouse is furious about the unaffordable cost of the, ahem, co-pay for Avonex, but if it helps a bit, well…Good luck, I hope this capsule will be helpful for you! 🍀
Hello again Italien- Thanks for a reply. Well, I thought you were a man :-(. Nevertheless, good info. Sounds like it would be worth a look-see. I'm not a suppliment type yoga excercise person myself; but everything is a suppliment depending on how you look at it. I started Beta when that was it. I was doing pretty bad in the beginning, falling apart. Started Beta and the nasty stuff stopped. Took 5 or so years to build myself back up to "not too bad". But my leg went hey-wire and we thought it was MS 5 years ago, but wasn't really. It improved greatly pain wise, and we know that 30 years in, MS is no longer a relapse thing, so it was something else (could share a long list of possibilities). Nevertheless, all this & bla bla bla, thanks for posting that and giving me a reply. Hang in there. Tom
Hello Italien. I was on Betaferon for 6 months, and developed 5 new lessions during that time. I would not be happy to return to interferons, not at all, but I am also afraid of constant immunosupression state in which Ocrevus put me. Right now, I'm having UTI, took Fosfimicin on Monday, it made the pain bearable but did not finish the job, so I started with Cefuroxim this morning :-(
I'm having appointment with Urologist in 6 days, so hopefully I will have a battle plan for this retention problem (bladder is not emptying, hence the UTIs).
I am sorry, I know. As Prof G said, interferon is the least effective, but like you, neuro was concerned about never ending UTIs. But how to avoid them with cathing? And the euro first wanted me to cath more! Like you, I’m on months of anti-Bs often for 2 different bacteria at a time. Not livable. :/ You are super active, I am neid. Yours is much harder, I think. But even though my damaged bladder never fully fills anymore, it’s been emptying with this Utiva. I’m sending you luck for a good battle plan.💕
Thank you for your kind words. I used pills similar to Utiva,different brand but same ingredients, but it had no effect once I started Ocrevus. Hopefully I will get some answers from urologist. My husband jokes that I get UTI when he as much as just looks at me :-)
Thank you! I will print this article out and use it to discuss options with urologist next week.
Please could you elaborate on PTNS, is that electrical stimulation? I read about a chip which is implanted inside you, which stimulates the bladder to contract properly, i.e. it helps with urine retention. Have you had patients with this implant, what is their experience?
And one more thing, could ISC work in a way that I do ISC after sex, drink d-mannose and lots of fluid, would that help in preventing post coital UTIs? Do you have patients which found this approach successful?
Would it be possible to start Teri before allowing b cell reconstitution then once b cells have reconstituted, take cladribine(while not stoping Teri)? Point here would try and prevent b-cell EBV reinfection during repopulation times.
Thank you for this - very interesting. I’m currently on Tysabri but my plan is to start Mavenclad next year and then if that fails to take Aubagio. Is your suggestion that Aubagio should be taken immediately after an IRT or would it still have the beneficial effect if taken once the IRT failed?
Another comment on the results aren’t BTKs best to slow / stop PIRA? There’s no way a trial this short can show that. It would take years as that’s not really something you can measure with an mri.
You can get a read out in 2 years with MRI (slowly expanding lesions, paramagnetic rim lesions and brain volume loss), but these can't be used as a primary outcome measure. The regulators won't accept them.
This really is wonderful news, particularly that Aubaugio is not a suppressing drug, but a modulator. There seem to be myriad advantages. Finally, my urologist and neurologist conferred about my worsening smouldering MS and failing bladder. And, voilá! In one day, I am back on the devil I know, interferon beta 1a! Avonex. The cost in the states is stratospheric; I would reckon that is because few pwMS use it now. I vote for Aubaugio with this information! It’s almost as costly. Yes, many, many generics for Aubaugio are approved, but unavailable due to patent. (Excuse my cynicism, but this is the states. We are talking quite a few years for an available generic. Bad thing!) In that vein (no pun) I have no idea why Avonex is still patented. I roll my eyes..But hallelujah! I’m finally on something. As always, many many thanks for this.
Here’s the scoop on Sanofi. Please correct me if I’m wrong on this…🌷
Thank you for the wonderful article (as always). Is there any results (Phase 2 or case reports) on individuals that switched from an Ocrelizumab/Anti-CD20 to teriflunomide (similar to the proposed iTeri study). Say on their BVL or ARR?
When you state that teri is especially good as a 2nd or 3rd DMT, do you know if that holds regardless of the prior DMT? In other words: is that mostly in a de-escalation scenario or does it also apply when switching from (other) so-called CRAB-DMTs?
Thanks for sharing - this is really interesting. Should I ask my neurologist to write me an off-label prescription for leflunomide? Waiting for the results of the international phase 3 iTeri trial (if it happens at all) will take some time.
Thank you for sharing. I have been on Sophie for just over a year now and I have not had any problems apart from a very very low lymphocytes level. However I have a very good base immunity and don't get any infections or very mild. Should I be considering a switch to teraflunomide?
On the NHS to be eligible for Siponimod you have to have active SPMS. At the moment the latter is a cul de sac and therefore you can't go back to having relapsing MS to be prescribed teriflunomide.
An email response:
Please read the Sormani et al. 2013, meta-analysis correlating the reduction in Gd-enhancing lesions in phase 2 trials and the subsequent reduction in the annualised relapse rate (ARR) in Ph3. For comparison, the reduction in GdEs observed in the evobrutinib Ph2b trial for the 75 mg b.i.d. arm (i.e., the dose originally chosen for Ph3) was 56%. Going back into the archives, the teriflunomide Ph2b trial (O’Connor, 2006) showed a 61% reduction in combined unique active lesions or (similar values for GdE reduction). Accordingly, the Sormani analysis predicted qualitatively the EVOLUTION RMS Ph3 ARR values.
A very good point and tells us the trial was poorly designed and creates breathing space for the other BTKi's in trial behind evobrutinib.
Let's see if the disability progression and brain volume loss.
Thank you for sharing this. Interesting that BTK trials set against teriflunomide are unintentionally promoting the antiviral and new disability parameters. Based on your previous posts on IRT therapy, and since teriflunomide is antiviral and not as immunosuppressive as other DMTs, it's my DMT choice for continued therapy after I complete my second year of Cladribine/Mavenclad in 2024--unless we have better options or a cure. ;)
" I have little doubt that teriflunomide after induction with a depletion therapy (alemtuzumab, mitoxantrone, cladribine, AHSCT or anti-CD20) will revolutionise the management and outcome of pwMS."
Can the revolution start right here right now?
Thank you, Prof. G, for another incredibly helpful post. That being said, this news is another punch to the gut!! Hope is dimming fast.
Thank you prof G, when I see new email from you it really lightens up my day. Would you consider switching to Teriflunomide from Ocrelizumab, if immunoglobuline levels are very low and the patient has frequent infections (UTIs, pneumonia)?
Hi Belma, I went back on interferon beta 1a (Avonex). Because of my age and the constant UTIs and colonized bacteria, I think she was afraid of a suppressant. But at least she put me on something! I’m using this bitter cranberry capsule with no additives called Utiva made in Canada. I’m having great results with with bladder emptying. Hope you are doing as well as you can. I share your frustrations. Best to you..🌷
Hello Italien- I'm curious on the Utiva. My bladder doesn't empty for a number of reasons which they are not sure on. Part of it is MS and part of it is being an older guy. I don't get UTIs but bladder control is partly random. I get "frequency" but it never empties, I'm left usually with something like 300 cc's. Would be great if it would empty out all the way. Without having to share too much detail, how did it work for you?? Could you tell the Utiva was "doing its thing" right away?
Congrats on the Avonex, I guess. I stopped Betaseron after 23 years (no rebound or anything), but wouldn't want to go back- it is so "normal" not to have to do shots. Love it!
Hi Tom, I stopped Avonex after neid and 21 years. Thrilled to get rid of the needle fatigue also! 5 years later, I went downhill quickly, particularly with bladder and bowel. As a woman, 300 is about all my now damaged bladder holds, so I was constantly peeing out 100 ml at a time with never ending UTIs, leaving the rest in. Cathing made UTIs worse. More and ugly varied bacteria. (My old uro wanted me on Flomax, but I have sulfa allergy. She kept yelling that the sulfa was “safe” in it. Package insert claims otherwise. I was otherwise. I roll my eyes..) So new uro said get on this bitter cranberry supplement, one a day, and it works for a lot of people. I’d just had another huge infection and I’m tired of cathing. Within 2 days, I was emptying my bladder almost fully and getting at least 6 hours of sleep. (Be still my heart! Not for good, of course..) I have been a supplement skeptic, however, it’s worked for me so far. Btw, I don’t see a lot of us in the era of the Betaseron lottery. Here in the U.S., my spouse is furious about the unaffordable cost of the, ahem, co-pay for Avonex, but if it helps a bit, well…Good luck, I hope this capsule will be helpful for you! 🍀
Hello again Italien- Thanks for a reply. Well, I thought you were a man :-(. Nevertheless, good info. Sounds like it would be worth a look-see. I'm not a suppliment type yoga excercise person myself; but everything is a suppliment depending on how you look at it. I started Beta when that was it. I was doing pretty bad in the beginning, falling apart. Started Beta and the nasty stuff stopped. Took 5 or so years to build myself back up to "not too bad". But my leg went hey-wire and we thought it was MS 5 years ago, but wasn't really. It improved greatly pain wise, and we know that 30 years in, MS is no longer a relapse thing, so it was something else (could share a long list of possibilities). Nevertheless, all this & bla bla bla, thanks for posting that and giving me a reply. Hang in there. Tom
Hello Italien. I was on Betaferon for 6 months, and developed 5 new lessions during that time. I would not be happy to return to interferons, not at all, but I am also afraid of constant immunosupression state in which Ocrevus put me. Right now, I'm having UTI, took Fosfimicin on Monday, it made the pain bearable but did not finish the job, so I started with Cefuroxim this morning :-(
I'm having appointment with Urologist in 6 days, so hopefully I will have a battle plan for this retention problem (bladder is not emptying, hence the UTIs).
I will look up this Utiva capsule now...
I am sorry, I know. As Prof G said, interferon is the least effective, but like you, neuro was concerned about never ending UTIs. But how to avoid them with cathing? And the euro first wanted me to cath more! Like you, I’m on months of anti-Bs often for 2 different bacteria at a time. Not livable. :/ You are super active, I am neid. Yours is much harder, I think. But even though my damaged bladder never fully fills anymore, it’s been emptying with this Utiva. I’m sending you luck for a good battle plan.💕
Thank you for your kind words. I used pills similar to Utiva,different brand but same ingredients, but it had no effect once I started Ocrevus. Hopefully I will get some answers from urologist. My husband jokes that I get UTI when he as much as just looks at me :-)
You may find this newsletter helpful:
https://gavingiovannoni.substack.com/p/infection
Thank you! I will print this article out and use it to discuss options with urologist next week.
Please could you elaborate on PTNS, is that electrical stimulation? I read about a chip which is implanted inside you, which stimulates the bladder to contract properly, i.e. it helps with urine retention. Have you had patients with this implant, what is their experience?
And one more thing, could ISC work in a way that I do ISC after sex, drink d-mannose and lots of fluid, would that help in preventing post coital UTIs? Do you have patients which found this approach successful?
Best regards!
Yes, that is one option. The others are interferon-beta, GA and cladribine.
Would it be possible to start Teri before allowing b cell reconstitution then once b cells have reconstituted, take cladribine(while not stoping Teri)? Point here would try and prevent b-cell EBV reinfection during repopulation times.
Correction: Siponimod not Sophie!!!
Thank you for this - very interesting. I’m currently on Tysabri but my plan is to start Mavenclad next year and then if that fails to take Aubagio. Is your suggestion that Aubagio should be taken immediately after an IRT or would it still have the beneficial effect if taken once the IRT failed?
The hypothesis is that teriflunomide needs to be on board before and during B-cell reconstitution to prevent the B-cells becoming reinfected with EBV.
Also what is your view of Mavenclad vs Ocrevus/Kesimpta?
It is horses for courses; there are many factors to consider when choosing between an IRT and a maintenance therapy. I suggest you read the following:
https://msselfie.co.uk/treatment-strategy/how-do-i-want-my-ms-to-be-treated/
Thank you!
Another comment on the results aren’t BTKs best to slow / stop PIRA? There’s no way a trial this short can show that. It would take years as that’s not really something you can measure with an mri.
You can get a read out in 2 years with MRI (slowly expanding lesions, paramagnetic rim lesions and brain volume loss), but these can't be used as a primary outcome measure. The regulators won't accept them.
Be interesting to get the data on bvl etc
I mean the ARR was the same as Kesimpta so it isn’t a total fail just aubagio was better than anyone expected.
This really is wonderful news, particularly that Aubaugio is not a suppressing drug, but a modulator. There seem to be myriad advantages. Finally, my urologist and neurologist conferred about my worsening smouldering MS and failing bladder. And, voilá! In one day, I am back on the devil I know, interferon beta 1a! Avonex. The cost in the states is stratospheric; I would reckon that is because few pwMS use it now. I vote for Aubaugio with this information! It’s almost as costly. Yes, many, many generics for Aubaugio are approved, but unavailable due to patent. (Excuse my cynicism, but this is the states. We are talking quite a few years for an available generic. Bad thing!) In that vein (no pun) I have no idea why Avonex is still patented. I roll my eyes..But hallelujah! I’m finally on something. As always, many many thanks for this.
Here’s the scoop on Sanofi. Please correct me if I’m wrong on this…🌷
https://www.drugs.com/availability/generic-aubagio.html
Leflunomide should be quite affordable and functionally the same drug (teri is the active metabolite of leflunomide) AFAICT
https://www.msard-journal.com/article/S2211-0348(23)00642-9/fulltext?fbclid=IwAR0OJCWQ0XyNkf-NqsWhMTIH1DQccB-JBRG7xGbGIm0d-vrEbcLUODndkcU
Good paper, Prof. G!
Will we see other endpoint data from that trial (ARR is not terribly interesting to PPMS)?
I’m worried about Steven’s Johnson Syndrome…
Thank you for the wonderful article (as always). Is there any results (Phase 2 or case reports) on individuals that switched from an Ocrelizumab/Anti-CD20 to teriflunomide (similar to the proposed iTeri study). Say on their BVL or ARR?
Not that I am aware of.
Thank you for a very interesting read.
When you state that teri is especially good as a 2nd or 3rd DMT, do you know if that holds regardless of the prior DMT? In other words: is that mostly in a de-escalation scenario or does it also apply when switching from (other) so-called CRAB-DMTs?
The data is mainly driven by the older injectable DMTs or CRAB-DMTs. But I suspect it will hold for all DMTs.
Thanks for sharing - this is really interesting. Should I ask my neurologist to write me an off-label prescription for leflunomide? Waiting for the results of the international phase 3 iTeri trial (if it happens at all) will take some time.
I think you should wait for the trial results.
Thank you. Who would support such a trial? I doubt that "big pharma" would be interested. What universities (outside the UK) might be interested?
Thank you for sharing. I have been on Sophie for just over a year now and I have not had any problems apart from a very very low lymphocytes level. However I have a very good base immunity and don't get any infections or very mild. Should I be considering a switch to teraflunomide?
On the NHS to be eligible for Siponimod you have to have active SPMS. At the moment the latter is a cul de sac and therefore you can't go back to having relapsing MS to be prescribed teriflunomide.