Wednesday, 27 April 2016

Alemtuzumab 10 years on

P2.086 - Incidence and Timing of Thyroid Adverse Events in Patients with RRMS Treated with Alemtuzumab through 5 Years of the CARE-MS Studies


P.A senior et al.

OBJECTIVE:
To summarize 5-year incidence and timing of thyroid adverse events following alemtuzumab treatment in the ongoing CARE-MS extension study.
BACKGROUND:
In the phase 3 CARE-MS studies, patients with active relapsing-remitting MS showed greater improvements in efficacy outcomes with alemtuzumab versus SC IFNB-1a over 2 years; efficacy was durable through 5 years in the extension study. Alemtuzumab’s consistent safety profile across the clinical trial program includes an identified risk of predominantly nonserious autoimmune thyroid disorders.
DESIGN/METHODS:
In the 2-year CARE-MS I and II (NCT00530348; NCT00548405) core studies, alemtuzumab-treated patients received 2 annual courses at Months 0 and 12. Patients could enter the extension study (NCT00930553) for ongoing follow-up and as-needed retreatment for relapse or radiological activity. As part of a comprehensive monitoring program, thyroid function testing was performed at baseline and quarterly thereafter. Thyroid monitoring is recommended for 4 years following last dose of alemtuzumab.
RESULTS:
During Years 0-5, thyroid events were reported in 39% (317/811) of patients; 4.4% had serious thyroid events. Most thyroid events were mild or moderate in severity. The proportion of patients with thyroid events peaked at Year 3 and subsequently declined (Year 1: 5.7%; Year 2: 10.7%; Year 3: 20.9%; Year 4: 12.6%; Year 5: 10.0%). No thyroid events resulted in study discontinuation. Most events were managed with first-line, conventional therapy; 3.2% of patients underwent thyroidectomy.
CONCLUSIONS:
The annual incidence of thyroid events following alemtuzumab treatment is consistent with previous reports, peaking in Year 3 and declining thereafter. Ongoing patient education and laboratory monitoring continue to enable timely detection and treatment of alemtuzumab-associated thyroid events.

Based on the CARE I/CARE II data on which Alemtuzumab was licenced the rate of autoimmunities was about 20% but based on follow-up we know this is closer to 50% and indeed in this study 40% of people treated developed thyroid problems by 5 years and one cannot believe it is going to go from 10% down to 0% in year 6 so more to come. Neuros perhaps are accepting about this because, thyroid problems are generally treatable.....which in 4% of cases is having your thyroid removed surgically. However some of these autoimmunities can be very serious if not picked up and the the original phase II was halted because of deaths due to ITP. We have to be ever vigilant for this as another poster at AAN points out


P2.103 Fatal Autoimmune Haemolytic Anemia Associated with Alemtuzumab in a MS Patient with Severe Relapsing Remitting Disease Course and Prior Immune Therapies —Peter Rieckmann, Arne Lenz, Markus Hoffmann, Udo Poske, Karin Behr, Boris Kallmann

Is this frightening neuros and pwMS from taking this drug? 


Ocrelizumab and now oral cladribine are coming from behind and do not have this problem. Is the clock ticking?

Yet the efficacy is good

ProfG has already shown you
P3.054 - Long-Term Responders from the CARE-MS I Study: No Evidence of Disease Activity for 4 Years Following 2 Courses of Alemtuzumab and No Further Treatment
Gavin Giovannoni



P3.022 - Patients with Active RRMS and an Inadequate Response to Prior Therapy Demonstrate Durable Improvements in Relapse and Disability Following Treatment with Alemtuzumab: 5-Year Follow-Up of the CARE-MS II Study
Coles AJ et al.

OBJECTIVE:To examine 5-year clinical efficacy and safety in CARE-MS II alemtuzumab-treated patients.
BACKGROUND: In CARE-MS II (NCT00548405), active relapsing-remitting MS (RRMS) patients with an inadequate response (≥1 relapse) to prior therapy at baseline, alemtuzumab showed superior efficacy versus SC IFNB-1a over 2 years. Efficacy was durable through 4 years.
DESIGN/METHODS: In the CARE-MS II core study, alemtuzumab patients received 2 annual treatment courses at Months 0 and 12. Patients could enter an extension (NCT00930553), with as-needed alemtuzumab retreatment for relapse or radiological activity. Endpoints included annualized relapse rate (ARR), 6-month sustained accumulation of disability (SAD)/confirmed disability progression (≥1-point EDSS increase [≥1.5-point if baseline EDSS=0] confirmed at 6 months), 6-month sustained reduction in disability (SRD; ≥1-point EDSS decrease [baseline score ≥2.0]), and no evidence of clinical disease activity (absence of relapse and 6-month SAD).
RESULTS: 393 (93%) alemtuzumab-treated patients completing CARE-MS II enrolled in extension. Through 5 years, 91% remained on study, 60% received no alemtuzumab since the initial 2 courses, and 8% received another disease-modifying therapy. Low ARR (0.21) was maintained over Years 3-5. Through Years 0-5, 76% of patients were free from 6-month SAD, 77% had stable or improved EDSS, and 43% achieved 6-month SRD. More than half of patients (52%) had no evidence of clinical disease activity over Years 3-5. Incidences of infusion-associated reactions and infections during extension decreased versus core study; serious adverse event (AE) incidence was low. Thyroid AE incidence peaked at Year 3, declining thereafter.
CONCLUSIONS: Alemtuzumab demonstrated durable improvements in clinical efficacy over 5 years despite most patients not receiving alemtuzumab for 4 years. Based on these findings, alemtuzumab may provide a unique treatment approach with durable efficacy in the absence of continued treatment for RRMS patients.

P3.053 - Durable Efficacy of Alemtuzumab Over 10 Years: Long-Term Follow-Up of Patients with RRMS from the CAMMS223 Study

OBJECTIVE:Evaluate 10-year efficacy and safety in treatment-naive patients who received alemtuzumab 12 mg in phase 2 CAMMS223, and enrolled in the ongoing CARE-MS extension study.

BACKGROUND: In CAMMS223, in patients with active relapsing-remitting MS (RRMS), alemtuzumab showed superior efficacy versus SC IFNB-1a. During 3 randomized studies, efficacy was durable through 5 years, with most patients not receiving retreatment for 4 years.
DESIGN/METHODS: In the CAMMS223 core study (NCT00050778), patients were randomized to receive 2 annual courses of alemtuzumab with a possible third course based on T-cell counts. Patients could enter the extension (NCT00930553) for additional follow-up and as-needed retreatment. Endpoints included annualized relapse rate (ARR) and 6-month sustained accumulation of disability (SAD)/confirmed disability progression (≥1-point Expanded Disability Status Scale [EDSS] increase [≥1.5-point if baseline EDSS=0]).
RESULTS: Of 108 alemtuzumab 12-mg-treated patients in CAMMS223, 60 entered the extension; based on rising T-cell counts, 39 received a third course (25 after Year 3). 57 (95%) of extension patients were followed through Year 10; of these, 12% and 10% received 4 or 5 alemtuzumab courses, respectively. Through Year 10, low ARR was maintained (0.07), 76% were free from 6-month SAD, and 78% had stable or ≥1-point improved EDSS versus baseline. Serious adverse event (AE) incidence was low. Incidence of infusion-associated reactions decreased after first treatment course (98%). Annual incidence of infections decreased after Year 1 (55%). Incidence of thyroid AEs peaked in Year 3 (17%) and declined thereafter.
CONCLUSIONS: Alemtuzumab demonstrated durable clinical efficacy through Year 10 despite most patients receiving ≤3 treatment courses. Safety findings were consistent with those of other alemtuzumab clinical trials. Based on these findings, alemtuzumab may provide a unique treatment approach with durable efficacy in the absence of continued treatment for patients with RRMS.

You asked for the ten year data and there you have it the 10 year data. More of the same compared to that already published by Tuohy et al. but as you can see it is not simply two doses and that's it, as many people need another dose. So is it really pulsed immune reconstitution therapy (PIRT) as suggested by profG or pulsed immune ablation therapy (PIAT), where by the pathogenic cells are wiped away for years and if and when they regenerate they need another dose of medicine. 

However what you want to know is what is the number of converters to secondary progression?

Based on the original 10 year Cambridge data it was about 4%

COI None relevant

30 comments:

  1. Thats encouraging :-)

    I'm due my second round next month and have developed an under-active thyroid. It doesn't worry me in the grand scheme of things as side effects are only really a cause for a concern if you are healthy to start with. Clearly with MS I'm not hence I have to pick my poison.

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  2. Can you show us the data you have on what happens to people who have had Cladribine, in the medium term? I know it is very scant compared to the data on Alemtuzamab but it would still be interesting.

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    1. Pretty good
      ProfG showed the 4 data of the CLARIMS extension 4 year study
      a few days ago

      http://multiple-sclerosis-research.blogspot.com/2016/04/researchspeak-will-you-be-able-to.html

      Basically Placebo group had 0.25 relapses a year in CLARIMS Trial it was 0.1 relapse in 2 year extension on drug it was 0.1 so same and for people
      on drug for a year and then nothing for further two years 0.15 relapses/year. This is as good as alemtuzumab I think. However secondard autoimmunity in alemtuzumab will be 40-50% and 0% in cladribine arm

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  3. PIAT is a more accurate description of what this drug is doing.

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  4. Hello

    You say that Ocrelizumab is coming from behind and the clock may be ticking on Alemtuzumab as neither it nor Cladribine have the same risk of SEs.

    Assuming Ocrelizumab were available, how does it stack up in terms of proven efficacy over the long term against Alemtuzumab? i.e. if presented with a patient with newly diagnosed active RRMS that was otherwise in good health and Ocrelizumab was an option, based on the existing clinical data of both Alemtuzumab and Ocrelizumab what would be your recommendation? What about administration of Ocrelizumab over the longer term - would continued six monthly infusions be required for life/until it ceases to be effective or SEs develop or is it likely that after a number of infusions the effects become more permanent as per the effects of alemtuzumab for the majority of patients? Would your advice change if the patient was a woman of child bearing age considering starting a family?

    Apologies - that is a lot of questions. Genuinely trying to understand how the existing and pipeline drugs stack up against each other

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    1. In terms of phase III data on treatment they are comparable in terms of efficacy, what happens in the long term we will have to wait and see as I don't know.

      The rituximab experience may tell us an based on a comment from Prof Hauser posted by ProfG then the conversion to SPMS rate may be favourable for alemtuzmab but for ocrelizumab we have to see the data

      As you say at the moment ocrelizumab is be touted as a once every six months for life...but the question is does this need to happen? Will we ever see the trial data and the extension study of people not treated i.e on drug for 2 years and then off.

      Alemtuzmab is a few treatments every no and then.

      What is my recommendation...it all depends on circumstance.

      If you are planning starting a family, ideally you need to be drug free as antibodies can cross the placenta so you need to discuss this with your neurologists

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  5. Thanks MD :) Two big questions:

    1) Prof G said the majority of patients received just two courses to achieve NEDA. Here it says 39/60 received a third course. This is obviously nearly 2/3 of patients requiring a third course. There is also no mention of MRI activity whatsoever. Was this a secondary end-point? Any data on this?

    2) retreatment based on T-cell levels... Shouldn't it be based on new MRI activity or clinical relapses? I thought the idea was for the T-cells to reconstitute without ms memory, so unless the quality can be measured why is this used as an indicator for retreatment?

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    1. 1. If you see the original cambridgge data it was about 50% needed just two does to get NEDA however in this trial it is only a third. The additional treatment will be based on development of clinical or I imagine MRI activity. We will have to weight until the data is published assuming that Genzyme include it

      2. Retreatment based on T cell levels. That was a suggestion for Cladribine to mitigate the risk of leucopaenia for alemtuzumab relapse and MRI would indicate non NEDA and time to retreat
      If we look at the data of T cell depletion after one treatment with Alemtuzumab in many cases there is long term depletion therefore do you need to be redosed. I think the retreatment

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  6. "Deaths" as a pleural? Not meaning to downplay the seriousness of ITP, but wasn't the single death due to undiagnosed ITP? Had it been detected earlier (which it now presumably would be with the monthly blood test), it would have had the opportunity to be successfully treated.

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  7. Retreatment based on T-cell levels? .... what is this... this is not shown anywhere else, what is the criteria to retreat?

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    1. Based on welsh studies disease break through occurs with increasing T cell numbers with Cambridge data it doesn't

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    2. Retreating based on T-cell levels completely discredits the whole mechanism on which Alemtuzumab is proposed to work!

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    3. And what is this mechanism?

      If T cells are not depleted then the antibody has not worked...maybe there are neutralising antibodies made. It is amazing that 95% of people make anti-alemtuzumab antibodies I was shocked when I saw this on the EMA website.

      I am guessing that it says something about the so called re boot and it is just a general wipe out hoping that the pathogenic cells do no re expand.

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    4. Yes an initial effect is created by bluntly & extremely suppressing T-cells (& B-cells). It's called an induction treatment for a reason, patients take it in the hope that it won't be a lifelong commitment. Why retreat someone whose cells numbers may have risen/normalised, but they are NEDA?!

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  8. These extension studies ...

    They don´t really say so much ... they are biased by the fact, that those patients who choose to continue, are the "fittest of the fittest", i.e. most of them probably would not have any progress anyhow.

    So these extension studies ... are only tools for the marketeting / sales department at Big Pharma

    D

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    1. You are completely wrong in your assertions. If anything those going onto alemtuzumab will have worse/more active disease than most pwMS.
      Extension studies are anything but tools for marketing. They are essential to show a drugs efficacy and safety over the long term.

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    2. Probably this will not be published, since I deeply disagree with MD.

      Of course there is a great risk of biasis with extension studies. It is even critiziced in the literature for carry forward the biasis i.e. the fittest of the fittest wil tsay on treatment.

      Hmmm ... Let us see if this will be allowed to be publihsed :-)




      I

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    3. "You are completely wrong in your assertions. If anything those going onto alemtuzumab will have worse/more active disease than most pwMS."

      Therefore, more than 60% of alem-treated patients felt the need to enter the extension, probably because they were not so satisfied with the 5-year results.

      The truth is that investigation is needed to tell why people drop off studies and extensions. No explanation should be a priori discredited.

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    4. Perhaps they were disappointed that they weren't offered "Liberation" therapy? ;-)

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    5. Will it be published....it is published as you are reading it. Will it come in the form of a paper. It is up to genzyme and whether they want to publish it. If they do it will arrive even with people lost to follow up. It is a discussion point. The naysayers use it as bad data and the marketeers as good data. All yo have to be aware are the caveats, but if is bad news it won't be published

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  9. 4% conversion rate for Secondary Progressive MS? If this even this is very good!
    I'm only afraid about the autoimmunity to the thyroid, because I have a sister with hypothyroidism, so I already have genetic predisposition for it, or not ...

    I know the data with Cladribine are scarce, but already have conversion rate data for Secondary Progressive MS in whom used the Cladribine as a treatment option for RRMS?

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  10. Is there a sense of why so many more patients have dropped between five and ten years? If patients drop because they're healthy and no longer interested in being lab rats, that's a very different story than dropping due to drug failure.

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    1. To have 90% out in one study and 40% in another seems severe. Especially if half those who have dropped have been NEDA as those numbers would be in agreement with the other trial.

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  11. I do not trust this general description of "first-line, conventional therapy" for thyroid disease. How much of this was the radioiodine therapy, which effectively is equivalent to thyroidectomy, as it means that a daily, lifelong levothyroxine supplementation is needed?

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  12. MD thank you kindly for posting all of this & answering questions you can. It would be much appreciated if Prof G could jump in or post his summary of the 10 year Alemtuzumab data. I find it perplexing that anyone would be retreated based on T-cell levels alone, even in trial phase. What if the cell levels have reconstituted without ms memory and the patient is otherwise NEDA?

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    1. Yes you are very correct the disease related t cells will be a very very minor population of the T cell pool and therefore it will be impossible to know what is happening to them. It is amazing that antigen specific cells are never followed. This was our plan in the clad v alemtuzumab trial which the nihr. Thought was too expensive to fund.
      It has been suggested that relapses are unrelated to T cell numbers if all you are looking at the wood then you miss the point as it will be absolutely dependent on the number of trees.

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