A little more early hard hitting data…same answer!

A

After this weekends post you said “How much more “hit it hard and early” evidence do we need before neuros actually begin to adopt this and abandon the escalation strategy?

I suspect abit more evidence, which they need to read

However, one option could be to keep the escalation approach and just avoid using the CRAB drugs etc.

The advantage of early effective treatment has been shown again (diagram below). However, I would also say that both lines continue to worsen and this is why we need combinations to do more than just target the peripheral immune system. Yes, I know some people do vey well on the CRAB drugs but many people do not. But Time is Brain and we can hear Tick, Tick Tick.

Here, the escalation (ESC=orange) group started their treatment history with one of following DMTs: IFN beta 1a/b or glatiramer acetate or azathioprine. All of these patients escalated to a higher-efficacy DMT after a median time of 6.3 years, and remained exposed to these high efficacy DMTs for a median of 4.0 years. Early intensive therapy (EIT=red) group were exposed to fingolimod, natalizumab, mitoxantrone and cladribine. No one included in the EIT study cohort received alemtuzumab and ocrelizumab. Again a no brainer to guess what happened.

Long-term disability trajectories in relapsing multiple sclerosis patients treated with early intensive or escalation treatment strategies.Iaffaldano P, Lucisano G, Caputo F, Paolicelli D, Patti F, Zaffaroni M, Brescia Morra V, Pozzilli C, De Luca G, Inglese M, Salemi G, Maniscalco GT, Cocco E, Sola P, Lus G, Conte A, Amato MP, Granella F, Gasperini C, Bellantonio P, Totaro R, Rovaris M, Salvetti M, Torri Clerici VLA, Bergamaschi R, Maimone D, Scarpini E, Capobianco M, Comi G, Filippi M, Trojano M; Italian MS Register.Ther Adv Neurol Disord. 2021 May 31;14:17562864211019574 Background and aims: No consensus exists on how aggressively to treat relapsing-remitting multiple sclerosis (RRMS) nor on the timing of the treatment. The objective of this study was to evaluate disability trajectories in RRMS patients treated with an early intensive treatment (EIT) or with a moderate-efficacy treatment followed by escalation to higher-efficacy disease modifying therapy (ESC). Methods: RRMS patients with ⩾5-year follow-up and ⩾3 visits after disease modifying therapy (DMT) start were selected from the Italian MS Registry. EIT group included patients who received as first DMT fingolimod, natalizumab, mitoxantrone, alemtuzumab, ocrelizumab, cladribine. ESC group patients received the high efficacy DMT after ⩾1 year of glatiramer acetate, interferons, azathioprine, teriflunomide or dimethylfumarate treatment. Patients were 1:1 propensity score (PS) matched for characteristics at the first DMT. The effect of early versus late start of high-efficacy DMT was assessed by the mean annual Expanded Disability Status Scale (EDSS) changes compared with baseline values (delta-EDSS) in EIT and ESC groups. Results: The study cohort included 2702 RRMS patients. The PS matching procedure produced 363 pairs, followed for a median (interquartile range) of 8.5 (6.5-11.7) years. Mean annual delta-EDSS values were all significantly (p < 0.02) higher in the ESC group compared with the EIT group. In particular, the mean delta-EDSS differences between the two groups tended to increase from 0.1 (0.01-0.19, p = 0.03) at 1 year to 0.30 (0.07-0.53, p = 0.009) at 5 years and to 0.67 (0.31-1.03, p = 0.0003) at 10 years. Conclusion: Our results indicate that EIT strategy is more effective than ESC strategy in controlling disability progression over time.

They say “No RCT has directly compared so far the impact of an early versus a delayed use of high-efficacy DMTs on the long-term MS disability outcomes”. However this is not true! The CARE-MS trials do just this. I missed reporting on this…sorry. However we have:

Alemtuzumab CARE-MS I the follow up (CARE-MS I and CARE MS extension) = EIT

Beta interferon 2 year switch to Alemtuzumab (CARE-MSI Extension)

Beta interferon 3 years startAlemtuzumab (CARE-MS II extension)

Interferon (pre care -MS II 3 years)-Interferon 2 years switch to alemtuzumab (CARE-MS II extension)

6 years of follow-up. What happened?

Efficacy and safety of alemtuzumab over 6 years: final results of the 4-year CARE-MS extension trial Coles AJ et al. Ther Advan Neurrol Disease https://journals.sagepub.com/doi/10.1177/1756286420982134 Background: In the 2-year CARE-MS I and II trials, alemtuzumab 12mg administered on 5
consecutive days at core study baseline and on 3 consecutive days 12months later significantly
improved outcomes versus subcutaneous interferon beta-1a (SC IFNB-1a) in relapsing–
remitting multiple sclerosis patients. Here, we present the final 6-year CARE-MS extension
trial results (CAMMS03409), and compare outcomes over 6years in patients randomized to
both treatment groups at core study baseline. Methods: Over a 4-year extension, alemtuzumab patients (alemtuzumab-only) received asneeded additional alemtuzumab (⩾12months apart) for disease activity after course 2. SC IFNB1a patients who entered the extension discontinued SC IFNB-1a and received 2 alemtuzumab 12mg courses (IFN–alemtuzumab), followed by additional, as-needed, alemtuzumab.
Results: Through year 6, 63% of CARE-MS I and 50% of CARE-MS II alemtuzumab-only patients
received neither additional alemtuzumab nor other disease-modifying therapy, with lasting
suppression of disease activity, improved disability, and slowing of brain volume loss (BVL). In
CARE-MS I patients (treatment-naive; less disability; shorter disease duration), disease activity
and BVL were significantly reduced in IFN–alemtuzumab patients, similar to alemtuzumab-only
patients at year 6. Among CARE-MS II patients (inadequate response to prior treatment; more
disability; longer disease duration), alemtuzumab significantly improved clinical and magnetic
resonance imaging outcomes, including BVL, in IFN–alemtuzumab patients; however, disability
outcomes were less favorable versus alemtuzumab-only patients. Safety profiles, including
infections and autoimmunities, following alemtuzumab were similar between treatment groups.
Conclusion: This study demonstrates the high efficacy of alemtuzumab over 6 years, with a
similar safety profile between treatment groups.

We have shown that both first-line treatment with alemtuzumab and switching to alemtuzumab from SC IFNB-1a lead to sustained reduction in disease activity, along with slowing of disability accumulation and brain atrophy. However, prolonged delay in switching to alemtuzumab leads to potentially unrecoverable loss of function.

So it rather suggests that you have 2 years to get on alemtuzumab (or probably other high-efficacy treatment) but delay this by a few more years and you lose some level of benefit in slowing progression that you are not going to get back. This mirrors benefits in slowing conversion to SPMS. It also says to me that the decision by the EMA and FDA to use alemtuzumab essentially third line is meaning the drug is being neutered and that the big benefit that alemtzumab has to offer is being lost by people not getting access quick enough.

This papers has an altmetric of 1 and essentaially no news coverage…but the contents are important, so get this paper Tweeted and read…Maybe my Dyslexia has kicked in and I am reading this wrong? Maybe

This work further shows that it is a shame that alemtuzumab can’t really be used first line in UK . It likewise a shame that cladribine is hampered by its label in Europe. Malcolm QALY (yes I know, it is Qualie) has said a special application needs to done to allow it to be used in “active MS” verses “highly active MS”. Will this ever get filed?

ProfK is trying to get people onto high efficacy DMT as quick as possible. it is called AttackMS…at least one Neuro can see the light:-)

COI Multiple

General Disclaimer: Please note that the opinions expressed here are those of the author and do not necessarily reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust.

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MouseDoctor

14 comments

  • MD – i have a question on the therapeutic window for Alemtuzumab. A patients presents with CIS and a few years later (say 5) a second event occurs and a diagnosis of MS is made. In reality, it has always been MS. Has this patient missed the therapeutic window? to me, this is one of the main deficiencies of the treat hard and early approach. Gaining access to high efficacy treatments is hard enough once diagnosed but if the diagnosis itself is delayed then you may already be fighting a losing battle

    • Good point. This of course says there is wobble room around what is being suggested

      In the animals it is all about damage accumulation after one attack for some strains after two attacks in others and after 4 attacks in others.

    • Mouse doctor
      Good point. This of course says there is wobble room around what is being suggested

      In the animals it is all about damage accumulation after one attack for some strains after two attacks in others and after 4 attacks in others.

  • Are there any benefits at all for someone starting alemtuzumab after say, 12 years, even so they had been on another EID for the last 10 years (i.e. within 2 ys of diagnosis)?

  • Nice post

    Have this question that is not directly related to the post, and was planing to do a separate post on the Q&A but you mention on this post already

    What altmetric means?

    Obrigado

  • Whether the DMTs are approved for first or second line therapies also has a major impact on using the drug as a EIT. In Canada, the DMTs are covered, however, many of the HE DMTs are second line.

  • Thank you for posting this.
    It is something I struggle with: I was diagnosed 10 years ago (but had symptoms even 10 years before that).
    After one year, I was put on DMTs (interferon, DMF, now teriflunomide).
    So that’s 11 years without treatment, and 9 years of various low-efficacity DMTs.
    Meanwhile, I have proved to be quite infection-prone even on those low-efficacity DMTs.
    So now I wonder: is it worthwile to pursue a high-efficacity DMT after all this time?
    I notice there are benefits to be made from a switch, even after 2 years or 6 years, but my time-frame adds up to 20 years. Also, I do not only stand to gain from a switch, as I fear the added risk of infections. I already experienced long periods of reduced quality of life due to infections (bed-ridden).
    I realize I have to make the cost/benefit decision in the end, but any thoughts on this are very welcome.

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