Monday, 9 June 2014

Natalizumab: the 5-year extension study results

What have we learnt from the natalizumab open-label extensions study? #MSBlog #MSResearch

"The 5-year open-label natalizumab extension study tells us 5 things:
  1. Delaying access to natalizumab, and arguably other DMTs, by 2-years comes at cost. MSers on placebo for 2-years never catch-up. This should reignite the debate about whether or not we can justify starting placebo-controlled trials in the current era.
  2. MSers started early on natalizumab, and presnumably other DMTs, do better. It appears that waiting to start a DMT comes at a cost of a lower response rate to the treatment. Why? I suspect that uncontrolled inflammation changes the micro-environment of the CNS, which makes it more difficult to modulate with DMTs. This observation argues for early therapy. Is it ethical to delay access to highly-effective therapies?
  3. Short-term exposure to natalizumab (1 or 2 infusions only) results in the development of neutralizing antibodies and subsequent hypersensitivity and infusion reactions. In other words if you are going to use natalizumab you need to use for several months to overcome this phenomenon. The low NAB rate to natalizumab is an active process; the high-dose of natalizumab must educate the immune system over the initial months to switch-off NAB production. In immunology we call this high-zone tolerance.
  4. How effective natalizumab actually is; the majority of MSers on natalizumab remained stable.
  5. How important long-term extension studies are at providing additional data about the effectiveness and safety of a drug after launch. It is a great pity Biogen-Idec have pulled the plug on STRATA after 8 years; it would have been a great opportunity to see how many natalizumab-treated MSers developed SPMS. Based on my own anecdotal observations a lot fewer than expected. I have also noted therapeutic lag; MSers with more advanced EDSS are more likely to progress within the first 3-4 years and to then stabilise. I have asked Biogen-Idec to look into this observation to see if actually exists."



OBJECTIVES: Report long-term safety and effectiveness of natalizumab over 240 weeks in the prospective, observational, open-label safety of natalizumab re-dosing and treatment (STRATA) study.

METHODS: MSers (N = 1,094) previously enrolled in natalizumab multiple sclerosis clinical trials received natalizumab 300 mg IV every 4 weeks, up to 240 weeks. Serious adverse events, Expanded Disability Status Scale (EDSS) scores, and annualized relapse rates were analyzed.

RESULTS: At data cutoff (February 9, 2012), natalizumab exposure was 3,460 MSer-years; a median of 56 (range 1-70) infusions were received. Serious adverse events, including progressive multifocal leukoencephalopathy, were consistent with natalizumab's known profile. Upon natalizumab re-exposure, rates of anti-natalizumab antibodies and hypersensitivity reactions were 3% and 5% overall, and 40% and 24% among MSers with 1 to 2 prior natalizumab doses. MSers originally randomized to placebo/another disease-modifying therapy vs natalizumab in previous studies had significantly higher EDSS scores at STRATA baseline; this difference persisted over 240 weeks. EDSS scores generally remained stable. MSers initially randomized to natalizumab had lower annualized relapse rates over 240 weeks.

CONCLUSIONS: Serious adverse events were consistent with natalizumab's known safety profile; short exposure with a gap before redosing was associated with higher incidences of anti-natalizumab antibodies and hypersensitivity reactions. Stability of EDSS scores and consistently low relapse rates over 5 years of natalizumab treatment are consistent with its known efficacy profile.

CoI: multiple

3 comments:

  1. Prof G,

    Can this sort of data tell us anything about what's happening in MS. Stopping the immune system cells from getting into the cns looks to be a good thing. But what is happening in the cns once the immune cells are prevented from entering? Are they ( say ebv infected b cells actually doing any damage on their own)? Can't a spinal tap of those where nataluzimab or alemtuzumab has been effective show what's happening. Dr Coles told a friend that the chance of needin additional alemtuzumab infusions after the first two was 50 per cent. I guessing this means that the target of the immune attack rears it's ugly head. I feel we must be close to working out whats is going on, but never quite get there!

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  2. If treating early is so important, what can be done to speed diagnosis? I'm sitting here, in my 40's, on one of your 'effective' drugs, doing everything I can. I was only diagnosed in the last year. I have had doctors tell me that odd sensations were simply depression. I have thought I was crazy because motor symptoms disappeared before I could get in to be examined.

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    Replies
    1. Apart from therapies for progressive ms, a definitve test for ms should be at the top of the priorities list.

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