ResearchSpeak: daclizumab and black hole formation
Do you want to prevent end-organ damage or loss of brain tissue? #ResearchSpeak #MSBlog #MSResearch
“Preventing end-organ damage is the what we should all be aiming for as a treatment target in MS. The end-organ is the brain and spinal cord. We know that MS, or the shredder, damages the end-organ acutely in MS lesions by transecting axons and killing nerves (relapse). Those axons and nerves that survive the shredder acutely are damaged and soldier on to die off gradually over time (progression). Therefore it makes sense to switch off lesion formation as best we can as soon as possible in the disease; by doing this we prevent further axonal transections (relapses) and priming of nerves to die off in the future (progression). This is the philosophy that underpins the early effective treatment paradigm. To me this is common sense, but not all people in the field agree with me.”
“It was only this week that I read a proposal that still suggested we should only start DMTs in people with MS presenting with a clinically isolated syndrome if they had 9 or more lesions on MRI. In other words if you have only 2 lesions on MRI let’s wait for the shredder to leave another 7 or more lesions before we try and turn it off. Never mind the risk the individual that lesion 5 may be the one that leaves him or her paraplegic and doubly incontinent. One of the differences between someone who has 2 lesions vs. 15 lesions, at baseline, when they present with their first attack is time. The person with 15 lesions has probably had asymptomatic MS for sometime and may have already acquired a lot of damage. In comparison the person who presents with 2 lesions has probably had MS for a much shorter period of time, has less damage and may have the most to benefit from early treatment. The person with 2 lesions is lucky that he/she has presented early. The person with 15 lesions is unlucky in that the shredder has been quietly shredding the brain without causing overt symptoms. As this person has less reserve it is not surprising that they don’t do as well longterm when compared to people with fewer lesions at baseline. Prognosis is determined by reserve capacity, which gives you the ability to recover and maintain function. I simply can’t see the rationale in waiting for damage to occur to the end-organ before starting a treatment. This particularly pertinent as new more effective treatments come on line.”
“The good news is that as we move into the upper echelons of effectiveness the treatments have greater impact on preventing or delaying end-organ damage. One marker of end-organ damage is the so called black hole on T1-weighted MRI. We know from pathology studies that black holes are correlated with loss of nerve fibres. It is therefore reassuring to see that daclizumab is effective at reducing the accrual of black holes (damage) on MRI. Interestingly, in a meta-analysis of baseline variables that predict outcome in pwMS treated with placebo that was presented at ECTRIMS last year, T1 black holes was the third best predictor of outcome behind the PASAT (cognition) and the SF-36 physical component (quality of life). In short if I had MS I would want to be on a drug that had been shown to prevent end-organ damage. This is why our treatment target will have to evolve beyond NEDA-3 to incorporate markers of end-organ damage in MS, for example the normalisation of brain volume loss and spinal fluid neurofilament levels. Maybe you disagree?”
“I know many of you dislike the term shredder; it is not my term but it captures in a word what is happening to the brain and spinal cord in people with active MS. If you don’t believe me just come and sit-in with me when I do my MS clinic on a Thursday afternoon.”
BACKGROUND AND PURPOSE: In the SELECT study, treatment with daclizumab high-yield process (DAC HYP) versus placebo reduced the frequency of gadolinium-enhancing (Gd(+) ) lesions in patients with relapsing-remitting multiple sclerosis (RRMS). The objective of this post hoc analysis of SELECT was to evaluate the effect of DAC HYP on the evolution of new Gd(+) lesions to T1 hypointense lesions (T1 black holes).
METHODS: SELECT was a randomized double-blind study of subcutaneous DAC HYP 150 or 300 mg or placebo every 4 weeks. Magnetic resonance imaging (MRI) scans were performed at baseline and weeks 24, 36 and 52 in all patients and monthly between weeks 4 and 20 in a subset of patients. MRI scans were evaluated for new Gd(+) lesions that evolved to T1 black holes at week 52. Data for the DAC HYP groups were pooled for analysis.
RESULTS: Daclizumab high-yield process reduced the number of new Gd(+) lesions present at week 24 (P = 0.005) or between weeks 4 and 20 (P = 0.014) that evolved into T1 black holes at week 52 versus placebo. DAC HYP treatment also reduced the percentage of patients with Gd(+) lesions evolving to T1 black holes versus placebo.
CONCLUSIONS: Treatment with DAC HYP reduced the evolution of Gd(+) lesions to T1 black holes versus placebo, suggesting that inflammatory lesions that evolved during DAC HYP treatment are less destructive than those evolving during placebo treatment.
CoI: multiple, I am a co-author on this paper and was member of the DECIDE steering committee