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#ClinicSpeak & #ResearchSpeak: daclizumab's impact on cognitive function

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How important is your cognition to you? Will it influence your choice of DMT? #ClinicSpeak #ResearchSpeak

I have made the case many times to reclassify, or rebrand, MS a preventable dementia. The majority of people with MS have cognitive impairment and it is almost certainly the most important cause of unemployment in early MS. 50% of pwMS in Europe are unemployed at an EDSS level (3.0-3.5); a level of disability that is not associated with overt physical disability. PwMS at these low EDSS levels rarely complain of specific cognitive symptoms, but rather the more pernicious symptom of cognitive fatigue. The brain is remarkably good at compensating for cognitive deficits by working harder by using new areas of undamaged brain (plasticity), which increases energy consumption; the result is cognitive fatigue. 

Many patients tell me that 30 minutes of deep concentration makes them feel like they have just studied all night and completed a 3 hour school of university examination. This level of cognitive exhaustion is why so many pwMS simply can't compete in the knowledge economy. 

On this backdrop it is reassuring to finally have data to support the use of daclizumab, one of the high-efficacy DMTs, over an existing interferon-beta formulation, to delay, or prevent, worsening of MS-related cognitive problems. Subjects who received daclizumab in the DECIDE phase 3 trial had greater improvement from baseline in the performance of the Symbol Digit Modalities Test (SDMT) compared to subjects treated with IFN beta-1a. More pwMS treated with daclizumab had a clinically meaningful improvement in SDMT and less chance of worsening than subjects  treated with interferon-beta. The SDMT is a well-validated cognitive outcome measure that correlates with cognitive impairment on formal testing, long-term disease outcomes or disability and gray and whole brain atrophy. 

Are these observations unique to daclizumab, or will they be seen with all high-efficacy DMTs? These results are possibly unique to daclizumab. DECIDE is the first trial to convincingly show that a specific DMT has a positive impact on cognitive outcomes. Could the unique mode of action of daclizumab be relevant? Daclizumab expands a population of cells from the hard-wired, or innate, immune system called natural killer cells (NK cells). NK cells have many properties, but one of them are antiviral effects. If MS is due to a virus then these NK cells may target and clear the virus from the central nervous system. This may be particularly relevant if low-grade viral infection(s), for example with EBV or HERVs (human endogenous retroviruses), are what is driving the slow burn within the brains of pwMS. Daclizumab may be protecting your cognition by clearing the virus in the cortical gray matter. 

I think the importance of  this data cannot be under-estimated. People with MS in the know may value their cognition more than other neurological functions and hence this data is likely to become an important differentiator of daclizumab from the other high-efficacy DMTs.

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BACKGROUND: Cognitive impairment is common in multiple sclerosis (MS), with cognitive processing speed being the most frequently affected domain.

OBJECTIVE: Examine the effects of daclizumab beta versus intramuscular (IM) interferon (IFN) beta-1a on cognitive processing speed as assessed by Symbol Digit Modalities Test (SDMT).

METHODS: In DECIDE, patients with relapsing-remitting multiple sclerosis (RRMS) (age: 18-55 years; Expanded Disability Status Scale (EDSS) score 0-5.0) were randomized to daclizumab beta ( n = 919) or IM IFN beta-1a ( n = 922) for 96-144 weeks. SDMT was administered at baseline and at 24-week intervals.

RESULTS: At week 96, significantly greater mean improvement from baseline in SDMT was observed with daclizumab beta versus IM IFN beta-1a ( p = 0.0274). Significantly more patients treated with daclizumab beta showed clinically meaningful improvement in SDMT (increase from baseline of ⩾3 points ( p = 0.0153) or ⩾4 points ( p = 0.0366)), and significantly fewer patients showed clinically meaningful worsening (decrease from baseline of ⩾3 points ( p = 0.0103)). Odds representing risk of worsening versus stability or improvement on SDMT were significantly smaller for daclizumab beta ( p = 0.0088 (3-point threshold); p = 0.0267 (4-point threshold)). In patients completing 144 weeks of treatment, the effects of daclizumab beta were generally sustained.

CONCLUSION:  These results provide evidence for a benefit of daclizumab beta versus IM IFN beta-1a on cognitive processing speed in RRMS.

CoI: multiple

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