Will daclizumab prove to be a man or a boy / woman or girl? #ClinicSpeak #MSBlog #MSResearch
“I have made the point many times on this blog that the best human model for studying relapsing MS is natalizumab withdrawal. When natalizumab washes out of your system and immune surveillance restarts the immune system finds what is causing MS and MS flares up with a vengeance. The level of MRI activity, i.e. gadolinium-enhancing activity, associated with post-natalizumab rebound can be so prominent that some of us say the scan looks like a christmas tree, the lights being the active MS lesions.”
“Rebound post-natalizumab is one of the observations for the field hypothesis; i.e. there is something in the brain of MSers (the field) that is causing MS and in the absence of an immune system it does no harm. However when you let the immune system in it finds what is there and tries to kill it, this cause direct and indirect damage that results in relapses and primes the nervous system for secondary, or delayed, neurodegeneration in the future (secondary progressive MS).”
“I am therefore thrilled to hear that one Pharma company is using rebound post-natalizumab to see how effective their putative drug is. If a drug can’t prevent rebound then it is not that effective. This is a very high hurdle to pass as most DMTs, or putative DMTs, that have been tried in this setting have failed to prevent rebound. This list includes steroids, glatiramer acetate, interferon-beta and dimethyl fumarate. The drugs that do prevent rebound are fingolimod and rituximab. The rituximab data is not published yet but comes from Sweden. In Sweden, rituximab, despite it being used off-label, is now the standard treatment for MS post-natalizumab. This augurs well for ocrelizumab, which works in the same way rituximab. The jury is still out regarding teriflunomide, but early indicators are that it is also not up to the job. I am reluctant to comment on alemtuzumab, because of the short term dangers associated with an induction therapy in MSers at risk of PML (see earlier posts).”
“Therefore the ability of DMTs to prevent rebound post-natalizumab is the litmus test that has the ability to separate out the men (highly-effective DMTs) from the boys (less effective DMTs). Is this particular Pharma company being brave, bold or stupid? I think they are being very clever; they are simply saying that if our new drug is not good enough to punt with the men then there is little place for it in the market.”
“Everyone says that we can’t, and we shouldn’t, compare the results of clinical trials, but we all do. The purists say that the only way to compare drugs is in head-to-head studies. May be they are correct. But when it comes to relapses another option is to simply ask is drug x good enough to prevent natalizumab rebound? If it prevents natalizumab rebound then it is a highly-effective therapy, if it doesn’t it is not a highly-effective therapy. This is why I can’t wait to see how daclizumab does in this setting. Based on the phase 3 results I suspect it will be man and not a boy. The mode of action of daclizumab appeals to me and if it can prevent rebound post-natalizumab it may become the drug of choice for natalizumab-switchers. I hope Biogen and Abbvie starts a natalizumab switch study soon to answer this question. Daclizumab is not an immunosuppressive drug; T and B cell function appear normal in MSers on daclizumab and there is no opportunistic infection signal on the drug. Daclizumab does reduce T-reg cell function, which may explain why some MSers get secondary autoimmunity on daclizumab as a side effect. More importantly daclizumab expands a population of natural killer cells (NK cells) that are part of the innate immune system that is designed to fight infections, particularly viral infections. Therefore if someone transitions from natalizumab onto daclizumab, and has early or asymptomatic PML, daclizumab may help the immune system to fight the PML. This is all theoretical, which is why we need a clinical trial.”
Gueguen et al.Abnormal inflammatory activity returns after natalizumab cessation in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2014 May.
OBJECTIVE: To characterise recurrence of multiple sclerosis (MS) inflammatory activity during the year following natalizumab (NTZ) cessation.
METHODS: Thirty-two patients with MS were included in a monocentric cohort study. Data were collected prospectively during and after NTZ, with serial clinical and MRI evaluations. The first relapse occurring after interrupting NTZ was the primary outcome measure. The numbers of gadolinium-enhancing lesions before, during and after NTZ treatment, were compared.
RESULTS: During the year following NTZ cessation, the cumulative probability of relapses was estimated at 52.9% and an unusually high MRI inflammation was noticed. It was defined by a number of gadolinium-enhancing lesions >5 and exceeding the gadolinium lesions existing before NTZ initiation. Rebound of MS activity after NTZ cessation was characterised by association of relapses and unusual MRI inflammation. Cumulative probability of rebound was estimated at 39% and mostly occurring between 3 months and 9 months after interrupting NTZ. Risk of rebound appears related with a higher annualised relapse rate and a lower Expanded Disability Status Scale score before NTZ initiation. Rebound was associated with severe recurring relapses in 9% of the patients.
CONCLUSIONS: This study identifies rebound after NTZ cessation as an association of relapses and high MRI activity.