Saturday, 1 August 2015

ClinicSpeak: separating the men from the boys

Will daclizumab prove to be a man or a boy? #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.

CoI: multiple

Another new model of EAE in primates

Stassart RM, Helms G, Garea-Rodríguez E, Nessler S, Hayardeny L, Wegner C, Schlumbohm C, Fuchs E, Brück W A New Targeted Model of Experimental Autoimmune Encephalomyelitis in the Common Marmoset. Brain Pathol. 2015. doi: 10.1111/bpa.12292. [Epub ahead of print]

Multiple Sclerosis (MS) is the most common cause for sustained disability in young adults, yet treatment options remain very limited. Although numerous therapeutic approaches have been effective in rodent models of experimental autoimmune encephalomyelitis (EAE), only few proved to be beneficial in patients with MS. Hence, there is a strong need for more predictive animal models. Within the last decade, EAE in the common marmoset evolved as a potent, alternative model for MS, with immunological and pathological features resembling more closely the human disease. However, an often very rapid and severe disease course hampers its implementation for systematic testing of new treatment strategies. We here developed a new focal model of EAE in the common marmoset, induced by MOG immunization and stereotactic injections of proinflammatory cytokines. At the injection site of cytokines, confluent inflammatory demyelinating lesions developed that strongly resembled human MS lesions. In a proof of principle treatment study with the immunomodulatory compound laquinimod, we demonstrate that targeted EAE in marmosets provides a promising and valid tool for preclinical experimental treatment trials in multiple sclerosis research.

Marmosets are rat sized primates, born as twins. Primates may have their part to play in the development of treatments for MS. 

There is a tendency of people working with primates, and often many clinicians to blame the lack of drugs for MS on rodents.

"Rodent models of experimental autoimmune encephalomyelitis (EAE), only few proved to be beneficial in patients with MS". 

Whilst this may in part be the case we, first have to address the human failings.

Likewise, we can ask where primates have been more successful over their rodent counterparts? 

The literature is full of marmoset studies on treatments that have gone nowhere. Is that the fault of the idea, model or the clinical trial. 

The disastrous "elephant head" anti-CD28 super agonist trial  that made people loose their toes and fingers was tested in marmosets. Five minutes of thinking could have save lots of rodents, primates an humans hard as the end result was entirely predictable based on what anti-CD28/anti-CD3 (proliferation signal of the T cell receptor which is similar in function to the proliferation signal delivered by CD28) does. 

The speed at which animals accumulate damage depends on which strain you use and how you induce the disease. In this study they induce sub-clinical EAE and them put inflammatory cytokines in the brain. This model was developed in rodents years before, as it has some refinement capacities over standard EAE because animals. This is because often you do not get clinical disease and you know where the lesion is. This is probably more of a key issue.

You get better demyelination in non-human primates than you do in a mouse and you get brain lesions. This a fact that I would not argue with. However, what about a rat or a guinea pig, do you need to use a primate? 

I am sure you can make the case, but certainly for looking at whether laquinimod is an immunmodulator? 

In rodents it has immunmodulating effects and the efficacy is known in humans already

They will have had  to undergo ethical review for this studies. The views may dependent of the national psyche of the panels. So countries do not bat an eyelid about primate work and in others this means death threats are coming your way and so researcher do not undertake this work lightly.

Laquinimod is very poor at stopping relapses compared to other DMT. So it is not clear why you would validate a model using a drug that is not very good in humans as surely it has to be not very good in animals too for the model to be valid. 

There is a question mark about whether laquinimod has a good neuroprotective effect, could this not be assessed in other ways?

Why do we use non-human primates a safety tool before going into humans or as a research tool to find treatments? But can you ever do experiments in enough marmosets to be confident? 

Should animals studies be used as marketing tools to keep drugs in the news, whilst the trials are being done? 

Hopefully this new tool can help find a treatment that works.
There are no groups in the UK performing EAE experiments on non-human primates.

Unrelated Blogger Comments-August 2015

       What to say something unrelated to the thread. Here you go