The smaller you are the better the effect on progression

T

Cross A et al. Ocrelizumab treatment reduced levels of neurofilament light chain and numbers of B cells in the cerebrospinal fluid of patients with relapsing multiple sclerosis in the OBOE study

Objective: To provide interim analysis (IA) results from the relapsing multiple sclerosis (RMS) cohort of OBOE (Ocrelizumab Biomarker Outcome Evaluation; NCT02688985), a cerebrospinal fluid (CSF) and blood biomarker study.

Background: Serum and CSF levels of neurofilament light chain (NfL) and CSF lymphocyte numbers are emerging biomarkers of axonal damage and inflammation, respectively. Responses of these biomarkers to ocrelizumab (OCR) may improve the understanding of MS pathophysiology and therapeutic mechanism of action.

Design/Methods: Patients with RMS received OCR 600-mg infusions every 24 weeks. CSF samples were obtained by lumbar puncture (LP) before OCR and at 12, 24 or 52 weeks after initial OCR treatment. Patients in a nonrandomized RMS reference arm underwent two LPs 12 weeks apart prior to initiation of OCR. The primary endpoint is change in CSF NfL levels and lymphocyte numbers between pre- and posttreatment time points. All enrolled patients (n=100) are included in this IA.

Results: Pretreatment CSF and serum NfL levels correlated strongly (r=0.78; p<0.001). Both serum and CSF NfL levels correlated with numbers of T1 gadolinium-enhancing lesions and new/enlarging T2 lesions on brain MRI. OCR significantly reduced serum NfL (−13.1%, −18.6% and −30.8%), CSF NfL (−24.5%, −40.0% and −54.7%) and CSF B cells (−85.5%, −84.8% and −94.0%) at Weeks 12, 24 and 52, respectively. CSF T cells were reduced by ≈60% across the same time points, but reductions were significant only at Week 12. Reference-arm samples showed no significant changes in CSF/serum NfL or CSF lymphocyte numbers over 12 weeks.

Conclusions: In RMS patients, ocrelizumab significantly decreased CSF/serum NfL and CSF B cells, suggesting that treatment reduces ongoing axonal injury and compartmentalized CNS inflammation. CSF B cells were almost completely depleted in most patients at Weeks 12, 24 and 52, whereas CSF T cells were moderately reduced in many but not all patients.

So inhibit inflammation and you save nerves. However it is not all good news As profHauser presented data to indicate that size matters when it comes to progression.

Pharmacokinetics, Pharmacodynamics and Exposure-Response Analyses of Ocrelizumab in Patients With Multiple Sclerosis

Heidemarie Kletzl , Ekaterina Gibiansky , Claire Petry , Francois Mercier, Andreas Guenther , Qing Wang , Fabian Model , Ludwig Kappos , Stephen Hauser

Objective: To describe the population pharmacokinetics, pharmacodynamics, and exposure-efficacy/safety relationships of ocrelizumab in patients with multiple sclerosis (MS).

Background: Ocrelizumab is a CD20+ B cell-selective monoclonal antibody approved for treatment of relapsing MS (RMS) and primary progressive MS (PPMS).

Design/Methods: Ocrelizumab Phase II/III data were analyzed using a non-linear mixed-effects model to describe ocrelizumab pharmacokinetics and assess covariate effects. Exposure-response relationships for clinical efficacy (annualised relapse rate [ARR], 12-/24-week confirmed disability progression [CDP]) and safety parameters (serious adverse events, serious infections, infusion related reactions) were assessed.

Results: A two-compartment model with time-dependent clearance and body weight as main covariate described accurately ocrelizumab pharmacokinetics in patients with RMS (N=941) and PPMS (N=482). Exposure (area under the serum concentration–time curve) was 26% higher in patients with RMS <60kg and 21% lower in those >90kg versus a 75kg reference patient.

Blood B-cell depletion correlated with ocrelizumab exposure. Patients with RMS obtained similar benefit with regards to ARR independent of exposure, however, risk reductions in 12-/24- week CDP was exposure-dependent in patients with RMS (12-week CDP hazard ratios by exposure quartile 1–4: 0.77, 0.80, 0.45 and 0.33 versus interferon-beta 1a, respectively) and PPMS (12-week CDP hazard ratios by exposure quartile 1–4: 0.87, 0.83, 0.78 and 0.59 versus placebo, respectively). All safety parameters assessed were similar across the exposure quartiles.

Conclusions: Higher ocrelizumab exposure led to greater B-cell depletion. Clinical benefit on ARR was independent of exposure, but greater risk reduction in CDP was observed with higher ocrelizumab exposure in patients with RMS and PPMS, suggesting that higher ocrelizumab exposure (and greater B-cell depletion) is important for control of disability progression. The fact that effects are more pronounced in patients in higher exposure groups indicates that the current approved dose is closer to the lower part of the dose-response curve. The safety profile was similar across all exposure quartiles.

So lets us more drug!

It is amazing that when we do our studies in animals that we dose according to weight, but when it come to humans you just give one single dose. This is easier but if may mean some people are either underdosed or over dosed.

Cladribine is different it is dosed according to weight perhaps meaning that there is bias in treatment, if you are controlling the purse strings, as fatter people will cost more to treat.

Anyway, In this study they looked at the effect of ocrelizumab and didn’t find an influence of size on relapses, but bigger people seemed to progress more. The also appeared to get less B cell depletion. So the upper weight here was I believe about 170Kg compare this to a 40kg person and it is not hard to see that the overweight person is over 4 times larger. So is it surprising that they may deplete less or is it they repopulate quicker? Is the reason for more propression due to less depletion fo CD19 in the blood or is it because less antibody gets into the brain. Less antibody in the brain, less effect on B cells in the brain and so more progression. Alternatively is it because people who are overweight are going to have more co-morbidities like high blood pressure, maybe type II diabetes, alter cholesterol etc,etc etc,etc. Therefore they are more likely to progress quicker.

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  • Conclusion: These findings provide evidence that obesity is associated with smaller subcortical gray matter volumes. In addition,
    obesity was associated with higher coherence but lower magnitude of white matter microstructure, which suggests differential influences
    of obesity on the geometric organization of white matter microstructure.

    Less drug , but, before you have allready less brain

    Obesity, Brain Volume, and White Matter
    Microstructure at MRI: A Cross-sectional UK
    Biobank Study

    https://doi.org/10.1148/radiol.2019181012

  • Have heard you say manny times that antibodies protein dont get in the brain

    Here you are suggesting otherwise?

    Obrigado

  • Forgot this one 🙂

    Body mass index, but not vitamin D status, is associated with brain volume change in MS.

    RESULTS:

    Among 469 participants, each 1-kg/m2 higher BMI was independently associated with reduced nGMV in multivariate models (-1.1 mL, 95% confidence interval [CI] -1.8 to -0.5, p = 0.001). BMI was likewise independently associated with nBPV (nBPV per 1-kg/m2 greater BMI: -1.1 mL, 95% CI -2.1 to -0.05, p = 0.039). Vitamin D levels did not appear to be meaningfully associated with brain volumes.

    CONCLUSIONS:

    Higher BMI appears to be associated with greater reductions in nGMV and nBPV, which is relevant because, in particular, nGMV loss portends greater longer-term disability. Because obesity is modifiable, further studies should explore these relationships in detail, and evaluating the effect of reducing BMI on imaging and clinical outcomes in MS may be warranted.

    https://www.ncbi.nlm.nih.gov/pubmed/30429274

    “let s get physycal”

  • Another commentator posters the following under Prof Gs Jetlag post:

    ”Has anyone analyzed subgroups based on grade of lymphopenia? And not just relative numbers (as patients do not start from the same levels!), but absolute numbers?”

    Has there been any analysis of this kind? If not it could be Done for Cladribine right? Because Merck has released all the data.

    Very intrested to hear you take on this. If b-cell depletion is the mode of action, the more lymphophemia the better?

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