“I have been praising the study since it was presented at ECTRIMS 2012 in Lyon. In this study MSers with SPMS and PPMS were treated with natalizumab and monitored with spinal fluid analyses and MRI. It shows that natalizumab has favourable effects on all metrics studied in a relatively short timeframe of 60 weeks.
This study achieves many things.
- It clearly shows that progressive MS is inflammatory. There is a self-perpetuating myth that progressive MS is not inflammatory but simply neurodegenerative and hence anti-inflammatory therapies are not required, but only neuroprotective therapies. This study should slay that myth. When people with progressive MS die their brains and spinal cord are stuffed full of T-cells, B-cells, plasma cells and activated microglia and macrophages. Therefore if we want to tackle progressive MS we need a potent anti-inflammatory and a second therapy that targets neurodegeneration. This is why I have been promoting the combination therapy strategy for over 10 years and why we are testing this strategy in the PROXIMUS trial.
- Multiple lumbar punctures are possible. Progressive MSers in this study agreed to have two lumbar punctures. A lot of people have been saying that MSers are not prepared to have LPs. This is clearly not true. If the purpose of the study is explained and MSers understand why LPs are necessary they tend to say yes. In addition we have new ways of making LPs safer to do with less complications. I personally think LPs will be come the norm in progressive MS trials.
- Spinal fluid analysis is valuable. This study shows that we can measure markers of inflammation, demyelination and neuroaxonal damage in the spinal fluid and we impact on these favourably with a treatment. This may be a game changer when it comes to doing similar studies in the future. What we (academia and pharma) need is a quick way of doing phase 2 studies in progressive MS. Using serial lumbar punctures is away of doing this.
- Neurofilaments are responsive to treatment in progressive MS. In this study natalizumab reduced, but did not normalise spinal fluid neurofilament levels in progressive MSers. This indicates that more is needed to reduce spinal fluid neurofilament levels. Either further follow-up is required in progressive MS to see the levels become normal or an add-on therapy is needed to protect neurons and axons that are continuing to degenerate or die. I suspect that both are playing a role. Long nerve processes may take many months or even years to degenerate and release their contents; 60 weeks is too short for this process to run its course. In addition, switching off trafficking of inflammatory cells into the central nervous system is not enough to eliminate ongoing damage in progressive MS. Other therapies are need to address the ongoing damage.
- This study is a proof of principle study and shows that natalizumab may work in progressive MS. This is why Biogen-Idec are doing the ASCEND trial; to test whether or not natalizumab can slow down the rate of disability progression in SPMS. I have concerns that the trial is not long enough and does not take into account the therapeutic lag. Therapeutic lag is an observation that anti-inflammatory treatments in progressive MS only have an impact on disease progression after 2 years of follow-up. I have posted on this before and recommend you read my previous post. I would therefore urge Biogen-Idec to have an extended follow-up of the study subjects in ASCEND to see what happens in the future.
- Hope. This study gives hope to MSers with both SPMS and PPMS that just may be their disease is modifiable and it has taken a highly-active treatment to have the potency to show an effect. I also don’t want to raise false hopes; my expectation is that the ASCEND trial will be positive in that it will slow down the rate of disease progression, but not flatline it or reverse disability. Why do I say this? I think the processes that drive disease progression are not simply inflammatory cells from the periphery, but also process from within the nervous system. In addition, most people with progressive MS have very little reserve capacity and hence don’t have the ability for recovery; hence slowing down. We also have lessons from other highly active treatments in progressive MS to reflect on; alemtuzumab, rituximab and mitoxantrone have all been tried in progressive MS. Although these agents switch off relapses and MRI activity they don’t stop disease progression. I have little reason to believe natalizumab will be any different. Therefor it is important to realise that if you have progressive MS and are on one of these drugs that just slows down the rate of disease progression you may think it is not working.
|Therapeutic Lag Hypothesis|
Epub: Romme Christensen et al. Natalizumab in progressive MS: Results of an open-label, phase 2A, proof-of-concept trial. Neurology. 2014 Mar.
OBJECTIVE: Natalizumab inhibits the migration of systemic immune cells to the CNS and may be beneficial in progressive MS. The objective of the study was to examine the effects of natalizumab in progressive MS.
METHODS: In an open-label phase 2A study, 24 progressive MSers were included to receive natalizumab treatment for 60 weeks. Response to natalizumab was assessed in CSF and MRI studies. The primary endpoint was change in CSF osteopontin, a biomarker of intrathecal inflammation, from baseline to week 60.
RESULTS: Seventeen MSers completed the study. No new safety issues were encountered. CSF osteopontin decreased by 65 ng/mL (95% confidence interval 34-96 ng/mL; p = 0.0004) from baseline to week 60 in conjunction with decreases in other CSF biomarkers of inflammation, axonal damage, and demyelination. Magnetization transfer ratio increased in both cortical gray and normal-appearing white matter and correlated with decreases in CSF neurofilament light chain.
CONCLUSIONS: Natalizumab treatment of progressive MS reduces intrathecal inflammation and tissue damage, supporting a beneficial effect of natalizumab treatment in progressive MS and suggesting that systemic inflammation contributes to the pathogenesis. Moreover, the study establishes the feasibility of using CSF biomarkers in proof-of-concept trials, allowing a low number of participants and short study duration.