#ResearchSpeak & #ThinkSpeak: a new form of therapeutic nihilism
How can we prevent a new era of therapeutic nihilism in progressive MS? #ResearchSpeak #ThinkSpeak
A commentator asked about data to support the use of cladribine in PPMS. In reality there has not been a study particularly targeting PPMS, but several studies have investigated the impact of cladribine in chronic progressive MS, i.e. a population that includes both secondary and primary progressive MS. In general these trials have been under-powered and too short, based on recent insights, to give a definitive answer. The best study was the Rice or J&J (Johnson & Johnson) study that included 48 (30%) patients with PPMS. Importantly, in this study 71% of patients had a baseline EDSS score of >=5.5, which based on our therapeutic lag modelling would require a study duration of well over 3 years to give an answer using a lower limb outcome (EDSS). However, despite this study being too small and too short cladribine had a robust impact on T2 lesions, albeit more pronounced in the SPMS subgroup. It is clear from this study that cladribine is an effective anti-inflammatory in more advanced MS.
Cladribine as a DMT has the added advantage of being CNS penetrant and targets both dividing and non-dividing lymphocytes and may even target plasma cells. Therefore we hypothesise that cladribine is the ideal DMT to be studied in more advanced MS and should form the base of the pyramid on top of which we can build a therapeutic pyramid to address neuroprotection, remyelination and neurorestoration.
When I was at the EAN meeting last weekend, in Amsterdam, a MSology colleague expressed an opinion I had not heard since the interferon-beta-1b results were released in 1993. He stated that ‘if ocrelizumab got licensed in Europe for PPMS and relapsing forms of MS it would become very difficult to do placebo-controlled progressive MS trials’. He implied that an ocrelizumab license would be disadvantageous to the progressive MS community, i.e. the academic community. He is one of the MSologists who are not impressed with the ocrelizumab trial results. The problem I have with this attitude is that it is a form or therapeutic nihilism, only this time it is being directed at people with progressive MS. If this person really understood the biology of MS he would realise that a 25% and 45% reduction in disability progression in the legs and arms, respectively, over a 24-36 month period is as good as it gets and that we need to use this as a platform to improve on.
As a group we at Barts-MS have realised this and as a result are not wanting to target early progressive MS, but more advanced MS including people in wheelchairs. We estimate that our proposed subcutaneous cladribine trial (Chariot Trial) will cost in the region of £5M to complete. So if there any wealthy philanthropists out there who want to see people in wheelchairs in trials with the primary outcome the 9HPT, I am sure DrK would love to speak to you.
If anything angers you in this post, please feel free to express yourself and to complete our survey. As suggested by someone on the blog, we will analyse the results and make them known to the MS community and the EMA. We need ocrelizumab licensed for PPMS and I personally don’t give a toss about academics wanting to protect the status quo so that they continue to study untreated progressive MS. Can you imagine what it must be like to be a person with PPMS with walking difficulties and you start to notice subtle problems with your hands? You would be desperate to be treated with ocrelizumab. This is the human story of MS and academics should not forget that.
OBJECTIVE: To evaluate the safety and efficacy of two doses of cladribine in patients with progressive MS.
BACKGROUND: Treatment of progressive MS patients with cladribine in a previous single-center, placebo-controlled clinical trial was associated with disease stabilization.
METHODS: In the current study, 159 patients with a median baseline Kurtzke’s Expanded Disability Status Scale (EDSS) score of 6.0 were randomly assigned to receive placebo or cladribine 0.07 mg/kg/day for 5 consecutive days every 4 weeks for either two or six cycles (total dose, 0.7 mg/kg or 2.1 mg/kg, respectively), followed by placebo, for a total of eight cycles. Thirty percent had primary progressive MS (PPMS) and 70% had secondary progressive MS (SPMS). EDSS and Scripps Neurologic Rating Scale (SNRS) scores were assessed bi-monthly and MRI was performed every 6 months. The primary outcome measure was disability (mean change in EDSS).
RESULTS: Mean changes in disability did not differ among the groups at the end of the 12-month double-blind phase. Both cladribine treatments were superior to placebo for the proportion of patients having gadolinium-enhanced T1 lesions and for the mean volume and number of such lesions (p < or = 0.003). Differences were statistically significant at the 6-month evaluation time, with < or =90% reduction in volume and number of enhanced T1 lesions, which was maintained through final evaluation. This effect segregated largely with the SPMS group. The T2 burden of disease showed a modest improvement in cladribine-treated patients and worsened in placebo-treated patients. Most adverse events were mild or moderate in severity and not treatment limiting.
CONCLUSION: No significant treatment effects were found for cladribine in terms of changes in EDSS or SNRS scores. Both doses of cladribine produced and sustained significant reductions in the presence, number, and volume of gadolinium-enhanced T1 brain lesions on MRI, and cladribine 2.1 mg/kg reduced the accumulation of T2 lesion load. Cladribine at doses up to 2.1 mg/kg was generally safe and well tolerated.
We compared the changes of the volumes of T(1)-hypointense lesions seen on the magnetic resonance imaging scans of the brain from 159 progressive multiple sclerosis (MS) patients who were enrolled in a double-blind, placebo-controlled trial assessing the efficacy of two doses of cladribine. Although in patients treated with cladribine there was a tendency to have a lower increase of T(1)-hypointense lesion volumes than those treated with placebo, no statistically significant effect of cladribine on T(1)-hypointense lesion accumulation was found over the one-year double-blind phase. Furthermore, no significant treatment effect was also detected in a subset of 22 patients who received placebo during the double-blind phase of the study and cladribine during the subsequent one-year open-label phase. We conclude that cladribine does not have a major impact on the mechanisms leading to severe tissue destruction in progressive MS.