Posted on behalf of Tom Jenkins:
In the clinic before I left for this conference, one of my patients expressed his hope that there would be a new treatment available this year. I travelled to Brussels for the annual MND Association meeting with his words in my ears, hopeful that I could take some encouraging news back from this annual gathering of world experts. In the 2nd Century, Tertullian wrote that hope is patience with the lamp lit and this seems apposite today for people with MND, so often patient and optimistic even in the face of such short time. So, it was with my patient’s words in mind that I sat in the Trials and Trial Design session, our forum for new treatments in MND. The session opened with an important reminder by Dr Schoenfeld from Boston of the difficulties we face, and he elegantly outlined an underappreciated concept known as the nocebo effect. This term describes potentially harmful effects of placebo interventions in clinical trials. He gave the example of the recent ceftriaxone trial, in which the placebo arm was also delivered via central venous catheter to maintain blinding, with associated risks. In addition to ethical problems, the nocebo effect can cause false positive trial results; if placebo is actually harmful compared with standard care, then drugs that produce no benefit compared to standard care can still prove better than nocebo. Potential solutions include adding an additional “standard of care” group (expensive) or incorporating interventions with a potential nocebo effect into existing trials of less invasive treatments, such as oral medications, and use their control group. This is likely to become increasingly important in the future, as more invasive interventions are tested, for example, stem cell approaches.
The nocebo concept was potentially relevant to the next talk, by Dr Van Damme from Leuven, who presented original and exciting data from a phase I trial of intraventricular vascular endothelial growth factor (VEGF), delivered via a neurosurgically implanted pump. VEGF, a neurotrophic factor, has previously shown promise in animal models of MND. Fifteen of the 18 patients completed the randomised controlled trial, which lasted for three months. One patient developed seizures, which resolved with treatment, two patients reported headache and three patients suffered pulmonary emboli, but these were not attributable to VEGF. The authors noted some slowing of disability progression at the higher dose (measured using the ALS-FRS scale), although the trial was not powered to assess efficacy. Patients could continue open label treatment. After up to three years of follow-up, average survival was 44 months and two patients were alive 59 and 137 months from symptom onset. The conclusion was that intraventricular VEGF appears safe and efficacy now needs to be evaluated in a stage II trial.
The next talk was from Dr Andrews, from San Francisco, who presented further results of the tirasemtiv trial. Tirasemtiv is an oral troponin activator, which increases muscle contractility. Unfortunately, this multi-centre phase IIb, randomised controlled trial did not meet its primary outcome measure of influencing disability progression (ALS-FRS). Dr Andrews reported improvements in a secondary outcome measure, slow vital capacity, but associations with other respiratory measures were not found and there were some problems with tolerability.
Next up was Dr McGrath, also from San Francisco, who presented a subgroup analysis of intravenous sodium chlorite (NP001), a systemic anti-inflammatory agent. They investigated groups of patients who did not progress in disability over the study. This included 10% of the placebo group and 27% of patients taking higher dose NP001. The aim of this analysis was to determine whether the treated patients had an inflammatory cytokine profile, which they did. The authors suggested this supported the drug’s proposed biological mechanism, but it is important to note that this was not the primary outcome measure and the data presented was a post-hoc subgroup analysis.
So, what message can I take home from Brussels for my patient? Our arsenal of interventions to improve survival in MND remains, for now, riluzole, non-invasive ventilation and multidisciplinary care in specialist centres. But this session did offer hope, reinforcing the efforts that are being made worldwide, with activity in California and promise from Belgium. There appears to be a move toward more radical treatments, such as intraventricular drug delivery, and this is likely to continue with ongoing stem cell trials. I think this is a direction our patients will support. Hope is a risk that must be run, as Georges Bernanos wrote. Let us all hope for positive trial data by the next MND Association meeting in Orlando 2015.