Updates in Parkinson's, ICH, Migraine, and Muscular Dystrophy

Dear colleagues, I'm Christoph Diener from the Faculty of Medicine at the University Duisburg-Essen in Germany. This month, I found five interesting studies that were published recently. 

GLP-1s and Monoclonal Antibodies in Parkinson's Disease

Let me start with Parkinson's disease. We have reasonably good therapy in terms of drugs and deep-brain stimulation, but we still do not have effective neuroprotective therapy. Now, there is a new group of substances, the so-called glucagon-like peptide-1 (GLP-1) receptor agonists. These are small molecules that have shown to be effective in the treatment of diabetes and obesity. 

Preclinical models have shown that these drugs also have inflammatory properties, and they are neuroprotective in animal experiments. This is a new study with lixisenatide in early Parkinson's disease, published in The New England Journal of Medicine. This is a double-blind, placebo-controlled study in Parkinson's disease and the stable dopaminergic therapy with daily subcutaneous lixisenatide or placebo for 12 months.

In 156 patients after 12 months, there was no deterioration in the MDS-UPDRS part III scale on lixisenatide, but there was a decline by 3 points in the placebo group. Admittedly, this is a small difference. The secondary endpoints in this study did not show a difference. 

There were significant problems with tolerability. Almost 50% of patients complained of nausea and vomiting, and one third had to reduce the dose of lixisenatide due to adverse events. This is an interesting observation because this rate of nausea and vomiting has not been observed in patients with diabetes. 

There was another study with pegylated exenatide, the NLY01 study, which was negative. In this study, however, the patients were not treated with dopaminergic drugs. What we need now is a large-scale, long-term study with GLP-1 agonists to see whether they are neuroprotective in patients with early Parkinson's disease.

The second approach uses antibodies against aggregated alpha-synuclein. Prasinezumab is one of these drugs. The target, again, is treatment of early Parkinson's disease, and the initial PASADENA study failed the primary endpoint, which was MDS-UPDRS parts I, II, and III. This study recruited 316 patients with early-stage Parkinson's disease and used two doses of monoclonal antibody compared with placebo every 4 weeks. 

In Nature Medicine, the investigators published a subgroup analysis. They looked overall at 10 different subgroups and identified one subgroup which seems to benefit from this monoclonal antibody. These are patients with rapidly progressive disease. This also means that we now need a large-scale study with this monoclonal antibody in patients with initial Parkinson's disease and rapid progression. 

ICH Surgery 

My third topic is the neurosurgical treatment of intracerebral hemorrhage. This has been a disaster until now because all the studies that have been done were negative, or neurosurgery was not superior to best medical treatment. Now, obviously, we have a new, effective treatment. TheNew England Journal of Medicine published the ENRICH study, which was done in 300 patients, and the neurosurgeons used minimally invasive neurosurgical procedures. 

They randomized 300 patients and the majority had a lobar hemorrhage. It turned out that, in lobar hemorrhage, this method is effective both in terms of functional outcome measured with modified Rankin scale and with a significant decrease in mortality, from 18% in the control group to 9% in the neurosurgical group. This is dramatic because, for the first time, a new neurosurgical procedure has shown efficacy in lobar hemorrhage. 

Muscular Dystrophy

Now, let me move to muscular dystrophy. Facioscapulohumeral muscular dystrophy is a hereditary disease caused by abnormal expression of the transcription factor DUX4 in skeletal muscles. Losmapimod is a small molecule that inhibits p38 alpha MAPK, which is important for the inhibition of DUX4. 

This is a small, randomized study in 80 patients with this form of muscular dystrophy, treated over 48 weeks, and published in The Lancet Neurology. The primary endpoint, which was DUX4 gene expression, was not affected. However, there was a reduction in fatty infiltration in the muscle and the global impression of the patients. Here, too, we need larger studies. 

Migraine

My final topic is the prevention of episodic migraine via the calcitonin gene-related peptide (CGRP) pathway. We have two approaches now for the prevention of migraine. One is monoclonal antibodies against CGRP or the CGRP receptor, which are injected, and then we have oral small-molecule drugs that work directly on the CGRP receptor. 

Atogepant is one of these drugs and has shown efficacy in the prevention of episodic and chronic migraine. For reimbursement purposes, companies have to show that these new drugs are also effective in people who failed to respond to prior oral therapies. The ELEVATE study, published in The Lancet Neurology, recruited 313 patients in whom two to four oral migraine preventive therapies failed in the past. 

The primary endpoint was the reduction in monthly migraine days. This was significantly higher, with -4.2 days for atogepant compared with -1.9 days for placebo. Atogepant is very well tolerated. There are some issues with constipation and nausea, but otherwise, no major problems with side effects. 

I think we now have evidence for all these new migraine preventive drugs showing that they work in patients who didn't respond to, for example, beta-blockers, flunarizine, topiramate, amitriptyline — you name it. I think this is an important study to get reimbursement for this drug, in particular, in Europe. 

Dear colleagues, I've presented five studies from four different areas in neurology. Thank you very much for watching and listening. I'm Christoph Diener from the medical faculty of the University Duisburg-Essen.