Finally, a Promising Drug in Huntington's

Hans-Christoph Diener, MD, PhD


August 29, 2019

This transcript has been edited for clarity.

Dear colleagues, I'm Christoph Diener from the University of Duisburg-Essen in Germany. Today I will report about four studies published in June 2019. I have to admit, June was not a very productive month for exciting new studies.

Let me start with the most exciting piece of scientific information, which is a study on Huntington's disease that was published in the New England Journal of Medicine.[1] You all know that Huntington's disease is an inherited, dominant disease due to a CAG trinucleotide repeat, which encodes a protein called huntingtin. Mutant huntingtin is deposited in different areas of the brain, which leads to neural death.

There is now a new antisense oligonucleotide, which reduces the messenger RNA for the mutated huntingtin and reduces the concentration of this protein. This approach works in transgenic mice. This was the first dose-finding study in humans. This antisense oligonucleotide was injected intrathecally every 4 weeks for 16 weeks.

The study recruited 46 patients and investigated four doses of active drug and placebo. The primary endpoint was the concentration of huntingtin in the CSF. First, there were no safety issues, which is very reassuring. Second, there was a dose-dependent reduction of the concentration of mutant huntingtin in the CSF, which is really exciting.

Now, the number of patients was much too small and the duration of the study was too short to show that it's clinically effective. This is now under investigation in a large phase 3 trial. I think this is another study showing that there is hope for neurodegenerative diseases.

The second study was published in Lancet Neurology.[2] It was designed to investigate the role of dopamine for the reorganization of the brain after stroke. There were a number of small studies, which indicated that L-dopa could improve motor function and other functions in patients who had a stroke on top of rehabilitation and occupational therapy.

This study was done in the UK. The investigators recruited 593 patients who had strokes, with the majority being ischemic stroke. They were recruited 18 days after stroke and then either treated with L-dopa and carbidopa or placebo. The primary endpoint was the ability to walk independently, which was measured after 6 weeks.

Unfortunately, there was no difference between the two groups in terms of primary and secondary endpoints and mortality. In contrast to the smaller studies, which were done earlier, this large-scale, properly powered study could not show a positive effect of L-dopa on top of rehabilitation in terms of physiotherapy and occupational therapy.

Now let me move to a migraine paper published in Brain.[3] Lasmiditan is a serotonin 5-HT1F receptor agonist. This drug, in contrast to the triptans, has no vasoconstrictive properties. The drug was investigated in three different doses and compared with placebo in 3000 patients who were treated in acute migraine attacks.

The primary endpoint was the proportion of pain-free patients after 2 hours and freedom from the most bothersome additional symptoms, which was phonophobia in most patients. The mean age of patients was 42 years and the majority were females. The percentage of patients who were pain free after 2 hours with the highest dose was 39% versus 21% with placebo. The effect was dose dependent.

The most important issue is adverse events. There were clearly central CNS side effects in terms of dizziness, paresthesia, fatigue, nausea, and muscle weakness. This clearly shows that this drug is penetrating into the brain and works in the brain, in contrast to triptans, which probably work outside of the brain.

Now, this is the second study. There was a huge study published in Neurology with 1856 patients, and it also showed that 100 and 200 mg of lasmiditan are superior to placebo.[4] Unfortunately, there was no active comparator. I really would have liked to know whether lasmiditan works in patients who fail a triptan.

This drug will be indicated for patients who have contraindications for triptans, including acute coronary syndrome, myocardial infarction, angina, and ischemic stroke. At the end of the day, it likely will be a niche product.

The last study deals with headache in children and adolescents. Published in Cephalalgia, this was an epidemiologic study in Germany, which included 2706 children and adolescents in schools from grade 1 to grade 12, which is 6 years to 18 years of age.[5] Approximately 37% of these children had at least one headache day per month and 32% had two or more headache days per month.

The frustrating issue here is that in the majority of these children and adolescents, there was no proper diagnosis of the headache medicine. The majority treated their headaches with ibuprofen or with acetaminophen. As you would expect, the prevalence of migraine increased with age and girls were more frequently affected than boys.

They also looked at predictors, which included—not surprisingly—frequent intake of analgesics. Another important predictor was intake of caffeine, and the most important was absence of sports.

This demonstrates, again, that the issue is not treating headaches with drugs. It's about making a proper diagnosis and teaching these children how important it is to exercise regularly and to reduce time in front of a screen, whether it's an iPad, iPhone, computer, or TV. Children and adolescents are clearly neglected in terms of treatment.

There is good news because there are ongoing trials with monoclonal antibodies against CGRP (calcitonin gene-related peptide) or the CGRP receptor in adolescents. If these drugs are effective, we would have a proven preventive therapy for this age group, in particular, of patients with migraine.

Ladies and gentlemen, I have discussed four interesting new studies in June 2019 in neurology, covering Huntington's disease, rehabilitation, and headache.

I am Christoph Diener from the Department of Neurology at the University of Duisburg-Essen in Germany. Thank you very much for listening and watching.

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