The Axon – Issue #1, April 2024

If this is your first time here, thanks for joining us! If you're a repeat reader of NeurologyLive®, welcome back! For the former, we're a team of editors for a clinical news publication that provides the latest coverage of neurology-related FDA news and the therapeutic pipeline, expert opinions and insights, in-clinic care and advocacy, and major medical meetings throughout the year. Our mission is to deliver quality and relevant information to health care professionals treating neurological diseases to help them achieve the best patient care possible.

This is The Axon, your new go-to place to get that insight, right here on LinkedIn.

On the first of each month, we'll bring you a new edition that highlights the trending topics and important updates our editorial staff reports on. We'll point you to the news that matters and the specialist insight that can help your clinical practice.

Parkinson Disease Awareness Month

April was, of course, Parkinson disease (PD) awareness month. This is a major awareness event for those in the field of movement disorders, as PD remains among the most common movement disorders, affecting roughly 1% of the world's population over 60 years. Much was top of mind about PD for the clinical community, and many thought leaders were kind enough to bring their insights to our readers, including Kenneth Ngo, MD, FAAPMR, FACHE , the medical director for the Brain Injury Program at Brooks Rehabilitation ’s 3 inpatient hospitals, who wrote how cotreatment between music therapy and physical therapy can significantly improve the overall quality of life for patients with Parkinson disease; Larry Gifford , a patient living with Parkinson Disease and the president of the PD Avengers , who wrote sleep issues and nighttime symptoms faced by millions of patients with the disease worldwide; and Neal K. Shah , CEO of CareYaya Health Technologies, who wrote how technology is poised to transform the fight against Parkinson, with the potential to improve millions of lives and advance health equity.

Additionally, Anne Marie Morse , DO, a neurologist with special qualifications in child neurology and a sleep medicine specialist, best known for putting the DAMM in DAMM Good Sleep, put together a concise episode of the joint Sleeping Around the Podcast × NeurologyLive providing a clinical overview of a newly published study highlighting extracellular vesicle-associated miRNA features that could be diagnostically informative of REM sleep behavior disorder in patients with PD.

With all of this in mind, our team was hard at work this past month tracking down the latest news related to this disease. One such bit of PD news that caught our eyes was a study published in NPJ Parkinson’s Disease that suggested that genetic variants associated with lysosomal function—specifically autophagy—were enriched among patients with PD who were exposed to agricultural pesticides. Ultimately, the findings suggest that altered lysosomal function may generate an underlying susceptibility for developing PD through pesticide exposure.

Senior author Brent L. Fogel, MD, PhD, a professor of neurology and human genetics at David Geffen School of Medicine at UCLA , told us that he and his colleagues "examined genetic data from nearly 800 California Central Valley residents with PD, many of whom had long-term exposure to 10 pesticides used on cotton crops for at least a decade prior to developing the disease, and looked for enrichment of genetic variants in patients with high exposure to pesticide use compared with a representative sample of the general population."

"These genetic variants appeared to be deleterious to proteins that function in lysosomes, cellular compartments that break down waste and debris, thought to be associated with the development of PD. This suggests that disruption of lysosomal activity may be underlying the development of PD in people with pesticide exposure," he said.

On the therapy front, we were on top of news from the phase 2 LixiPark trial (NCT03439943) of lixisenatide (Adlyxin; Sanofi ), published in the New England Journal of Medicine; and an unnamed phase 1b study (NCT04167540) of the gene therapy AB-1005 ( Asklepios BioPharmaceutical, Inc. (AskBio) ), presented at the American Academy of Neurology (AAN) Annual Meeting.

The former trial showed that treatment with lixisenatide—a glucagon-like peptide-1 receptor agonist used as a therapy for diabetes—resulted in less progression of motor disability compared with placebo at 12 months in patients with early PD, but was associated with gastrointestinal adverse effects. Overall, the investigators, including Michael S Okun , MD, of UF Health , suggest that the data imply a need for longer and larger trials to determine the effects and safety of lixisenatide in patients with PD.

Okun told us that “we should appreciate that the results 'fell short' of this important metric [the clinically meaningful threshold], so it is not ready for prime time in patients. In my view, we should not rush to prescribe this drug or to try to creatively acquire it for our patients. We have been down this road many times including leukemia drugs, cough syrups, and lithium for Parkinson. The data is not yet there to proceed to prescribing. More importantly, the weight loss associated with GLP-1’s is not desirable in the majority of cases of Parkinson disease and the nausea and vomiting will not be a welcome symptom. The drug and trial is a step in the right direction, though there is much work to do.”

For the latter trial of AB-1005, the AAV2 gene therapy met its primary end point of successful putamen coverage and was safe over an 18-month period, with treatment resulting in putamen coverage of 63% (±2%)—exceeding the goal of greater than 50% coverage. According to the company, despite the study's small scale size—11 patients were included (6 with mild and 5 with moderate forms of PD)—patients experienced improvements in ON and OFF time. The mild cohort of patients showed relative stability of PD symptoms, as assessed through the Movement Disorder Society-Unified Parkinson’s Disease Rating Scale–Part 2, and similar effects were seen on Part 3 of the scale, which evaluates clinician-rated motor examination scores in ON and OFF medication states.

Krystof Bankiewicz , MD, PhD, the scientific chair of Parkinson’s and MSA at AskBio, said in a statement that "these early findings are encouraging and show AB-1005 to be well tolerated in this study in patients with mild to moderate Parkinson’s disease. Further, they highlight areas of potential future exploration in our upcoming phase 2 REGENERATE PD trial, which will look more closely at the potential efficacy of AB-1005 in the treatment of Parkinson disease."

American Academy of Neurology

The aforementioned AAN Annual Meeting also takes place in April each year, and our team always looks forward to attending the meeting to connect with as many experts as we can! This year was no different, and for those of you who follow us on LinkedIn, you probably saw a couple of our photos from Denver come across your feed! In our few days on site, we spoke with more than 20 clinicians, researchers, and advocates who presented at the meeting.

One of our favorite interviews (though it is so hard to pick!) was with Sean Pittock, MD, the director of the Mayo Clinic Center for Multiple Sclerosis and Autoimmune Neurology, who sat down to discuss the safety profile of ravulizumab (Ultomiris; Alexion Pharmaceuticals, Inc. ), a terminal complement C5 inhibitor that was approved for NMOSD in March 2024—specifically, the risk of meningococcal infection. He discussed the importance of following the medication closely to its label description and why patients should have appropriate vaccinations before receiving the therapy. Pittock also stressed this can be an effective and well-tolerated therapy when administered correctly.

Another of our favorite conversations was with Jaime Imitola, MD., FAAN, FANA , the chief of the Division of MS and Neuroimmunology at UConn Health , who talked about the unevenly distributed progress in multiple sclerosis care, impacting minority populations who often face worse disease outcomes. He noted that "By increasing self-agency in patients and raising awareness of early red flags and warning signs of MS, we can improve the number of patients who seek timely medical care." Taking a leaf from the stroke field's book with B.E.-F.A.S.T., and after consulting with culturally competent bilingual physicians and patients, Imitola and colleagues designed a mnemonic called VISIBL-MS to encompass early signs of MS for medical students, general neurologists, and the population at large. This bilingual framework, which offers directions in English and Spanish, provides a novel structure for MS-specific awareness that addresses the interconnection between language, culture, health literacy, and health outcomes.

Another among our favorites was a tri-interview we conducted with the coauthors of a parent-directed survey aimed at thoroughly describing and investigating the incidence and mechanism of gait swelling in patients with Dravet syndrome, a rare epilepsy. Those coauthors from University Hospitals—Mandy Alhajj DO, a dermatology resident; James Dolbow, DO, a senior neurology resident; and Neel Fotedar , MD, an epileptologist—discussed certain medications and how they may a play role in the prevalence of limb swelling in patients with DS, and how better control of epilepsy can potentially relate to improved gait and lower limb swelling. In addition, the experts spoke about the possibility of other sodium channel mutations contributing to peripheral nerve problems in DS. Of the 265 survey responses they received that were completed, 17% reported past or current limb swelling—present in 35% of those older than 16, 13% of those between 7 and 16 years old, and 3% of those younger than 7 years old.

FDA and Other News

Keeping us in the realm of epilepsy, in the month of April, there were a pair of important FDA decisions that our team was on top of (in addition to nonregulatory news we'll note shortly).

The first was to approve 2 new administration options for SK Life Science, Inc. ’s cenobamate CV (Xcopri), a previously approved antiseizure medication for adults with partial-onset seizures. The treatment tablets can now be crushed and mixed with water and either administered by mouth as an oral suspension or via a nasogastric tube, providing additional flexibility for dosing.

The second, coming just a few weeks later, brought the approval of Aquestive Therapeutics 's diazepam buccal film, marketed as Libervant, for the treatment of pediatric patients with intermittent, stereotypic episodes of frequent seizure activity (including seizure clusters and acute repetitive seizures). Indicated for those between 2 and 5 years of age, the therapy offers patients a compact, easily administered diazepam formulation. Shortly after that decision, Michael Rogawski , MD, PhD, the distinguished professor of neurology and pharmacology at the University of California, Davis Health Medical Center, commented on the significance of having a new administration route for diazepam, what clinicians should be aware of with its use, and some of the major points of emphasis from its clinical program.

Rogawski noted that until recently, "there was only one FDA-approved form of diazepam for clinical use in this indication, and that is rectal diazepam or Diastat. While this is a useful dosage form—in some cases, for example, in small children, it's a feasible route of administration—it's generally not preferred by caregivers, for obvious reasons. It can be embarrassing for the patient and the caregiver. It is a route of administration that is generally not feasible for larger patients and adults because of the difficulty of simply positioning an adult appropriately for rectal administration. Of course, there is also the embarrassment factor on the part of both the patient and the caregiver. In recent years, there have been approvals of newer dosage forms, but the diazepam buccal film product provides an entirely new way of administering diazepam that hasn't heretofore been available in the United States, or actually, anywhere in the world. This is a very innovative and new product concept, if you will."

There were 2 other key pieces of news: the first being the American Headache Society 's (AHS) call for the use of CGRP-targeting agents as first-line options for patients with migraine—which is a complete contrast to the standard process. In the previous AHS consensus statements, the society noted that patients must try at least 2 classes of previous first-line medications for at least 8 weeks before being considered for these therapies. Overall, the mounting evidence that has established CGRP as a fundamental mechanism of migraine and CGRP-targeting therapies as "migraine-specific" helped lead to the organization’s position statement. Migraine expert Stephen Samples , MD, the chair of Allegheny Health Network 's department of neurology, provided commentary on the treatment possibilities of having calcitonin gene-related peptide–targeting therapies as first-line options and how this may lead to further personalized approaches. Additionally, he stressed the need to continue to educate the patient community on the treatment options available and the ways to lower rates of chronic migraine. He expressed his "disappointment at [the time of first CGRP approval in 2018] that insurance companies were asking migraine patients to try a conventional preventative group of medications first for at least 4 to 6 weeks, showing lack of efficacy or tolerability, prior to starting CGRP antagonist pathway treatments. As you know, conventional preventative therapy for migraines includes beta-blockers, treatments used to control blood pressure, antiepileptic medication, treatments used to control epilepsy, and antidepressant therapy used for anxiety and depression. Although those therapies showed efficacy, they are not migraine-specific treatments and are associated with myriad side effects. For the first time in the history of headache medicine, migraine was seen as a true neurological and extraordinarily prevalent disorder, for which patients had an opportunity to start with migraine-specific treatments, designed and developed specifically for migraine management. However, patients and providers encountered different rules and regulations from the insurance companies, preventing the use of CGRP antagonists as a first line of treatment."

Our final piece of news came out of a conversation our team had with Mark Bain, MD, a neurosurgeon at Cleveland Clinic ’s Cerebrovascular Center, on the positive results of the full data from the ENRICH trial (NCT02880878), a large-scale study evaluating NICO Corporation 's technology, BrainPath and Myriad, as a method of treatment for patients with intracerebral hemorrhage (ICH). The study included 300 patients with ICH who were randomly assigned 1:1 within 24 hours after the time last known to be well, to minimally invasive surgical removal of the hematoma plus guideline-based medical management (surgery group) or to guideline-based medical management alone (control).

Bain discussed the NICO technology in detail, its safety profile, and how it can be implemented going forward; as well as on the specific differences in outcomes for those with hemorrhages located in lobar vs anterior basal ganglia regions and what these results might indicate. In addition to noting that this was the first trial to show that a minimally invasive surgical approach can improve patients' functionally and in recovery, he expressed his happiness with the technology and its ease of use, saying "The way it works is that a very small tube is inserted in a special way where we're able to spare the nerve fibers in the brain. When you place it into the brain, it displaces the nerve fibers instead of transecting, the nerve fibers, and it allows us to access the parts of the brain, or even superficial parts of the brain, in a very minimally invasive way, in a way that doesn't cause any collateral damage."

That wraps up this month's issue of The Axon—thanks for reading! Got a lead on a story you want to share? Let us know—email Matt Hoffman, our editorial director, at mhoffman@neurologylive.com.

See you next month!