The latest news and research presented in multiple sclerosis and related disorders.

Live Coverage of MS Virtual 2020: The 8th Joint ECTRIMS-ACTRIMS Meeting

The latest research and news from the International Congress on Parkinson's Disease and Movement Disorders.

Live Coverage of the 2020 MDS Virtual Congress

"Mind Moments," a podcast from NeurologyLive, brings you an exclusive interview with Costantino Iadecola, MD.

Episode 19: The Vascular Implications of Alzheimer Disease

In August, Fibrogen announced that the first patient was enrolled into its phase 3, randomized, double-blind, placebo-controlled LELANTOS trial (NCT04371666) of pamrevlumab in patients with non-ambulatory Duchenne muscular dystrophy (DMD). Pamrevlumab, a first-in-class antibody that inhibits the activity of connective tissue growth factor (CTGF), a common factor in fibrotic and proliferative disorders, will aim to become the next FDA-approved treatment for DMD if the trial is successful.

The study will feature approximately 90 patients randomized to receive pamrevlumab plus systemic corticosteroids, or placebo plus systemic corticosteroids, for up to 52 weeks. Patients will be evaluated on the change in the total score of performance of upper limb (PUL) assessment from baseline. Elias Kouchakji, MD, senior vice president, clinical development, drug safety, and pharmacovigilance at Fibrogen, pointed to pamrevlumab’s unique formulation as what separates it from currently FDA-approved DMD treatments.

 to discuss the parameters of the LELANTOS study, including specific end points, and what has been shown in previous studies of the therapy. He also discusses pamrevlumab’s mechanism of action and what he feels are the most pressing unmet needs in DMD currently.

: Can you discuss the parameters of the phase 3 LELANTOS study? What goals are you looking to accomplish?

: The answer to that question is multi-layered. We have completed the phase 2, open-label study of pamrevlumab. During that study, we were trying to identify the best end point that could be served in this population, specifically using an anti-fibrotic. One of the things that has been less understood in DMD is the fibrosis, which has garnered more attention recently, along with the role of myofibroblast, and the invasion of fibrosis that occurs in multiple organs, not just in muscles. We know that at the same time, they can lead to some scarring in the heart. Cardiac scarring has been well documented before. Based on our results, we identified that pamrevlumab can sustain or maintain muscle function much longer and slow down the progression of that muscle function loss. That is one of the major aims of the LELANTOS study in non-ambulatory patients. Maintaining muscle function is a very key component for these young men to be able to a maintain a better quality of life.

At the same time, we are looking into a multitude of secondary end points that is of interest not only to regulators, but to the patient at the same time. Forced vital capacity (FVC) is one of them. The idiopathic pulmonary fibrosis (IPF), or reduction of disease progression, has not been seen by any other currently used treatment. Similarly, we’ve seen a slowed progression of FVC in non-ambulatory DMD. The last important part that we look at the cardiomyopathy, specifically the cardiac scarring. We have seen that we are slowing or stopping the scarring from progressing and in some cases and we are even seeing a reduction in amount of scarring. That is an important part because one of the key mortality reasons in these patients is the cardiomyopathy. Although our primary end point is to assess muscle function by the PUL, we are looking at these other parameters that we think collectively as combined data have additional benefits. We are hoping that this combined data can indicate that the drug can slow the progression of the disease. One of the basis of this thought comes from the results from the phase 2 study, in which patients were treated for over 4 years. That is a prolonged time for DMD. We have seen that that is has slowed the progression of the disease among these patients. Even with the COVID-19 pandemic increasing the difficulty to get to a clinic and receive the infusion, patients were still dedicated to it.

Can you discuss the mechanism of pamrevlumab and what separates it as a first-in-class antibody that inhibits the activity of CTGF?

Let’s start with the connective tissue growth factors, or CTGF. In reality, it’s not a growth factor. It is a misnomer as its being called, just to be clear. CTGF is an extracellular matrix protein that interacts with TGF beta interleukin-13 integrin. We know that the result of these interactions leads to cellular responses. The main cellular responses are the myofibroblasts activation, the proliferation of the fibrosis, and the survival of the fibrosis in the motility and invasion. We’ve seen that this monoclonal antibody can block that CTGF from continuing to activate the myofibroblasts, reduce the motility and invasion, or the proliferation of the fibrosis. There are many diseases that fibrosis is well defined, including the IPF, interstitial lung diseases in general, DMD, invasive liver cirrhosis, and other cardiovascular diseases. Fibrosis does not stop there though. There are many solid tumors, seen in diseases such as pancreatic cancer for example, where the mass of the tumor is fibrotic and aisled within the fibrosis. Many other solid tumors have been seen in gastric or livor cancers. By blocking CTGF, we are reducing the invasion of the fibrosis, blocking the activation of myofibroblasts, and reducing the deposition in the remodeling of the fibrosis.

What do you feel are the greatest unmet treatment needs for patients with DMD currently?

In my opinion, the aim of these fatal diseases is to make them more chronic, and less fatal. Curing DMD is going to take much more elaborate work even after someone is given a gene therapy. Maintaining that independence and the capability to be able to perform with less dependency is the key aspect of additional treatment needed at this time. Replacing the dystrophin in some of this disease has improved little by little. Blocking the fibrosis will do the same things as well. This could all lead to an improvement of the independency of DMD populations, but we should not be waiting for them to become non-ambulatory. That would be the wrong message. I’ve been asked many times why Fibrogen will start with non-ambulatory patients and there’s a multitude of reasons why.

One of them is that this population is the least addressed in any of the clinical trials, even when collecting data on the disease history. When we try to understand more of the disease history, we find that a lot of these studies are so small that they are not even bigger than our phase 2 study. That by itself gives us an aspect at them. We thought about the pulmonary function once we saw the result of the IPF. We noted that we can be able to help these patients, their lung functions and their breathing, as well as improve the capabilities in reducing down need for oxygen support. That to me is step 1. Now, what does this patient need? This is what we need to start concentrating on when thinking about how we can modify this disease from a failed disease into a chronic one. We as researchers, did this successfully with HIV. At the beginning, HIV was extremely fatal. We made it chronic. There are millions living with HIV, but they will die with HIV, not from HIV. Similarly, I look forward for the patient to live with DMD, but not die from it. That will be the greatest accomplishment.

Articles

Elias Kouchakji, MD, provides details of the phase 3 LELANTOS study of novel antibody pamrevlumab for the treatment of Duchenne muscular dystrophy.

Pamrevlumab Aims to Join Growing DMD Treatment Landscape

 staff prepares this preview of what to expect from our coverage. 

, there are a number of hot topics that we will be posting throughout the week.

Episode 20 of the "Mind Moments" podcast will go live this Friday, October 23, 2020. It features an interview with Raman Malhotra, MD, associate professor of neurology, Washington University in St. Louis, and board of directors, American Academy of Sleep Medicine. Malhotra will discuss the current state of sleep care, some of the challenges faced by physicians and patients, and what's to come for the field in the near future.

To subscribe on your favorite podcast player, 

The first half of a recent conversation with Elias Kouchakji, MD, senior vice president, clinical development, drug safety, and pharmacovigilance, Fibrogen, who sat down to discuss the company’s investigational drug, pamrevlumab, for the treatment of Duchenne muscular dystrophy (DMD) and its upcoming phase 3 trials. Additionally, he detailed the current state of DMD, the treatment landscape within it, and the importance of trying to treat patients earlier in their disease progression.

To check out previous coverage of pamrevlumab, 

A conversation with Howard Fillit, MD, founding executive director and chief science officer, Alzheimer's Drug Discovery Foundation (ADDF), will air on 

 channel this Thursday, October 22, 2020. Fillit discussed the recent ADDF International Conference, highlighting some of the key presentations and state of boundary-pushing research in Alzheimer

To check out our latest conversations with Fillit, 

In partnership with the Consortium of Multiple Sclerosis Centers (CMSC) and the International Organization for Multiple Sclerosis Nurses (IOMSN), the second of 2 upcoming webcast programs on multiple sclerosis (MS) taking place in October, "Cannabis and MS: Helping Patients Understand Risks and Benefits," will air its second of 3 parts this Wednesday, October 21, at 7PM EDT (the following session will air on the 28th). This progressive webcast series features Allen C. Bowling, MD, PhD, director of the NeuroHealth Institute and clinical professor of neurology at the University of Colorado. Participants will earn 1 CE credit for completing each session.

Here's what is coming soon to NeurologyLive.

This Week on NeurologyLive

Results from a retrospective and prospective diagnostic study provided proof-of-concept that skin a-synuclein (aSynP) seeding activity may serve as a novel biomarker for antemortem diagnoses of Parkinson disease (PD) and other synucleinopathies, such as Lewy body dementia (LBD) and multiple system atrophy (MSA).

The researchers, led by Zerui Wang, MD, PhD, postdoctoral research associate, Case Western Reserve University School of Medicine, analyzed 160 autopsied skin specimens from 140 cadavers (85 male cadavers [60.7%]; mean age at death, 76.8 years [standard deviation (SD), 10.1]) and 41 antemortem skin biopsies (27 male participants [66%]; mean age at time of biopsy, 65.3 years [SD, 9.2]).

Real-time quaking-induced conversion (RT-QuIC) and protein misfolding cyclic amplification (PMCA) assays were used to analyze skin aSynP seeding activity. Analysis of autopsy abdominal skin samples from 47 PD cadavers and 43 nonneurodegenerative controls (NNCs) using RT-QuIC revealed 94% sensitivity (95% CI, 85–99) and 98% specificity (95% CI, 89–100).

The data also showed that RT-QuIC yielded 93% sensitivity (95% CI, 85–97) and 93% specificity (95% CI, 83–97) among 57 cadavers with synucleinopathies (PD, LBD, and MSA), and 73 cadavers without synucleinopathies (Alzheimer disease [AD], progressive supranuclear palsy [PSP], corticobasal degeneration [CBD], and NNCs).

Investigational New Drug Application Accepted for Mesdopetam in Parkinson Disease

All told, the skin RT-QuIC assay was also able to highly accurately differentiate synucleinopathies (n = 57) from nonsynucleinopathies (n = 73; mean area under curve [AUC], 0.9696 [standard error (SE), 0.0135]; 95% CI, 0.9431–0.9961; 

"To our knowledge this study has demonstrated for the first time that skin αSynP has aggregation seeding activity that was significantly higher in individuals with PD and other synucleinopathies than in those with tauopathies and NNCs. The skin-based analyses provided comparable diagnostic sensitivity and specificity to CSF-based assays,” Wang and colleagues concluded.

The investigators examined autopsy skin samples from PD cadavers (n = 24), LBD cadavers (n = 5), MSA cadavers (n = 3), PSP cadavers (n = 5), CBD cadavers (n = 5), and NNCs (n = 8) using PMCA. The sensitivity and specificity of PMCA to differentiate synucleinopathies from nonsynucleinopathies were 82% (95% CI, 76–88) and 96% (95% CI, 85–100), respectively.

Consistent with RT-QuIC findings, PMCA maximum thioflavin T (ThT) fluorescence responses from skin samples were highly accurate in discriminating synucleinopathies (n = 32) from nonsynucleinopathies (n = 18; mean area under curve, 0.9444 [SE, 0.0298]; 95% CI, 0.8860–1.0000; 

Wang and colleagues noted that phosphorylated aSynP was detectable with pS129-Syn, otherwise known as the antibody directed against phosphorylated a-synuclein, colocalized with PGP9.5 (an axonal marker), revealing the presence of aSynP in the skin nerve fibers of PD cadavers but not cadavers without PD by immunohistochemistry (IHC) and immunofluorescence (IF) microscopy.

From posterior cervical and leg skin biopsy tissues from patients with PD and controls without PD, the sensitivity and specificity were 95% (95% CI, 77–100) and 100% (95% CI, 84–100), respectively, for RT-QuIC and 80% (95% CI, 49–96) and 90% (95% CI, 60–100) for PMCA.

When analyzing the agreement levels of RT-QuIC and PMCA for aSynP seeding activity in the cadavers who were examined by both assays, researchers found that the PD agreement percentage was 78.6% (95% CI, 62.2–95.0), with RT-QuIC having slightly higher observed sensitivity than PMCA. The percentage agreement for the other diagnosis groups was 100%. Among PD cases only, there was 75% agreement, and the McNemar test indicated no significant difference (

 = .69), which also supports agreement between methods.

Wang and colleagues concluded, “To our knowledge, there is currently no antemortem diagnostic test to reliably differentiate tauopathies from synucleinopathies in living patients with parkinsonism. Such a test would aide in treatment planning, prognostication, and guiding enrollment in clinical studies. Here, we showed that RT-QuIC and PMCA analyses of skin aSynP seeding activity among patients with parkinsonism can differentiate synucleinopathies (PD, MSA, and LBD) from tauopathies (PSP and CBD), which is consistent with previous reports of detecting aSynP deposits in the skin nerve fibers of patients with LBD and MSA with IHC or IF microscopy.”

Wang Z, Becker K, Donadio V, et al. Skin a-synuclein aggregation seeding activity as a novel biomarker for Parkinson disease. 

. Published online September 28, 2020. doi: 10.1001/jamaneurol.2020.3311

The use of real-time quaking-induced conversion and protein misfolding cyclic amplification assays accurately allowed researchers to differentiate synucleinopathies from nonsynucleinopathies.

Skin A-Synuclein May Accurately Diagnose Parkinson Disease, Other Synucleinopathies

This content was originally published on HCPLive, a sister publication of NeurologyLive. To view the original post,

While there are many assumptions as to how the ongoing 

 around the world, there is not much known how sleep has ultimately been impacted for parents and children.

A team, led by Ghadir Zreik, PhD, Psychology Department, The Center for Psychobiological Research, The Max Stern Yezreel Valley College, examined the possible consequences the pandemic and home confinement is having on maternal anxiety, maternal insomnia, and maternal reports of sleep problems among 264 children between 6-72 months in Israel.

The study population included 120 male children, with a mean age of 31.27 months. Approximately 38% of the infants in the study were firstborns, while families had a mean of 2.15 children. The mean age of mothers in the study was 33.97 years old and their mean duration of education was 16.37 years. In addition, 54.2% of mothers reported a change in the family income because of the crisis.

Zreik and colleagues specifically explored whether mothers experience change in their own insomnia symptoms and child’s sleep between pre-crisis and crisis. Furthermore, they conducted a web-based study 4 weeks into the national lockdown in Israel.

The investigators found a high frequency of maternal clinical insomnia in recent months—23% during the pandemic compared to 11% in the 1-2 months prior to the pandemic. Additionally, approximately 80% of mothers reported no change in their child’s sleep quality, duration, and sleeping arrangement during the COVID-19 pandemic.

On the other hand, approximately 30% of these mothers reported a negative change in their child’s sleep quality, as well as a decrease in sleep duration. There was also mothers who reported a positive change.

"These findings suggest that the changes in sleep patterns during the COVID‐19 pandemic are varied and that no unified change for the worse should be expected,” the authors wrote. “Further consideration of changes in sleep within the family context during this ongoing crisis is needed.”

The ongoing pandemic has been linked to a number of psychiatric and other issues, including depression, anxiety, and sleep. The disruption of traditional work and school hours has only exacerbated those issues.

Researchers have long believed sleep is critical for both adult and child psychical and psychosocial well-being.

“The current stressful circumstances of home confinement and major changes to daily routines, higher levels of anxiety, decrease in daylight exposure, increased blue light exposure due to massive reliance on digital media, changes in diet, and reduced physical activity may all have negative implications for sleep quality,” the authors wrote.

Recently, researchers in Greece found 37.6% of participants scored above the cut-off score for insomnia, significantly higher than the 10% worldwide prevalence estimated prior to the pandemic.

Maternal perceptions of sleep problems among children and mothers during the coronavirus disease 2019 (COVID‐19) pandemic in Israel,

The rate of maternal clinical insomnia increased from 11% pre-pandemic to 23% during the COVID-19 pandemic. 

COVID-19 Pandemic Associated With Sleep Issues

's Friday 5! Every week, the staff compiles 5 highlights of 

's widespread coverage in neurology, ranging from newsworthy study findings and FDA action to expert interviews and peer-to-peer panel discussions.

 Early Awareness Towards Epilepsy Transition

Sucheta M. Joshi, MD, MS, FAES, FAAP, and Nicholas Beimer, MD, discussed the reasons why EpiTRAQ may influence earlier discussions with patients prior to the epilepsy transition process.

 Ana Pereira, MD: Studying Riluzole in Alzheimer Disease

The assistant professor of neurology and neuroscience at Mount Sinai Medical Center discussed the literature that influenced a pilot trial of riluzole in Alzheimer disease.

 Remote Ischemic Post-Conditioning Shows Significant Benefit With IVT

Investigators noted changes in plasma vascular endothelial growth factor and S100 ß levels indicate a protection-based mechanism derived from the combined treatment.

 COVID-19 Associated With New Neurologic Disorders, Increased Risk of In-Hospital Mortality

Patients with neurologic disorders were more often older, male, white, hypertensive, diabetic, intubated, and had higher sequential organ failure assessment scores.

Safety of CGRP Receptor Antagonists vs 5-HT1F Agonists

Peter J. Goadsby, MD, PhD, DSc; Dawn C. Buse, PhD; Jelena Pavlovic, MD, PhD; Wade M. Cooper, DO; and Paul G. Mathew, MD, 

assess the differences in dosing and adverse-effect profiles when using small-molecule CGRP receptor antagonists rimegepant and ubrogepant vs lasmiditan.

Take 5 minutes to catch up on NeurologyLive's highlights from the week ending October 16, 2020.

NeurologyLive Friday 5 — October 16, 2020

Data from the overall survival analysis from the phase 2/3 CENTAUR trial (NCT03127514) of AMX0035 (Amylyx Pharmaceuticals), an orally administered, fixed‐dose coformulation of sodium phenylbutyrate‐taurursodiol (PB‐TURSO) for the treatment of amyotrophic lateral sclerosis (ALS) suggest that the therapy is associated with a 6.5-month longer median survival compared with placebo.

The analysis included 135 patients randomized in the trial, with median overall survival being 25 months (95% CI, 19.0–33.6) for those treated with AMX0035 compared with a median survival of 18.5 months in the placebo group (95% CI, 13.5–23.2) for a hazard ratio (HR) of 0.56 (95% CI, 0.34–0.92; 

 =.023), equating to a 44% lower risk of death.

The investigators, led by Sabrina Paganoni, MD, PhD, of the Healey & AMG Center for ALS at Massachusetts General Hospital, noted that these data in combination with the previously reported results of the study suggest that the therapy provides patients both functional and survival benefits.

"The newly released data suggests that treatment with AMX0035 is associated not only with functional benefits, as previously reported, but also with a long-term survival benefit," Paganoni told 

These results provide substantial evidence supporting the role of AMX0035 for the treatment of ALS. The next steps will depend on ongoing conversations with regulatory authorities."

In the randomized trial, included individuals were randomized in 2:1 fashion to AMX0035 (3-g PB and 1-g TURSO per sachet) or matching placebo, administered twice daily by mouth or feeding tube for a planned duration of 24 weeks. Additionally, patients eligible for the open-label extension (OLE) were given the option to enroll in an OLE (NCT03488524) and receive the active drug for up to 132 weeks. In total, 92% of the study population enrolled.

The estimated probability of survival at 1 year for those in the treatment group was 80.9% (95% CI, 71.1–87.7) and for placebo was 72.9% (95% CI, 58.0–83.3%). For 2 years, the estimates were 51.6% (95% CI, 38.9–62.9) and 33.9% (95% CI, 19.4–49.1), respectively. The median time to censoring was 21.3 months.

Elias Kouchakji, MD: Importance of Non-Ambulatory Patients in DMD Trials

The median exposure duration for all patients who were randomized, including those who did not opt into the OLE, was 8.8 months (range, 0.1–33.0). Those originally randomized to placebo had a median exposure of 1.9 months (range, 0–22.5), all of which were during the OLE. The average AMX0035 exposure duration was 10.6 months in the treatment group and 4.7 months in the placebo group.

The 2 groups also had similar rates of death-equivalent events—defined as tracheostomy or permanent assisted ventilation (PAV) for >22 hours daily for >7 days, with date of PAV onset being the first of the 7 days. All told, 6 (6.7%) participants originally randomized to treatment and 4 (8.3%) originally randomized to placebo experienced death-equivalent events.

“These results support that AMX0035 has both functional and long-term survival benefits,” said Merit Cudkowicz, MD, director, Healey & AMG Center for ALS; chief, Neurology, Mass General; chief medical officer, ALS Finding a Cure; and Julieanne Dorn Professor of Neurology, Harvard Medical School, in a statement. “ALS is a serious disease that progresses rapidly. With these results, we have shown that AMX0035 may provide patients hope and the chance to function better and live longer lives. On behalf of ALS Finding a Cure, our colleagues, and foundations that supported us, I want to thank all participants not only in this study, but also in all previous ALS studies, for their critical role in helping to reach wonderful milestones like this.”

These findings are notable in the context of the landscape of ALS therapy, as there are only 2 available disease-modifying agents for ALS, riluzole and edaravone, and as of yet, only riluzole has been shown to prolong survival in clinical study. Edaravone’s effect on survival is currently unknown. Paganoni et al. noted that the findings of the 3 sensitivity analyses they ran to account for the concomitant use of 1 or both of those agents at baseline—77% of patients were on at least 1—maintained its statistical significance of benefit over placebo. “These results suggest that the benefit of PB-TURSO was independent of baseline concomitant medication use,” they wrote.

Amylyx noted that it is submitting the long-term functional and safety data from the CENTAUR and OLE studies to a peer-reviewed journal and expects those data to be published in the near future. Interim data from the ongoing extension study will be presented later this year.

“We want to thank all of the CENTAUR participants for their involvement in the study,” said Justin Klee, co-CEO and co-founder, Amylyx, in a statement. “The commitment of so many people with ALS to this research over the course of nearly three years, especially when weighing just how valuable time is for this patient community, has led us to this critical development milestone where we can now reimagine outcomes for ALS. We know there is nothing more valuable than time to these and other patients, so we hope to share updates on our progress with AMX0035 with the ALS community as soon as possible.”

to detail the status of the OLE study of AMX0035 and its analyses and expanded on what she hopes future assessments might reveal about the agent’s impact on survival in ALS. Watch her share her thoughts below.

REFERENCES
1. Paganoni S, Hendrix S, Dickson SP, et al. Long‐Term Survival of Participants in the CENTAUR Trial of Sodium Phenylbutyrate‐Taurursodiol in ALS.

. Published online October 16, 2020. doi: 10.1002/mus.27091.
2. Amylyx Pharmaceuticals Announces Publication of CENTAUR Survival Data Demonstrating Statistically Significant Survival Benefit of AMX0035 for People with ALS. News release. Cambridge, MA. Amylyx Pharmaceuticals. Published October 16, 2020. Accessed October 16, 2020. businesswire.com/news/home/20201016005397/en/Amylyx-Pharmaceuticals-Announces-Publication-of-CENTAUR-Survival-Data-Demonstrating-Statistically-Significant-Survival-Benefit-of-AMX0035-for-People-with-ALS

The combination agent resulted in a 44% lower risk of death for patients with ALS, with a 6.5-month longer median survival compared with placebo.

AMX0035 Extends Survival in Amyotrophic Lateral Sclerosis

“Our FDG-PET measures also correlated very well with cognitive measures including the ADAS-cog…as well as the MMSE.”

Even with the excitement around the possible first approval in Alzheimer disease slated for early 2021 with aducanumab, those physicians working in this specialty, the pending action at the FDA is still lit with the backdrop of the hundreds of failed drugs that have left the treatment paradigm rather slim.

These failures have led some to look to repurpose already proven agents to explore their potential in making an impact on the disease’s progression. One such effort, led by Ana Pereira, MD, assistant professor of neurology and neuroscience, Mount Sinai Medical Center, was recently presented at the virtual Alzheimer’s Drug Discovery Foundation International Conference. This pilot clinical trial featured the therapy riluzole, which has long been used in the treatment of amyotrophic lateral sclerosis (ALS).

This study evaluated riluzole in patients with Alzheimer disease, and it met the primary end point, with fluorodeoxyglucose (FDG)-positron emission tomography (PET) measures showing significantly less decline in areas of interest in the brain. Additionally, the second outcome measure showed a strong correlation between cognitive measures and FDG-PET brain metabolism with riluzole treatment.

To find out more about the study and its findings, 

 spoke with Pereria in an interview. She offered some details on the overall findings of the study, which support a larger, phase 3 assessment, and gave her perspective on some of the more interesting aspects of the data.

Videos

The assistant professor of neurology and neuroscience at Mount Sinai Medical Center detailed the findings of a recent pilot trial of riluzole in Alzheimer disease she and colleagues conducted.

Ana Pereira, MD: Pilot Study of Riluzole in Alzheimer Disease

Post-hoc analysis results from a 15-month study period that included patients with chronic (CM) and episodic migraine (EM) demonstrated that treatment with either monthly or quarterly fremanezumab (Ajovy; Teva Pharmaceuticals) dosing did not show a wear-off effect towards the end of the dosing interval.

The analysis included 1043 patients with CM (n = 611) and EM (n = 432) in a long-term, 12-month phase 3 study (NCT02638103) who were initially enrolled in the HALO CM (NCT02621931) and HALO EM trials (NCT02629861) and were double-blinded to monthly or quarterly fremanezumab.

At months 3, 6, 9, and 15, there were no substantial differences in mean weekly migraine days between weeks 1–2 and weeks 3–4 or between weeks 1–3 and week 4 with quarterly or monthly fremanezumab in the CM or EM subgroups.

"This is an important analysis for the migraine community since clinical symptoms often return or worsen before the next dose of many preventive migraine medications is due,” Andrew Blumenfeld, MD, director, Headache Center of Southern California, said in a statement.

In the first quarter, patients with CM on quarterly dosing experienced a mean number of 2.8 and 2.7 weekly migraine days in weeks 1–2 and weeks 11–12, respectively, compared to 2.5 and 2.5 weekly migraine days in those respective weeks during the second quarter.

Similar results were shown for those with EM. A total of 1.5 and 1.3 mean weekly migraine days were reported in weeks 1–2 versus weeks 11–12 in the first quarter decreased to 1.2 and 1.1 weekly migraine days, respectively, in weeks 1–2 and weeks 11–12 in the second quarter.

​WATCH MORE: Evolution of Acute Treatment of Migraine

Patients with CM who took monthly fremanezumab reported a mean number of 2.6 migraine days during weeks 1–3 at the beginning of dosing, which decreased to 1.8 at week 4 at the end of the 15-month treatment period. Within that time period, there were no statistically significant differences between weeks 1–3 and week 4 during any of the 3-month intervals.

Patients with EM on monthly fremanezumab experienced a mean number of 1.2 weekly migraine days in weeks 1–3 after initiation and 1.0 mean number of weekly migraine days in week 4 at the end of the study period.

During the first 2 weeks of fremanezumab quarterly and monthly treatment decreases of approximately 31% and 30% weekly migraine days from baseline were observed for patients with CM, respectively, as well as decreases of approximately 37% and 42% in patients with EM.

For context, the mean weekly number of migraine days at baseline was 4.0 for patients with CM taking quarterly or monthly fremanezumab. Among patients with EM, the mean weekly number of migraine days at baseline in the quarterly and monthly fremanezumab groups were both 2.3 days.

"Migraine can be a debilitating disease, so evaluating migraine days throughout a dosing regimen can be significant for healthcare providers when considering treatment options. Whenever the brain is exposed to a migraine attack, there is the possibility of increased sensitization with progressive worsening of the frequency of migraine. A key clinical goal is to limit the amount of time the brain is exposed to migraine to reduce this risk and the number of migraine days impacting a patient before their next dose,” Blumenfeld added.

Across both dosing subgroups in patients with CM and EM, the mean weekly number of migraine days decreased by 30% to 42% during the first 2 weeks. Investigators noted that decreases in weekly migraine days remained steady during the last 2 weeks of the first quarter, with a similar maintenance of response during the second quarter.

No new safety signals were identified in this population that were inconsistent with the known safety profile of fremanezumab. The most commonly reported adverse events (AEs) were injection-site reactions, with similar incidence rates between treatment groups. Among those injection-site reactions, induration (CM quarterly, 30%; CM monthly, 35%; EM quarterly, 29%; EM monthly, 38%), injection-site pain (29%, 33%, 30%, and 32%, respectively), and injection-site erythema (25%, 31%, 22%, and 27%, respectively) were the most common types.

 for the prevention of migraine in adults. At the time, the drug was made available for administration via a prefilled syringe indicated for 1-time use.

autoinjector for the delivery of fremanezumab

 was approved by the FDA in January of this year.

1. Teva announces new analysis of consistency in migraine days over the course of a dosing regimen for Ajovy (fremanezumab-vfrm) injection published in headache. News release. Teva Pharmaceuticals. October 7, 2020. Accessed October 15, 2020. 

https://www.tevausa.com/news-and-media/press-releases/teva-announces-new-analysis-of-consistency-in-migraine-days-over-the-course-of-a-dosing-regimen-for-ajovy/

2. Blumenfeld AM, Stevanovic DM, Ortega M, et al. No ‘wearing-off effect’ seen in quarterly or monthly dosing of fremanezumab: sub-analysis of a randomized long-term study. 

. Published October 2, 2020. doi: 10.1111/head.13994

3. Teva Announces U.S. Approval of AJOVYTM (fremanezumab-vfrm) Injection, the First and Only Anti-CGRP Treatment with Both Quarterly and Monthly Dosing for the Preventive Treatment of Migraine in Adults. News release. Teva Pharmaceutical.Published September 2018. Accessed October 15, 2020. https://www.businesswire.com/news/home/20180914005613/en/Teva-Announces-U.S.-Approval-AJOVYTM-fremanezumab-vfrm-Injection.

4. Teva announces FDA approval of ajovy (fremanezumab-vfrm) injection autoinjector. News release. Teva Pharmaceuticals. January 28, 2020. Accessed October 15, 2020. businesswire.com/news/home/20200128005810/en.

Decreases in weekly migraine days remained steady during the last 2 weeks of the first quarter, with a similar maintenance of response during the second quarter.

Fremanezumab Efficacy Shows Consistency Across Monthly, Quarterly Dosing Regimens

This content was originally published on Diagnostic Imaging, a sister publication of NeurologyLive. To view the original post,

There is a connection between impaired blood flow and the build-up of tau protein in patients who have Alzheimer disease (AD), according to findings revealed on MRI and PET scans.

 a team of investigators from the University of Southern California (USC) in Los Angeles shed more light onto the 

, noting that their findings point to the potential of a combination treatment.

“Our results demonstrate vascular-tau association across the [Alzheimer disease] spectrum and suggest that early vascular-tau associations are exacerbated in the presence of amyloid, consistent with a two-hit model of [Alzheimer disease] on cognition,” said the team led by Daniel Albrecht, PhD, a neuroimaging research fellow. “Combination treatments targeting vascular health, as well as amyloid-β and tau levels, may preserve cognitive function more effectively than single-target therapies.”

To date, the connection between vascular dysfunction and tau pathology and how it affects cognition has not been well understood. Still, there is a growing body of evidence that shows vascular dysfunction plays a large part in AD pathophysiology.

“Like the proverbial chicken and egg, it remains unclear if impaired blood flow causes or is caused by errant protein building,” they said, “or if these two symptoms occur for unrelated reasons.”

Neflamapimod Meets Primary End Point in Dementia With Lewy Bodies

To dig deeper into this connection, Albrecht’s team used MRI and PET scans to compare blood flow and tau build-up in older adults. They examined 68 patients from USC who ranged from having normal cognition to showing signs of mild cognitive impairment (MCI), as well as a validation group of 138 individuals with MCI or AD who were enrolled in the Alzheimer’s disease Neuroimaging Initiative. Alongside their MRI and PET scans, all patients completed neuropsychological testing and were assessed for executive brain function, attention, and memory.

Based on their analysis, the team discovered that spots in the brain with more significant tau build-up also had decreased blood flow. This was particularly apparent in the inferior temporal gyrus – the area of the brain which typically experiences tau build-up in patients with AD. The team pointed out that this relationship also held true for the validation group.

"The correlation between tau and vascular function was stronger in people with greater cognitive impairment and higher amyloid-β levels,” they said. “It also appeared in more brain regions as the disease progressed in severity.”

Consequently, Albrecht’s team said, their results suggest that targeting vascular function could be key to avoiding and treating AD.

"Results from the current study provide the first evidence of associations between elevated tau PET signal and vascular dysfunction,” they said. “Take together, combination treatments targeting vascular health, as well as amyloid-β and tau levels, may be more effective in preserving cognitive function than single-target therapies.”

Albrecht D, Isenberg AL, Stradford J, et al. Associations between vascular function and tau PET are associated with global cognition and amyloid. 

. Published online October 12, 2020. doi:10.1523/JNEUROSCI.1230-20.2020

To date, the connection between vascular dysfunction and tau pathology and how it affects cognition has not been well understood.

Link Identified Between Blood Flow, Tau Accumulation in Alzheimer Disease

Positive topline data from a phase 3 study (NCT03533114) of the investigational use of calcium, magnesium, potassium, and sodium oxybates (Xywav; Jazz Pharmaceuticals) oral solution have been announced that suggest the agent is effective and safe for adult patients with idiopathic hypersomnia.

The double-blind, multicenter, randomized clinical trial featured patients who had excessive daytime sleepiness associated with their idiopathic hypersomnia. All of those who were treated with the agent, formerly known as JZP-258, experienced clinically meaningful improvements in Epworth Sleepiness Scale (ESS) scores during the open-label titration period.

Jazz noted that it plans to submit the data for presentation at an upcoming medical meeting and will use them to support its upcoming submission of a supplemental New Drug Application (sNDA) to the FDA, which is expected to be filed as early as the first quarter of 2021. The FDA granted a fast track designation to the therapy in September 2020.

"We are excited by these compelling results and the magnitude of improvement observed in the study, in particular for people living with idiopathic hypersomnia who currently have no approved treatment option. We are deeply grateful to the patients and investigators who participated in the study and look forward to working quickly with the FDA to make Xywav available to patients as soon as possible," said Robert Iannone, MD, MSCE, executive vice president, research and development, Jazz Pharmaceuticals, in a statement.

The primary end point of the study—ESS score—and the key secondary end points—Patient Global Impression of Change (PGIC) and Idiopathic Hypersomnia Severity Scale (IHSS)—were measured during the randomized withdrawal portion of the study. That section included 115 patients, and those given the oxybates combination reported clinically meaningful maintenance of efficacy as measured by all 3 evaluations. 

Additionally, highly statistically significant worsening was observed for those administered placebo in comparison with the Jazz agent for ESS (

"There is a significant need for greater awareness of idiopathic hypersomnia, which can severely impact a person's daily life, and can often be misdiagnosed or undiagnosed over a substantial period of time," said lead investigator Yves Dauvilliers, MD, director, Sleep Disorders Centre, Gui de Chauliac Hospital, in Montpellier, France. "Currently, there are no approved treatment options for idiopathic hypersomnia, and these data are a welcome advance for patients.”

This study in idiopathic hypersomnia included a titration and optimization period lasting up to 14 weeks, followed by a 2-week stable-dose period and a 1:1 randomization to either the study treatment or placebo for 2 weeks. After the completion of the double-blind, placebo-controlled treatment period, patients entered a 24-week open-label safety extension period.

"For more than 15 years, Jazz has been at the forefront of sleep medicine,” Iannone added. “Our purpose is to innovate to transform the lives of patients and we are committed to bringing new options for people living with serious sleep disorders where there are no or limited treatments available."

FDA Approves Pitolisant for Cataplexy in Narcolepsy

The oxybate product contains a unique composition of cations resulting in 92% less sodium, or approximately 1000 to 1500 mg/night, than sodium oxybate (Xyrem; Jazz), the only other approved agent for this indication. The treatment does not carry warnings about sodium content but does include safety risks for those under the drug. Designated as a Schedule III medicine, JZP-258 also contains a boxed warning as a central nervous system depressant and for its potential for abuse and misuse. Therefore, the treatment is only available through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the Xywav and Xyrem REMS Program.

Jazz has noted previously that taking the therapy along with other central nervous system (CNS) depressants such as medicines used to make a patient or their child fall asleep, including opioid analgesics, benzodiazepines, sedating antidepressants, antipsychotics, sedating anti-epileptic medicines, general anesthetics, muscle relaxants, alcohol, or street drugs, may cause serious medical problems, including respiratory depression, hypotension, drowsiness, syncope, and death. Gamma hydroxybutyrate (GHB) is the active ingredient of Xywav and abuse of illegal GHB alone or with other drugs can cause serious side effects. Among them include seizures, trouble breathing, changes in alertness, coma, and death.

The oral solution was recently approved in July 2020 for the treatment of cataplexy or excessive daytime sleepiness in patients 7 years of age or older with narcolepsy. The basis of that approval came from data displaying that the drug demonstrated statistically significant differences (

 <.0001) in the weekly number of cataplexy attacks and ESS scores compared to placebo in a phase 3 study. During the double-blind withdrawal period, participants randomized to placebo experienced 2.35 (interquartile range [IQR], 0.00 to 11.61) weekly cataplexy attacks compared to 0 (IQR, –0.49 to 1.75) in the JZP-258 group. Additionally, significant increases in median ESS scores were observed in the placebo group (median, 2.0 [IQR, 0.0 to 5.0]) compared to the treatment group (median, 0 [IQR, –1.0 to 1.0]; 

REFERENCES
1. Jazz Pharmaceuticals Announces Positive Top-line Results from Phase 3 Study of Xywav™ (calcium, magnesium, potassium, and sodium oxybates) Oral Solution in Adult Patients with Idiopathic Hypersomnia. News release. Dublin, Ireland. Jazz Pharmaceuticals. Published October 8, 2020. Accessed October 15, 2020. prnewswire.com/news-releases/jazz-pharmaceuticals-announces-positive-top-line-results-from-phase-3-study-of-xywav-calcium-magnesium-potassium-and-sodium-oxybates-oral-solution-in-adult-patients-with-idiopathic-hypersomnia-301148512.html
2. Jazz Pharmaceuticals announces US FDA approval of Xywav (calcium, magnesium, potassium, and sodium oxybates) oral solution for cataplexy or excessive daytime sleepiness associated with narcolepsy. News release. Dublin, Ireland. Jazz Pharmaceuticals. Published July 22, 2020. Accessed October 15, 2020. jazzpharma.com/news-releases/news-release-details/jazz-pharmaceuticals-announces-us-fda-approval-xywavtm-calcium
3. Jazz Pharmaceuticals Announces FDA Acceptance of New Drug Application for JZP-258 for Cataplexy and Excessive Daytime Sleepiness Associated with Narcolepsy. News release. Dublin, Ireland. Jazz Pharmaceuticals. Published March 25, 2020. Accessed October 15, 2020. investor.jazzpharma.com/news-releases/news-release-details/jazz-pharmaceuticals-announces-fda-acceptance-new-drug

The recently approved oral solution, known as JZP-28 (Xywav), was associated with clinically meaningful improvements in Epworth Sleepiness Scale, Patient Global Impression of Change, and Idiopathic Hypersomnia Severity Scale scores.

Sodium Oxybate Oral Solution Proves Positive in Topline Hypersomnia Data

Data from a prospective study conducted by clinicians from the NYU Langone Grossman School of Medicine demonstrated patients with COVID-19 may be at risk for developing new neurologic disorders and were also associated with an increased risk of in-hospital mortality and decreased likelihood of discharge home.

Led by Jennifer Frontera, MD, professor of neurology, NYU Langone Grossman School of Medicine, the study observed that 606 of 4491 patients (13.5%) with COVID-19 hospitalized during the study timeframe developed a new neurologic disorder in a median of 2 days from COVID-19 symptom onset.

Among those newly diagnosed, the most commonly observed neurologic disorders were toxic/metabolic encephalopathy (6.8%), seizure (1.6%), stroke (1.9%), and hypoxic/ischemic injury (1.4%). Among patients with seizure, 34 of 74 (46%) had no prior history of seizure or epilepsy.

No patients reported with meningitis/encephalitis or myelopathy/myelitis referable to SARS-CoV-2 infection and 18 of 18 patients that underwent cerebrospinal fluid (CSF) analyses were reverse transcription polymerase chain reaction (RT-PRC) negative for SARS-CoV-2.

“In contrast to prior retrospective studies that focused on the conglomerate prevalence of non-specific neurologic symptoms (agitation, dysexecutive function, myalgia, dizziness, headache) along with neurologic diagnoses (e.g. stroke, seizures, Guillian-Barre syndrome etc.), we applied rigorous, standardized diagnostic criteria to identify the prevalence of specific neurologic diagnoses in a prospective fashion,” Frontera et al concluded.

Overall Stroke Risk Appears Low With COVID-19 Infection

Patients who were diagnosed with neurologic disorders after admission were significantly older, and more severely ill based on Sequential Organ Failure Assessment (SOFA) scores, intubation rates and acute renal failure rates. Additionally, patients who had neurologic disorders post-admission were more often diagnosed with stroke, hypoxic/ischemic brain injury, seizure, neuropathy, and myopathy (all 

Frontera and colleagues documented that patients diagnosed with neurologic disorders post-admission were less likely to be discharged home than those with events prior to, or at the time of admission. In total, 22% of those with neurologic disorder post admission (n = 180) were discharged compared to 38% of those with neurologic disorder pre-admit or at time of admission (n = 219).

After adjusting for age, sex, SOFA scores, intubation, past history, medical complications, medications and comfort-care-status, COVID-19 patients with neurologic disorders had increased risk of in-hospital mortality (hazard ratio [HR], 1.38; 95% CI, 1.17–1.62; 

 <.001) as well as previously mentioned decreased likelihood of discharge home (HR, 0.72; 95% CI, 0.63–0.85; 

In comparison to the 3885 patients with COVID-19 hospitalized without neurologic disorders, patients with neurologic disorders were significantly older (median age 71 vs 63 years), male (66% vs 57%), and white (63% vs 45%). Additionally, those patients also had significantly more common comorbidities including hypertension, diabetes, atrial fibrillation, venous thromboembolism and history of neurologic illness, compared to those without neurologic disorders.

Investigators found that the median time from first COVID-19 symptom, including fever, cough, nausea, vomiting, or diarrhea, to neurologic disorder onset was 2 days (interquartile range [IQR], 0–13). Furthermore, the median time from hospital admission to first neurologic symptom was –0.6 days (IQR, –1.8 to 4.1). Investigators concluded that the data indicates that most patients had neurologic symptoms prior to admission but after initial COVID-19 symptom onset.

Overall, 419 of 606 (69%) patients with COVID-19 who developed a new neurologic disorder were determined that they had symptoms prior to hospital admission.

Frontera and colleagues noted that 10 (2%) patients developed neurologic symptoms prior to traditional viral symptoms associated with COVID-19 (cough, shortness of breath, fever, sore throat, gastrointestinal abnormalities), while 263 (43%) developed neurologic and traditional COVID-19 symptoms at approximately the same time, and 326 (54%) developed neurological symptoms after traditional COVID-19 symptoms in a median of 12 days (IQR, 5–22).

Of the 326 patients who developed neurologic disorders after COVID-19 symptom onset, 172 (53%) had neurologic disorder onset while hospitalized.

Median hospital length of stay (9.8 vs 5.9 days) and ventilator days (11.8 versus 5.0) were longer among those with neurologic disorders compared to those without (both P <.001). Corticosteroid use was independently associated with a reduced risk of in-hospital mortality (adjusted hazard ratio [aHR], 0.81; 95% CI, 0.69–0.95; 

 in May to share her experience working on the front line during the pandemic in providing care for patients with the virus who have preexisting conditions. Click below to listen to episode 10 of the Mind Moments podcast with Frontera, where she detailed her firsthand experience with COVID-19 in a hospital setting, as well as what neurologic symptoms have been observed in these patients.

Frontera J, Sabadia S, Lalchan R, et al. A prospective study of neurologic disorders in hospitalized COVID-19 patients in New York City. Neurology. Published online October 5, 2020. doi: 10.1212/WNL.0000000000010979

Patients with neurologic disorders were more often older, male, white, hypertensive, diabetic, intubated, and had higher sequential organ failure assessment scores. 

COVID-19 Associated With New Neurologic Disorders, Increased Risk of In-Hospital Mortality

Biohaven Pharmaceuticals has announced that its supplemental new drug application (sNDA) for 

 for the prevention of migraine has been accepted by the FDA, with a planned Prescription Drug User Fee Act (PDUFA) action date set for the second quarter of 2021.

The orally disintegrating anti-calcitonin gene-related peptide (CGRP) tablet was originally approved in a 75-mg dose for the 

acute treatment of migraine in February 2020

, marking the first approval for Biohaven.

 If approved for this second indication, rimegepant will be the first and only CGRP-targeting therapy with indications for both preventive and acute treatment of migraine.

The basis of this new sNDA is built on data from the company’s pivotal study—known as Study 305—in migraine prevention, which showed the same dosage was associated with a significant 4.3-day reduction in monthly migraine days.

“Patients with migraine deserve the simplicity of managing their disease with a single medication that alleviates acute episodes and also works to prevent future attacks. Our goal with the Nurtec ODT development program has been to offer a fast-acting, quick-dissolve oral tablet with ‘dual-acting’ properties—acute and preventive—to treat migraine across its full spectrum,” said Vlad Coric, MD, chief executive officer, Biohaven, in a statement. “We believe that the ease of use associated with a single oral medication will benefit people with migraine so that they can take back their days, and also provides the health care system with a cost-effective approach as opposed to paying for two separate drugs for acute and preventive treatment.”

Study 305 included 348 patients with migraine randomized to receive 75-mg every other day and 347 patients on placebo. All told, those on rimegepant experienced the aforementioned 4.3-day reduction from baseline compared to the placebo group’s 3.5-day reduction (difference, 0.8; 

 <.05). Notably, of those in the rimegepant group, 49.1% reported a ≥50% reduction from the baseline number of moderate to severe migraine days compared to 41.5% in the placebo group (

The Changing Treatment Landscape for Acute Migraine

Additionally, the sNDA is supported by data from the long-term, open-label safety study, Study 201, which was included in the original NDA for rimegepant’s acute treatment indication. That study included 1800 participants who used the agent once per day, including 1131 individuals who were exposed to the drug for at least 1 year. Every patient included in the 1-year data treated a mean of 2 migraine attacks per month.

If approved, rimegepant will be the first and only anti-CGRP agent indicated for both the preventive and acute treatment of migraine.

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