Marco Meglio

This article, "COVID-19 Associated With New Neurologic Disorders, Increased Risk of In-Hospital Mortality," was originally published in NeurologyLive.

 (COVID-19) has been linked to a number of new 

 disorders, as well as an increase in the risk of in-hospital mortality.

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,” the authors wrote.

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; 

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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.

COVID-19 Linked to Several Neurological Disorders

This article, "Neflamapimod Meets Primary End Point in Dementia With Lewy Bodies," was originally published in NeurologyLive.

New study results show neflamapimod could help treat 

EIP Pharma announced that the phase 2 AscenD-LB study, which assessed neflamapimod in patients with mild-to-moderate DLB, met its primary end point of demonstrating an improvement in cognition as assessed by the Neuropsychological Test Battery (NTB).

Patients who received neflamapimod 3 times daily (TID) demonstrated significant improvement on the NTB compared to those who received neflamapimod twice daily (BID) or placebo (effect size 

 = .015). Furthermore, statistically significant improvements (

 <.01) were evident on multiple secondary clinical end points.

“Not only was the prespecified primary outcome met for the 3 times daily dose arm but supportive trends were observed in several of the secondary outcomes, setting the stage for more extensive testing,” Jeffrey Cummings, MD, ScD, Joy Chambers-Grundy Professor of brain science, and director, Chambers-Grundy Center for Transformative Science, UNLV School of Integrated Health Sciences, said in a statement.

There were no patients who discontinued the study due to drug-related adverse events (AEs). In total, there were 10 early treatment discontinuations, 4 of which were from intercurrent mental illness (2 in each placebo and neflamapimod BID recipients) and 6 from withdrawal of consent and/or disease worsening (2 in placebo and 4 in neflamapimod BID).

Researchers noted that there were 4 serious AEs (SAEs) reported in the placebo group and 3 in neflamapimod BID recipients, all of which were considered unrelated to the study drug administration. Notably, neflamapimod TID recipients did not report any SAEs or early treatment discontinuations.

AscenD-LB was a double-blind, placebo-controlled, proof-of-concept study that randomized patients 1:1 to receive 40-mg neflamapimod capsules or matching placebo capsules over a 16-week period. Patients who weighed ≤80 kg were given BID, as opposed to those who weighed >80 kg who were placed in the TID group. As patients were evaluated on NTB, secondary analyses included additional composites built from a subset of tests in the NTB, 10-item Neuropsychiatric Inventory, Timed Up and Go test, and the Clinical Dementia Rating scale Sum of Boxes.

According to EIP, the ability to demonstrate proof-of-concept in a phase 2 setting will allow them to advance the development of neflamapimod into a phase 3 study. The company did not announce a timetable for when that may occur.

"The exciting results of the Phase 2 AscenD-LB study showing benefit of the investigational drug neflamapimod for cognition in DLB will bring hope to patients and their caregivers," Stephen Gomperts, MD, PhD, director, Lewy Body Dementia Unit, and assistant professor of neurology, Massachusetts General Hospital, said in a statement. “If these findings are confirmed in a phase 3 study, the potential impact for patients with DLB will be significant.”

granted fast track designation by the FDA

 for the treatment of DLB in November 2019. At the time, the company also announced results of the REVERSE-SD study that examined neflamapimod in early stage Alzheimer disease (AD).

The randomized, double-blind, placebo-controlled, proof-of-concept study included 161 participants with early-stage AD who were randomly assigned to receive neflamapimod 40-mg or placebo twice daily for 24 weeks. While the study met its target engagement and demonstrated a statistically significant reduction in phosphorylated tau and tau levels in the cerebrospinal fluid (CSF), it failed to meet its primary end point of improved episodic memory as measured by the Hopkins Verbal Learning Test.

In addition to being accepted as a late-breaking abstract, the full results of AscenD-LB will be shared on November 7, 2020 during an oral presentation at the 13th Clinical Trials in Alzheimer’s Disease (CTAD) meeting.

Cummings, on the importance of these results, commented, “There are no approved treatments for DLB, the second most cause of neurodegenerative dementia, and there is an urgent need to find therapies for this and related disorders such as Alzheimer’s disease."

ELP Pharma readying plans to continue to study the drug in a phase 3 trial.

Neflamapimod Shows Promise in Treating Dementia with Lewy Bodies

Sumifilam Improves Multiple Alzheimer Disease Biomarkers in Phase 2b Study

," was originally published in NeurologyLive.​ 

New data shows sumifilam could be a beneficial treatment for patients with 

 (AD) by improving several disease biomarkers, something previous drugs failed to show the ability to do so.

Patients with AD administered sumifilam in the randomized, placebo-controlled, double-blind, multicenter clinical study showed improvements in tests of episodic and spatial working memory compared with patients on placebo.

Additionally, improvements in cognition correlated most strongly with decreases in phosphorylated tau (P-tau181), of which an 8-11% reduction was recorded versus placebo.

“Filamin-binding molecules are new to Alzheimer research and may represent an important advance if these data can be replicated in larger studies,” Jeffrey Cummings, MD, ScD, founding director, Cleveland Clinic Lou Ruvo Center for Brain Health, and Chambers Professor of Brain Science, University of Nevada–Las Vegas, said in a 

. “I am pleased to see early evidence of disease-modifying effects in patients with this investigational drug. The data appear to represent a step forward toward urgently needed treatments for Alzheimer disease.”

The phase 2b study funded by the National Institutes of Health (NIH) included 64 patients with mild to moderate Alzheimer disease, age 50 to 85, who were randomized 1:1:1 to 50- or 100-mg oral sumifilam or matching placebo twice daily for 28 days.

Sumifilam is a small molecule drug that restores the normal shape and function of altered filamin A (FLNA), a scaffolding protein.

Upon conclusion of the trial, both active treatment doses showed statistically significant (

 <.05) improvements in biomarkers of disease pathology, neurodegeneration, and neuroinflammation compared with placebo.

Core markers of AD pathology including total-tau decreased by 15% and 18% for patients in the 50- and 100-mg groups, respectively (all 

 <.01). P-tau decreased by 8% for patients in the 50-mg group and 11% in the 100-mg group (all 

) increased by 17% and 14% in the 50- and 100-mg groups, respectively (all 

Elevated cerebrospinal fluid (CSF) levels of neurogranin (ng) and neurofilament light chain (NfL), which indicate neurodegeneration, decreased by 36% and 28% in the 50-mg group, respectively, and by 43% and 34% in patients in the 100-mg group, respectively.

Proinflammatory IL-6 (interleukin 6), produced in response to tissue stress and injury, decreased by 10% in the 50-mg group and 11% in the 100-mg group (all 

Investigators also noted that patients in the 50-mg group had decreased levels of YKL-40 by 10% (

 <.01). Those in the 100-mg group saw similar results, with decreases of 12% (

 <.01). sTREM2, a neuroinflammation biomarker, decreased by 43% and 46% in the 50- and 100-mg groups, respectively (all 

Cognition, which was assessed via the Cambridge Neuropsychological Test Automated Battery (CANTAB) at baseline and day 28, showed directional improvements on tests of episodic memory and spatial memory in patients treated with sumifilam compared with placebo, with an effect size of 46% to 17%.

Furthermore, episodic memory improved by –5.7 and –4.3 for patients with AD in the 50- and 100-mg groups, respectively, compared to –1.5 for patients in the placebo group. Spatial memory also improved by –1.6 for patients with AD in the 50-mg group and –3.3 for patients in the 100-mg group compared with –0.4 in the placebo group.

The investigators noted that improvements in cognition correlated most strongly (statistical R2 = 0.5) with decreases in cerebrospinal fluid P-tau181, with decreases of 8% to 11% recorded in the treatment groups compared with placebo.

Overall, findings observed in this study are consistent with prior clinical and preclinical results. The drug was deemed both safe and tolerable, with no treatment-related discontinuations recorded.

There is currently an ongoing long-term, open-label study of sumifilam 100-mg twice-daily for 12 months. The study is currently at 50% enrollment, with a target enrollment of approximately 100 patients with mild to moderate AD.

"Other than a few drugs to help ease the decline, there’s really nothing out there to treat people with Alzheimer," Remi Barbier, chairman, president and chief executive officer, Cassava Sciences, said in a statement. "The improvement on multiple biomarkers in this clinical study is a first and offers hope that sumifilam has potential to become a transformative treatment for people with Alzheimer disease."

Notably, Cassava initially reported disappointing topline results from the phase 2b study in May of this year after an initial bioanalysis showed highly "anomalous data" that included major swings in levels of biomarkers observed in patients in the placebo group. Deemed invalid, a new bioanalysis of the full results was undertaken and is reported herein.

Sumifilam could be the first Alzheimer treatment to improve several biomarkers.

New Medication Helps Improve Multiple Alzheimer Disease Biomarkers

This article, "Alzheimer Disease Treatment Pipeline: Hope is Trending," was originally published in NeurologyLive.

The annual review of all ongoing research and treatments for 

 shows a renewed emphasis on nonamyloid targets, including candidate treatments addressing for inflammation, synapse and neuronal protection, vascular factors, neurogenesis, and epigenetic interventions.

Led by Jeffrey Cummings, MD, ScD, director emeritus of the Lou Ruvo Center for Brain Health at Cleveland Clinic, and vice chair of the Department of Brain Health at the University of Nevada - Las Vegas, the study reviewed and identified all trials of pharmacologic agents currently being developed for treatment of Alzheimer disease as of February 2020.

Overall, 121 agents are being evaluated in clinical trials, with 29 being assessed in 36 phase 3 trials, 65 agents in 73 phase 2 trials, and 27 evaluated in 27 phase 1 trials. Specifically, there are 12 agents (9.9%) in trials that target cognitive enhancement and 12 (9.9%) intended to treat neuropsychiatric and behavioral symptoms.

Notably, when evaluating total number of agents year-over-year, there are fewer agents in the Alzheimer disease pipeline in 2020 than in 2019 (121 vs 134).

Among the therapies being evaluated are 97 (80.2%) agents that intend to achieve disease modification, 16 (16.5%) of which target amyloid and 11 (11.3%) that target tau as the primary target or as 1 of several effects seen in preclinical or previous clinical studies.

Among the 16 amyloid agents, 6 are small molecules and 10 are monoclonal antibodies or biological therapies.

The longitudinal 5-year pipeline report showed that there is a trend for increasing diversification, with a greater number of tau-targeted, anti-inflammatory, synaptic and neuroprotective, metabolic, neurogenesis, and epigenetic agents.

“it’s clear that the use of biomarkers has been so informative in terms of helping us know whether the drugs are working and whether they are working on the biology that we are trying to target. Although we don’t have a new approved drug yet, we can see that we’re definitely affecting the part of the brain that we want,” Cummings said in an interview with 

A closer look at the agents currently in phase 3 revealed that 12 of the 29 (41%) are symptomatic, 4 (13.8%) are cognitive enhancers, and 8 (27.6%) target behavioral symptoms. 

Of the 17 (59%) putative disease-modifying agents, 5 are biological therapies and 12 are oral agents or small molecules. Since 2019, there are 5 new agents that have progressed in the pipeline to phase 3.

There are reportedly 65 agents in 73 phase 2 clinical trials. Six (9%) cognitive enhancers and 4 (6%) agents targeting behavioral symptoms were among 10 symptomatic agents. The other 55 (85%) were potential disease-modifying therapies (DMTs), 14 of which were biologics and 41 were small molecules.

When assessing biomarkers as outcome measures in Alzheimer disease clinical trials, cerebrospinal fluid (CSF) amyloid is the most common in phase 3, accounting for 10 trials (48%), while CSF tau is being used in 17 (28%) phase 2 trials, accounting for the most used in that phase.

Notably, tau imaging has become an increasingly prominent end point used in drug development programs, with use as a secondary outcome in 3 (14%) phase 3 and 4 (7%) phase 2 trials of DMTs.

“There were a number of things that stuck out to me. One was the great increase in the number of repurposed compounds that are in the pipeline,” Cummings said. “One of the things that alarmed me though was the relatively small number of agents coming into phase 1. We really have to get those drugs out of the lab, out of the animals, and into humans more successfully.”

Alzheimer's disease drug development pipeline: 2020

Translational Research & Clinical Interventions

As of February, 121 unique therapies are involved in clinical trials for Alzheimer disease, with putative disease-modifying agents targeting disease onset or progression accounting for the largest number.

Author | Marco Meglio

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