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This article, "Biogen Files Aducanumab BLA for Alzheimer Disease," was originally published in NeurologyLive.

Biogen has submitted a biologics license application (BLA) to the US Food and Drug Administration (FDA) for aducanumab, an investigational agent for the treatment of 

The BLA submission is supported by data from the phase 3 EMERGE and ENGAGE clinical trials, in addition to the phase 1b PRIME (study. 

Biogen noted that it has requested a priority review designation, as if approved, aducanumab would become the first treatment for the reduction of clinical decline in Alzheimer, as well as the first to demonstrate clinical benefit through amyloid-beta removal.

“Alzheimer’s disease remains one of the greatest public health challenges of our time. It robs memories, independence, and eventually the ability to perform basic tasks from the people we love,” said Michel Vounatsos, chief executive officer, Biogen, in a statement. “The aducanumab BLA is the first filing for FDA approval of a treatment that addresses the clinical decline associated with this devastating condition, as well as the pathology of the disease. We are committed to driving progress for the Alzheimer’s disease community and look forward to the FDA’s review of our filing.”

EMERGE (n= 1638) and ENGAGE (n = 1647) featured patients with early-stage Alzheimer disease—mild cognitive impairment (MCI) and mild Alzheimer disease dementia (Mini-Mental State Examination [MMSE] scores, 24—30).

ENGAGE did not meet its primary end point, though Biogen claims that a subset of data from the study is supportive of the outcome in EMERGE. 

The trials had been planned to be discontinued in March 2019, only to reverse course later on, based on the findings of the analysis of an expanded dataset from EMERGE.

James Kupiec, MD, chief medical officer for ProMIS Neurosciences, told

 that this re-analysis of the larger dataset showed that aducanumab was effective in slowing the progression of Alzheimer at a higher dose, and then data released at the Clinical Trials in Alzheimer’s Disease (CTAD) meeting in San Diego in December 2019 strengthened its potential to become the first disease-modifying therapy (DMT) for Alzheimer.

"This stunning reversal not only resurrected hope for a near-term therapy for Alzheimer, it also—perhaps more importantly&mdash;reinvigorated innovation supporting next-generation therapies that demonstrate more precise selectivity for amyloid-beta oligomers, not amyloid-beta plaque. At CTAD, Biogen provided additional analyses to support their conclusion: high-dose, long-duration aducanumab exposure can modify the Alzheimer process and provide clinical benefit," Kupiec said.

Those who received the agent in EMERGE reported a significant slowing of decline on measures of cognition and function such as memory, orientation, and language, as well as for activities of daily living.

The trial ultimately hit its pre-specified primary end point, with high-dose aducanumab showing a statistically significant reduction of clinical decline from baseline in Clinical Dementia Rating-Sum of Boxes (CDR-SB) scores at the 78-week point (22% versus placebo; 

Those treated with aducanumab also showed a consistent reduction of clinical decline as measured by the pre-specified secondary endpoints: the MMSE (18% versus placebo; 

= .05), the Alzheimer’s Disease Assessment Scale-Cognitive Subscale 13 Items (ADAS-Cog 13; 27% versus placebo; 

 = .01) and the Alzheimer’s Disease Cooperative Study-Activities of Daily Living Inventory Mild Cognitive Impairment Version (ADCS-ADL-MCI; 40% versus placebo; 

The imaging of amyloid plaque deposits showed that both low- and high-dose aducanumab reported reduced burden compared to placebo at 26 and 78 weeks (

“People living with Alzheimer’s, their families, caregivers and so many others in the community are fighting this disease every day, and the global social burden of the disease is expected to grow as the population ages,” said Haruo Naito, chief executive officer, Eisai Co., Ltd, in a statement. “The BLA submission is an important step in the fight against this disease, for which pathophysiological progression currently cannot be stopped, delayed or prevented.”

The aducanumab clinical development program also included the aforementioned phase 1b PRIME study and its long-term extension in those with prodromal Alzheimer disease or mild Alzheimer disease dementia (MMSE scores, 20—30). Those results suggest that aducanumab reduced amyloid-beta plaque in a dose- and time-dependent fashion, and exploratory clinical endpoints showed a reduction of clinical decline on CDR-SB and MMSE, which were nominally statistically significant for the 10 mg/kg dose at 12 months.

Those findings continued out to 48 months in the long-term extension.

The estimated enrollment is 2400 participants, and it aims to evaluate these end points in those who previously participated in aducanumab clinical trials, including those who had received the study drug as well as those who received placebo. Participants in the phase 3b study will hail from all 4 previous clinical trials in the aducanumab development program.

“The protocol of the re-dosing study that aims at offering access to aducanumab to all eligible patients who were actively enrolled in the aducanumab studies in March 2019 has been successfully submitted to the FDA,” Biogen said in a statement to 

 at the time. “We are now working with US trial sites to initiate this open-label clinical trial, which does not include a placebo-controlled arm. In the US, we expect the first patients to be re-dosed starting in March of this year.”

The BLA submission will be reviewed by the FDA and a decision returned in the next 60 days. Biogen noted that it is also continuing dialogue with other regulatory agencies in Europe and Japan.

Articles

Biogen Submits BLA for Investigational Alzheimer Disease Agent

This article, "COVID-19 Linked to Potential New Neurologic Symptoms in Children," was originally published in NeurologyLive.

 symptoms impacting pediatric patients with the 

Results from a case-series study involving 27 children with COVID-19 pediatric multisystem inflammatory syndrome showed that a small subset of participants presented with new neurological symptoms involving both the central and peripheral nervous systems and splenial changes on imaging.

Among the patient cohort observed in the study, 4 (14.8%) who were previously healthy had new-onset neurological symptoms. The symptoms documented were encephalopathy (n = 4), headaches (n = 3), brainstem (n = 2) and cerebellar signs (n = 1), muscle weakness (n = 4), and reduced reflexes (n = 2).

Senior author Yael Hacohen, MD, PhD, National Institute for Health Research academic clinical lecturer in pediatric neurology, Queen Square Multiple Sclerosis Center, University College London, and colleagues noted that all 4 of the patients needed intensive care unit (ICU) admission for the treatment of their COVID-19 pediatric multisystem inflammatory syndrome.

Their ICU stays lasted a median 6.5 days (range, 2—14), and mechanical ventilation duration was a median of 5 days (range, 1–7). Additionally, magnetic resonance imaging (MRI) revealed splenium signal changes in all 4 of the patients.

Among the 2 patients whose cerebrospinal fluid (CSF) was tested, acellular samples showed no evidence of infection on polymerase chain reaction or culture, as well as negative oligoclonal band test results. 

“The negative cerebrospinal fluid results, the response to immunosuppression, and the clinical overlap with hemophagocytic lymphohistiocytosis suggest that this is likely to be immune mediated,” the authors wrote.

Electroencephalography was found in 3 patients and showed a mild excess of slow activity. Mild myopathic and neuropathic changes were observed in all 3 patients tested on nerve conduction studies and electromyography.

Fever (n = 4), cardiovascular shock (n = 4), rash (n = 4), and dyspnea (n = 2) were all among systemic manifestations observed in the study. 

Tests for N-methyl-Daspartate receptor, myelin oligodendrocyte glycoprotein, and aquaporin-4 autoantibodies had negative results in all patients.

As part of the COVID-19 pediatric multisystem inflammatory syndrome management, immunomodulatory therapies such as intravenous methylprednisolone (n = 2), dexamethasone (n = 2), intravenous immunoglobulin (n = 2), anakinra (n = 2), and rituximab (n = 1) were used.

By the end of the study, neurological improvement was seen in all patients, with 2 making a complete recovery. The remaining 2 were discharged from the ICU and remained inpatients.

Each patient included in the study was younger than 18 years of age and presented with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and neurological symptoms between March 1, 2020 and May 8, 2020. 

Confirmation of the infection was done by either a quantitative reverse transcription-polymerase chain reaction assay by nasopharyngeal swab or a positive test result for IgG antibodies against SARS-CoV-2 in serum.

Data on demographics, comorbidities, neurological symptoms, relevant investigations (of CSF, neuroimaging, and neurophysiology), treatments, and outcomes were retrieved from the electronic patient records.

“Although the imaging finding is not specific to SARSCoV-2, in that it has been previously seen with other viral infections, clinicians should be adding SARS-CoV-2 to their differential diagnosis for children presenting with new neurologic symptoms and this imaging finding while still exploring other possible causes,” the study authors concluded.

Previously published data has drawn links between symptoms of COVID-19 and their effects on neurological status, but few have focused solely in the pediatric population. 

One of the first multi-case studies of neurologic manifestations of COVID-19 demonstrated complex central nervous system involvement and raised further questions about pathological mechanism.

More specifically, those with confirmed infections of COVID-19 commonly had peripheral nervous system and skeletal muscular manifestations as well.

In early June, another case-based study confirmed those data. This time, results from a systematic review of patients diagnosed with COVID-19 admitted to a hospital in a Spanish population during March 2020 revealed that neurological manifestations were common, with more than half of the patients presenting with some variation of neurological symptoms. 

Of 841 patients hospitalized with COVID-19 (mean age, 66.4 years; 56.2% men), 57.4% (n = 483) developed a neurological symptom. At the early stages of infection, nonspecific symptoms such as myalgias (17.2%), headache (14.1%), and dizziness (6.1%) were the most reported.

In an attempt to understand the risk factors involved for patients with multiple sclerosis (MS) to possibly develop a severe form of the novel COVID-19 infection, results of a recent study suggested that neurological disability, age, and obesity were all associated with severe infection.

The data also showed there was no link between exposure to disease-modifying therapies (DMTs) and COVID-19 severity.

New Neurologic Symptoms Found in Children with COVID-19

This article, "Severe COVID-19 in Multiple Sclerosis Linked to Disability Status, Age, Obesity," was originally published in NeurologyLive.

 (COVID-19) might be more severe, according to new research.

In a recent attempt to understand the risk factors involved for patients with MS to possibly develop a severe form of the novel COVID-19 infection, results suggest that neurological disability, age, and obesity were all associated with severe infection.

No link was observed between exposure to disease-modifying therapies (DMTs) and COVID-19 severity.

Conducted by Céline Louapre, MD, PhD, of the Clinical Investigation Center, L'Institut du Cerveau et de la Moelle Épinière, and colleagues, the cohort study included 347 patients with MS. Infection severity was assessed on a 7-point ordinal scale ranging from 1—denoting no hospitalization with no limitations on activities&mdash;to 7&mdash;denoting death.

There was a cutoff at 3 on the scale, which was defined as hospitalized and not requiring supplemental oxygen.

All told, 21% (n = 73) of patients had a severity score of ≥3, and 3.5% (n = 12) died from COVID-19.

A higher proportion of those with a severity score of ≥3 had no DMT exposure (46%) compared to those with DMT exposure (15.5%; 

As mentioned, age was independently associated with a higher risk of an infection severity ≥3 (odds ratio [OR] per 10 years: 1.9; 95% CI, 1.4—2.5), as was Expanded Disability Status Scale (EDSS) score ≥6 (OR, 6.3; 95% CI. 2.8-–4.4), and obesity (OR, 3.0; 95% CI, 1.0–8.7).

Notably, EDSS was associated with the highest variability of COVID-19 severe outcome (

, 0.01). The median EDSS score was 2.0 (range, 0—9.5), and 81.8% (n = 284) of the population were receiving a DMT.

“The identification of these risk factors could provide a rationale for an individual strategy of clinical management in patients with MS during the COVID-19 pandemic,” Louapre and colleagues wrote. “Risk factors associated with the severity of COVID-19 in patients with MS are unknown. DMTs may modify the risk of developing a severe COVID-19 infection, besides identified risk factors such as age and comorbidities.”

This registry, dubbed Covisep, is a multicenter, retrospective, observational cohort study conducted in MS expert centers and general hospitals and with neurologists collaborating with MS expert centers and members of the Société Francophone de la Sclérose en Plaques. Those included were patients presenting with a confirmed or highly suspected diagnosis of COVID-19 between March 1, 2020, and May 21, 2020.

“COVID-19 has significantly changed medical practice for several weeks, and it is likely to remain an issue for months,” the authors concluded. “Our data do not support an increased risk of a severe outcome associated with DMTs, which should reinforce the recommendation of not stopping current DMTs and not delaying treatment initiation in patients who have higher disease inflammatory activity, the risk for relapses, or subsequent disability.”

These results echo the previous understanding of MS specialists as well as add to the literature that has been collected thus far from other assessments. A number of neurologic complications have been observed in patients with COVID-19 infection, and the infection has shown links to conditions such as stroke.

The results echo the previous understanding of MS specialists as well as add to the literature that has been collected thus far from other assessments.
 

Author | HCPLive

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