Cecilia Pessoa Gingerich

The FDA has granted a Breakthrough Device Designation to the Elecsys beta-Amyloid (1-42) and Elecsys Phospho-Tau (181P) cerebrospinal fluid assays, which can be used in the diagnosis of Alzheimer disease.

The diagnostic immunoassays measure the beta-Amyloid (1-42) and Phospho-Tau concentrations in cerebrospinal fluid (CSF) in adult patients with cognitive impairment who are being evaluated for Alzheimer disease or other causes of dementia. The assays are intended to help diagnose Alzheimer disease as opposed to age-related memory disorders through the use of biomarkers associated with Alzheimer disease.

The Elecsys beta-Amyloid (1-42) CSF, Elecsys Phospho-Tau (181p) CSF, and Elecsys(R) Total-Tau CSF immunoassays are currently approved in countries accepting the CE Mark. Voluntary participation in the Breakthrough Device Program will help expedite the development and FDA review of the CSF assays.

"We are excited about FDA's recognition of the potential clinical benefit the Elecsys CSF assays can bring to clinicians, laboratories, and their patients in diagnosing AD at an early stage," Roland Diggelmann, CEO of Roche Diagnostics, the company developing the test, said in a statement. “Roche was one of the first companies to use biomarkers in clinical trials and we will continue to explore high-performing diagnostic and disease-monitoring solutions.”

Earlier this year, the FDA announced a draft guideline to help advance the development of novel treatments for neurological conditions, through a modernization of the FDA's review process. As part of this decision, the agency noted that symptoms and progression of diseases, like Alzheimer, can go unchecked for years, placing emphasis on proper diagnosis.

"The FDA has been working closely with patients and the scientific community to gain the knowledge that will support intervention in very early Alzheimer disease in ways that have the potential to stop the disease before it causes clinical problems," FDA Commissioner Scott Gottlieb, MD, said in a statement.

"[The FDA's Draft Guidance for Industry: Early Alzheimer’s Disease: Developing Drugs for Treatment describes innovative approaches to studying very early disease before the onset of dementia, including strategies for trials incorporating patients with Alzheimer’s who haven’t experienced any visible impairment (in the form of cognitive or functional deficits), but who may be identified through the use of sensitive cognitive screening, imaging tests, or biomarkers," he said.  

However, despite this push for better diagnostics and treatment, research done by Shana Stites, PsyD, at the Perelman School of Medicine, University of Pennsylvania, highlighted distinct stigmas that exist for patients with Alzheimer disease, which have led to many denying a diagnosis. This also highlights potential pitfalls of biomarker-based information about Alzheimer disease.

"These are important topics for clinicians to talk about with their patients who either have or are concerned about an Alzheimer diagnosis," said Stites. "By understanding what the biggest concerns are about the disease, we can help develop programs and policies to reduce the stigma about Alzheimer disease."

In their research, a sample of 317 adults with a median age of 49 years read and reacted to a fictional vignette of a person with Alzheimer disease dementia. The study randomly assigned participants to 1 of 3 groups for comparison. These groups were based on whether participants were told the person’s condition would worsen, improve, or remain unchanged.

In analyses adjusted for differences between the 3 study groups, over half of participants expected a person with Alzheimer disease dementia would be discriminated against by employers (55.3%; 95% CI, 47.0-65.2) and would be excluded from medical decision-making (55.3%; 95% CI, 46.9-65.4). Many also expressed concern that the person would have healthcare insurance limited because of data in the medical record (46.6%; 95% CI, 38.0—57.2) or have his healthcare insurance limited due to a brain imaging result (45.6%; 95% CI, 37.0–56.3).

The most common beliefs were expecting that the person would not remember most recent events (73.8%), would face employment discrimination (55.3%), and would be excluded from medical decision-making (55.3%).

"The Genetic Information Nondiscrimination Act of 2008 (GINA) helps to protect against discrimination on the basis of genetic data so this may offer assurance and protection to those who learn their genetic risk of Alzheimer's," said Stites. "But currently there are no policies to offer similar protections for individuals on the basis of a biomarker result. In addition to policies, like GINA, there's a need for programs to educate the public about those policies. In our study, 45% of those surveyed were worried a genetic result could lead to insurance-based discrimination even though this study was conducted years after GINA was created."

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FDA Grants Alzheimer Biomarker Test Breakthrough Status

The FDA has approved cannabidiol oral solution (Epidiolex) for the treatment of seizures associated with Lennox-Gastaut syndrome (LGS) and Dravet syndrome for patients 2 years of age and older, based on findings from 3 randomized, controlled studies.

In a phase III trial, recently reported in the 

 2 doses of cannabidiol were compared with placebo for patients with LGS. There was a 41.9% reduction in drop seizures in patients prescribed a 20 mg/kg/day cannabidiol regimen, a 37.2% reduction in those on a 10 mg/kg/day cannabidiol regimen, and a 17.2% reduction in the group given placebo (

 =.005 for the 20-mg cannabidiol group versus placebo group, and 

 = .002 for the 10-mg cannabidiol group vs. placebo group).

Cannabidiol is the first drug approved by the FDA to contain a marijuana-derived, purified drug substance. This is also the first FDA approval of a drug for the treatment of patients with Dravet syndrome. The FDA statement highlights that cannabidiol does not cause intoxication or the euphoria that is associated with tetrahydrocannabinol, the primary psychoactive component of marijuana.

“This approval serves as a reminder that advancing sound development programs that properly evaluate active ingredients contained in marijuana can lead to important medical therapies. And, the FDA is committed to this kind of careful scientific research and drug development,” said FDA commissioner Scott Gottlieb, MD.

This approval follows the unanimous support of an FDA committee which recommended the approval of cannabidiol oral solution in April 2018. “As a physician who treats LGS and Dravet syndrome, I know that patients and their families usually face significant difficulties getting seizures under control using existing therapies,” Elizabeth Thiele, MD, PhD, director of pediatric epilepsy, Massachusetts General Hospital, professor of neurology, Harvard Medical School, said in a statement at that time.

The double-blind, placebo-controlled trial was conducted at 30 clinical centers and enrolled 225 patients with LGS, between the ages of 2—55 years old, who had 2 or more drop seizures per week during a 28-day baseline period. Participants were randomly assigned to receive cannabidiol oral solution at either 20 mg per kilogram of body weight (76 patients) or 10 mg per kilogram (73 patients) or a matching placebo (76 patients). All medications were administered in 2 equally divided doses daily, for 14 weeks.

There was at least a 50% reduction in drop-seizure frequency for 39% of patients in the 20-mg group, 36% in the 10-mg arm, and for 14% with placebo. This decline represented a significant improvement with cannabidiol versus placebo for the 20-mg dose (odds ratio [OR], 3.85; 

A decline in drop-seizures of at least 75% was achieved for 25% of those in the 20-mg group and for 11% and 3% in the 10-mg and placebo arms, respectively. No patients achieved a complete decline in drop-seizures, although some patients were free during a maintenance phase that began at day 15.

In a separate study for Dravet syndrome, which was also published in 

 the median frequency of convulsive seizures per month declined by -6.5 from 12.4 at baseline for patients treated with cannabidiol. In the placebo group, seizures declined by just 0.8 from baseline. There were 43% of patients achieving a 50% reduction with cannabidiol compared with 27% with placebo (OR, 2.00; 

The third study for the approval focused on LGS and was published in the 

 In this 171-patient group, drop-seizures declined by 43.9% with cannabidiol compared with 21.8% with placebo. The mean difference between the groups was -17.21%.

Across all 3 trials of cannabidiol in patients with LGS or Dravet syndrome, the most common adverse events included sleepiness, sedation and lethargy; elevated liver enzymes; decreased appetite; diarrhea; rash; fatigue, malaise and weakness; insomnia, sleep disorder and poor quality sleep; and infections.

The drug will be dispensed with a Medication Guide that addresses the serious risks of cannabidiol, including suicidal ideation, attempts to commit suicide, feelings of agitation, new or worsening depression, aggression, and panic attacks.

“Controlled clinical trials testing the safety and efficacy of a drug, along with careful review through the FDA’s drug approval process, is the most appropriate way to bring marijuana-derived treatments to patients. Because of the adequate and well-controlled clinical studies that supported this approval, prescribers can have confidence in the drug’s uniform strength and consistent delivery that support appropriate dosing needed for treating patients with these complex and serious epilepsy syndromes,” said Gottlieb.

CBD is currently a Schedule I substance under the Controlled Substances Act (CSA) as a chemical component of cannabis. The FDA statement emphasized the “known risks” of marijuana and their commitment to protecting people from opportunistic producers of unapproved products containing CBD.

“We’ll continue to take action when we see the illegal marketing of CBD-containing products with unproven medical claims. We’re especially concerned when these products are marketed for serious or life-threatening diseases, where the illegal promotion of an unproven compound could discourage a patient from seeking other therapies that have proven benefits,” said Gottlieb.

Devinsky O, Patel AD, Cross JH, et al. Effect of Cannabidiol on Drop Seizures in the Lennox—Gastaut Syndrome. 

Devinsky O, Cross JH, Laux L, et al. Trial of Cannabidiol for Drug-Resistant Seizures in the Dravet Syndrome. 

Thiele EA, Marsh ED, French JA, et al. Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): a randomised, double-blind, placebo-controlled phase 3 trial. 

The FDA has approved cannabidiol oral solution for the treatment of seizures associated with Lennox-Gastaut syndrome and Dravet syndrome for patients 2 years of age and older.

FDA Approves Cannabidiol for Lennox-Gastaut, Dravet Syndromes

The FDA has approved the EmboTrap II Revascularization Device for thrombectomy within 8 hours of the appearance of symptoms for patients with ischemic stroke, according to Cerenovus, the company developing the device.

Patients who are ineligible for intravenous tissue plasminogen activator (IV t-PA) or who fail IV t-PA therapy are candidates for treatment with Embotrap II. The approval was based on findings from the ARISE II study, in which those with large-vessel occlusion strokes had high reperfusion rates.

For the primary endpoint of successful reperfusion, 80.2% had a modified treatment in cerebral infarction (mTICI) score of grade 2b to grade 3 within 3 passes (95% CI; 74%—85%; 

<.0001). Additionally, 64.8% of patients had mTICI grade 2c-3 (near complete or complete reperfusion) within 3 passes. Final procedural revascularization (mTICI grade 2b to 3) was achieved by 92.5% of patients.

"Mechanical thrombectomy with newer generation devices is increasingly becoming standard treatment for acute ischemic stroke," lead author Osama Zaidat, MD, Stroke and Neuroscience Medical Director of St. Vincent Mercy Hospital, said in a statement. "The EmboTrap II Device with its high first pass rate and its ability to address such a broad range of clot is a crucial step forward for stroke treatment in America."

This study included 228 patients with large vessel occlusions and moderate to severe neurological deficits at 11 US and 8 European sites. The mean age of patients was 68 years and 66.1% had been treated with IV-tPA. The pre-stroke modified Ranking score was 0 for 78% of patients and 1 for 21.6%. The remainder had a score of 2.

After 90 days, 67.3% of patients were functionally independent, with 516% being highly functional. At the 90-day follow-up, all-cause mortality was 9% and the symptomatic intracerebral hemorrhage (sICH) rate was 5.4%.

More than half of patients (51.5%) had mTICI grade 2b to grade 3 reperfusion with EmboTrap II after just 1 pass. Moreover, 40.1% had excellent (mTICI grade 2c-3) reperfusion after the first pass.

"EmboTrap II is the product of deep collaboration between engineers and clinicians to better understand the science of blood clot, what causes them to form and how a mechanical thrombectomy device can interact with them to help improve outcomes," Daniella Cramp, Worldwide President, Cerenovus, said in a statement. "Cerenovus is committed to advancing treatment with evidence-based solutions so that fewer and fewer people are affected by the ravages of stroke."

The Embotrap II was previously approved for use in Europe, where more than 3,000 patients have been treated.

The FDA has approved the EmboTrap II Revascularization Device for thrombectomy within 8 hours of the appearance of symptoms for patients with ischemic stroke.

FDA Approves EmboTrap II for Thrombectomy in Ischemic Strokes

The hand-held gammaCore device, which is a non-invasive vagus nerve stimulation (nVNS) therapy, significantly improved pain-free rates compared with a sham device for patients with episodic cluster headache and migraines, according to findings from the PRESTO trial presented at the American Academy of Neurology (AAN) annual meeting.

PRESTO found that treatment with gammaCore led to significantly higher pain-free rates in treated patients versus the sham patient population at both the 30-minute mark for migraine treatment (12.7% versus 4.2%; 

 = .012) and the 60-minute mark (21.0% versus 10.0%; 

 = 0.023). However, the study missed its primary endpoint of improvement in pain at 120 minutes.

“Migraine is the third most common disease in the world, and one of the 10 most disabling diseases, which highlights a need for novel treatment options,” principal trial investigator Cristina Tassorelli, MD, PhD, Director of the Headache Science Centre, National Neurological Institute C. Mondino Foundation, Professor at the University of Pavia, Pavia, Italy, said in a statement.

The multicenter, double-blind, randomized trial evaluated the efficacy, safety, and tolerability of nVNS in 243 patients with episodic migraine. The study consisted of 3 timeframes, a baseline period where participants used standard of care treatments, a 4-week randomized, controlled, and double-blind period, and a subsequent 4-week open-label period where all participants used the gammaCore device.

The device missed clinical and statistical significance for the study’s primary endpoint, reduction of pain at 120 minutes (nVNS 30.4% versus sham 19.7%; 

 = .067). However, a post-hoc repeated-measures test suggested that nVNS treatment was superior to sham at 120 minutes (odds ratio: 2.3; 95% CI: 1.2, 4.4; 

“The PRESTO data suggests that gammaCore was rapidly effective, well tolerated and practical for the acute treatment of episodic migraine. The data supports the use of gammaCore to successfully treat a migraine, making the device a potentially valuable treatment for the millions of people who suffer from migraine,” said Tassorelli.

Secondary endpoints for the study showed clinically meaningful and statistically significant results. These endpoints included mild or no pain at 120 minutes (nVNS 40.8% vs sham 27.6%; 

 = .030) and mean percent pain reduction at 120 minutes (nVNS 34.8% vs sham 5.4%; 

“Migraine is a debilitating disease affecting 39 million Americans, the majority of whom do not seek medical care for their pain,” said Stephen D. Silberstein, MD, Professor of Neurology and Director of the Headache Center, Thomas Jefferson University. “With the FDA’s decision to release gammaCore for migraine, patients now have access to an effective and safe therapy which can be self-administered to acutely treat the pain associated with migraine.”

The device is already available for the acute treatment of pain due to 

 in adults, and electroCore, the company developing the device, expects commercial availability of gammaCore for the acute treatment of pain associated with migraine headache in adults in the second quarter of 2018.

A non-invasive vagus nerve stimulation therapy significantly improved pain-free rates compared with a sham device for patients with episodic cluster headache and migraines.

Cecilia Pessoa Gingerich

Articles

FDA Grants Alzheimer Biomarker Test Breakthrough Status

FDA Approves Cannabidiol for Lennox-Gastaut, Dravet Syndromes

FDA Approves EmboTrap II for Thrombectomy in Ischemic Strokes

Vagus Nerve Stimulation Improves Headache, Migraine Pain