Author: Rachael Hansford

Breakthrough device for glioblastoma

Carthera receives FDA breakthrough device designation for SonoCloud-9 system, allowing for enhanced interaction with FDA and recognising SonoCloud system as innovative and promising approach for treatment of recurrent glioblastoma

Carthera, a French company that designs and develops SonoCloud, an ultrasound-based medical device to treat a wide range of brain diseases, announced on June 22 2022 that its SonoCloud-9® system has been listed as a Breakthrough Device by the Center for Devices and Radiological Health (CDRH) at the US Food and Drug Administration (FDA).


 The SonoCloud device uses low intensity pulsed ultrasound to temporarily disrupt the Blood-Brain Barrier (BBB), to allow higher brain exposure to therapeutic compounds. By using SonoCloud, the therapeutic efficacy of new and existing therapies can be unlocked and harnessed to improve the treatment of a wide range of brain diseases, such as glioblastoma.
 
“There is a significant unmet need for new treatments for glioblastoma patients, who have very few available therapeutic options,” said Michael Canney, chief scientific officer at Carthera. “We’re excited that the FDA has acknowledged the innovative potential of the SonoCloud approach through the granting of this Breakthrough Designation.”
 
The Breakthrough Devices Designation, intended to expedite the development and review of the medical device, was based on preliminary phase 1/2a clinical data that indicates substantial improvement over available second-line therapy (publication under preparation).
 
“The FDA Breakthrough Device Designation will help Carthera to efficiently advance to a pivotal trial and Premarket Approval (PMA),” said Sandra Thiollière, head of quality and regulatory affairs at Carthera. “We look forward to working closely with the FDA through this accelerated process to bring SonoCloud to patients with recurrent glioblastoma.”
 
This designation will give Carthera access to priority review, more intensive FDA interaction to build an efficient device development programme and commitment from experts and senior managers from the FDA, who will assist the company in addressing any potential challenges during the premarket review phase.

“Following the recent successful completion of our phase 1/2 trial in recurrent glioblastoma, this Breakthrough Device Designation is another important milestone supporting the potential of SonoCloud.”

Frédéric Sottilini, CEO of Carthera.

About SonoCloud-9
The SonoCloud-9 device is implanted in a skull window, below the skin; once in place it is invisible. When activated for few minutes using a transdermal needle connection to an external control unit, the BBB is disrupted for several hours; a window during which drug therapies can be administered. By administering therapies when the BBB is disrupted, drugs can reach the brain in higher and more effective concentrations. This treatment can be repeated at each cycle of drug therapy.
 
About the FDA Breakthrough Device Programme
The goal of the Breakthrough Devices Program is to provide patients and health care providers with timely access to certain medical devices by speeding up their development, assessment and review, while preserving the statutory standards for Premarket Approval, 510(k) clearance and De Novo marketing authorization, consistent with the Agency’s mission to protect and promote public health.

Study: Improvements in TBI Patients with Persistent Brain Fog

A new study has shown that plasticity-based brain training can drive improvements in patients with persistent symptoms of Traumatic Brain Injury (TBI). Gains were observed in standard measures of cognition, standard measures of self-reported symptoms, and the connectivity between brain regions. The intervention used in the study was brain exercises from BrainHQ, made by Posit Science.

Traumatic Brain Injury affects millions of Americans every year, with an estimated 2.5 million treated in emergency rooms. Most recover fully, but for some, the symptoms persist for years and disrupt earning a livelihood and personal relations. An estimated two percent of Americans live with these long-term effects.

Researchers at New York University enrolled 21 patients with chronic TBI that had persisted, on average, for more than seven years. Patients were diagnosed with mild, moderate, or severe TBI, and assigned to either an intervention group or a control group. The intervention group was asked to complete a total of 40 hours of training over 13 weeks (or about 3 hours per week). Before and after the 13-week period, cognitive function was measured with standardised neurocognitive tests, and brain connectivity was measured with fMRI brain imaging.

The researchers found that the brain training group showed significant improvements in standard cognitive tests of attention, memory, and executive function, as well as in standard measures of self-reported symptoms, as compared to the control group. Imaging revealed significant improvement in the functional connectivity across a key network of brain regions – known as the Default Mode Network (DMN). Lower connectivity is associated with cognitive dysfunction and deficits.

“This new study confirms and extends what has been seen in seven prior studies of chronic TBI and BrainHQ, which have shown study participants improved measures of cognitive abilities and symptoms, with imaging showing functional re-organization of the brain” observed Dr. Henry Mahncke, CEO of Posit Science.

These type of persistent symptoms — following not just Traumatic Brain Injuries, but other types of injuries such as “chemobrain,” “cardiobrain,” and “long COVID” — are increasingly known as “brain fog.” Researchers increasingly believe that common brain mechanisms underly the brain fog seen across these disparate conditions – which may explain the similar pattern of results seen in three studies of BrainHQ in cancer patients and seven studies in heart failure patients showing similar types of improvement.

More than 100 published studies of the exercises in BrainHQ have shown benefits, including gains in standard measures of cognition (attention, speed, memory, executive function, social cognition), in standard measures of quality of life (mood, confidence and control, managing stress, health-related quality of life) and in real world activities (gait, balance, driving, everyday cognition, maintaining independence). BrainHQ is now offered, without charge, as a benefit by leading national and 5-star Medicare Advantage plans and by hundreds of clinics, libraries, and communities. Consumers can also try BrainHQ for free at http://www.brainhq.com.

In Vitro diagnostic test for assessment of Alzheimer’s disease

The U.S. Food and Drug Administration (FDA) has granted De Novo marketing authorisation for Fujirebio Diagnostics’ Lumipulse® G β-Amyloid Ratio (1-42/1-40) in vitro diagnostic (IVD) test for the assessment of β-Amyloid pathology in patients being evaluated for Alzheimer’s disease (AD) and other causes of cognitive decline. The test, which was granted Breakthrough Device Designation by the FDA, is the first FDA-authorised in vitro diagnostic test in the U.S. to aid in the assessment of Alzheimer’s disease and other causes of cognitive decline.

Alzheimer’s disease is a leading cause of disability and death internationally, but current diagnostic methods are limited. AD develops over many years, long before symptoms are evident, but the lack of accessible diagnostics results in many patients remaining undiagnosed until the disease is well advanced, when few effective interventions remain.

A key feature of AD is the presence of β-Amyloid plaques in the brain. β-Amyloid plaques are believed to contribute to the loss of cognitive function that characterises AD, but accurately evaluating amyloid pathology has been difficult. Clinicians have relied primarily on cognitive assessments, including standardised cognitive screening tests. However, in early stages of the disease, a diagnosis of Alzheimer’s disease relying primarily on cognitive tests has been shown to be incorrect in approximately 50-60% of patients1. The Lumipulse G β-Amyloid Ratio (1-42/1-40) offers an alternative to the current standard for determining amyloid-pathology, amyloid positron emission tomography (PET) brain imaging which is expensive, subjective, time consuming, inaccessible to many Americans, and often not covered by health insurance.

The Lumipulse G β-Amyloid Ratio (1-42/1-40) test is an accurate, minimally invasive, accessible measure of β-Amyloid that can detect the formation of amyloid plaques early in the disease. It is intended for use in adult patients aged 55 years and older presenting with cognitive impairment who are being evaluated for Alzheimer’s disease and other causes of cognitive decline. The β-Amyloid Ratio test measures the concentrations of β-Amyloid 1-42 and β-Amyloid 1-40 in the CSF to calculate a numerical ratio as a proxy for the presence of β-Amyloid plaque in the brain.

“FDA authorisation of the Lumipulse G β-Amyloid Ratio (1-42/1-40) test and the upcoming U.S. launch are important milestones in the campaign to transform AD into a manageable disease,” says Monte Wiltse, President and CEO at Fujirebio Diagnostics, Inc. “Patients, physicians and families now have a valuable new tool to help identify those individuals whose early symptoms may be indicative of AD, providing the opportunity to adopt life style changes and potentially to access new therapies aimed at slowing or stopping disease progression. FDA authorisation of this first IVD biomarker test reflects our ongoing commitment to working with the healthcare community and AD advocates to achieve significant progress against this devastating disease.”

William Hu, MD, PhD is Chief, Division of Cognitive Neurology at Robert Wood Johnson Medical School and Principal Investigator of the Hu Lab, which focuses on researching fluid biomarkers for AD and other neurodegenerative disorders. Dr. Hu says, “The development of accurate tests for AD using biomarkers found in the CSF or other bodily fluids is a requirement if we are to make real progress against this dreaded disease. The importance of early diagnosis in AD is widely acknowledged, but until now, there has been no approved biomarker test available to clinicians and patients. FDA authorisation of the Fujirebio β-Amyloid Ratio test is a significant advance that marks the advent of a new era, facilitating more efficient clinical trials for new AD therapies and enabling patients and their doctors to make more informed decisions and take action much earlier in the disease process.”

The Lumipulse G β-Amyloid Ratio (1-42/1-40) test is not intended as a screening or standalone assay to diagnose AD. Results must be interpreted in conjunction with other patient clinical information. The assay is analysed on Fujirebio’s fully automated Lumipulse G1200 instrument system.

www.fujirebio.com.

References

1. Schneider, Julie A. Arvanitakis, Z. Leurgans, S.E. Bennet DA. The Neuropathology of Probable Alzheimer’s Disease and Mild Cognitive Impairment. Ann Neurol. 2009;66(2):200-208. doi:10.1002/ana.21706.

2. Gobom J, Parnetti L, Rosa-Neto P, et al. Validation of the LUMIPULSE automated immunoassay for the measurement of core AD biomarkers in cerebrospinal fluid. Clin Chem Lab Med. 2022;60(2):207-219. doi:10.1515/cclm-2021-0651.

Brain-computer interface helps paralysed patient drive again

Almost ten years ago, Aldana Zuniga was paralysed from the waist down in a car accident. Now, a microchip implanted in his brain has helped him get behind the wheel of a car again.

Using only his thoughts to control the speed, Zuniga drove laps in a NASCAR Cup racecar on a track in the US, despite the 2013 car crash leaving him with no mobility below the waist and limited use of his hands and arms.

The brain-computer interface he used was developed by a team of physicians, researchers and engineers. The team was led by neurosurgeon Scott Falci, M.D., from the Falci Institute for Spinal Cord Injuries at Colorado’s Swedish Medical Center, who also founded Falci Adaptive Motorsports in 2012 to help people with mobility impairments drive again.

The team spent over a year adapting the brain-computer interface to read Zuniga’s thoughts. A microchip electrode placed on his brain communicates with a computer in the car to control the engine.

“The electrical changes get picked up on the electrode, travel down a cable underneath his skin to a computer processor,” Falci told CBS Denver. “When the computer recognises that particular fingerprint, it knows to send the signal to the computer in our racecar, and that computer knows to send it to the throttle and to actuate the throttle.”

A specialised helmet picks up Zuniga’s head movements to steer the car, and he can exhale into or inhale from an attached tube to help control the accelerator and brakes.

The initiative was developed largely to demonstrate the ultimate potential of brain-computer interfaces.

We can use this potentially for driving an electric wheelchair, a golf cart, [to] control a robotic arm, control an exoskeleton device, control an implanted medical device,” he explained. “Once we develop that science, that science can be used for all types of systems.

Falci’s system joins others that have found success in translating thoughts into actions in the last couple of years, from an FDA-approved wireless brace that improves hand function in stroke patients to a bionic arm that restores function and feeling in amputees.

Recently, Synchron unveiled study results showing that its stent-like Stentrode system remained safely in place and functional one year after the minimally invasive implant procedure. The device has so far been implanted in a handful of patients who are paralysed due to amyotrophic lateral sclerosis, and who can use the system to send text messages and emails, shop and bank online and even send tweets, all using only their thoughts—plus an eye-tracking device to move the cursor.

Management of urinary incontinence in adults with MS or SCI

Ipsen receives positive opinion in Europe for Dysport® in the management of urinary incontinence in adults with neurogenic detrusor overactivity due to Multiple Sclerosis or Spinal Cord Injury

  • Submission based on data from the pivotal international Phase III CONTENT clinical programme, also recently published in European Urology1
  • CONTENT showed that Dysport® decreased incontinence episodes, detrusor pressure and increased bladder capacity versus placebo, and improved quality of life1

Ipsen announced on June 9th that Dysport® (abobotulinumtoxinA) has received positive opinion in Europe for the management of urinary incontinence (UI) in adults with neurogenic detrusor overactivity (NDO) due to spinal cord injury (SCI) (traumatic or non-traumatic) or multiple sclerosis (MS), who are regularly performing clean intermittent catheterisation (CIC).

This positive opinion for Dysport® now permits individual European country Health Authorities to grant national approvals, according to their country regulations. In addition, Ipsen is also currently in the process of obtaining approvals in other countries outside the European Union.

Dysport® is an injectable form of a botulinum neurotoxin type A (BoNT-A) product, which has previously shown clinically meaningful benefit in the symptomatic treatment of focal spasticity and cervical dystonia.

References

1. Kennelly M et al., Efficacy and Safety of AbobotulinumtoxinA in Patients with Neurogenic Detrusor Overactivity Incontinence Performing Regular Clean Intermittent Catheterization: Pooled Results from Two Phase 3 Randomized Studies (CONTENT1 and CONTENT2). European Urology. 2022; S0302-2838(22)01680–3
2. Mehnert U, et al., The Management of Urine Storage Dysfunction in the Neurological Patient. SN Comprehensive Clinical Medicine. 2019; 1:160–182
3. Alsulihem A and Corcos J. Evaluation, treatment, and surveillance of neurogenic detrusor overactivity in spinal cord injury patients. Neuroimmunol Neuroinflammation. 2019; 6:13
4. Ginsberg, D. The Epidemiology and Pathophysiology of Neurogenic Bladder. Am J Manag Care. 2013; 19(10)191–6

Chronic pain: discovery in the brains of army veterans could pave way for personalised treatments

Study is first to investigate the neural hallmarks of co-occurring chronic pain and trauma in veterans, finding high, medium, and low symptom groups       

Chronic pain and trauma often co-occur. However, most previous research investigated them in isolation and using subjective measures such as surveys, leading to an incomplete picture. A new study in Frontiers in Pain Research found three unique brain connectivity signatures that appear to indicate veteran susceptibility or resilience to pain and trauma, regardless of their diagnostic or combat history. The study could pave the way for more objective measurements of pain and trauma, leading to targeted and personalised treatments.

Chronic pain and trauma are linked but not studied together

“Chronic pain is a major public health concern, especially among veterans,” said first author Prof Irina Strigo of the San Francisco Veterans Affairs Health Care Center, US. “Moreover, chronic pain sufferers almost never present with a single disorder but often with multiple co-morbidities, such as trauma, posttraumatic stress, and depression.”

Researchers already understand that both pain and trauma can affect connections in our brains, but no-one had studied this in the context of co-occurring trauma and pain. Much pain and trauma research also relies on subjective measurements, such as questionnaires, rather than objective measurements, such as brain scans.

Identifying brain connectivity signatures of pain and trauma

Taking a different approach, the researchers behind this new research studied a group of 57 veterans with both chronic back pain and trauma. The group had quite varied symptoms in terms of pain and trauma severity. By scanning the veterans’ brains using functional magnetic resonance imaging, the researchers identified the strength of connections between brain regions involved in pain and trauma. They then used a statistical technique to automatically group the veterans based on their brain connection signatures, regardless of their self-reported pain and trauma levels.

Based on the veterans’ brain activity, the computer automatically divided them into three groups. Strikingly, these divisions were comparable to the severity of the veterans’ symptoms, and they fell into a low, medium, or high symptom group.

The researchers hypothesised that the pattern of brain connections found in the low symptom group allowed veterans to avoid some of the emotional fallout from pain and trauma, and also included natural pain reduction capabilities. Conversely, the high symptom group demonstrated brain connection patterns that may have increased their chances of anxiety and catastrophising when experiencing pain.

Interestingly, based on self-reported pain and trauma symptoms, the medium symptom group was largely similar to the low symptom group. However, the medium symptom group showed differences in their brain connectivity signature, which suggested that they were better at focusing on other things when experiencing pain, reducing its impact.  

Putting the findings into future practice

“Despite the fact that the majority of subjects within each subgroup had a co-morbid diagnosis of pain and trauma, their brain connections differed,” said Strigo.

“In other words, despite demographic and diagnostic similarities, we found neurobiologically distinct groups with different mechanisms for managing pain and trauma. Neurobiological-based subgroups can provide insights into how these individuals will respond to brain stimulation and psychopharmacological treatments.”

So far, the researchers don’t know whether the neural hallmarks they found represent a vulnerability to trauma and pain or a consequence of these conditions. However, the technique is interesting, as it provides an objective and unbiased hallmark of pain and trauma susceptibility or resilience. It does not rely on subjective measures such as the surveys. In fact, subjective measurements of pain in this study would not differentiate between the low and medium groups.

Techniques that use objective measures, such as brain connectivity, appear more sensitive and could provide a clearer overall picture of someone’s resilience or susceptibility to pain and trauma, thereby guiding personalised treatment and paving the way for new treatments.

Despite demographic and diagnostic similarities, we found neurobiologically distinct groups with different mechanisms for managing pain and trauma. Neurobiological-based subgroups can provide insights into how these individuals will respond to brain stimulation and psychopharmacological treatments.

Prof Irina Strigo, San Francisco Veterans Affairs Health Care Center, US

NICE recommends Sleepio app for insomnia

Sleepio is recommended as a cost saving option for treating insomnia and insomnia symptoms in primary care for people who would otherwise be offered sleep hygiene or sleeping pills.

Sleepio app image

For people who may be at higher risk of other sleep disorder conditions, such as in pregnancy, or in people with comorbidities, a medical assessment should be done before referral to Sleepio.

More research or data collection is recommended on Sleepio for people who are eligible for face-to-face cognitive behavioural therapy for insomnia (CBT‑I) in primary care. This is because there is limited clinical evidence to show how effective Sleepio is compared with face-to-face CBT‑I. Find out more.

Why NICE made these recommendations

Usual treatment for people with sleep problems is advice about sleep hygiene. Sleeping pills may also be considered if insomnia symptoms are likely to resolve soon. If insomnia symptoms are not likely to resolve soon, best practice is to refer for face-to-face CBT‑I, although its availability in the UK is limited. This clinical pathway is outlined in the British Association for Psychopharmacology (BAP) consensus statement on insomnia. People who may be at higher risk of other sleep disorders including sleep apnoea should have a medical assessment before referral to Sleepio.

Sleepio is a digital self-help programme that includes CBT‑I. It could therefore increase patients’ access to CBT‑I. It also increases the options available to GPs treating insomnia.

Clinical evidence shows that Sleepio reduces insomnia symptoms compared with sleep hygiene and sleeping pills. There is no direct evidence of its effectiveness compared with face-to-face CBT‑I, so further research is recommended in this context.

At a price of £45 per person, Sleepio is cost saving compared with usual treatment in primary care. This is based on an analysis of primary care resource use data before and after Sleepio was introduced in 9 GP practices. Healthcare costs were lower at 1 year, mostly because of fewer GP appointments and sleeping pills prescribed.

Positive CHMP opinion for Upstaza™ for the treatment of AADC deficiency

PTC Therapeutics, Inc. announced on May 20th that Upstaza™ (eladocagene exuparvovec; PTC-AADC) received a positive opinion by the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA). Once ratified by the European Commission, Upstaza will be the first approved disease-modifying treatment for aromatic L-amino acid decarboxylase (AADC) deficiency for patients 18 months and older and the first marketed gene therapy directly infused into the brain. 

We are thrilled with the positive opinion from the CHMP, and are eager to bring Upstaza to patients living with AADC deficiency.Upstaza will be the first marketed gene therapy that is directly administered into the brain, the first gene therapy approved in a major market in several years, the third gene therapy that is on the market now, and only the fourth in vivo gene therapy ever approved. It’s important for the biotech community to have gene therapy products achieving approvals at regulatory bodies, as well as it being an important milestone for PTC that will help us build the gene therapy franchise and grow our revenue base.

Stuart W. Peltz, Ph.D., Chief Executive Officer, PTC Therapeutics

The CHMP opinion is based on the findings of clinical studies conducted in Taiwan. In addition, data from the compassionate use treatment of patients in Europe were included in the application. In the clinical studies, patients went from no display of any motor milestone development to developing clinically meaningful motor skills and neuromuscular function from as early as three months following treatment, with transformational improvements shown to continue up to nine years after treatment.1 Cognitive and communication skills improved in all treated patients.1,2

“The difference Upstaza, a one-time gene therapy, can make is life-changing. AADC deficiency is a devastating neurological disorder with no effective treatment. Before therapy, affected children couldn’t even lift their head, but now many can sit, stand with help, feed themselves and some can walk and talk.” 

Paul Wuh-Liang Hwu, M.D., Ph.D., lead investigator, National Taiwan University Hospital

PTC expects the European Commission to ratify the marketing authorisation for Upstaza under exceptional circumstances in approximately two months. The decision will be applicable to all 27 European Union member states, as well as Iceland, Norway and Liechtenstein. 

About Upstaza™ (eladocagene exuparvovec)

Upstaza, formerly PTC-AADC, is a one-time gene replacement therapy for the treatment of AADC deficiency. It is a recombinant adeno-associated virus serotype 2 (AAV2)-based gene therapy, containing the human DDC gene.1 It is designed to correct the underlying genetic defect, by delivering a functioning DDC gene directly into the putamen, increasing the AADC enzyme and restoring dopamine production.2,3

The efficacy and safety profile of Upstaza has been demonstrated across clinical trials and compassionate use programmes.The first patient was dosed more than 10 years ago. In the clinical trials, Upstaza demonstrated transformational neurological improvements, which have continued for up to nine years following treatment. The most common side effects were initial insomnia, irritability and dyskinesia. The full indication proposed by the CHMP for ratification is: Upstaza is indicated for the treatment of patients aged 18 months and older with a clinical, molecular, and genetically confirmed diagnosis of aromatic L‑amino acid decarboxylase (AADC) deficiency with a severe phenotype.

Administration of Upstaza occurs through a stereotactic surgical procedure, a minimally invasive neurosurgical procedure used for the treatment of a number of paediatric and adult neurological disorders. The Upstaza administration procedure will be performed by a qualified neurosurgeon in a centre specialised in stereotactic neurosurgery.

References

1 Tai CH, et al. Long-term efficacy and safety of eladocagene exuparvovec in patients with AADC deficiency. Mol Ther. 2022;30(2):509-518.

2 Chien et al. AGIL-AADC gene therapy results in sustained improvements in motor and developmental milestones through 5 years in children with AADC deficiency. Poster presented at the 48th Annual Meeting of the Child Neurology Society, Charlotte, NC, USA, Oct 23-26, 2019.

3 Chien YH, et al. Efficacy and safety of AAV2 gene therapy in children with aromatic L-amino acid decarboxylase deficiency: an open-label, phase 1/2 trial. Lancet Child Adolesc Health. 2017;1(4):265-273.

A music based walking app for MS?

Biogen is looking to utilise a music-based digital therapeutic to help improve the gait of multiple sclerosis patients who may have difficulty walking.

Developed by MedRhythms, the prescription app aims to do more than simply connect the beat of the music with walking cadence. The US-based company has been working on sensors and rehabilitation software for people with a range of neurological conditions—such as those recovering from stroke as well as Alzheimer’s and Parkinson’s patients—with the goal of retraining the brain and its motor systems.

Sensors attach to the shoes to analyse a person’s gait, while algorithms within the app alter the music’s cues in response to deliver rhythmic auditory stimulation.

MedRhythms has launched two pilot feasibility studies for MR-004, including at the Cleveland Clinic. If successful, a registrational trial will be initiated.