Study introduces a machine-learning model to synthesise high-quality MRIs from lower-quality images
There is growing interest in using machine learning to enhance imaging data captured by magnetic resonance imaging (MRI) technology. Recent studies show that ultra-high-field MRI at 7 Tesla (7T) could have far greater resolution and clinical advantages over high-field MRI at 3T in delineating anatomical structures that are important for identifying and monitoring pathological tissue, particularly in the brain.
Most clinical MRI exams in the U.S. are performed with 1.5T or 3T MRI systems. As recently as 2022, the National Institutes of Health documented only about 100 7T MRI machines being used for diagnostic imaging worldwide.
Researchers from UC San Francisco developed a machine learning algorithm to enhance 3T MRIs by synthesising 7T-like images that approximate real 7T MRIs. Their model enhanced pathological tissue with more fidelity for clinical insights and represents a new step toward evaluating clinical applications of synthetic 7T MRI models.
Reza Abbasi-Asl, PhD, UCSF Assistant Professor of Neurology and senior study author said: “Our paper introduces a machine-learning model to synthesize high-quality MRIs from lower-quality images. We demonstrate how this AI system improves the visualization and identification of brain abnormalities captured by MRIs in Traumatic Brain Injury. Our findings highlight the promise of AI and machine learning to improve the quality of medical images captured by less advanced imaging systems.”
Better able to see TBI and Multiple Sclerosis
UCSF researchers collected imaging data from patients diagnosed with mild traumatic brain injury (TBI) at UCSF. They designed and trained three neural network models to perform image enhancement and 3D image segmentation using the generated synthetic-7T MRIs from the standard 3T MRIs.
The images generated with the new models provided enhanced pathological tissue for patients with mild TBI. They selected an example region with white matter lesions and microbleeds in subcortical areas to use for comparison. They found pathological tissue was easier to see in synthesised 7T images. This was evident in the separation of adjacent lesions and the sharper contours of subcortical microbleeds. Additionally, the synthesised 7T images better captured the diverse features within white matter lesions. These observations also highlight the promise of using this technology to improve diagnostic accuracy in neurodegenerative disorders such as Multiple Sclerosis.
While synthesisation techniques based on machine learning frameworks demonstrate remarkable performance, their application in clinical settings will require extensive validation. The researchers believe that future work should include extensive clinical assessment of the model findings, clinical rating of model-generated images, and quantification of uncertainties in the model.
VYALEV™ (also known as PRODUODOPA) is the first and only subcutaneous 24-hour continuous infusion of levodopa-based therapy for the treatment of motor fluctuations in advanced Parkinson’s disease
Adults treated with VYALEV reported superior improvement in “on” time without troublesome dyskinesia, compared to oral immediate-release carbidopa/levodopa1
VYALEV allows for personalised dosing based on individual needs, morning, day and night
AbbVie announced on 17th October that the US Food and Drug Administration (FDA) has approved VYALEV™ (foscarbidopa and foslevodopa) as the first and only subcutaneous 24-hour infusion of levodopa-based therapy for the treatment of motor fluctuations in adults with advanced Parkinson’s disease (PD). The treatment is approved in 35 countries.
The approval was supported by the pivotal Phase 3, 12-week study evaluating the efficacy of continuous subcutaneous infusion of VYALEV in adult patients with advanced PD compared to oral immediate-release carbidopa/levodopa (CD/LD IR)1, along with a 52-week, open-label study which evaluated the long-term safety and efficacy of VYALEV.2
“For too long, the Parkinson’s community has had limited treatment options for advanced disease. Due to the progressive nature of the disease, oral medications are eventually no longer as effective at motor symptom control and surgical treatment may be required,” said Robert A. Hauser, M.D., MBA, Professor of Neurology and Director of the Parkinson’s and Movement Disorder Center at the University of South Florida. “This new, non-surgical regimen provides continuous delivery of levodopa morning, day and night.”
Findings from the pivotal study showed patients receiving VYALEV demonstrated superior improvement in motor fluctuations, with increased “on” time without troublesome dyskinesia and decreased “off” time, compared with oral CD/LD IR.1 “On” time refers to the periods of time when patients are experiencing optimal motor symptom control while “off” time is when symptoms return.3,4
The majority of adverse reactions (ARs) with VYALEV were non-serious and mild or moderate in severity. The most frequent ARs (greater than or equal to 10 percent and greater than CD/LD IR incidence) were infusion site events, hallucinations, and dyskinesia.1,2
“People living with advanced Parkinson’s disease experience daily challenges as a result of uncertainty in managing motor fluctuations, especially as their disease progresses,” said Roopal Thakkar, M.D., Executive Vice President, Research & Development, and Chief Scientific Officer, AbbVie. “We are proud to bring this innovation to patients who may benefit from motor symptom control through continuous 24-hour administration of VYALEV.”
PD is a progressive and chronic movement disorder resulting in tremor, muscle rigidity, slowness of movement and difficulty with balance resulting from the loss of dopamine-producing brain cells.5
Timing for a US patient’s access to VYALEV is dependent on their individual insurance plan. Coverage for Medicare patients is expected in the second half of 2025.
This new, non-surgical regimen provides continuous delivery of levodopa morning, day and night
Robert A. Hauser, M.D., MBA, Professor of Neurology and Director of the Parkinson’s and Movement Disorder Center at the University of South Florida
About the Phase 3 M15-736 Study1 The Phase 3 randomised, double-blind, double-dummy, active-controlled study compared the efficacy, safety and tolerability of VYALEV to oral CD/LD IR in patients with advanced PD. Participants were provided with a home diary (the PD Diary) to assess their motor state during the day. The primary endpoint of good “on” time (defined as “on” time without dyskinesia plus “on” time with non-troublesome dyskinesia), was collected and averaged over three consecutive days and normalised to a typical 16-hour waking period. Baseline values are defined as the average of normalised good “on” time collected over the three PD Diary days before randomisation. Approximately 130 adult participants with advanced PD were enrolled in the study across 80 sites in the U.S. and Australia. Participants were randomised 1:1 to receive either the VYALEV solution as a continuous delivery under the skin (subcutaneous) plus oral placebo capsules for CD/LD or oral capsules containing CD/LD IR plus continuous subcutaneous delivery of placebo solution for VYALEV. The treatment duration was 12 weeks. The increase in “on” time without troublesome dyskinesia at week 12 was 2.72 hours for VYALEV versus 0.97 hours for oral CD/LD IR (p=0.0083). Improvements in “on” time were observed as early as the first week and persisted throughout the 12 weeks. More information on the study can be found on http://www.clinicaltrials.gov (NCT04380142) and in The Lancet Neurology (https://doi.org/10.1016/S1474-4422(22)00400-8).
Link discovered between two human-specific genes and the SYNGAP1 gene, which is associated with intellectual disability and autism spectrum disorders
14th October 2024: A team of researchers led by Prof. Pierre Vanderhaeghen (VIB-KU Leuven), in collaboration with scientists from Columbia University and Ecole Normale Supérieure, has discovered a link between two human-specific genes, SRGAP2B and SRGAP2C, and the SYNGAP1 gene, which is associated with intellectual disability and autism spectrum disorders. Their study, published in Neuron (open access), provides a direct connection between human brain evolution and neurodevelopmental disorders.
The human brain is unique among mammals due to its prolonged development, particularly in the maturation of synapses in the cerebral cortex, which takes years compared to months in other species like macaques or mice. This extended development, known as neoteny, is believed to be crucial for advanced cognitive and learning abilities in humans. However, disruptions in this process may lead to neurodevelopmental disorders.
Previously, Vanderhaeghen’s lab identified that the prolonged development of the human cerebral cortex is driven by human-specific molecular mechanisms. In their latest study, they explored the role of SRGAP2B and SRGAP2C genes, which were initially identified by Cécile Charrier in Prof. Franck Polleux’s lab at Columbia University. These genes slow down synapse development when introduced into mouse neurons. To understand their function in human neurons, Dr. Baptiste Libé-Philippot, a postdoctoral fellow in Vanderhaeghen’s lab, switched off these genes in human neurons and transplanted them into mouse brains, monitoring synapse development over 18 months.
The results showed that turning off SRGAP2B and SRGAP2C in human neurons accelerated synaptic development to levels comparable to those seen in children aged five to ten years. This mirrors the accelerated synapse development observed in some forms of autism spectrum disorder.
Further investigation revealed that SRGAP2B and SRGAP2C interact with the SYNGAP1 gene to regulate the speed of synapse development. Remarkably, these genes can increase SYNGAP1 levels and even reverse some defects in neurons lacking SYNGAP1. This discovery enhances our understanding of how human-specific molecules influence neurodevelopmental disease pathways, shedding light on the prevalence of such disorders in humans.
Prof. Vanderhaeghen expressed optimism about the future, noting that this research provides a clearer picture of the molecular mechanisms shaping the slow development of human synapses and highlights the potential of these genes to modify neurodevelopmental disease pathways.
Reference:
Libé-Philippot, B., et al. (2024) Synaptic neoteny of human cortical neurons requires species-specific balancing of SRGAP2-SYNGAP1 cross-inhibition.Neuron. doi.org/10.1016/j.neuron.2024.08.021.
Monday 14th October, 2024: Birmingham scientists have shown light therapy delivered transcranially can aid tissue repair after mild traumatic brain injury (mTBI).
Their research, published in Bioengineering & Translational Medicine, indicates that this novel method could result in a new treatment option in an area of medicine that currently has few, if any, treatment options.
Traumatic brain injury (mTBI) results when the initial trauma of head injury is magnified by a complex set of inflammatory changes that occur in the brain. These secondary processes, which take place from minutes to hours after head injury, can dramatically worsen outcomes for patients.
The method invented by scientists at the University of Birmingham, U.K. and patented by University of Birmingham Enterprise aims to protect against this secondary damage, and stimulate faster, and better recovery for patients.
In the study, the Birmingham team, comprising researchers Professor Zubair Ahmed, Professor Will Palin, Dr Mohammed Hadis and surgeons Mr Andrew Stevens and Mr David Davies, examined the effect of two wavelengths of near infrared light (660nm and 810nm) on recovery following injury.
The study in preclinical models used daily two-minute bursts of infrared light, delivered by a laser, for three days post-injury.
The findings showed significant reductions in the activation of astrocytes and microglial cells, which are heavily implicated in the inflammatory processes in the brain that follow head trauma, and significant reductions in biochemical markers of apoptosis (cell death).
At four weeks, there were significant improvements in performance in functional tests involving balance and cognitive function. The red light therapy also accelerated recovery compared to controls, with superior outcomes for light with a wavelength of 810nm.
The study builds on research published earlier this year which showed near infrared light delivered directly to the site of spinal cord injury both improves survival of nerve cells and stimulates new nerve cell growth.
Professor Ahmed, who led the study, said:
We want to develop this method into a medical device that can be used to enhance recovery for patients with traumatic brain or spinal cord injury, with the aim of improving outcomes for patients.
The researchers are seeking commercial partners to co-develop the device and take it to market. For commercial enquiries contact Dr Veemal Bhowruth, email: v.bhowruth@bham.ac.uk
Brain molecule reverses movement deficits of Parkinson’s, offering new therapeutic target
October 4th 2024: A research team from the University of California, Irvine is the first to reveal that a molecule in the brain – ophthalmic acid – unexpectedly acts like a neurotransmitter similar to dopamine in regulating motor function, offering a new therapeutic target for Parkinson’s and other movement diseases.
In the study, published in the October issue of the journal Brain, researchers observed that ophthalmic acid binds to and activates calcium-sensing receptors in the brain, reversing the movement impairments of Parkinson’s mouse models for more than 20 hours.
The disabling neurogenerative disease affects millions of people worldwide over the age of 50. Symptoms, which include tremors, shaking and lack of movement, are caused by decreasing levels of dopamine in the brain as those neurons die. L-dopa, the front-line drug for treatment, acts by replacing the lost dopamine and has a duration of two to three hours. While initially successful, the effect of L-dopa fades over time, and its long-term use leads to dyskinesia – involuntary, erratic muscle movements in the patient’s face, arms, legs and torso.
“Our findings present a groundbreaking discovery that possibly opens a new door in neuroscience by challenging the more-than-60-year-old view that dopamine is the exclusive neurotransmitter in motor function control,” said co-corresponding author Amal Alachkar, School of Pharmacy & Pharmaceutical Sciences professor. “Remarkably, ophthalmic acid not only enabled movement, but also far surpassed L-dopa in sustaining positive effects. The identification of the ophthalmic acid-calcium-sensing receptor pathway, a previously unrecognised system, opens up promising new avenues for movement disorder research and therapeutic interventions, especially for Parkinson’s disease patients.”
Alachkar began her investigation into the complexities of motor function beyond the confines of dopamine more than two decades ago, when she observed robust motor activity in Parkinson’s mouse models without dopamine. In this study, the team conducted comprehensive metabolic examinations of hundreds of brain molecules to identify which are associated with motor activity in the absence of dopamine. After thorough behavioural, biochemical and pharmacological analyses, ophthalmic acid was confirmed as an alternative neurotransmitter.
“One of the critical hurdles in Parkinson’s treatment is the inability of neurotransmitters to cross the blood-brain barrier, which is why L-DOPA is administered to patients to be converted to dopamine in the brain,” Alachkar said. “We are now developing products that either release ophthalmic acid in the brain or enhance the brain’s ability to synthesise it as we continue to explore the full neurological function of this molecule.”
Team members also included doctoral student and lab assistant Sammy Alhassen, who is now a postdoctoral scholar at UCLA; lab specialist Derk Hogenkamp; project scientist Hung Anh Nguyen; doctoral student Saeed Al Masri; and co-corresponding author Olivier Civelli, the Eric L. and Lila D. Nelson Chair in Neuropharmacology – all from the School of Pharmacy & Pharmaceutical Sciences – as well as Geoffrey Abbott, professor of physiology & biophysics and vice dean of basic science research in the School of Medicine.
Alachkar and Civelli are inventors on a provisional patent that covers products related to ophthalmate and calcium-sensing receptors in motor function.
Ain Shams University Virtual Hospital (AVH) on behalf of the Global South Health Alliance (GSHA) is inviting specialists to contribute to research on The Demand for Integrating Digital Health Curricula into Medical Education Programmes.
Technologies like electronic medical records, telemedicine and artificial intelligence are increasingly being used in all fields of healthcare. Aim Shams University Hospital wants to understand perceptions of its value in practice and if it is important to add it to medical education in medical schools or in postgraduate studies.
The researchers hope to gain valuable insights by collecting data from diverse health professionals working and/or studying under the broad umbrella of health, public health, and healthcare in clinical, non-clinical, research, administrative or supportive roles in both digital and non-digital settings from several countries.
They have collected 200 entry from Egypt, and hope to collect a similar number of entries from each country in order to have a representative sample.
The Ain Shams University Virtual Hospital is a pioneering healthcare and technology hub based in Egypt. It operates under the “Treat, Teach, and Innovate” initiative, aiming to enhance healthcare services and facilitate capacity-building, especially in underserved areas of Egypt and Africa.
Key aspects include:
Telemedicine Services: ASUVH provides various telemedicine models, including provider-to-provider (P2P) consultations, which are used for timely diagnosis and treatment, such as in stroke cases
Remote Patient Monitoring: The hospital offers 24/7 remote monitoring for patients in the ICU, integrating both virtual and physical care delivery systems
Medical Research and Training: ASUVH focuses on e-health research and provides innovative medical training through a blend of online and onsite methods
Consultancy and Hospital Management: The hospital offers consultancy services to healthcare providers and uses advanced hospital management systems to improve efficiency and care delivery
Avextra announces the approval of NEUROBIS by the Italian Medicines Agency: A Phase II clinical trial
The Italian Medicines Agency AIFA and the Italian Ministry of Health have granted formal approval for NEUROBIS; a multi-centre Phase II study to evaluate safety, and efficacy of an Avextra oral cannabinoid formulation for managing the symptoms of patients suffering from neurodegenerative diseases such as ALS, Alzheimer’s disease and Parkinson’s disease.
NEUROBIS is the second Phase 2 clinical trial supported by Avextra.
NEUROBIS is one of the few randomised, placebo controlled, double-blind trial with a Cannabis-based medicine to be conducted at multiple sites in Italy and a study of this robust scientific nature aligns perfectly with Avextra’s clinical plan.
The study is funded by a grant from the Italian Ministry of Health signifying the support of regulators in gathering of clinical evidence for Cannabis-based medicines.
Avextra AG, a European manufacturer and developer of Cannabis-based medicines located in Germany, has announced that both the Italian Medicines Agency AIFA and the Italian Ministry of Health have granted formal approval for a multi-centre Phase II study to evaluate safety, and efficacy of an Avextra oral formulation in managing the symptoms of patients suffering from Amyotrophic Lateral Sclerosis (ALS), Alzheimer’s disease and Parkinson’s disease. The study, being conducted under the name NEUROBIS, is one of the few randomised, placebo controlled, double-blind trials to be conducted with a Cannabis-based medicine at multiple sites in Italy.
Avextra is partnering with the sponsor of NEUROBIS, the AOU Maggiore della Carità in Novara, Italy for a second company-supported Phase II clinical trial. The principal investigator is Prof. Dr. Letizia Mazzini, a Neurologist with over thirty years of experience in clinical research and Director of the Neurology Division at AOU Maggiore della Carità as well as Director of the ALS Regional Expert Centre at Department of Translational Medicine at the University of Piemonte Orientale. The study was funded by the Bando Ricerca Finalizzata through a grant from the Italian Ministry of Health as part of the National Health Research Programme and will be conducted across two sites over a 36-month period.
Preclinical studies and anecdotal evidence suggest that a specific CBD to THC ratio may play a role in managing symptoms such as pain, sleep deficiency and psychological stress for patients suffering from neurodegenerative conditions such as Alzheimer’s, Parkinson’s and Multiple Sclerosis. Avextra is committed to supporting and conducting clinical trials with the objective of developing safe, effective and regulatory approved medicines for patients where available treatment options fall short. Both the approval and the funding of NEUROBIS signify the supportive stance on the part of European regulatory bodies for gathering robust clinical evidence for Cannabis-based medicines.
“We are excited to support a second Phase II clinical trial NEUROBIS in partnership with a leading university hospital in Italy, the AOU Maggiore della Carità Novara,” said Dr. Bernhard Babel, CEO, at Avextra. “With two active Phase II clinical trials in BELCANTO in Germany and NEUROBIS in Italy, Avextra is uniquely positioned with the necessary skills and capabilities to design clinical trials and develop pharmaceutical IP with Cannabis-based medicines with the potential to improve patient’s quality of life.”
At our hospital, which is a reference centre for many neurodegenerative diseases, we observe an increase in the number of individuals affected by Dementia, Parkinson’s disease and ALS who require help with their symptoms. It is imperative to increase disease awareness and availability of treatment options to address these patient needs. As such we are grateful for the support of Avextra with their excellent clinical team and patient-centred approach
Prof. Letizia Mazzini, Principal Investigator for NEUROBIS
NEUROBIS is one component of Avextra’s larger clinical plan to gather the robust evidence to support use of its unregistered products in specific indications as it undergoes development of EMA-Registered Cannabis-based Medicines. The company is dedicated to working in collaboration with the medical community, regulators and other stakeholders to drive evidence-based innovation forward.
About Avextra AG Avextra is one of Europe’s leading vertically-integrated medical cannabis operators focused on the development and production of regulator-approved medicines. Founded in 2019 and based out of Germany, the company works in close collaboration with doctors and pharmacists and researchers to develop and produce innovative cannabis-based medicines. Avextra controls the entire value chain – from cultivation in Portugal to EU-GMP certified extraction and manufacturing in Germany. Avextra operates across continental Europe through an expansive distribution network of multiple channels and strategically developed assets for these key markets.
Researchers at the University of Birmingham have uncovered a surprising role
26 September 2024: Researchers at the University of Birmingham have uncovered a surprising role of the hippocampus – linking this part of the brain to the control of skilled actions such as handwriting, typing, and playing music.
The hippocampus is traditionally associated with memory for events and spatial navigation, but a new study challenges these long-held distinctions and opens new possibilities for rehabilitation of neurological and neurodegenerative disorders that affect movement.
Publishing their findings on 26 September in The Journal of Neuroscience, the research team reveal evidence suggesting that the hippocampus plays a role in retrieving and organising flexible movement sequences from memory.
The research team reanalysed functional MRI (fMRI) data to focus on brain activity in key subcortical regions as participants performed well-practiced finger sequences from memory on a force-sensitive keyboard, resembling piano playing.
While motor areas in the basal ganglia and the cerebellum – typically associated with the development of “muscle memory” for learned motor skills – showed increased activity during the sequence task, the study uncovered that it was the hippocampus, rather than these motor areas, that held information about the finger order of the sequence a participant was about to perform. This is like predicting whether a person would type “fears” or “fares” from the activity in the hippocampus alone.
Associate Professor and senior author of the study, Dr Katja Kornysheva, from the University of Birmingham, commented: “This result is interesting because it shows that the brain systems for episodic and procedural memory work together more than we thought. This is especially true when we need to remain flexible and switch between learned sequences, for example when typing on a computer keyboard or playing music with others.”
Dr Rhys Yewbrey, a former doctoral student in Kornysheva’s research group and first author of the study added “Our research suggests that the hippocampus may be important in skilled and flexible motor control, for setting up a course plan of action. This knowledge could help develop more effective training programs for neurological rehabilitation of actions, as well as for speeding up the acquisition of new skills.”
This knowledge could help develop more effective training programs for neurological rehabilitation of actions, as well as for speeding up the acquisition of new skills – Dr Rhys Yewbrey
The researchers hope their findings will encourage further exploration into the interaction between memory systems and inspire novel therapies that can enhance both motor function and cognitive health.
31% delay in time to onset of confirmed disability progression in non-relapsing Secondary Progressive Multiple Sclerosis (SPMS)
Phase 3 study data presented at ECTRIMS show that tolebrutinib, a brain-penetrant BTK inhibitor, addresses disability accumulation that occurs independently from relapse activity
Global regulatory submissions will begin in H2 2024
20 September, 2024: Positive results from the HERCULES phase 3 study in people with non-relapsing secondary progressive multiple sclerosis (nrSPMS) demonstrated that tolebrutinib delayed the time to onset of 6-month confirmed disability progression (CDP) by 31% compared to placebo (HR 0.69; 95% CI 0.55-0.88; p=0.0026). Further analysis of secondary endpoints demonstrated that the number of participants who experienced confirmed disability improvement increased by nearly two-fold, 10% with tolebrutinib compared to 5% with placebo (HR 1.88; 95% CI 1.10 to 3.21; nominal p=0.021). These results were presented on 20th September as a late-breaking presentation at the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) 2024 conference in Copenhagen, Denmark.
“Secondary progressive multiple sclerosis is characterized by insidious worsening of disability over time, independent of relapses, and represents a critical unmet need because we don’t have effective treatments. The results of HERCULES show clearly that tolebrutinib delayed disability progression in people with nrSPMS – and some people even improved disability – by uniquely targeting the biological processes driving disease progression in the brain.” Dr. Fox is a paid advisor to Sanofi for the HERCULES trial.
Robert Fox, MD, Vice Chair of Research at Cleveland Clinic’s Neurological Institute, Cleveland, Ohio and Chair of the HERCULES Global Steering Committee
Based on preliminary analysis of the HERCULES study, there was a slight increase in tolebrutinib-treated patients of some adverse events. Liver enzyme elevations (>3xULN) were observed in 4.1% of participants receiving tolebrutinib compared with 1.6% in the placebo group, a side effect also reported with other BTK inhibitors in MS. A small (0.5%) proportion of participants in the tolebrutinib group experienced peak ALT increases of >20xULN, all occurring within the first 90 days of treatment. All but one case of liver enzyme elevations resolved without further medical intervention. Prior to the implementation of the revised study protocol with more stringent monitoring, one participant in the tolebrutinib arm received a liver transplant and died due to post-operative complications. To date, the implementation of more frequent monitoring has mitigated such serious liver sequelae. Other deaths in the trial were assessed as unrelated to treatment by investigator; deaths were even across the placebo and tolebrutinib arms at 0.3%.
Adverse events (≥10%*)
tolebrutinib N=752 (%)
placebo N=375 (%)
COVID-19 infections
192 (25.5%)
85 (22.7%)
Urinary tract infections
85 (11.3%)
49 (13.1%)
*For participants receiving tolebrutinib
“With no treatment options currently available for the broad population of patients with secondary progressive multiple sclerosis, tolebrutinib has demonstrated its ability to delay disability by targeting underlying drivers of the disease. We look forward to discussing these results with healthcare authorities and are eager to see the results of tolebrutinib in primary progressive MS when they become available next year. We extend our deepest appreciation to the study participants, their families, and the healthcare professionals involved in these trials. Houman Ashrafian, MD, PhD, Head of Research & Development, Sanofi
The GEMINI 1 and 2 phase 3 study results of tolebrutinib compared to Aubagio (teriflunomide), a standard-of-care treatment, in participants with relapsing multiple sclerosis (RMS) were also presented as a late-breaking presentation at ECTRIMS. Both studies did not meet their primary endpoints of statistically significant improvement in annualised relapse rates (ARR) compared to Aubagio. However, in the key secondary endpoint, a pooled analysis of data from GEMINI 1 and 2, tolebrutinib delayed the time to onset of 6-month confirmed disability worsening (CDW) by 29% (HR 0.71; 95% CI: 0.53-0.95; nominal p=0.023). The results of the 29% delay in CDW endpoint in participants with RMS are in line with the 31% delay in CDP observed in participants with nrSPMS. The significant impact of tolebrutinib on disability accumulation versus Aubagio, in the absence of a statistically superior impact on relapses, suggests that tolebrutinib may address smoldering neuroinflammation, which manifests as progression independent of relapses.
Furthermore, results showed historically low ARR in the Aubagio arm in both GEMINI 1 and 2, and no difference was observed between Aubagio and tolebrutinib in a pooled analysis. These relapse rates amount to approximately 1 relapse every 8 years.
tolebrutinib ARR
Aubagio ARR
GEMINI 1 (adjusted rate ratio 1.06; 95% CI: 0.80 to 1.39; p=0.67)
0.13
0.12
GEMINI 2 (adjusted rate ratio 1.00; 95% CI: 0.75 to 1.32; p=0.98)
0.11
0.11
Pooled analysis (adjusted rate ratio 1.03; 95% CI: 0.84 to 1.25; p=0.80)
0.12
0.12
In preliminary analysis of the GEMINI 1 and 2 pooled safety data, adverse events observed between the tolebrutinib and Aubagio arms were generally balanced. Liver enzyme elevations (>3x ULN) were observed in 5.6% of participants receiving tolebrutinib compared with 6.3% of participants receiving Aubagio, a side effect reported with other BTK inhibitors in MS and resolved without further medical intervention. A small (0.5%) proportion of participants in the tolebrutinib group experienced peak ALT increases of >20xULN, all occurring within the first 90 days of treatment. Deaths were balanced across the Aubagio and tolebrutinib arms, at 0.2% and 0.1% respectively, and were assessed as unrelated to treatment by investigator.
Adverse events (≥10%*)
Tolebrutinib N=933 (%)
Aubagio N=939 (%)
COVID-19 infections
225 (24.1%)
252 (26.8%)
Nasopharyngitis
119 (12.8%)
105 (11.2%)
Headache
117 (12.5%)
98 (10.4%)
*For participants receiving tolebrutinib
Study results will form the basis for future discussions with global regulatory authorities with submissions starting in H2 2024. Tolebrutinib is currently under clinical investigation, and its safety and efficacy have not been evaluated by any regulatory authority.
The PERSEUS phase 3 study in primary progressive MS is currently ongoing with study results anticipated in H2 2025.
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