European Commission Approval of ZTALMY® (ganaxolone) for the Adjunctive Treatment of Epileptic Seizures Associated with CDKL5 Deficiency Disorder
31 July 2023: Marinus Pharmaceuticals announced that the European Commission (EC) has granted approval of ZTALMY® (ganaxolone) oral suspension for the adjunctive treatment of epileptic seizures associated with cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) in patients two to 17 years of age. ZTALMY may be continued in patients 18 years of age and older. ZTALMY is the first treatment approved by the European Commission for seizures associated with CDKL5 deficiency disorder in children and adolescents.
The EC approval of ZTALMY in CDD is supported by data from the Phase 3 Marigold double-blind placebo-controlled trial, in which 101 patients were randomised and individuals treated with ZTALMY showed a median 30.7% reduction in 28-day major motor seizure frequency, compared to a median 6.9% reduction for those receiving placebo, achieving the trial’s primary endpoint (p=0.0036). In the Marigold open label extension study, patients treated with ZTALMY for at least 12 months (n=48) experienced a median 49.6% reduction in major motor seizure frequency. In the clinical development programme, ZTALMY demonstrated efficacy, safety and tolerability with the most common adverse reactions (incidence ≥5% and at least twice the rate of placebo) in the ZTALMY group being somnolence, pyrexia, salivary hypersecretion and seasonal allergy. In May 2022, the results from the Marigold study were published in The Lancet Neurology.1
The approval follows a positive opinion issued in May 2023 by the Committee for Medicinal Products for Human Use of the European Medicines Agency and is applicable to all 27 European Union member states plus Iceland, Norway and Liechtenstein. In July 2021, Marinus and Orion Corporation entered into a collaboration agreement which grants Orion the right to commercialise ZTALMY in Europe.
CDKL5 deficiency disorder (CDD) is a serious and rare genetic disorder characterised by early‑onset, difficult‑to‑control seizures and severe neuro‑developmental impairment.2 It is caused by a mutation of the cyclin-dependent kinase-like 5 (CDKL5) gene, located on the X chromosome.The CDKL5 gene produces a protein that is important for normal brain development and function.3
ZTALMY (ganaxolone) is a neuroactive steroid GABAA receptor modulator that acts on a well-characterised target in the brain known to have anti-seizure effects. ZTALMY is an oral prescription medicine approved by the European Commission for the adjunctive treatment of epileptic seizures associated with CDKL5 deficiency disorder in patients two to 17 years of age. ZTALMY may be continued in patients 18 years of age and older.
AI solution will help improve patient outcomes by providing timely and accurate detection of critical abnormalities
Milton Keynes University Hospital NHS Foundation Trust (MKUH) will use Qure’s qER for automating the detection of critical and life-threatening abnormalities in head CT scans, including intracranial haemorrhages (ICH) caused by trauma, accidents or strokes.
It is an FDA cleared and EU MDR Class IIb certified solution, and will be used for all non-contrast CT scans at the Trust. The solution aids in triaging critical cases, within three minutes, in the emergency department, especially during out-of-hour shifts when a larger team may not be available.
“This is a great step forward for frontline A&E patient care and we are delighted to partner with Blackford to bring qER to Milton Keynes University Hospital,” said Darren Stephens, Senior Vice President & Commercial Head UK and Europe of Qure.ai. “Our AI solution will help improve patient outcomes by providing timely and accurate detection of critical abnormalities, enabling clinicians to make informed decisions and take appropriate actions.”
The partnership between Blackford and Qure.ai is part of an ongoing effort to leverage AI technology to enhance clinical decision-making. MKUH procured the Blackford Platform to underpin its AI strategy and make evaluation, adoption, monitoring, and support of AI more efficient. qER by Qure.ai is one of the first AI solutions to be successfully evaluated and deployed via the Blackford Platform at MKUH. By automating the detection of critical abnormalities in head CT scans, qER can help clinicians save time and focus on providing the best possible care for patients.
Blackford are pioneers in the radiology AI space, with over a decade of experience working in partnership with leading hospitals and ground-breaking technology providers. They operate as a strategic AI partner, providing access to a tried-and-tested core platform, tailored services and a portfolio of 100+ applications to help healthcare providers unlock the value of AI and improve patient outcomes. The company’s collaboration and recent arms-length acquisition by Bayer ensures that customers and partners have the support and long-term security needed to underpin successful AI strategies.
If approved, it will be first-of-a-kind biosimilarnatalizumab in Europe,for use in all indications of reference biologic
Positive CHMP opinion is based on evidence from extensive analytical characterisation confirming similarity of biosimilar with reference biologic, in addition to Phase I and confirmatory Phase III studies in RRMS patients
July 24, 2023 — Sandoz, a global leader in off-patent (generic and biosimilar) medicines, today announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA), has adopted a positive opinion for marketing authorisation for first-of-a-kind biosimilar natalizumab developed by Polpharma Biologics.
The authorisation covers treatment as a single disease-modifying therapy (DMT) in adults with highly active relapsing-remitting multiple sclerosis (RRMS), the same indication as approved by the EMA for the reference biologic.1
Sandoz entered into a global commercialisation agreement for biosimilar natalizumab with Polpharma Biologics in 2019. Under this agreement, Polpharma Biologics will maintain responsibilities for development of medicine, manufacturing, and supply of drug substance. Through an exclusive global license, Sandoz has the rights to commercialise and distribute it in all markets.
Access to affordable, high-quality treatments like disease-modifying therapies – which are a cornerstone in the treatment of multiple sclerosis – remains limited for many people living with this disease. At Sandoz, we are committed to accelerating access to potentially life-changing treatments to patients in need around the world. Today’s positive opinion from the CHMP is a clear step in the right direction to address the burden of the disease for those living with multiple sclerosis while also delivering savings for healthcare systems.
Pierre Bourdage, Chief Commercial Officer
The comprehensive analytical, preclinical, and clinical data regulatory submission package included evidence derived from an extensive analytical characterisation, in addition to results from a Phase I PK/PD study and a confirmatory Phase III Antelope study in RRMS patients. Both studies met their primary endpoints, showing that the biosimilar matches the reference biologic in terms of pharmacokinetics as well as efficacy, safety and immunogenicity.
10 July 2023: The Janssen Pharmaceutical Companies of Johnson & Johnson announced further findings from the ESCAPE-TRD study. Data shows that treatment with esketamine nasal spray (NS) increased the likelihood of remission versus treatment with quetiapine extended release (XR) in sub-groups of treatment resistant depression (TRD) patients that had 2 and ≥3 prior treatment failures in the current episode.1 At Week 32, significantly more patients treated with esketamine NS vs quetiapine XR achieved remission in both sub-groups, 59.6% vs 41.3% in the group with 2 prior treatment failures (P≤0.001); 48.1% vs 29.8% in the group with ≥3 prior treatment failures (p<0.01). 1 Furthermore the time to remission was shortened with esketamine NS in both sub groups; patients with 2 and ≥3 prior treatment failures were respectively 1.5 ([1.21, 1.98]; p<0.001) and 2.0 times ([1.47, 2.91]; p<0.001) as likely to achieve remission at any timepoint versus quetiapine XR, when both were dosed as per their respective labels and used in combination with a continuing selective serotonin reuptake inhibitor (SSRI) or serotonin and norepinephrine reuptake inhibitor (SNRI). 1
The findings were presented at the Royal College of Psychiatrists International Congress (RCPsych 2023) 10 July to 13 July in Liverpool, United Kingdom, following earlier top line data from the study presented at the German Association for Psychiatry, Psychotherapy and Psychosomatics (DGPPN) Congress last year, and further findings presented at the 31st European Congress of Psychiatry (EPA 2023) in March of this year.1,2,3 “We are excited that new treatments for depression are being developed, particularly for severe depression where patients have not responded to existing medications and other interventions,” says Marjorie Wallace, Chief Executive of SANE. “There has been a dearth of new ideas, which is why so many patients are given repeat prescriptions of drugs made available over 30 years ago. The only way forward is to encourage those in a position to do so to develop innovative treatments that may potentially transform the future of those whose suffering may drive them to debilitation and despair.” Approximately a third of people who experience major depressive disorder (MDD) do not respond to treatment and are considered to have TRD – a term for people living with MDD who have tried two or more antidepressant treatments without experiencing any relief.4,5 MDD and TRD can be serious and debilitating conditions and are much more common in the UK than people may think – MDD affects around one in five people in the UK at some point in their lives.6
ESCAPE-TRD is a long-term, comparative, randomised, open-label, rater-blinded Phase IIIb clinical study designed to evaluate the short- and long-term efficacy, safety and tolerability of flexibly dosed esketamine NS compared with quetiapine XR, both in combination with a continuing SSRI or SNRI, in adults with TRD.2,7
“We are pleased to be presenting our latest data at RCPsych 2023 today. Our findings further inform us of the types of patients that may benefit the most from esketamine nasal spray and the potential positive effect it could have on their daily lives.” said Megan Walker, Therapeutic Area Medical Director, Neuroscience, Janssen-Cilag GmbH, part of the Janssen Pharmaceutical Companies of Johnson & Johnson.
Findings presented at RCPsych 2023 showed that the percentage of patients who achieved remission increased over time with either 2 or >3 prior treatment failures in both treatment options but was consistently higher in the esketamine NS treatment arm compared with quetiapine XR treatment arm.1 Esketamine NS was shown to demonstrate a superior remission rate in patients with >3 prior treatment failures, with patients 2.6 times as likely to achieve remission* at Week 8 versus quetiapine XR.1 At Week 8, 28.0% of patients treated with esketamine NS achieved remission compared to the 10.9% of patients being treated with quetiapine XR. 1
In addition, a significantly† greater proportion of patients with >3 prior treatment failures were relapse-free through Week 32 after remission at Week 8.1 Notably at Week 32, 18.2% of patients treated with esketamine NS were relapse-free after remission at Week 8 compared with 7.8% of patients treated with quetiapine XR. 1
Participants in the esketamine NS study arm with 2 prior treatment failures demonstrated a higher rate of remission at Week 8, compared with patients in the quetiapine XR study arm, 26.5% versus 21.8% respectively. 1 After remission at Week 8, 24.0% of patients in the esketamine NS study arm were relapse-free through Week 32 compared with the 18.0% of patients in the quetiapine XR treatment arm. 1
*Remission was defined as Montgomery-Åsberg Depression Rating Scale [MADRS] total score ≤10. MADRS is a clinician‐rated measure of depression severity.1
† Tested at a two-sided 0.05 significance level without adjustment for multiple testing. 1
1 Young AH. et al., Esketamine nasal spray improves rate and time to remission versus quetiapine extended release in subgroups of patients with treatment resistant depression and two or three plus prior treatment failures: Results from ESCAPE-TRD, a randomised phase IIIb trial. Presented at RCPsych 2023, July 10-13. Poster PO-424. 2 Reif A. et al., Esketamine nasal spray improves short‐ and long‐term outcomes compared with quetiapine extended release in patients with treatment resistant depression: First results from ESCAPE‐TRD, a randomised, multi‐centre phase IIIb clinical trial. Presented at DGPPN 2022, November 23-26. Poster P-01- 04. 3 Reif A. et al., Esketamine nasal spray shows higher remission and response rates over 32 weeks of treatment compared with quetiapine extended-release in patients with treatment resistant depression: Results from EXCAPE-TRD, a randomized, phase IIIb clinical trial. Presented at EPA 2023, March 25-28. Poster PO0067. 4 Ionescu DF, et al., Dialogues Clin Neurosci 2015;17(2):111–126. European Medicines Agency, 2013. Guideline on clinical investigation of medicinal products in the treatment of depression. Available at: https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-clinical-investigation-medicinal-products-treatment-depression_en.pdf. Last accessed: July 2023. CP- 399452 July 2023 5 National Institute for Health and Care Excellence. Implanted vagus nerve stimulation for treatment-resistant depression. Available at: https://www.nice.org.uk/guidance/ipg679/resources/implanted-vagus-nerve-stimulation-for-treatmentresistant-depression-pdf-1899874293371845. Last accessed: July 2023. 6 Smith, D., et al., Prevalence and Characteristics of Probable Major Depression and Bipolar Disorder within UK Biobank: Cross-Sectional Study of 172,751 Participants. 2013. Plos ONE, 8(11), e75362. doi: 10.1371/journal.pone.0075362. 7 Clinicaltrials.gov. A long-term comparison of esketamine nasal spray versus quetiapine extended release, both in combination with a selective serotonin reuptake inhibitor/serotonin-norepinephrine reuptake inhibitor, in participants with treatment resistant major depressive disorder (ESCAPE-TRD). NCT 04338321.Available at: https://clinicaltrials.gov/ct2/show/NCT04338321?term=escape-trd&draw=2&rank=1. Last accessed: July 2023. 8 Mrazek DA, et al., A review of the clinical, economic, and societal burden of treatment-resistant depression: 1996-2013. Psychiatr Serv. 2014 Aug 1;65(8):977-87. doi: 10.1176/appi.ps.201300059. 9 Amos TB, et al., Direct and Indirect Cost Burden and Change of Employment Status in Treatment-Resistant Depression: A Matched-Cohort Study Using a US Commercial Claims Database. J Clin Psychiatry. 2018 Mar/Apr;79(2):17m11725. doi: 10.4088/JCP.17m11725. 10 Souery D, et al., Clinical factors associated with treatment resistance in major depressive disorder: results from a European multicenter study. J Clin Psychiatry. 2007 Jul;68(7):1062-70. doi: 10.4088/jcp.v68n0713. 11 Hillhouse TM, Porter JH. A brief history of the development of antidepressant drugs: from monoamines to glutamate. Exp Clin Psychopharmacol. 2015 Feb;23(1):1-21. doi: 10.1037/a0038550. 12 Electronic Medicines Compendium. Spravato 28 mg nasal spray, solution. Available at: https://www.medicines.org.uk/emc/product/10977/smpc#gref. Last accessed: July 2023 13 Paul R, et al., Comparison of racemic ketamine and S-ketamine in treatment-resistant major depression: report of two cases. World J Biol Psychiatry. 2009;10(3):241-4. doi: 10.1080/15622970701714370. 14 European Medicines Agency. Summary of Product Characteristics. Spravato 28 mg nasal spray. Janssen Cilag International
Meta-analysis shows fewer complications and higher occlusion rates for ruptured wide-neck intracranial aneurysms, using Rapid Medical’s COMANECI™ Embolisation Assist Device
19 July 2023: Rapid Medical™, developer of advanced neurovascular devices, has announced new clinical data showing significant advantages of its novel COMANECI™ embolisation assist device over established techniques to treat ruptured wide-neck intracranial aneurysms. A recent meta-analysis published in World Neurosurgery found that COMANECI is associated with lower haemorrhagic and thromboembolic complication rates, higher complete occlusion rates, and similar residual retreatment rates than stent-assisted and balloon-assisted coiling techniques.
As the only adjustable, non-occlusive device for haemorrhagic stroke treatment, COMANECI’s visible mesh conforms to the anatomy, providing stent-like support without the complications of a permanent stent or halting blood flow like a balloon. It has been used in over 12,000 procedures worldwide in wide-neck aneurysm treatments–and in Europe only–to open arteries constricted by vasospasm.
Researchers at the University at Buffalo and George Washington University compared the three devices by pooling over 3200 ruptured aneurysms across 64 studies. No significant differences were found between SAC and BAC. However, COMANECI-assisted coiling showed significantly lower thromboembolic and aneurysmal complication rates and periprocedural complications – than both SAC and BAC. Furthermore, COMANECI demonstrated statistically better complete occlusion rates than SAC and equivalent rates to BAC.
Phase III trial results could strengthen Ocrevus’s position in multiple sclerosis
GlobalData, 19th July 2023: Genentech recently announced positive results from its phase III trial, OCARINA II (NCT05232825), investigating the efficacy of Ocrevus (ocrelizumab) as a subcutaneous injection, administered twice yearly for ten minutes, in patients diagnosed with relapsing multiple sclerosis (RMS) and primary progressive multiple sclerosis (PPMS). Roche announced the trial met all of the primary and secondary endpoints, which could help strengthen Ocrevus’s position in the multiple sclerosis (MS) market, according to data and analytics company GlobalData.
Barbora Salcman, Neurology Analyst at GlobalData, comments: “Ocrevus, in its intravenous (IV) form, has been approved for use in MS since 2017. It quickly established itself on the market after approval, not only due to its favourable efficacy and positive safety profile, but also because the agent treats all forms of MS, which is not the case for most other products. However, the IV administration of Ocrevus can be time consuming and uncomfortable for patients, as they need to receive the medication twice a year over the course of a two-hour infusion.”
Ocrevus is expected to dominate the MS market. However, sales are expected to decline due in part to patients switching to newer agents with more convenient methods of administration, such as Novartis’ Kesimpta, which is administered in the form of a subcutaneous injection every four weeks.
Salcman concludes: “The approval of new agents in recent years with positive clinical profiles and convenient routes of administration for MS, such as Kesimpta, may drive patients to switch from their previous medications. However, if the subcutaneous version of Ocrevus gains FDA approval, the agent might have an easier time retaining its customer base and even start attracting new patients who are searching for a reliable and safe agent with a convenient administration route.”
BrainTale has been developing non-invasive, accessible, effective and clinically validated measurement and prediction tools for patients suffering from brain diseases
BrainTale, a medtech deciphering white matter to enable better brain care, presented preliminary results demonstrating the effectiveness of its digital biomarker platform for the early and differential diagnosis of Parkinson’s disease. Results were presented during the European Academy of Neurology (Budapest, July 1 – 4, 2023) and the World Parkinson congress (Barcelona, July 4 – 7, 2023). Vincent Perlbarg, co-founder, scientific director and president of BrainTale, has presented the results showing the relevance of BrainTale’s digital biomarker platform for the care of patients suffering from the disease and the development of new therapies.
White matter, which represents 60% to 80% of the human brain, plays a key role in its proper functioning, development, and ageing, whether normal or pathological. Since its creation in 2018, BrainTale has been developing non-invasive, accessible, effective and clinically validated measurement and prediction tools for patients suffering from brain diseases.
Affecting around 8.5 million people worldwide, the incidence of Parkinson’s disease continues to rise and is still diagnosed far too late to effectively slow its progression, despite white matter lesions being identifiable at an early stage, particularly in the basal ganglia responsible for initiating and harmonising muscle movements.
The results were presented from July 1-4th during EAN and on Thursday, July 6th with a poster entitled “Evaluation of a clinically validated digital platform to provide Diffusion MRI biomarkers in Parkinsonian syndrome”. The prospectively acquired data from 81 subjects (46 subjects with Parkinson’s disease [PD], 18 subjects suffering from tauopathy [PSP], 10 subjects with ⍺-synucleinopathy [(MSAc] and 7 subjects with multiple system atrophy with phenotypes [MSAp]) were studied together with the team of Professor Stéphane Lehéricy, head of the Neuroradiology department at the Hôpital de la Pitié-Salpêtrière, Paris Region Greater Hospitals, France).
The results demonstrated the ability of differentiating patients’ population based on statistically different (p<0.05) white matter quantification assessments for the different subject categories. Main outputs were as follows: decreased anisotropy fraction (AF) between the MSAc and PSP groups compared to the PD group and increased radial diffusivity (RD) between the MSAc group compared to the PD group.
These preliminary data highlight the relevance and sensitivity of BrainTale’s white matter biomarkers to Parkinsonian syndromes, including early stages of Parkinson’s disease. It paves the way for the possibility of using those brain biomarkers not only for a reliable, non-invasive and early differential diagnosis of Parkinson’s syndromes, but also to help accelerate the development of new therapies. With the new version of the BrainTale-care biomarker platform available since February 2023, centres and partners equipped with BrainTale’s technology can now improve the care of these patients and help securing patients diagnosis.
Annovis Bio recently received a positive safety review for the Phase III trial of buntanetap in patients with early Parkinson’s Disease (PD) (NCT05357989) from the Data and Safety Monitoring Board (DSMB). Should buntanetap demonstrate good efficacy and safety profiles in the trial, it could be the first α-synuclein-targeting product to enter the market and one of the first potentially disease-modifying agents, but it faces a complex road ahead, says data and analytics company GlobalData.
The positive safety review from the DSMB enables the trial to move forward as planned, with an estimated completion date in December 2023. GlobalData forecasts that buntanetap will launch in the US and 5EU (France, Germany, Italy, Spain, and the UK) in Q4 2026 and Q4 2028, respectively.
Christie Wong, Pharma Analyst at GlobalData, comments: “The current medications used for the treatment of PD are limited to dopaminergic therapies that provide only symptomatic relief of motor symptoms, leaving ample opportunities for new entrants into the PD market. Importantly, buntanetap may actually possess disease-modifying properties by inhibiting α-synuclein, potentially preventing the formation of toxic aggregates and, in turn, halting disease progression.”
Key opinion leaders (KOLs) previously interviewed by GlobalData agreed that if a disease-modifying or neuroprotective agent was approved for PD, it could bring a major shift in the way these patients are treated. Like Annovis, many companies have been developing first-in-class programmes that target α-synuclein. According to GlobalData’s Drugs Database, there are currently 12 products in Phase I-III clinical trial development for PD in the US and 5EU that list α-synuclein as a molecular target.
Roche/Prothena’s prasinezumab, a monoclonal antibody targeting α-synuclein, administered via intravenous (IV) infusion is set to compete with buntanetap. There are two ongoing Phase IIb trials, PASADENA and PADOVA (NCT03100149 and NCT04777331). GlobalData forecasts that prasinezumab will launch in the US in Q4 2029.
Wong adds: “Buntanetap has a few winning attributes over prasinezumab. As well as a first-to-market advantage, it has a convenient daily oral administration compared to prasinezumab’s monthly IV infusion that typically requires administration and monitoring in a healthcare institution.”
However, KOLs expressed concerns about both products’ likelihoods of success, largely because it is still unclear whether targeting extracellular α-synuclein protein with buntanetap or prasinezumab will slow the progression of PD and offer enough functional benefit to PD patients.
Wong continues: “Furthermore, the lack of validated endpoints and biomarkers available to quantify disease-modifying properties of PD drugs remains a major hurdle in the development of novel treatments. Unfortunately, unlike amyloid imaging for Alzheimer’s disease, an α-synuclein imaging tool is not available. As such, advancement in assessing α-synuclein as a biomarker for PD is considered to be a very important step towards developing disease-modifying therapies.”
Targeting α-synuclein as a mechanism of action has yet to be proven in larger Phase III clinical trials, and previous attempts to target this protein have failed. For example, Biogen’s cinpanemab failed in its Phase II trial SPARK (NCT03318523) in February 2021, leading the company to halt its development for PD.
Easy-to-use, concise guidance for the return-to-school (RTS) following concussion has been produced by UKABIF National Acquired Brain Injury Learning and Education Syndicate (N-ABLES). This two-page document entitled ‘Concussion Return-to-School Guidance’ reiterates the staged return-to-education advocated in the Government’s new grassroots sports guidance but is aimed directly at teachers and parents supporting the young person’s RTS following concussion from any cause.
Dr Emily Bennett, N-ABLES Chair and Consultant Clinical Neuropsychologist at Nottingham University Hospitals NHS Trust said: “Concussion is not just limited to sports injuries, this mild brain injury can happen in the playground, park or in the home. A return-to-learning has to take priority over a return-to-sport. N-ABLES recommends this easy-to-use guide for use in all schools to help raise awareness of the effects of concussion and also to improve the understanding of its impact on learning.”
Dr Gemma Costello, N-ABLES Steering Committee member and Educational Psychologist in Paediatric Neuropsychology said: “It’s important that parents understand how to monitor their child during the concussion recovery stage, and for teachers to be aware of the symptoms and the individual’s possible needs in the classroom”.
Page 1 of the guidance provides an overview of concussion, the symptoms, red flags, advice on when a student can RTS and resume normal activities, examples of support and further information. Page 2 is a step-by-step RTS guidance. N-ABLES wants to disseminate this resource as widely as possible across the UK, to all target audiences involved in the education and support of children and young adults with ABI, their parents/carers.
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