Author: Rachael Hansford

Ipsen and World Stroke Organisation partnership focuses on improving post-stroke care

Research highlights financial challenges and knowledge gaps faced by stroke survivors

Results of a new Ipsen survey highlight the stark reality faced by stroke survivors, revealing the personal and financial burdens that stroke can have on individuals and their families. The survey raises critical concerns, suggesting that many stroke survivors are not proactively made aware by their neurologist of the long-term complications that can occur following a stroke.

The survey of over 500 stroke survivors found that 9 in 10 (90%) people who were employed at the time of their stroke, said it has had an impact on their working life. One in four (25%) stroke survivors stated they have had to leave their jobs and 1 in 3 (34%) said they had to reduce their work hours.  Data shows that younger stroke survivors are particularly hard hit in terms of the impact on their careers and livelihoods, as for those who said that they had to reduce their working hours, close to half (45%) were aged 30 to 44. Similarly, of those who said they had to leave work altogether, more than a third (34%) were 30 to 44 and of the stroke survivors who said they had to find alternative employment, almost six out of ten (59%) were aged 30-44.

In addition, findings highlight that stroke also heavily impacts family members’ ability to work. Almost three quarters (74%) of all individuals who have experienced a stroke in the past three years report that a family member has had to either give up or reduce their working hours to provide care and assistance. In the UK specifically, one in five (21%) said a family member had to give up their job long-term (over a year) to care for them, while one in four (25%) said they had to reduce their work hours.

Announcing a global partnership between Ipsen and the World Stroke Organisation, focused on improving post-stroke care, Michelle Nelson, VP of Stroke Support Organizations of the World Stroke Organization said “Increasing global stroke rates among those under age 55, coupled with a projected 35% rise in stroke survivors in Europe by 2040, will significantly impact the global economy. Without action, stroke-related costs, including direct expenses and income losses, are estimated to rise to $2.31 trillion worldwide by 2050. It is therefore vital that we ensure that stroke survivors and their families have access to good quality post-stroke services to prevent recurrent strokes and optimize health and wellbeing post stroke.”

As clinicians we sometimes face significant obstacles to efficient care delivery due to a lack of patient awareness of critical symptoms of post-stroke complications and clear lines of communication between physicians, stroke survivors and caregivers. Timely and comprehensive care is vital for optimising long-term health outcomes post-stroke, particularly when it comes to spasticity. Ensuring stroke survivors are made aware and have access to accurate information and support post-discharge is critical to the success of rehabilitation.

Dr Ganesh Bavikatte, Consultant and Clinical Lead, UK

When respondents were asked what they hoped their post-stroke treatment and rehabilitation programme would deliver, almost half of all individuals questioned said the prevention of another stroke (49%). A similar proportion (46%) said they wanted to improve their mobility and movement, highlighting the high value that patients place on being able to move freely.

Despite being a top priority for patients, the survey uncovered a concerning gap in care: at least one in three stroke survivors reported that they were not proactively informed by their neurologists about potential post-stroke complications, including mobility issues such as muscle stiffness (spasticity) (38%) and muscle weakness (paresis) (38%). In addition, in Europe 1 in 3 (33%) stroke survivors who do not primarily see a stroke specialist regarding their post-stroke care, say their general practitioner does not refer them to see a stroke specialist when they experience new stroke related complications.

The findings highlight the need for a comprehensive approach to long-term stroke management that limit the economic impact and alleviates the multifaceted burdens faced by survivors and their families.

“Delayed and uncoordinated post-stroke care is costly for patients, society and healthcare systems. We know that many patients are not referred for rehabilitation and post-stroke care in a timely manner,” explains Dr Sandra Silvestri, Chief Medical Officer at Ipsen. “Ipsen is committed to improving stroke outcomes for patients. As part of this commitment, we are currently conducting a major scientific study in over 1000 patients in 7 countries to fully assess the incidence, timing, severity and patterns of post-stroke spasticity so that better treatment pathways can be identified globally for patients.”

Are CGRP medications effective against migraine in men?

Via Medscape: Most patients with migraine are women. This female predominance is reflected in the clinic and in clinical trials, where ~85% are women. A pharmacologist and a neurologist from the United States argue that the efficacy of calcitonin gene-related peptide (CGRP)-based migraine therapies has been proven in women but not in men, and that men should be informed of this.

In their article, which was published in JAMA Neurology, Frank Porreca, PhD, associate head of pharmacology at the University of Arizona in Tucson, and David W. Dodick, MD, professor emeritus of neurology at the Mayo Clinic Arizona in Phoenix, refer to medication that targets CGRP or its receptors.

Porreca and Dodick base their argument that CGRP-based therapies, especially the new active-substance class of gepants, are less effective in men than in women on preclinical data:

  • In mice, the injection of CGRP directly into the dura mater led to migraine-like headaches. Much lower doses were required for this in female animals than in males.
  • CGRP antibodies alleviate migraine-like pain in female mice considerably better than they do in male mice.

They also drew on observations from human studies:

  • One study with seven women and one man showed that in women, the CGRP level was elevated during a migraine attack and could be normalised again with sumatriptan. In the man, the levels were not elevated, nor could they be reduced through the application of the triptan.
  • Provocation studies, in which migraine headaches were triggered through an infusion of CGRP to prove its role in the formation of migraines, were conducted almost exclusively in women.
  • Pooled data on ubrogepant and rimegepant showed no therapeutic benefit in men. While ubrogepant demonstrated a therapeutic benefit, compared with placebo, in 8.3% (freedom from pain) and 12.4% (burdensome symptom after 2 hours) of women, a benefit was only observed in 0.2% or 0.7% of men, compared with placebo. Similar results were seen in studies of rimegepant.

Read more at Medscape.com

Reducing migraine in Major Depressive Disorder

Teva Phase IV UNITE study shows AJOVY® (fremanezumab) reduced migraine attacks and depression symptoms in migraine sufferers with Major Depressive Disorder

  • Almost half of all migraine patients experience depression and anxiety[1]
  • Migraine patients treated with AJOVY® (fremanezumab) showed significant reductions in depressive symptoms and clinically meaningful improvements in disability outcomes
  • Data revealed at the World Congress of Neurology, Montreal, Canada

17th October, 2023: Teva Pharmaceutical Industries Ltd has announced that data from the UNITE study presented today at the World Congress of Neurology in Montreal, Canada, show that AJOVY® (fremanezumab) reduced migraine attacks and depression symptoms in migraine patients with major depressive disorder. AJOVY® is currently approved for the preventive treatment of migraine in adults.

Depression is one of the most prevalent psychiatric co-morbidities in migraine and patients with comorbid depression experience an increased risk of migraine ‘chronification’.1 This is characterised by an increase in the number of headache days, a greater degree of headache disability, decreased quality of life and a poorer response to migraine treatments.[2],[3],[4],[5]

UNITE[6] is a double-blind, randomised, placebo-controlled, Phase 4 study sponsored by Teva investigating the efficacy, safety, and impact of fremanezumab on patients with migraine and major depressive disorder.

Data revealed in an oral presentation by Dr Verena Ramirez Campos, Global Senior Medical Director at Teva, showed that patients in the study treated with fremanezumab experienced a significant reduction in Monthly Migraine Days (MMD) compared to patients on placebo, a reduction in MMD of –5.1 vs –2.9 for fremanezumab vs placebo (p<0.0001). Furthermore, a significantly higher number of patients (33%), receiving fremanezumab achieved ≥50% reduction in MMD compared to placebo (13%) during the 12 week double blind period (p<0.0001), with a sustained reduction over the longer-term.[7]

Patients who suffer from migraine and mental health disorders such as depression face a far greater burden than those suffering from either migraine or depression alone. The UNITE data presented at WCN provides further insights into the potential efficacy, safety, and quality of life benefits of AJOVY® for people with migraine and major depressive disorder.

Dr. Verena Ramirez Campos

Two further data sets were presented as posters on the study’s secondary endpoints that evaluated the impact of fremanezumab on depression[8] and disability. [9]

Treatment with fremanezumab resulted in significant reductions in depression symptoms as measured by two commonly used depression rating scores.  The mean change at week 12 for fremanezumab and placebo using the Hamilton Rating Scale for Depression (HAM-D 17) was -6.7 vs -5.4 respectively (p=0.0228) and using the Patient Health Questionnaire-9 (PHQ-9) score was -7.8 vs -6.3 respectively (p=0.0108).

Furthermore, fremanezumab demonstrated clinically meaningful improvements in disability outcomes in the study patients with a sustained reduction in their disability over the longer term. The mean change at week 12 for fremanezumab and placebo using the Headache Impact Test score (HIT-6) was -8.8 vs -5.2 respectively, (p≤0.0001) and using the Clinical Global Impression-Severity (CGI-S) score was -1.1 vs -0.8 respectively (p=0.0030).

These encouraging results indicate that fremanezumab has the potential to reduce the symptoms and cumulative burden of migraine and associated depression.  

Depression is commonly associated with migraine, and clinicians are increasingly aware of the impact of co-morbidities. We are moving towards more personalised treatment decisions in migraine which are tailored to the patient’s profile, and it is very important for treatments to demonstrate efficacy and safety in migraine patients with this particular co-morbidity.” 

Study lead author Richard Lipton M.D., Department of Neurology, Psychiatry and Behavioural Sciences at Albert Einstein College of Medicine, New York

AJOVY® (fremanezumab), a humanised monoclonal antibody (mAb) developed by Teva Pharmaceuticals, selectively targets the calcitonin gene-related peptide (CGRP), and is approved for the prevention of migraine in adults who have at least 4 migraine days per month.


References

[1] Minen MT, et al. Migraine and its psychiatric comorbidities. J Neurol Neurosurg Psychiatry. 2016; 87: 741–749.

[2] Lipton RB, et al. Migraine, quality of life and depression.  A population-based case-control study. Neurology.  2000; 55: 629–635.

[3] Buse DC, et al. Comorbid and co-occurring conditions in migraine and associated risk of increasing headache pain intensity and headache frequency: results of the migraine in America symptoms and treatment (MAST) study. J Headache Pain. 2020; 21:23.

[4] Heckman BD, et al. Do psychiatric comorbidities influence headache treatment outcomes? Results of a naturalistic longitudinal treatment study.  Pain. 2009; 146: 56-64.

[5] Walter S, Bigal ME. TEV-48125: a review of a monoclonal CGRP antibody in development for the preventive treatment of migraine. Curr Pain Headache Rep. 2015; 19:6.

[6] UNITE study protocol NCT04041284.

[7] Lipton RB, et al. Efficacy of fremanezumab treatment in reducing monthly migraine days in patients with migraine and major depressive disorder: Results from the UNITE study. Presented at World Congress of Neurology (WCN); 15–19 October 2023; Montreal.

[8] Lipton RB, et al. Efficacy of fremanezumab in reducing depression in patients with migraine and major depressive disorder: results of the UNITE study.  Presented at World Congress of Neurology (WCN); 15–19 October 2023; Montreal.

[9] McAllister P, et al. Impact of fremanezumab treatment on disability outcomes in patients with migraine and major depressive disorder: results of the UNITE study. Presented at World Congress of Neurology (WCN); 15–19 October 2023; Montreal.

New twice weekly Alzheimer’s disease patch

Alzheimer’s disease treatment can help reduce symptoms and lessen the care burden for patients and their caregivers

September 2023: Zeyzelf® twice weekly rivastigmine transdermal patch is for the symptomatic treatment of mild to moderately severe Alzheimer’s dementia and it is the first ever patch to be launched in the UK that does not need daily application.

A study showed Zeyzelf® twice weekly is bioequivalent to daily rivastigmine patches,[i] but because it only has to be applied twice weekly, it can be easier to administer and help the patient and caregiver maintain adherence.[ii] Zeyzelf® twice weekly is also 52% less expensive than some rivastigmine patches.[iii]

In elderly patients, transdermal delivery of rivastigmine may have advantages over other delivery routes, such as oral medications, as it provides ease of use for the patient and carer, gives greater adherence to prescribed regimens and has less risk of toxicity and ‘dose dumping’.[iv] Transdermal delivery of rivastigmine, which works by blocking certain enzymes in the brain to help reduce symptoms, is also useful when elderly patients are unable to tolerate or unwilling to swallow tablets.[v]

In a comparative study, Zeyzelf® twice weekly demonstrated better adhesion properties than the daily rivastigmine patch – in 95% of patients there was satisfactory adhesion, compared to 67% with the comparison patch.[vi] Skin adhesion is one of the most important functional properties for a transdermal patch and is critical for the safety, efficacy and quality of the patch.[vii] Poor adhesion can lead to improper dosing, with additional patches having to be used, which takes up more carer and healthcare professional time. [vii]

There are currently 900,000 people with dementia in the UK, which is projected to rise to 1million by 2025 and nearly 1.6million in 2040.[viii] Alzheimer’s disease, which affects multiple brain functions, is the most common form of dementia and it is a progressive condition, with symptoms developing gradually over many years and eventually becoming more severe.[ix]

alzheimers disease patch packaging

The cost of dementia to the UK is currently £34.7billion annually – an average cost of £32,000 per person, two-thirds of which is paid by the patients and their families either in unpaid care of private social care.[x] Treatments such as Zeyzelf® which can be easier to administer and improve compliance can help reduce this care burden.

Zeyzelf® twice weekly is launched by Luye Pharma Ltd, which specialises in diseases of the central nervous system (CNS). The company believes Zeyzelf® twice weekly will offer a significant development in the treatment of Alzheimer’s and it has been well received by patients, clinicians and carers in Spain, where the product launched last year.

Zeyzelf® twice weekly patches are an important development in the treatment of Alzheimer’s dementia, where a small change can make a big difference. We know that transdermal delivery can be advantageous to both patients and carers and by having a patch that only has to be applied twice a week, rather than daily, will significantly reduce the carer burden and also potentially improve compliance. Healthcare professionals and carers all recognise that compliance is a major issue in the treatment of Alzheimer’s and Luye has launched Zeyzelf® twice weekly to help meet this unmet need. The product has been incredibly well received in Spain and is being widely used with patients and we hope this will be the same in the UK.

Andy Farrant, General Manager of Luye Pharma Ltd

ABOUT ZEYZELF®

Zeyzelf® twice weekly transdermal patches are for the treatment of mild to moderately severe Alzheimer’s dementia. The active substance of Zeyzelf® twice weekly is rivastigmine. Rivastigmine belongs to a class of substances called cholinesterase inhibitors. In patients with Alzheimer’s dementia, certain nerve cells die in the brain, resulting in low levels of the neurotransmitter acetylcholine (a substance that allows nerve cells to communicate with each other). Rivastigmine works by blocking the enzymes that break down acetylcholine: acetylcholinesterase and butyrylcholinesterase. By blocking these enzymes, rivastigmine allows levels of acetylcholine to be increased in the brain, helping to reduce the symptoms of Alzheimer’s.

Zeyzelf® twice weekly patches are available in 4.6mg or 9.5mg dose strengths.

Read more about Zeyzelf® twice weekly.


[i] Zeyzelf® twice weekly is bioequivalent to the originator Exelon daily transdermal patch (Schurad B et al. Current Alzheimer Research, 2022, 19, 541-553)

[ii] Zeyzelf® twice weekly transdermal patch, Summary of Product Characteristics, Luye Pharma Ltd. September 2023

[iii] Zeyzelf® twice weekly patches provides a considerable cost saving compared to the daily transdermal patch Exelon, with >50% cost savings. Source: NHSBSA Drug Tariff (England and Wales). September 2023

[iv] Dose dumping is a phenomenon of drug metabolism which can cause the premature and exaggerated release of a drug, which can greatly increase the concentration of a drug in the body and thereby cause adverse events or even drug-induced toxicity. Dose dumping is most commonly seen in drugs taken orally (by mouth) and digested in the gastrointestinal tract

[v] Vadivelu N, Hines R L. Clin Interv Aging, 2008 Sep; 3(3): 421-430

[vi] In a study comparing the twice weekly Zeyzelf® patch and Exelon daily patch, Zeyzelf® showed better adhesion properties than the Exelon patch despite the longer dosing intervals (Schurad B et al. Current Alzheimer Research, 2022, 19, 541-553). The EMA (European Medicines Agency) Guideline defines satisfactory adhesion as ≥ 90% of area that remained adhered at assessment. Assessments were taken 24h post application of the patches. Available online at: https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-pharmacokinetic-clinical-evaluation-modified-release-dosage-forms_en.pdf

[vii] Wokovich A M et al. Eur J Pharm Biopharm. 2006 Aug;64(1):1-8

[viii] Alzheimer’s Society. https://www.alzheimers.org.uk/blog/how-many-people-have-dementia-uk#:~:text=Research%20conducted%20shows%20that%2C%20in,the%20current%20rate%20of%20prevalence (accessed September 2023)

[ix] NHS. https://www.nhs.uk/conditions/alzheimers-disease/ (accessed September 2023)

[x] Alzheimer’s Society. How much does dementia care cost. https://www.alzheimers.org.uk/blog/how-much-does-dementia-care-cost (accessed September 2023)

Switching to second line MS DMTs associated with decreased relapse rate

People with multiple sclerosis (MS) who switch between more than two disease-modifying therapies (DMTs) have a higher risk of relapses compared with those who never switch, regardless of how well these patients adhere to their prescribed medications, according to real-world study in Canada.

According to the researchers, these findings are consistent with a greater number of treatment switches in individuals with a poor response to different therapies and/or higher disease activity.

However, among patients who ever switched treatments, those who changed to second-line DMTs had a 56% lower risk of relapse after the switch compared with those who remained on a first-line DMT. That result suggests that higher-efficacy therapies can more effectively control relapses in these patients.

Front. Neurol., 06 September 2023. Volume 14 – 2023 | https://doi.org/10.3389/fneur.2023.1243589

This provides a strong rationale for escalating therapy among those who have relapses requiring intervention

Gut bacteria and PD

Could changes in gut bacteria contribute to the development of Parkinson’s disease in those with genetic risk?

Via World Parkinson’s Congress: Mutations in the GBA1 gene are one of the most common genetic risk factors associated with Parkinson’s disease (PD). However, it’s important to note that not all people with GBA1 mutations will necessarily develop PD. Furthermore, if they do, the onset may occur at different ages and with different clinical presentations. This variability highlights the critical need to identify additional factors, both environmental and genetic, that may influence the likelihood of developing PD in individuals with GBA1 mutations.

Individuals with GBA1-related PD often have a higher prevalence of non-motor symptoms, such as a reduced sense of smell and constipation, which typically precede the onset of motor symptoms. The characteristic tremors, rigidity, slowness of movement, and freezing in PD have been attributed to the loss of certain brain cells called dopaminergic neurons, along with the accumulation of a protein called α-synuclein in the brain. A hypothesis emerged in 2003 that the initial pathology of α-synuclein may originate in the gastrointestinal tract before progressing to the brain. Specifically, people with PD often have alterations in their gut microbiota, resulting in changes in the maintenance of the intestinal lining, inflammation, and the body’s ability to defend itself against invading pathogens.

The research laboratory of Christin Weissleder, PhD is investigating how GBA1 mutations might interact with microbial molecules to promote inflammation and α-synuclein accumulation using various cell culture systems. Read more.

Watch the Hot Topics presentation on this subject from WPC 2023.

UK-wide research platform for brain injury treatment

TBI-REPORTER, a new research platform led by the University of Cambridge, will bring together leading experts to enable better and more coordinated research into traumatic brain injury. It is hoped that this will result in more people receiving appropriate treatment due to better forecasting of how a particular injury is likely to impact a patient with TBI.

The platform will focus on research into populations previously underserved, including unhoused people, prisoners and those who have experienced domestic violence. 

Collaborating for better outcomes

TBI-REPORTER, standing for UK-TBI REpository and data PORTal Enabling discoveRy, is a new initiative supported by key UK health and research organisations, including the National Institute for Health and Care Research (NICE), the Medical Research Council (MRC), the Ministry of Defence (MOD), and Alzheimer’s Research UK.

The brain injury research platform will bring together data from existing research into brain injury and work closely with the UK Biobank and Dementias Platform UK to coordinate new investigations with the aim of accelerating our understanding of traumatic brain injury, commonly known as TBI. 

TBI-REPORTER is also developing a network of hospitals and other institutions specialising in neuroscience, all prepared to explore new methods of diagnosing and treating traumatic brain injuries.

It is a privilege to lead this ambitious platform, which brings together a breadth of experts and draws on the lived experience of TBI survivors and their families, to improve care of traumatic brain injury. We also believe that our work, in combination with that of international partners, will re-energise drug development in TBI and deliver new treatments for patients.

Professor David Menon, Head of the Division of Anaesthesia at the University of Cambridge and Project lead

Read more.

Positive CHMP opinion for generalised myasthenia gravis treatment

UCB receives CHMP positive opinion of zilucoplan for the treatment of adults with generalised myasthenia gravis in Europe

  • The Committee for Medicinal Products for Human Use (CHMP) positive opinion1 is based on the pivotal Phase 3 RAISE study in generalised myasthenia gravis (gMG) in adult patients which demonstrated that treatment with zilucoplan resulted in statistically significant and clinically meaningful improvements in gMG-specific efficacy outcomes2
  • If approved by the European Commission, zilucoplan will be the first once-daily subcutaneous (SC) targeted peptide inhibitor of complement component 5 (C5 inhibitor) and the only gMG-targeted therapy for self-administration by adult patients with AChR antibody positive gMG
  • CHMP positive opinion in Europe follows recent FDA approval of rozanolixizumab-noli for the treatment of generalized myasthenia gravis (gMG) in adult patients in the U.S. who are anti-acetylcholine receptor (AChR) or anti-muscle-specific tyrosine kinase (MuSK) antibody positive3
  • UCB’s two different medicines for gMG, each with a distinct mechanism of action, aim to offer a unique portfolio of treatments that embody our commitment to addressing the gMG community’s unmet needs

15 September 2023 – UCB, a global biopharmaceutical company, has announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has issued a positive opinion recommending granting marketing authorisation for zilucoplan in the European Union (EU) as an add-on to standard therapy for the treatment of generalised myasthenia gravis (gMG) in adult patients who are anti acetylcholine receptor (AChR) antibody positive.1

The CHMP’s positive opinion is now being reviewed by the European Commission, which grants centralised marketing authorisations for medicinal products in the EU. Feedback from the commission is anticipated before the end of the year. 

Following approval, zilucoplan will be the first once-daily subcutaneous (SC), targeted peptide inhibitor of complement component 5 (C5 inhibitor) and the only self-administered gMG therapy for use by adult patients with AChR antibody positive gMG.

As a C5 inhibitor, zilucoplan inhibits complement-mediated damage to the neuromuscular junction through its targeted dual mechanism of action.2 Benefits of SC self-administration can include reduced traveling time to and from hospitals, decreased interference with work obligations, and increased independence. Unlike monoclonal antibody C5 inhibitors, as a peptide, zilucoplan can be used concomitantly with intravenous immunoglobulin and plasma exchange, without the need for supplemental dosing.2

UCB’s RAISE study2, published earlier this year in the Lancet Neurology journal, demonstrated that zilucoplan delivered rapid, consistent, statistically significant and clinically meaningful benefits in different patient-and-clinician-reported outcomes – Myasthenia Gravis-Activities of Daily Living (MG-ADL) score, Quantitative Myasthenia Gravis (QMG) score, Myasthenia Gravis Composite (MGC) score and Myasthenia Gravis Quality of Life 15-item scale (MG-QoL15r)* – at week 12 in a broad population of mild to severe adult patients with AChR antibody positive gMG. Additionally, rapid improvements in fatigue were observed as an exploratory endpoint. 

Until now, people living with gMG have only had access to C5 therapy intravenously, which can be inconvenient and time-consuming. This positive CHMP opinion for zilucoplan is a significant step towards our goal of delivering a treatment to address the unmet needs of people living with gMG. If approved, we hope zilucoplan, a self-administered, once daily, subcutaneous targeted C5 inhibitor, will be able to help a broad population of mild to severe adult patients with AChR-antibody positive gMG. We would like to extend our thanks to the patients, care partners, and investigators who participated in the RAISE study, and to our employees and collaborators, whose dedication and commitment to the gMG community made this important milestone possible.

Iris Loew-Friedrich, Executive Vice-President and Chief Medical Officer at UCB.

gMG is a rare, chronic, heterogeneous, unpredictable autoimmune disease characterised by dysfunction and damage at the neuromuscular junction (NMJ).4,5,6 gMG has a global prevalence of 100–350 cases per every 1 million people.5 

The CHMP positive opinion recommending the approval of zilucoplan is supported by safety and efficacy data from the Phase 3 RAISE study (NCT04115293), published in The Lancet Neurology in May 2023.2 The primary endpoint for the RAISE study was change from baseline to Week 12 in the Myasthenia Gravis-Activities of Daily Living (MG-ADL) score. A statistically significant and clinically meaningful difference favouring zilucoplan in comparison to placebo was observed in the MG-ADL total score change from baseline: least squares mean change −4·39 [95% CI –5·28 to –3·50] vs −2·30 [–3·17 to –1·43], least squares mean difference −2·09 [−3·24 to −0·95]; p=0·0004. Secondary endpoints included change from baseline to Week 12 in QMG, MGC and MG-QoL15r. A statistically significant and clinically meaningful difference favoring zilucoplan compared to placebo was observed in the QMG total score change from baseline to Week 12 (p<0.0001), least squares mean change −6.19 [95% CI −7.29 to −5.08] vs −3.25 [−4.32 to −2.17]. Change from baseline to Week 12 in MGC in comparison to placebo was clinically meaningful and statistically significant. MG-QoL 15r change from baseline to Week 12 compared to placebo was also statistically significant.2 Change from baseline to week 12 in the Neuro-QoL short-form fatigue scale was an exploratory end point, therefore, p value was nominal, not multiplicity controlled.

The most common adverse events (reported in at least 10% of patients treated with zilucoplan) were injection-site bruising, headache, diarrhea and MG worsening.2

Zilucoplan is also currently under review by the Japanese Pharmaceuticals and Medical Devices Agency (PMDA), the U.S. Food and Drug Administration (FDA), the Australian Therapeutic Goods Administration (TGA) and Health Canada for the treatment of adults with gMG. Responses from the PMDA and FDA are expected by the end of Q4 2023. Responses from the TGA and Health Canada are expected by H1 2024. Orphan designation was granted by the European Commission in 2022 to zilucoplan for the treatment of myasthenia gravis.7 
    
The CHMP positive opinion of zilucoplan follows the recent FDA approval in the U.S. of rozanolixizumab-noli for the treatment of generalised myasthenia gravis (gMG) in adult patients who are anti-acetylcholine receptor (AChR) or anti-muscle-specific tyrosine kinase (MuSK) antibody positive3. Rozanolixizumab-noli is currently only approved in the U.S. and is under review by the Japanese Pharmaceuticals and Medical Devices Agency (PMDA) and the European Medicines Agency (EMA) for the treatment of adults with gMG. Responses from regulatory agencies to these submissions are expected during H2 2023 and H1 2024.

* The threshold for clinical meaningfulness for MG-QoL 15r has not be established

References

  1. EMA CHMP Confirmation. Data on file, UCB September 2023.
  2. Howard JF Jr et al. Safety and efficacy of zilucoplan in patients with generalised myasthenia gravis (RAISE): a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Neurol. 2023;22:395-406. 
  3. US Food and Drug Administration. Novel Drug approvals for 2023. https://www.fda.gov/drugs/new-drugs-fda-cders-new-molecular-entities-and-new-therapeutic-biological-products/novel-drug-approvals-2023. Accessed September 2023.
  4. National Institute of Neurological Disorders and Stroke. 2022. Myasthenia Gravis Fact Sheet. https://www.ninds.nih.gov/myasthenia-gravis-fact-sheet. Accessed September 2023.
  5. Punga AR, et al. Epidemiology, diagnostics, and biomarkers of autoimmune neuromuscular junction disorders. Lancet Neurol. 2022;21(2):176-88.
  6. Howard JF. Myasthenia gravis: The role of complement at the neuromuscular junction. Ann N Y Acad Sci. 2018;1412:113-128.
  7. European Medicines Agency. EU/3/22/2650: Orphan designation for the treatment of myasthenia gravis. https://www.ema.europa.eu/en/medicines/human/orphan-designations/eu-3-22-2650. Accessed August 2023
  8. Myasthenia Gravis Foundation of America. MG Quick Facts. https://myasthenia.org/MG-Education/MG-Quick-Facts. Accessed September 2023.
  9. Juel VC, Massey JM. Myasthenia gravis. Orphanet J Rare Dis. 2007;2:44.

Phase 3 Study Results Compare IPX203 to Immediate-Release Carbidopa/Levodopa for PD

IPX203 demonstrated statistically significant improvement in daily “Good On” time compared to optimised IR CD/LD, with fewer daily doses

August 24th, 2023: Amneal Pharmaceuticals, Inc announced that JAMA Neurology has published results from the RISE-PD clinical study assessing the efficacy and safety of IPX203 versus optimised immediate-release carbidopa/levodopa (IR CD/LD) for the treatment of Parkinson’s disease (PD). The study met its primary and secondary endpoints finding that IPX203 provided more hours of “Good On” time per day, less “Off” time per day, and more “Good On” time per dose than optimised IR CD/LD, even when dosed less frequently. “Good On” time is defined as the sum of “On” time without dyskinesia and “On” time with non-troublesome dyskinesia. The manuscript titled, “IPX203 vs Immediate-Release Carbidopa-Levodopa for the Treatment of Motor Fluctuations in Parkinson Disease,” was published online on August 14, 2023.

When it comes to Parkinson’s disease, the community is looking for treatments that provide a longer duration of benefit per dose of LD and simplified dosing regimens. We are very encouraged by the recently published data in JAMA Neurology which illustrate how IPX203 could fill this need, potentially leading to a better patient experience, more ‘Good On’ time, and improved patient adherence.

Robert A. Hauser, M.D., Professor of Neurology at the University of South Florida and Director of the Parkinson’s Disease and Movement Disorders Center.

Following a Complete Response Letter (CRL) from the FDA earlier this year on its New Drug Application for IPX203, Amneal has shared a reanalysis of the data and requested a Type A meeting as it looks to bring the treatment to market.

About the RISE-PD Trial

The multicenter, randomised, double-blind, double-dummy, active-controlled, parallel-group RISE-PD trial evaluated the efficacy and safety of IPX203 CD/LD extended-release capsules compared with IR CD/LD in the treatment of patients with PD who have motor fluctuations.

The trial consisted of a 3-week, open-label immediate-release CD/LD dose adjustment period and a 4-week, open-label period for conversion to IPX-203. This was followed by a 13-week double-blind treatment period in which patients were randomised 1:1 to receive either IPX203 (with matching immediate-release CD/LD placebo) optimised IR CD/LD (with matching IPX-203 placebo). Baseline for all endpoints was Week 7 (Visit 4), which occurred pre-randomisation. The most common adverse reaction (incidence ≥ 3% and greater than immediate-release CD/LD) was nausea (4.3%).

The primary endpoint of the trial assessed the change from baseline in “Good On” time in hours per day at the end of the double-blind treatment period (Week 20 or early termination). “Good On” time is defined as the sum of “On” time without dyskinesia and “On” time with non-troublesome dyskinesia. Secondary endpoints assessed the change from baseline in “Off” time in hours per day, proportion of patients who were either “much improved” or “very much improved” in Patients’ Global Impression of Change (PGI-C) scores, change from baseline in the Movement Disorder Society – Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Part III score, and the change from baseline in sum of MDS-UPDRS Parts II and III scores.

The trial was conducted at 105 clinical sites in the U.S. and European countries, including Czechia, France, Germany, Italy, Poland, Spain and the United Kingdom. The study randomised 506 patients who had received a PD diagnosis at age 40 or older. The study design was reviewed by the FDA and conducted pursuant to a Special Protocol Assessment. A nine-month safety extension study was completed in 2022.