Author: Rachael Hansford

Using telemedicine in neuro-oncology – practical guidance

The COVID-19 pandemic has ensured the expansion of telemedicine into nearly every medical specialty. This article summarises current practice and makes recommendations for integrating virtual care in the practice of neuro-oncology. It identifies current telemedicine practice, provides practical guidance for conducting telemedicine visits, and generates recommendations for integrating virtual care into neuro-oncology practice. Practical aspects of telemedicine are summarised including when to use and not use telemedicine, how to conduct a virtual visit, who to include in the virtual encounter, unique aspects of telehealth in neuro-oncology, and emerging innovations. Read the article in Neuro-Oncology Practice.

Study links gut microbiota strains with more severe strokes and poorer post-stroke recovery

A new study has identified strains of gut microbiota that are associated with more severe strokes and worse post-stroke recovery, revealing that the gut microbiome could be an important factor in stroke risk and outcomes1.

The study, presented 28 April 2022 at the European Stroke Organisation Conference (ESOC 2022) pinpointed specific groups of bacteria associated with poorer neurological recovery from ischaemic stroke both in the acute phase (24 hours) and after three months.

The research identified multiple types of bacteria were associated with ischemic stroke risk, including Fusobacterium and Lactobacillus. Negativibacillus and Lentisphaeria were associated with a more severe stroke in the acute phase (at 6 and 24 hours respectively) and Acidaminococcus related to poor functional outcomes at three months. 

Dr Miquel Lledós, lead author from the Sant Pau Research Institute Stroke Pharmacogenomics and Genetics Laboratory, Barcelona, Spain, commented “The influence of the gut microbiome – the trillions of bacteria and other microorganisms that live in the gut – is a modifiable risk factor associated with the risk of stroke and with post-stroke neurological outcomes. However, most research has previously been done in animal models.”

“In this study we took faecal samples – the first samples taken after the event – from 89 humans who’d suffered an ischaemic stroke. Comparing with a control group, we were able to identify multiple groups of bacteria that were associated with a higher risk of ischaemic stroke.”

An ischaemic stroke occurs when a clot or other blockage blocks the blood supply to the brain and is the most common type of stroke. In Europe, 1.3 million people suffer a stroke every year and it is the second most common single cause of death2.

“The discovery opens the exciting prospect that, in the future, we may be able to prevent strokes or improve neurological recovery by examining the gut microbiota. In other pathologies, clinical trials are being carried out where researchers replace the intestinal flora through dietary changes or faecal transplantation from healthy individuals and this should be studied further in the stroke field.”

The association between certain strains of gut bacteria and risk of ischaemic stroke was reinforced in another study presented at ESOC this week by a team from Yale University, Connecticut, USA3.

The researchers analysed statistics from the Flemish Gut Flora Project and the MEGASTROKE consortium, using a technique called Mendelian Randomisation (MR) which measures variation in genes to examine the causal effect of an outcome or exposure. The study identified 20 microbial traits significantly associated with the risk of developing at least one subtype of ischaemic stroke.

References

  1. Influence of the gut microbiome in ischemic stroke risk and ischemic stroke outcome, presented at the European Stroke Organisation Conference, 4 May 2022.
  2. Status and Perspectives of Acute Stroke Care in Europe | Stroke (ahajournals.org)
  3. The gut microbiome influences the risk of acute ischemic stroke: a mendelian randomization study, presented at the European Stroke Organisation Conference, 5 May 2022.
  4. https://www.ahajournals.org/doi/10.1161/STROKEAHA.120.029606
  5. https://www.euro.who.int/en/health-topics/noncommunicable-diseases/cardiovascular-diseases/data-and-statistics

Pregabalin may slightly increase risk of major congenital malformations

20 April 2022: The Medicines and Healthcare products Regulatory Agency (MHRA) has issued a drug safety update on the use of pregabalin in pregnancy, after a new study suggests that it may slightly increase the risk of major congenital malformations.

Advice for healthcare professionals is that potentially fertile women should continue to use effective contraception during treatment with pregabalin, and that use of the drug in pregnancy should be avoided unless it is “clearly necessary”.

The latest alert was prompted by the pregabalin pregnancy outcomes study, an observational cohort study in Denmark, Finland, Norway, and Sweden that included over 2700 pregnancies with pregabalin exposure during the first trimester, the largest population-based study to date. 

Read more.

EC marketing authorisation for Vydura for migraine

Pfizer Inc and Biohaven Pharmaceutical Holding Company Ltd announced on 27th April that the European Commission (EC) has granted marketing authorisation for VYDURA® (rimegepant), a calcitonin gene-related peptide (CGRP) receptor antagonist for both the acute treatment of migraine with or without aura, and prophylaxis of episodic migraine in adults who have at least four migraine attacks per month.

VYDURA®, an orally disintegrating tablet, is the first medicine approved for both acute and prophylactic treatment of migraine in the European Union (EU). Migraine is a leading cause of disability worldwide with approximately one in ten people living with the condition in Europe alone. Globally, migraine disproportionately affects women by three to four times compared to men.

There is a significant unmet need for people in the European Union living with the pain and disability caused by frequent migraines. The comprehensive clinical programme has established VYDURA’s efficacy and safety as both an acute and preventive treatment of migraine. Studies in acute migraine demonstrated a rapid and long-lasting relief of migraine headache and other symptoms with a single dose, while the prevention study found a significant reduction in migraine attacks with every other day dosing. We have great confidence in the positive impact VYDURA could have on people living with this debilitating condition in the EU.

Nick Lagunowich, Global President, Pfizer Internal Medicine.

Results from the Phase 3 study published in Lancet demonstrated that a single dose of rimegepant provided superior pain reduction and associated symptoms of migraine at two hours compared to placebo. The prevention study, also published in Lancet, demonstrated that rimegepant taken every other day provided superior reduction in the number of days per month with migraine in Weeks 9 –12 of the 12-week treatment period compared to placebo, that was maintained with continued dosing during the 12-month open-label extension period.

Today’s approval marks a huge step forward for patients in Europe who are living with migraine. Migraine is often overlooked and undertreated, resulting in substantial disability with suboptimal care for patients. VYDURA’s promising efficacy and favorable benefit-risk profile spark hope for people in need of new migraine treatment options. This approval has the potential to advance the standard of care for migraine in the EU and I am hopeful it will improve the quality of life for many people living with the burden of this prevalent neurological disease.

Professor Peter Goadsby, Director of the National Institute for Health and Care Research (NIHR) Clinical Research Facility and Professor of Neurology at King’s College London.

The Marketing Authorisation follows the recommendation for approval by the European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) in February. The EC approval will be valid for all 27 EU member states as well as Iceland, Liechtenstein, and Norway and local reimbursement approval will follow. Assessment of the marketing authorisation application by the Medicines & Healthcare products Regulatory Agency (MHRA) is underway and approval is expected to shortly follow in the UK.

About VYDURA® (rimegepant)
VYDURA® targets a key component of migraine by reversibly blocking CGRP receptors. CGRP is increased during a migraine attack, dilates blood vessels and is involved in nociceptor signaling. CGRP receptor antagonists work by reversibly blocking CGRP receptors, thereby inhibiting the biologic activity of the endogenous CGRP neuropeptide.

The Marketing Authorisation for VYDURA® was based, in part, on the review of the results from three Phase 3 studies for acute treatment, a long-term, open-label safety study in acute treatment of migraine and a Phase 3 study with a 1-year open-label extension in the preventive treatment of migraine. VYDURA® is taken orally as needed, up to once daily, to stop migraine attacks or taken every other day to help prevent migraine attacks.

The most frequent adverse event in clinical trials with VYDURA® was nausea, occurring in 3% of patients compared to 1% with placebo, while hypersensitivity reactions including rash occurred in less than 1% of patients. Less than 2% of patients discontinued from VYDURA® due to adverse events. VYDURA® does not have addiction potential and was not associated with medication overuse headache or rebound headache in clinical trials, although overuse of any type of medicinal products for headache can make them worse.

VYDURA® is commercialised as Nurtec® and Nurtec® ODT outside Europe. It is commercialised in the U.S. for the acute treatment of migraine and for the preventive treatment of episodic migraine in adults, and ex-U.S. is approved for the acute treatment of migraine in Kuwait and the United Arab Emirates, and for acute treatment of migraine and preventive treatment of episodic migraine in Israel.

Earlier this year, Pfizer and Biohaven entered into an agreement for the commercialisation of VYDURA®. Under the terms of the agreement, Pfizer has commercialisation rights to rimegepant in markets outside the U.S. Biohaven continues to lead research and development globally and retains the U.S. market.

US approval for ULTOMIRIS® for gMG

ULTOMIRIS® (ravulizumab-cwvz) approved in the US for Adults with Generalised Myasthenia Gravis

First and only long-acting C5 complement inhibitor to demonstrate clinical improvement in patients with generalised myasthenia gravis

ULTOMIRIS showed early effect and lasting improvement in activities of daily living and has potential to reduce treatment burden with dosing every 8 weeks

April 28, 2022: ULTOMIRIS®(ravulizumab-cwvz) has been approved in the US for the treatment of adult patients with generalised myasthenia gravis (gMG) who are anti-acetylcholine receptor (AChR) antibody-positive, which represents 80% of people living with the disease.1-5

The approval by the Food and Drug Administration (FDA) was based on positive results from the CHAMPION-MG Phase III trial, in which ULTOMIRIS was superior to placebo in the primary endpoint of change from baseline in the Myasthenia Gravis-Activities of Daily Living Profile (MG-ADL) total score at Week 26, a patient-reported scale that assesses patients’ abilities to perform daily activities.1

This FDA action marks the first and only approval for a long-acting C5 complement inhibitor for the treatment of gMG.

gMG is a rare, debilitating, chronic, autoimmune neuromuscular disease that leads to a loss of muscle function and severe weakness.6 The diagnosed prevalence of gMG in the US is estimated at approximately 90,000.7

Despite recent advances, managing gMG is complex. Earlier intervention can preserve function and quality of life. This approval offers patients, including those with milder symptoms, a long-acting C5 inhibitor with early onset and reliable efficacy.

Professor James F. Howard, Jr, MD, Department of Neurology at The University of North Carolina School of Medicine and lead primary investigator in the CHAMPION-MG trial.

Samantha Masterson, Chief Executive Officer, Myasthenia Gravis Foundation of America (MGFA), said: “gMG takes a physical and emotional toll on those living with the disease. We are grateful for continued innovation and research into new treatment and dosing options to meet the needs of more patients and reduce the treatment burden. With the approval of ULTOMIRIS, we’re excited that MG patients now have another option to consider as part of their personalized treatment strategies that may offer more convenience and improve muscle weakness.”

Marc Dunoyer, Chief Executive Officer, Alexion, said: “Since bringing forward thefirst complement inhibitor, we’ve continued to listen to the community and focused innovation on the needs of gMG patients. We’re proud to deliver on this commitment with today’s approval. ULTOMIRIS, the only long-acting C5 inhibitor, will benefit a broader range of patients, including those with milder symptoms. As presented at the 2022 American Academy of Neurology Annual Meeting, ULTOMIRIS has demonstrated clinical benefit through 60 weeks, with treatment every eight weeks, compared to SOLIRIS every two weeks.”

In the trial, the safety profile of ULTOMIRISwas comparable to placebo and consistent with that observed in Phase III trials of ULTOMIRIS in paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS). The most common adverse reactions in patients receiving ULTOMIRIS were upper respiratory tract infection and diarrhea.1

Results from the CHAMPION-MG trial were recently published online in NEJM Evidence and presented at the 2022 American Academy of Neurology Annual Meeting in April.

Regulatory submissions for ULTOMIRISfor the treatment of gMG are currently under review with multiple health authorities, including in the European Union (EU) and Japan.

References

  1. Ultomiris (ravulizumab-cwvz) US prescribing information; 2022.
  2. Anil, R., Kumar, A., Alaparthi, S., Sharma, A., Nye, JL., Roy, B., O’Connor, KC., Nowak, R., (2020). Exploring outcomes and characteristics of myasthenia gravis: Rationale, aims and design of registry – The EXPLORE-MG registry. J Neurol Sci. 2020 Jul 15;414:116830.
  3. Oh SJ., (2009). Muscle-specific receptor tyrosine kinase antibody positive myasthenia gravis current status. Journal of Clinical Neurology. 2009b Jun 1;5(2):53-64.
  4. Tomschik, M., Hilger, E., Rath, J., Mayer, EM., Fahrner, M., Cetin, H., Löscher, W., Zimprich, F., (2020). Subgroup stratification and outcome in recently diagnosed generalized myasthenia gravis. Neurology. 2020 Sep 8;95(10):e1426-e1436.
  5. Hendricks, TM., Bhatti, MT., Hodge, D., Chen, J., (2019). Incidence, Epidemiology, and Transformation of Ocular Myasthenia Gravis: A Population-Based Study. Am J Ophthalmol. 2019 Sep;205:99-105.
  6. Howard, J. F., (2017). Myasthenia gravis: the role of complement at the neuromuscular junction. Annals of The New York Academy of Sciences, 1412(1), 113-128.
  7. Westerberg, E., Punga, A., (2020). Epidemiology of Myasthenia Gravis in Sweden 2006–2016. Brain and behavior. 2020 Nov;10(11):e01819.
  8. Myasthenia Gravis. National Organization for Rare Disorders (NORD). Available here. Accessed March 2022.
  9. Howard, J. F., (2015). Clinical Overview of MG. Available here. Accessed March 2022.
  10. Sanders, D. B., Raja, S. M., Guptill J. T., Hobson-Webb, L. D., Juel, V. C., & Massey, J. M., (2020). The Duke myasthenia gravis clinic registry: I. Description and demographics. Muscle & Nerve, 63(2), 209-216.
  11. Myasthenia Gravis Fact Sheet. (2020, April 27). National Institutes of Neurological Disorders and Stroke. Available here. Accessed March 2022.
  12. Ding, J., Zhao, S., Ren, K., Dang, D., Li, H., Wu, F., Zhang, M., Li, Z., & Guo, J., (2020). Prediction of generalization of ocular myasthenia gravis under immunosuppressive therapy in Northwest China. BMC Neurology, 20(238).
  13. ClinicalTrials.gov. Safety and Efficacy Study of Ravulizumab in Adults With Generalized Myasthenia Gravis. NCT Identifier: NCT03920293. Available here. Accessed March 2022.

Biogen withdraws marketing authorisation application for aducanumab for Alzheimer’s disease

  • Biogen has informed the European Medicines Agency (EMA) that it is withdrawing its application for marketing authorisation for aducanumab for the treatement of Alzheimer’s disease
  • The EMA had previously found on 16 December 2021 that the benefits of aducanumab did not outweigh its risks and recommended refusing marketing authorisation. Biogen then requested a re-examination.
  • Following Biogen’s discussions with the EMA’s Committee for Medicinal Products for Human Use (CHMP), in which the CHMP indicated that the “data provided thus far would not be sufficient to support a positive opinion”, the company has decided to withdraw the application.
  • It has been 20 years since the last approval of an Alzheimer’s medicine by the EMA.
  • Biogen is set to launch a phase IV trial of aducanumab in May 2022.

On 22 April 2022 Biogen announced that it had notified the European Medicines Agency (EMA) about the withdrawal of its marketing authorisation application for aducanumab for the treatment of early Alzheimer’s disease.

The agency had previously found on 16 December 2021 that the benefits of aducanumab did not outweigh its risks and had therefore recommended refusing marketing authorisation. Biogen requested a re-examination of the EMA’s decision and started discussions with the Agency’s Committee for Medicinal Products for Human Use (CHMP). In its press release issued today, Biogen highlighted that the CHMP had indicated that the “data provided thus far would not be sufficient to support a positive opinion”.

With the last approval of an Alzheimer’s medicine by the EMA dating back to 2002, people living in Europe affected by Alzheimer’s disease have been waiting to gain access to better treatments for 20 years. It will therefore be disappointing news for them to hear that there was insufficient scientific evidence for the EMA to support the authorisation of aducanumab, and that the wait for innovative, disease modifying treatments will have to continue in Europe.

The EMA discussions and the decision by Biogen to withdraw its marketing authorisation application follow developments in the US where the Food and Drug Administration (FDA) chose to grant conditional approval for aducanumab using its “accelerated approval pathway”. This approval was based on aducanumab’s proven effect on lowering amyloid beta, a surrogate endpoint that the FDA deemed “reasonably likely” to predict a clinical benefit to patients.

In its December recommendation, the EMA recognised that aducanumab reduces amyloid beta in the brain, but stated that “the link between this effect and clinical improvement has not been established”. The agency found that the results on cognition and executive function derived from the two phase III clinical trials conducted to date were conflicting, and highlighted potential difficulties in monitoring side effects of the medicine in clinical practice. As a result, the agency concluded that the risk-benefit balance was unfavourable and decided against approval. According to the EMA, “At the time of the withdrawal, while the re-examination was ongoing, the Agency was still of the opinion that the benefits of [aducanmab] did not outweigh its risks.”

https://www.ema.europa.eu/en/medicines/human/withdrawn-applications/aduhelm

Manoj Sivan to deliver keynote lecture at AFRM conference

The Australasian Faculty of Rehabilitation Medicine has invited Dr Manoj Sivan to deliver the keynote lecture at its conference in Melbourne, Australia on 12 May, 2022. Dr Sivan one of only three UK rehabilitation specialists to have ever been invited to give this prestigious lecture.

The AFRM’s annual keynote lecture was named the George Burniston Oration as part of efforts to showcase its history and pay homage to its founders. Further information about the history of the Oration can be found on the RACP website.

ZTALMY® (ganaxolone) Phase 3 Marigold Trial Results

Marinus Pharmaceuticals Announces Publication in The Lancet Neurology of ZTALMY® (ganaxolone) Phase 3 Marigold Trial Results

Results demonstrate safety and efficacy of ZTALMY, first FDA-approved treatment for seizures associated with CDKL5 deficiency disorder in patients two years and older

Marinus Pharmaceuticals, Inc., a pharmaceutical company dedicated to the development of therapeutics to treat seizure disorders, announced on 15 April 2022 that The Lancet Neurology has published results from the pivotal Phase 3 Marigold trial of ZTALMY® (ganaxolone) for the treatment of seizures associated with CDKL5 deficiency disorder (CDD). The paper, “Efficacy and safety of ganaxolone in patients with CDKL5 deficiency disorder: a randomized, double-blind, placebo-controlled, Phase 3 trial,” can be accessed on The Lancet Neurology website. This was the first double-blind placebo-controlled study providing evidence of efficacy in CDD-associated seizures.

The publication of these data highlights the importance of bringing new treatments to people affected by very refractory epilepsy, including the CDKL5 deficiency disorder community, and adds to the growing body of clinical research data currently available. The results demonstrate that ZTALMY was effective in treating seizures associated with CDKL5 deficiency disorder and provides physicians with a novel medication for the management of this difficult to treat patient population.

Dr. Elia M. Pestana Knight, M.D., a Principal Investigator for the Marigold trial and pediatric epileptologist at the Cleveland Clinic Neurological Institute.

Dr. Pestana Knight is a member of Marinus’ Scientific Advisory Board. She joined the Board after the completion of the Marigold randomised trial.

The paper presents the results of the Phase 3 Marigold trial, a 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). ZTALMY was generally well-tolerated and showed a safety profile consistent with previous clinical trials, with the most frequent adverse event being somnolence.

About CDKL5 Deficiency Disorder

CDKL5 deficiency disorder (CDD) is a serious and rare genetic disorder that is caused by a mutation of the cyclin‑dependent kinase‑like 5 (CDKL5) gene, located on the X chromosome. CDD is characterised by early‑onset, difficult‑to‑control seizures and severe neurodevelopmental impairment.

About ZTALMY® (ganaxolone) oral suspension

ZTALMY® is the first and only FDA-approved treatment indicated specifically for seizures associated with cyclin-dependent kinase-like 5 deficiency disorder (CDD) in patients two years of age and older. ZTALMY, a neuroactive steroid that acts as a positive allosteric modulator of the GABAA receptor, is taken three times daily. It is expected to be available in the US in July 2022 following scheduling by the US Drug Enforcement Administration.

Ganaxolone does not currently have a marketing authorisation in the UK for treating seizures caused by CDD. NICE began a Health Technology Appraisal in the UK in January 2022. Orion Corporation signed a European wide marketing and distribution agreement with Marinus Pharmaceuticals for ganaxolone in August 2021.

Indication and Usage

ZTALMY is indicated for the treatment of seizures associated with cyclin-dependent kinase like 5 (CDKL5) deficiency disorder (CDD) in patients 2 years of age and older.

About Marinus Pharmaceuticals

Marinus is a pharmaceutical company dedicated to the development of innovative therapeutics to treat seizure disorders. Ganaxolone is a neuroactive steroid GABAA receptor modulator that acts on a well-characterised target in the brain known to have anti-seizure effects. It is being developed in IV and oral dose formulations intended to maximise therapeutic reach to adult and pediatric patient populations in both acute and chronic care settings. For more information visit www.marinuspharma.com.

Diroximel fumarate receives positive recommendation from NICE for oral treatment of relapsing-remitting multiple sclerosis (RRMS)

  • Diroximel fumarate is a next generation, at-home, oral fumarate treatment, with established efficacy and well-characterised safety, for people living with relapsing-remitting multiple sclerosis (RRMS)1,2
  • Phase 3 data and real-world evidence (n=263, based in the US) have demonstrated that treatment with diroximel fumarate results in low discontinuation rates due to its gastrointestinal (GI) tolerability profile3,7 
  • The recommendation strengthens Biogen’s established MS portfolio and ongoing commitment to introducing therapies that positively impact the lives of those living with MS 

Biogen UK announced on April 13 2022 that the National Institute for Health and Care Excellence (NICE) has published a positive Final Appraisal Document (FAD) recommending VUMERITY® (diroximel fumarate), an oral fumarate, for the treatment of adults living with active RRMS[*] in England, Wales and Northern Ireland. The medicine was fast tracked to FAD enabling all eligible patients to have access to diroximel fumarate as soon as possible, providing another important option when considering the right treatment for their individual needs.

Approximately 115,880 people are currently living with MS in England, Wales and Northern Ireland.It is estimated that 85% are living with RRMS, the most common form of the condition.Diroximel fumarate offers those living with RRMS a treatment option with an improved gastrointestinal (GI) tolerability profile and comparable efficacy and safety characteristics to established treatment dimethyl fumarate (due to bioequivalence).3-6  The new oral fumarate treatment can reduce the severity and frequency of burdensome GI events like nausea, vomiting, diarrhoea and upper and lower abdominal pain, whilst also offering the convenience and flexibility to be taken with or without food.2-6,10

“For some people, their current oral fumarate may cause them to experience stomach issues which can affect their daily activities and productivity. Diroximel fumarate successfully decreases the chances of relapses but also causes fewer gastrointestinal side effects, which is critical in supporting people to start and stay on treatment. Today’s fast-tracked approval of diroximel fumarate follows approval in Scotland, providing equitable access across the UK. These positive recommendations enable us to offer an alternative at-home, oral DMT while avoiding a potential switch to an injectable therapy.

Dr Martin Duddy, Consultant Neurologist, Royal Victoria Infirmary, Newcastle

“Effective treatments that fit into daily life can help people live a life with MS that is not defined by MS. People living with MS can be confident in the established efficacy of this new oral treatment that has fewer stomach problems to manage. This can mean that they don’t have to factor their medication in relation to mealtimes.” said David Martin, CEO, MS Trust.

NICE’s decision was based on data from pivotal phase 3 trials (EVOLVE-MS-1 and EVOLVE-MS-2), which compared diroximel fumarate and dimethyl fumarate and demonstrated similar efficacy safety profiles.4,5 GI events, such as nausea, vomiting, diarrhoea and upper and lower abdominal pain were less severe and lasted fewer days with diroximel fumarate compared with dimethyl fumarate and therefore were less likely to interfere with patients’ daily lives.5,6  In addition, since diroximel fumarate’s launch in the US, real-world evidence has reinforced the GI tolerability profile and confirmed that patient experience demonstrated in clinical trials is consistent with clinical practice. The real-world retrospective analysis of persistence[†] and adherence in DRF-treated patients (n=263) showed high overall persistence over 12 months (~81.8%) [95% CI, 76.1–86.3], low discontinuation rate due to GI AEs (4.6%, 12/263) and high adherence to therapy (mean PDC 89.7%),[‡] aligning with expectations based on DRF clinical trials.7

“Following the Scottish Medical Consortium approval, the recommendation of diroximel fumarate by NICE marks our third MS product launched in the last 12 months. This is a significant milestone in our ambition to advance treatment and improve outcomes for people living with RRMS,” said Dr Mihaela Vlaicu, Head of Medical Affairs, Biogen UK and Ireland. “For nearly 25 years, we have led in the research and development of new MS therapies, continually striving to help address the diverse needs that people living with MS may have throughout their lives.” 

NICE’s recommendation follows the Scottish Medicine Consortium’s acceptance earlier this year, and the Medicines and Healthcare products Regulatory Agency (MHRA) and European Union authorisation in December 2021. The NICE FAD represents finalisation of the NICE Committee recommendations and forms the basis of the final Technology Appraisal Guidance (TAG) which is expected to be published in May. Once a positive recommendation is made through the fast-track appraisal process, NHS England commissioners have committed to providing funding for the technologies within 30 days of guidance publication. 

References

1.     National Institute for Health and Care Excellence. Final appraisal document. Diroximel fumarate for treating relapsing remitting multiple sclerosis. April 2022.

2.     Electronic Medicines Consortium. Vumerity 231 mg gastro-resistant hard capsules. Available at: https://www.medicines.org.uk/emc/product/13087/. Accessed: March 2022.

3.     Palte MJ, et al. Adv Ther 2019;36(11):3154-3165.

4.     Wehr YA, et al. Presented at 2018 American Academy of Neurology Annual Meeting; 21–27 April, 2018; Los Angeles, USA. P403.

5.     Naismith RT, et al. Mult Scler 2020 26(13):1729-1739. 

6.     Naismith RT, et al. CNS Drugs 2020;34(2):185-196. 

7.     Larger et al. Multiple Sclerosis Patients Treated With Diroximel Fumarate Over 1 Year in the Real-world Setting Have High Rates of Persistence and Adherence. 37th Congress of the European Committee for Treatment & Research in Multiple Sclerosis. 2021, P838.

8.     MS Trust. Available at: https://mstrust.org.uk/a-z/how-common-multiple-sclerosis. Accessed March 2022.

9.     NICE. Multiple Sclerosis: How common is it? Available at: https://cks.nice.org.uk/topics/multiple-sclerosis/background-information/prevalence/#:~:text=190%20per%20100%2C000%20in%20England%20(around%20105%2C450%20people.

10. MS Society. Relapsing Remitting MS. Available here: https://www.mssociety.org.uk/about-ms/types-of-ms/relapsing-remitting-ms. Accessed March 2022.

11. Diroximel fumarate. Patient Information Leaflet. DRF Patient Leaflet GB (medicines.org.uk). Accessed March 2022. 

12. Tecfidera Data on file #028. Post Marketing Exposure Experience. March 2021.

13. Electronic Medicines Consortium. Tecfidera 120mg and 240mg gastro-resistant hard capsules. Available at: https://www.medicines.org.uk/emc/medicine/28593. Accessed March 2022.

14. Wray et al. Diroximel Fumarate in Patients With Relapsing-Remitting Multiple Sclerosis: Interim Safety and Efficacy Results From the Phase 3 EVOLVE-MS-1 Study, 37th Congress of the European Committee for Treatment & Research in Multiple Sclerosis. October 13-15, 2021, P739.

About diroximel fumarate
Diroximel fumarate is indicated for the treatment of adult patients with relapsing remitting multiple sclerosis. It is an oral fumarate with an improved chemical structure to dimethyl fumarate. Once in the body, diroximel fumarate rapidly converts to monomethyl fumarate, the same active metabolite of dimethyl fumarate providing similar efficacy and safety profiles.2

Diroximel fumarate is another treatment option for RRMS and has a safety and efficacy profile consistent with dimethyl fumarate, with lower rates of GI AEs.3-6

Common adverse events are (may affect up to 1 in 10 people); inflammation of the lining of the intestines (gastroenteritis), being sick (vomiting), indigestion (dyspepsia), inflammation of the lining of the stomach (gastritis), digestive system problems (gastrointestinal disorder), burning sensation, hot flush, feeling hot, itchy skin (pruritus), rash, pink or red blotches on the skin (erythema). Side effects which may show up in blood or urine tests; proteins (albumin) in urine (proteinuria), increase in levels of liver enzymes (ALT, AST) in the blood. Very common (may affect more than 1 in 10 people); reddening of the face or body feeling warm, hot, burning, or itchy (flushing), loose stools (diarrhoea), feeling sick (nausea), stomach pain or stomach cramps. Side effects which may show in blood or urine tests; ketones in urine; low levels of white blood cells (lymphopenia, leukopenia) in the blood.1,11

Diroximel fumarate was first approved by the U.S. Food and Drug Administration in October 2019. Since its launch in the U.S., real-world data have reinforced the GI tolerability profile and confirmed that the experience demonstrated in clinical trials is consistent with clinical practice.7 Diroximel fumarate is approved for use in adult with RRMS in US, Europe, and Israel.

About dimethyl fumarate
Dimethyl fumarate, a treatment for RRMS in adults, has been shown to reduce the rate of MS relapses, slow the progression of disability and impact the number of MS brain lesions, while demonstrating a well-characterised safety profile in people with relapsing forms of MS. More than 537,432 patients have been treated with dimethyl fumarate (as of 1st of Sept 2021), representing 1,119,293 patient-years of exposure (as of 30th Jun 2021), across global clinical trial & post-marketing settings.12

Common (≥1/100 to <1/10) adverse reactions includes gastroenteritis, lymphopenia, leucopenia, burning sensation, hot flush, vomiting, dyspepsia, gastritis, gastrointestinal disorder, aspartate aminotransferase and alanine aminotransferase increased, pruritus, rash, erythema, proteinuria, feeling hot, albumin urine present and white blood cell count decrease. Very common (≥1/10) adverse reaction includes flushing, diarrhoea, nausea, abdominal pain upper, Abdominal pain, ketones measured in urine.13

For more information on dimethyl fumarate and diroximel fumarate please refer to the SmPC:  Summary of Product Characteristics (SmPC) – (emc) (medicines.org.uk)

About EVOLVE-MS-1 and EVOLVE-MS-25,6,14

EVOLVE-MS-1 is an ongoing, open-label, 96-week, phase 3 study assessing diroximel fumarate safety, tolerability, and efficacy in RRMS patients. The primary endpoint was safety and tolerability; efficacy endpoints were exploratory. The interim finding, as of September 2020; 1057patients were enrolled; median exposure was 2.0 (range, 0.0–2.1) years. Adverse events (AEs) occurred in 88% (932/1057) of patients, the majority were mild (29%; 307/1057) or moderate (50% 527/1057) in severity. Overall treatment discontinuation was 8%; and <1% due to GI AEs. At week 96, mean number of gadolinium-enhancing lesions was significantly reduced from baseline (63.6% p<0.0001) and adjusted annualised relapse rate (ARR)[§] was low 81% reduction (95% CI, 78.1–84.1) p < 0.0001) compared to 12 months before study entry.

EVOLVE-MS-2 was a phase 3, randomised, double-blind, head-to-head, 5-week study evaluating the gastrointestinal tolerability of diroximel fumarate 462 mg vs dimethyl fumarate 240 mg, administered twice daily in patients with relapsing–remitting multiple sclerosis, using two self-administered gastrointestinal symptom scales: Individual Gastrointestinal Symptom and Impact Scale (IGISIS) and Global Gastrointestinal Symptom and Impact Scale (GGISIS). The primary endpoint was the number of days with an IGISIS intensity score ≥2 relative to exposure. Other endpoints included the degree of gastrointestinal symptom severity measured by IGISIS/GGISIS and assessment of safety/tolerability. Results diroximel fumarate -treated patients experienced a statistically significant reduction (46%) in the number of days with an IGISIS symptom intensity score ≥2 compared with dimethyl fumarate -treated patients (rate ratio [95% confidence interval]: 0.54 [0.39–0.75]; p=0.0003). Lower rates of gastrointestinal adverse events (including diarrhoea, nausea, vomiting, and upper and lower abdominal pain) were observed with diroximel fumarate than dimethyl fumarate (34.8% vs 49.0%). Fewer patients discontinued diroximel fumarate than dimethyl fumarate because of adverse events (1.6% vs 5.6%) and gastrointestinal adverse events (0.8% vs 4.8%).

Biogen-163820 | Date of preparation: April 2022