Author: Rachael Hansford

NICE approves eptinezumab (Vyepti) to treat episodic and chronic migraine

On 25th January 2023, the National Institute for Health and Care Excellence (NICE) announced that eptinezumab (Vyepti) has been approved for use within the NHS in England for the treatment of episodic migraine.

Eptinezumab is given by infusion once every 12 weeks. It is one of a number of calcitonin gene-related peptide (CGRP) antibody drugs, which are the first medication specifically designed to prevent migraine.

The drug should be available for patients who experience migraine on four or more days a month and who have already failed to respond to at least three other migraine preventive drugs.

Integrated Care Systems (ICSs) in England now have three months to comply with this recommendation. 

NICE Recommends Reimbursement for Translarna™

Only approved treatment for the underlying cause of nonsense mutation Duchenne muscular dystrophy

PTC Therapeutics, Inc. today (19/1/23) announced that the National Institute for Health and Care Excellence (NICE) has issued a Final Evaluation Document recommending Translarna™ (ataluren) for reimbursement and use across the National Health Service (NHS) in England and Wales. Translarna is the only approved treatment for patients with nonsense mutation Duchenne muscular dystrophy aged 2 years and older who can walk.

Duchenne is a severe progressive disease that leads to rapidly worsening muscle function with children often using a wheelchair by early adolescence and eventually requiring artificial ventilation to breathe.1,2 The NICE recommendation was based on data from clinical trials and real-world evidence demonstrating Translarna’s potential to slow disease progression and improve patient outcomes.1-3

The positive NICE Evaluation and agreement with the NHS provide critical access to Translarna for newly diagnosed and existing patients with nonsense mutation Duchenne in England and Wales. This recommendation marks an important milestone for the Duchenne community and reinforces PTC’s longstanding commitment to pursue access for patients who can benefit from this treatment.

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

Read more: First Publication of Real-World Data Showing Translarna (ataluren) Significantly Preserves Ability to Walk for Longer in Children with Duchenne Muscular Dystrophy | ACNR

References

Birnkrant DJ et al. Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and neuromuscular, rehabilitation, endocrine, and gastrointestinal and nutritional management. Lancet Neurol. 2018; 17:251–67.

2 Duchenne Muscular Dystrophy. Muscular Dystrophy Association. Available at: https://www.mda.org/disease/duchenne-muscular-dystrophy. Last Accessed January 2023.

3Project documents | Ataluren for treating Duchenne muscular dystrophy with a nonsense mutation in the dystrophin gene (review of HST3) [ID1642] | Guidance | NICE

About Translarna™ (ataluren)

Translarna (ataluren), discovered and developed by PTC Therapeutics, is a protein restoration therapy designed to enable the formation of a functioning protein in patients with genetic disorders caused by a nonsense mutation. A nonsense mutation is an alteration in the genetic code that prematurely halts the synthesis of an essential protein. The resulting disorder is determined by which protein cannot be expressed in its entirety and is no longer functional, such as dystrophin in Duchenne. Translarna, the tradename of ataluren, is licensed in multiple countries including Great Britain, Northern Ireland and the European Economic Area for the treatment of nonsense mutation Duchenne muscular dystrophy in ambulatory patients aged 2 years and older. Ataluren is an investigational new drug in the United States.

About Duchenne Muscular Dystrophy (Duchenne)
Primarily affecting males, Duchenne is a rare and fatal genetic disorder that results in progressive muscle weakness from early childhood and leads to premature death in the mid-20’s due to heart and respiratory failure. It is a progressive muscle disorder caused by the lack of functional dystrophin protein. Dystrophin is critical to the structural stability of all muscles, including skeletal, diaphragm, and heart muscles. Patients with Duchenne can lose the ability to walk (loss of ambulation) as early as 10 years old, followed by loss of the use of their arms. Duchenne patients subsequently experience life-threatening lung complications, requiring the need for ventilation support, and heart complications in their late teens and 20s.

About PTC Therapeutics, Inc.

PTC is a science-driven, global biopharmaceutical company focused on the discovery, development and commercialization of clinically differentiated medicines that provide benefits to patients with rare disorders. PTC’s ability to innovate to identify new therapies and to globally commercialize products is the foundation that drives investment in a robust and diversified pipeline of transformative medicines. PTC’s mission is to provide access to best-in-class treatments for patients who have little to no treatment options. PTC’s strategy is to leverage its strong scientific and clinical expertise and global commercial infrastructure to bring therapies to patients. PTC believes this allows it to maximize value for all its stakeholders. To learn more about PTC, please visit us at www.ptcbio.com and follow us on Facebook, Instagram, LinkedIn and Twitter at @PTCBio.

Rozanolixizumab BLA for the treatment of generalised myasthenia gravis filed with US FDA and designated for priority review

  • Biologic License Application (BLA) designated Priority Review by FDA and seeks approval for rozanolixizumab for the treatment of adults with generalised myasthenia gravis (gMG) who are anti-acetycholine receptor (AChR) or anti-muscle-specific tyrosine kinase (MuSK) antibody positive 
  • Rozanolixizumab FDA Priority Review follows recent European Medicines Agency (EMA) validation of the Marketing Authorisation Application (MAA) for rozanolixizumab in adults with gMG 
  • FDA and EMA submissions based on pivotal Phase 3 MycarinG study in gMG which demonstrated treatment with rozanolixizumab resulted in clinically meaningful and statistically significant improvements in MG specific outcomes
  • UCB expects to receive feedback from the agencies in Q2 of 2023 

UCB, a global biopharmaceutical company, announced on 6th January 2023 that the US Food and Drug Administration (FDA) has accepted the company’s filing to review a Biologic License Application (BLA) for its investigational treatment rozanolixizumab, and that the Agency has granted Priority Review.1 Rozanolixizumab is a subcutaneous (SC) monoclonal antibody targeting the neonatal Fc receptor (FcRn) for the treatment of adults with generalised myasthenia gravis (gMG) who are anti-acetycholine receptor (AChR) or anti-muscle-specific tyrosine kinase (MuSK) antibody positive2

A FDA Priority Review designation is typically granted by the Agency to a medicine which, if approved, could deliver significant improvements in the safety or effectiveness of the treatment, diagnosis, or prevention of serious conditions when compared to standard applications3. Priority Review designation means the FDA’s goal is to take action on an application within 6 months, compared to 10 months under standard review3. In 2019, the US FDA granted orphan drug designation to rozanolixizumab for the treatment of MG.4

The safety and efficacy of rozanolixizumab have not been established and they are not currently approved for use in any indication by any regulatory authority worldwide.   

The FDA Priority Review designation follows the recent European Medicines Agency (EMA) validation of the Marketing Authorisation Application (MAA) for rozanolixizumab for the treatment of adults with AChR or MuSK antibody positive gMG who require treatment in addition to steroids or non-steroidal immunosuppressants. Validation confirms that the application is complete and the formal review process by the EMA’s Committee for Medicinal Products for Human Use (CHMP) can begin. Orphan designation was granted by the European Commission in April 2020 to rozanolixizumab for the treatment of myasthenia gravis.5

UCB expects to receive feedback from both the FDA and EMA during the second quarter of 2023. 

People living with MG suffer from unpredictable, fluctuating, and debilitating symptoms that have a huge impact on their lives, and there is a clear need for additional targeted treatments. We are firmly committed to supporting the gMG community by providing solutions to help improve outcomes for patients and reduce the day-to-day burden of the disease. The FDA’s decision to assess rozanolixizumab via their priority review process, as well as the recent filing of the MAA in Europe, brings us important steps further on our journey towards approvals for rozanolixizumab. We look forward to working with the FDA and EMA to help bring this new treatment option to patients.

Charl van Zyl,  Executive Vice President Neurology Solutions & Head of EU/International Markets, UCB

gMG is a chronic and unpredictable auto-immune disease in which pathogenic autoantibodies can impair synaptic transmission at the neuromuscular junction by targeting specific proteins on the post-synaptic membrane. This disrupts the ability of the nerves to stimulate the muscle and results in a weaker contraction.6 People living with gMG can experience a variety of symptoms, including drooping eyelids, double vision, and difficulty in swallowing, chewing and talking, as well as severe muscle weakness that can result in life-threatening weakness of the muscles of respiration.4,7 In the U.S. the prevalence of MG is estimated at 14 to 20 per 100,000 population; approximately 36,000 to 60,000 cases.4 In Europe, the prevalence is estimated at 10 per 100,000 population.8 

Data from the MycarinG study

The Priority Review BLA and the MAA are based on data from the pivotal Phase 3 MycarinG study (NCT03971422), in which rozanolixizumab demonstrated statistically significant and clinically meaningful improvements in MG-specific outcomes in patients with AChR MuSK antibody positive MG. In the primary endpoint, rozanolixizumab significantly reduced MG-ADL from baseline to Day 43. Rozanolixizumab showed an LS mean difference vs placebo (95% CI) of -2.59 points at the 7mg/kg dose and -2.62 points at the 10mg/kg dose.9

Furthermore, a greater percentage of patients in the rozanolixizumab 7mg/kg and 10mg/kg arms than the placebo arm achieved a 2.0-point or greater improvement (p<0.001) in MG-ADL, a 3.0-point or greater improvement in Quantitative Myasthenia Gravis (QMG) scores and a 3.0-point or greater improvement in Myasthenia Gravis Composite (MGC) scores7, demonstrating clinically meaningful reductions in these assessments.

Rozanolixizumab demonstrated an acceptable safety and tolerability profile with similar occurrences of TEAEs between both doses. A higher proportion of TEAEs occurred in the active treatment arms versus placebo (81.3% for 7 mg/kg, 82.6% for 10 mg/kg and 67.2% for placebo) and were comparable between the rozanolixizumab groups. The most frequently reported TEAEs were headache, diarrhea, pyrexia, and nausea. A higher incidence of headache was reported in the rozanolixizumab groups versus placebo, with most cases mild to moderate and severe cases generally managed with non-opioid analgesics.Treatment discontinuation rates due to TEAEs were low.7

In the MycarinG study, 200 patients were randomised 1:1:1 to receive weekly rozanolixizumab 7 mg/kg (N=66), 10 mg/kg (N=67) or placebo (N=67) for 6 weeks, which was followed by an 8-week observation period.6

Patients living with MG may experience high disease and treatment burden resulting in a significant impact on their daily lives. If approved, rozanolixizumab has the potential to address unmet needs of gMG patients,” said Iris Loew-Friedrich, Executive Vice-President and Chief Medical Officer at UCB. “Through rozanolixizumab and zilucoplan, we intend to bring two medicines with different mechanisms of action that have the potential to provide targeted treatment options to patients. With our gMG pipeline, we hope to address both drivers of disease pathology and which account for approximately 95% of people living with gMG. Priority Review Designation by the FDA for rozanolixizumab reflects the extent to which our science speaks for itself in potentially addressing the significant unmet needs still faced by the gMG community.”

UCB is currently investigating two potential therapies with different modes of action for the treatment of gMG. Alongside rozanolixizumab, a NDA for zilucoplan – a subcutaneous self-administered peptide inhibitor of complement component 5 (C5 inhibitor) has recently been filed with the U.S. FDA for the treatment of adults with AChR antibody positive gMG. Additionally, zilucoplan received MAA validation from the EMA for the treatment of adults with AChR antibody positive gMG and who require treatment in addition to steroids or non-steroidal immunosuppressants.10,11,12

References:

  1. Data on file.
  2. Smith B, et al. Generation and characterization of a high affinity anti-human FcRn antibody, rozanolixizumab, and the effects of different molecular formats on the reduction of plasma IgG concentration. MAbs. 2018;10:1111-30.
  3. US Food and Drug Administration, https://www.fda.gov/patients/fast-track-breakthrough-therapy-accelerated-approval-priority-review/priority-review, Accessed January 2023
  4. US Food and Drug Administration https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=669918 Accessed January 2023
  5. European Medicines Agency, EU/3/20/2272: Orphan designation for the treatment of myasthenia gravis https://www.ema.europa.eu/en/medicines/human/orphan-designations/eu3202272 Accessed January 2023
  6. Myasthenia Gravis Foundation of America. Clinical Overview of MG. https://myasthenia.org/Professionals/Clinical-Overview-of-MG. Accessed January 2023
  7. Hansen JS, et al. Mortality in myasthenia gravis: A nationwide population-based follow-up study in Denmark. Muscle Nerve. 2016;53:73-77.
  8. Salari N, et al. Global prevalence of myasthenia gravis and the effectiveness of common drugs in its treatment: a systematic review and meta-analysis. J Transl Med 19, 516 (2021). https://doi.org/10.1186/s12967-021-03185-7. Accessed January 2023.
  9. Bril V, et al. Rozanolixizumab in generalized myasthenia gravis: Responder analyses from the Phase 3 MycarinG study. Poster 204, AANEM 2022.
  10. Howard J, et al. Clinical Effects of the Self-administered Subcutaneous Complement Inhibitor Zilucoplan in Patients With Moderate to Severe Generalized Myasthenia Gravis: Results of a Phase 2 Randomized, Double-Blind, Placebo-Controlled, Multicenter Clinical Trial. JAMA Neurol 2022 1;77(5)
  11. US Food and Drug Administration https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=699319. Accessed January 2023
  12. Data on file.
  13. Chen J, et al. Incidence, mortality, and economic burden of myasthenia gravis in China: A nationwide population-based study. Lancet Reg Health West Pac: 2020;5:100063.
  14. National institute of Neurological Disorders and Stroke. 2022. Myasthenia Gravis Fact Sheet. https://www.ninds.nih.gov/myasthenia-gravis-fact-sheet. Accessed January 2023.
  15. Dong D, et al. Gender differences in quality of life among patients with myasthenia gravis in China. Health and Quality of Life Outcomes 2020 18;296
  16. Myasthenia Gravis Foundation of America. MG Quick Facts. https://myasthenia.org/MG-Education/MG-Quick-Facts Accessed January 2023
  17. ClinicalTrials.gov ‘A Study to Test Efficacy and Safety of Rozanolixizumab in Adult Patients With Generalized Myasthenia Gravis’:  https://clinicaltrials.gov/ct2/show/NCT03971422. Accessed January 2023.
  18. Kiessling P, et al. The FcRn inhibitor rozanolixizumab reduces human serum IgG concentration: A randomized phase 1 study. Sci Transl Med. 2017;9(414:eaan1208).

Adjunctive treatment of seizures associated with Lennox-Gastaut syndrome (LGS)

FINTEPLA®▼ (fenfluramine) oral solution recommended for approval in the EU

  • Recommendation based on Phase 3 study data demonstrating safety and efficacy in the most difficult to treat seizure types, including drop seizures1,2   
  • LGS is a rare severe form of epilepsy that typically starts during childhood and persists into adulthood. It is characterized by multiple types of drug-resistant seizures with high morbidity3,4  as well as serious impairment of neurodevelopmental, cognitive, and motor functions4

UCB, a global biopharmaceutical company, announced on 19th December 2022 that FINTEPLA®▼ (fenfluramine) oral solution has been recommended for marketing authorisation in the European Union (EU) for the treatment of seizures associated with Lennox-Gastaut syndrome (LGS) as an add-on therapy to other anti-epileptic medicines for patients 2 years of age and older. Fenfluramine is already approved in the US for the treatment of seizures associated with Lennox- Gastaut syndrome. In addition, it is also approved for the treatment of seizures associated with Dravet syndrome in the EU*, US, and Japan.5,6,7

The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency based its positive opinion on safety and efficacy data from a global, randomised, placebo-controlled Phase 3 clinical trial, in 263 patients with LGS (aged 2-35 years), that demonstrated adjunctive fenfluramine at a dose of 0.7/mg/kg/day, provided a significantly greater reduction in the frequency of drop seizures (p=0.001) compared to placebo.1 The most common treatment-emergent adverse events were decreased appetite, somnolence, fatigue and pyrexia.1 No cases of valvular heart disease or pulmonary arterial hypertension were observed.1

The CHMP’s positive opinion on fenfluramine will be referred to the European Commission (EC), which will deliver a final decision in Q1 2023. 

“This positive CHMP opinion is a significant regulatory milestone towards providing a new treatment option to individuals – and their families – living with this rare epilepsy in the EU,” said Mike Davis, Head of Global Epilepsy & Rare Syndromes, UCB. “We’re delighted by this recommendation, highlighting our ongoing commitment to the LGS community by ensuring we bring differentiated medicines to those with unmet needs.”

Additional data supporting the safety and efficacy of fenfluramine in LGS in the open label extension (OLE) part of the study was recently published in Epilepsia showing fenfluramine, when added to a patient’s current anti-epileptic treatment regimen for seizures associated with LGS, was effective in reducing the frequency of multiple seizure types and was generally well tolerated during a median treatment duration of 364 days.2 Study participants experienced a sustained reduction in the frequency of motor seizures including those that resulted in a drop or fall (Generalised Tonic-Clonic Seizures (GTCS), secondary GTCS (SGTC; focal to bilateral tonic-clonic), tonic seizures, atonic seizures, and tonic-atonic seizures).2 In the OLE phase, the most common treatment-emergent adverse events were decreased appetite, fatigue, nasopharyngitis and seizure. The cardiovascular safety in this study further corroborates the fenfluramine safety profiles observed; no cases of valvular heart disease or pulmonary arterial hypertension were observed. 2

LGS is a severe childhood-onset developmental and epileptic encephalopathy (DEE) characterised by multiple types of drug-refractory seizures with high morbidity3,4 as well as serious impairment of neurodevelopmental, cognitive, and motor functions.4 LGS affects an estimated 2 in 10,000 people in European Union (EU).8 LGS has far-reaching effects beyond seizures, including issues with developmental communication, psychiatric symptoms, sleep, behavioural challenges, and mobility.9 Drop seizures are hallmark features of LGS, particularly tonic seizures. Convulsive seizures (eg, generalised tonic-clonic [GTC] seizures) are also commonly observed and usually occur in later stages of LGS but sometimes may precede core seizure types. In addition to being associated with bodily injury and hospitalisations, GTC seizures are a primary risk factor of sudden unexpected death in epilepsy (SUDEP). Patients with GTC seizures have an approximately 10-fold greater risk for SUDEP than patients with other seizure types.5

This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions.

References

  1. Knupp K, Scheffer I, Ceulemans B, et al. Efficacy and safety of fenfluramine for the treatment of seizures associated with Lennox-Gastaut syndrome. A Randomized Clinical Trial. JAMA Neurol. 2022;79(6):554-564
  2. Knupp K, Scheffer I, Ceulemans B, et al. Fenfluramine provides clinically meaningful reduction in frequency of drop seizures in patients with Lennox-Gastaut syndrome: interim analysis of an open-label extension study. Epilepsia. 2022; doi: 10.1111/epi.17431
  3. Strzelczyk A, Schubert-Bast S. Expanding the Treatment Landscape for Lennox-Gastaut Syndrome: Current and Future Strategies. CNS Drugs. 2021;35(1):61-83.
  4. Specchio, N, Wirrell, EC, Scheffer, IE, Nabbout, R, Riney, K, Samia, P, et al. International League Against Epilepsy classification and definition of epilepsy syndromes with onset in childhood: Position paper by the ILAE Task Force on Nosology and Definitions. Epilepsia. 2022;63:1398– 1442.
  5. Fintepla EMA SmPC https://www.ema.europa.eu/en/documents/product-information/fintepla-epar-product-information_en.pdf Accessed December 2022
  6. Fintepla US PI https://www.ucb-usa.com/fintepla-prescribing-information.pdf Accessed December 2022
  7. Fintepla Japan PI. September 2022. フィンテプラ内用液2.2mg/mL (pmda.go.jp). Accessed December 2022
  8. EMA. EU/3/17/1855 : Orphan designation for the treatment of Lennox-Gastaut syndrome https://www.ema.europa.eu/en/medicines/human/orphan-designations/eu3171855#:~:text=At%20the%20time%20of%20designation,is%205%20people%20in%2010%2C000. Accessed December 2022
  9. LGS Foundation. LGS Characteristics and Major Concerns Survey. https://www.lgsfoundation.org/wp-content/uploads/2021/08/2019-PFDD-Caregiver-Survey-1.pdf. Accessed December

Ipsen at the World Congress for Neurorehabilitation

Ipsen had a robust presence at the 12th World Congress for Neurorehabilitation (WCNR) in Vienna, Austria and virtually, from 14-17 December 2022, further demonstrating the company’s long-standing partnership with the World Federation for Neurorehabilitation (WFNR) and ongoing commitment to neuroscience.

In addition to showcasing the company’s latest neuroscience clinical data, Ipsen hosted a satellite symposium entitled “About time: Optimising Long-Term Outcomes for Patients Treated with Botulinum Toxin”. Facilitated by global neuroscience experts Dr. Jorge Jacinto, Dr. Klemens Fheodoroff and Dr. Alberto Esquenazi, the session centred on new clinical data and around Ipsen’s patient-centric approach to educational training and the importance of focusing on long-term outcomes for patients treated with a botulinum toxin.

Data presented at WCNR 2022 included:

  1. A Phase IV, Prospective, Observational, Multicentre Study Evaluating the Effectiveness and Safety of abobotulinumtoxinA in Pediatric Lower Limb Spasticity (PLLS).
  2. A study exploring abobotulinumtoxinA efficacy and safety in children with upper limb spasticity previously treated with botulinum toxin.
  3. A study examining the change in Leg Activity Measure (LegA) sensitivity following treatment of lower limb spasticity with a single cycle of abobotulinumtoxinA in an ambulant population.
  4. Single centre, prospective, observational study methodology to assess the use of GripAble, a rehabilitation device, on patients with upper limb spasticity (ULS) receiving botulinum toxin A (BoNT-A).
  5. Baseline data from the AboLiSh study, exploring the most frequently injected muscles in patients undergoing treatment with abobotulinumtoxinA for lower limb spasticity in routine practice.
  6. The detrimental impact of the COVID-19 pandemic on the management of post-stroke spasticity in England.

Continuing to advance neuroscience and neurotoxin research

With over 25 years of experience in neurotoxins, neuroscience innovation remains central to the company’s future. Key data from Ipsen’s research and development programme reinforcing the company’s commitment to improving health outcomes for patients living with debilitating neurological disorders were at the WCNR. Clinical updates include a focus on the need to ensure treatment for spasticity is individualised, assessment of the impact of treatment with Dysport® (abobotulinumtoxinA) in pediatric and adult spasticity and a review of the impact of COVID-19 on stroke admissions and interventions in the UK.

“The breadth of data presented at the congress demonstrates our commitment to continued scientific innovation in neuroscience as well our focus on looking at patient care holistically to add value beyond our treatments. This aligns to our broader company strategy of thinking more holistically about how patients experience healthcare – not just how they experience a medicine – to advance neuroscience,” commented Steven Hildemann, Executive Vice President and Chief Medical Officer, Ipsen.

Committed to improving health outcomes

WCNR 2022 also marks the 10th anniversary of Ipsen’s Ixcellence Network®, an educational programme raising the standards of care for patients living with debilitating neurological disorders.

Since its launch, Ipsen has established 10 Ixcellence expert centres in Europe and Latin America, with nearly 800 physicians benefitting from the programme so far and improving the standard of care for thousands of patients with spasticity from around the world with its best-in-class injector training. 

Hamzah Baig, Vice President, Global Medical Affairs, Neuroscience, Ipsen, said: “With comprehensive and wide-ranging cutting-edge content, including use of advanced guidance techniques and implementation of multi-disciplinary care, the Ixcellence Network® is the only programme of its kind to have articles published in peer-reviewed journals; it is the gold-standard for advanced training in treating cervical dystonia and focal spasticity.”

As part of their commitment to physician education, Ipsen delivered an interactive educational training session at the WCNR, tailored around the management of complex patient cases.

Lecanemab: Clarity AD clinical study results

Results from Eisai’s large global Phase 3 confirmatory Clarity AD clinical study of lecanemab, an investigational anti-amyloid beta (Aβ) protofibril antibody for the treatment of mild cognitive impairment (MCI) due to Alzheimer’s disease (AD) and mild AD (collectively known as early AD) with confirmed presence of amyloid pathology in the brain, were presented at the 2022 Clinical Trials on Alzheimer’s Disease (CTAD) conference, in San Francisco, California. Simultaneously, the results were published in the New England Journal of Medicine read the full article here.

You can also read an interesting editorial in The Lancet: Lecanemab for Alzheimer’s disease: tempering hype and hope – ScienceDirect

Design of Clarity AD Study1

Eisai’s Clarity AD was a global confirmatory Phase 3 placebo-controlled, double-blind, parallel-group, randomised study in 1,795 people with early AD (lecanemab group: 898 placebo group: 897) at 235 sites in North America, Europe, and Asia. The participants were randomised 1:1 to receive either placebo or lecanemab 10-mg/kg IV biweekly, and the randomisation was stratified according to clinical subgroup (MCI due to AD or mild AD), presence or absence of concomitant approved AD symptomatic medication at baseline (e.g., acetylcholinesterase inhibitors, memantine, or both), ApoE4 status and geographical region.

The primary endpoint was change from baseline at 18 months in the CDR-SB (Clinical Dementia Rating Sum of Boxes), the global cognitive and functional scale, and key secondary endpoints were the change from baseline at 18 months in amyloid Positron Emission Tomography (PET) using centiloids, AD Assessment Scale – Cognitive Subscale 14 (ADAS-Cog14), AD Composite Score (ADCOMS) and AD Cooperative Study-Activities of Daily Living (ADCS MCI-ADL). In addition, longitudinal changes in brain tau pathology as measured by tau PET (n=257) and cerebrospinal fluid (CSF) biomarkers of AD pathology (n=281) were evaluated in optional sub-studies.

Efficacy results of Clarity AD2

Mean change of CDR-SB from baseline at 18 months as the primary endpoint was 1.21 and 1.66 for lecanemab (n=859) and placebo (n=875) groups, respectively. Lecanemab treatment resulted in highly statistically significant results, reducing clinical decline on the global cognitive and functional scale, compared with placebo at 18 months by -0.45 (95% Confidence Interval (CI): -0.67, -0.23; P=0.00005), representing a 27% slowing of decline. Starting as early as six months (difference: -0.17 [95% CI: -0.29, -0.05]; P<0.01), and increasing in absolute difference over time across all time points every 3 months, the treatment showed highly statistically significant changes in CDR-SB from baseline compared to placebo (all P-values are less than 0.01).

All key secondary endpoints also showed highly statistically significant results compared with placebo (P<0.001). In the amyloid PET sub-study, treatment with lecanemab showed statistically significant reduction in amyloid plaque burden at all timepoints starting at 3 months. Mean change in centiloids at 18 months was -55.5 and 3.6 for lecanemab (n=354) and placebo (n=344) groups, respectively (mean difference: -59.1 [95%CI: -62.6, -55.6]; P<0.00001). Lecanemab slowed decline of cognitive function by 26% on ADAS-Cog14 at 18 months (lecanemab (n=854), placebo (n=872); mean difference: -1.44 [95%CI: -2.27, -0.61]; P=0.00065). In the ADCOMS assessment, lecanemab slowed disease progression by 24% at 18 months (lecanemab (n=857), placebo (n=875); mean difference: -0.050 [95% CI: -0.074, -0.027; P=0.00002]). Lecanemab slowed decline of activities of daily living by 37% on ADCS MCI-ADL at 18 months (lecanemab (n=783), placebo (n=796); mean difference: 2.016 [95%CI: 1.208, 2.823]; P<0.00001).

Safety Results of Clarity AD3

The most common adverse events (>10%) in the lecanemab group were infusion reactions (lecanemab (n=898): 26.4%; placebo (n=897): 7.4%), ARIA-H (combined cerebral microhaemorrhages, cerebral macrohaemorrhages, and superficial siderosis; lecanemab (n=898): 17.3%; placebo (n=897): 9.0%), ARIA-E (edema/effusion; lecanemab (n=898): 12.6%; placebo 9n=897): 1.7%), headache (lecanemab (n=898): 11.1%; placebo (n=897): 8.1%), and fall (lecanemab (n=898): 10.4%; placebo (n=897): 9.6%). Infusion reactions were largely mild-to-moderate (grade 1-2: 96%) and occurred on the first dose (75%).

During the study period, deaths occurred in 0.7% and 0.8% of participants in the lecanemab and placebo groups, respectively and no deaths were related to lecanemab or occurred with amyloid-related imaging abnormalities (ARIA) in 18-month double-blind study period. Serious adverse events were experienced by 14.0% of participants in the lecanemab group and 11.3% of participants in the placebo group. Treatment-emergent adverse events occurred in 88.9% and 81.9% of participants in the lecanemab and placebo groups, respectively. Treatment-emergent adverse events leading to drug withdrawal occurred in 6.9% and 2.9% of participants in the lecanemab and placebo groups, respectively.

Overall, lecanemab’s ARIA incidence profile was within expectations based on the Phase 2b results.

Eisai serves as the lead of lecanemab development and regulatory submissions globally with both Eisai and Biogen co-commercialising and co-promoting the product and Eisai having final decision-making authority.

The results of Clarity AD are very encouraging, representing the first time a treatment has modified Alzheimer’s disease. The news is great for not only patients but those in the research field as well.

Prof. John Hardy, Chair of Molecular Biology of Neurological Disease, UCL

References

  1. Irizarry M. Clarity AD: Clinical Trial Background and Study Design Overview. Presented at: 15th Annual Clinical Trials on Alzheimer’s Disease (CTAD) Conference, November 29 – December 2, 2022, San Francisco, California, USA.
  2. van Dyck C. Lecanemab for the Treatment of Early Alzheimer’s Disease: Topline Efficacy Results from Clarity AD. Presented at: 15th Annual Clinical Trials on Alzheimer’s Disease (CTAD) Conference, November 29 – December 2, 2022, San Francisco, California, USA.
  3. Sabbagh M. Safety Profile of Lecanemab in Early Alzheimer’s Disease. Presented at: 15th Annual Clinical Trials on Alzheimer’s Disease (CTAD) Conference, November 29 – December 2, 2022, San Francisco, California, USA.

Zilucoplan for the treatment of generalised myasthenia gravis in adult patients

FDA acceptance of new drug application and EMA MAA validation

  • New drug application (NDA) for zilucoplan seeks approval for the treatment of generalised myasthenia gravis (gMG) in adult patients who are acetylcholine receptor antibody positive (AChR-Ab+) 
  • Acceptance by U.S. Food and Drug Administration (FDA) follows the recent European Medicines Agency (EMA) validation of Marketing Authorization Application (MAA) for treatment of adult patients with AChR-Ab+ gMG and who require treatment in addition to steroids or non-steroidal immunosuppressants 
  • Both NDA and MAA are based on pivotal Phase 3 RAISE study in gMG, which demonstrated treatment with zilucoplan resulted in clinically meaningful and statistically significant improvements in key MG-specific outcomes compared to placebo
  • UCB expects to receive feedback from the agencies in Q4 of 2023 

On 14th November 2022, UCB announced that the U.S. Food and Drug Administration (FDA) has accepted for review the New Drug Application (NDA) for its investigational treatment, zilucoplan. 

Zilucoplan is a subcutaneous (SC), self-administered peptide inhibitor of complement component 5 (C5 inhibitor) for the treatment of adult patients with acetylcholine receptor antibody positive (AChR-Ab+) generalised myasthenia gravis (gMG). 

In 2019, the U.S. FDA granted orphan drug designation to zilucoplan for the treatment of MG.1 The safety and efficacy of zilucoplan have not been established and it is not currently approved for use in any indication by any regulatory authority worldwide.

This acceptance follows the recent European Medicines Agency (EMA) validation of the Marketing Authorization Application (MAA) for zilucoplan for the treatment of adult patients with AChR-Ab+ gMG and who require treatment in addition to steroids or non-steroidal immunosuppressants. Validation confirms that the application is complete and the formal review process by the EMA’s Committee for Medicinal Products for Human Use (CHMP) can begin. Orphan designation was granted in 2022 by the European Commission to zilucoplan for the treatment of myasthenia gravis.2

gMG is a chronic and unpredictable auto-immune disease in which pathogenic autoantibodies can impair synaptic transmission at the neuromuscular junction by targeting specific proteins on the post-synaptic membrane. This disrupts the ability of the nerves to stimulate the muscle and results in a weaker contraction.4 People living with MG can experience a variety of symptoms, including drooping eyelids, double vision, and difficulty in swallowing, chewing and talking, as well as severe muscle weakness that can result in life-threatening weakness of the muscles of respiration.3 In the U.S. the prevalence of MG is estimated at 14 to 20 per 100,000 population; approximately 36,000 to 60,000 cases.4 In Europe, the prevalence is estimated at 10 per 100,000 population.5

People living with gMG experience high treatment burden, on top of the debilitating impact of the condition, and there is a clear need for additional targeted treatments to support the gMG community. Our goal is to provide a solution that can help meet these needs and transform lives. The acceptance of the NDA by the FDA as well as the acceptance of the MAA by the EMA, brings us one step further on our journey towards approval for this medicine. We look forward to working with the FDA and EMA to help bring this important new treatment option to patients.”

Charl van Zyl, Executive Vice President Neurology Solutions & Head of EU/International Markets, UCB.

The NDA and MAA are based on data from the pivotal Phase 3 RAISE study (NCT04115293), which demonstrated at week 12 that treatment with zilucoplan (0.3 mg/kg daily) resulted in clinically meaningful and statistically significant improvements in key gMG-specific outcomes compared with placebo in patients with AChR-Ab+ gMG. The study met its primary endpoint with zilucoplan showing a placebo-corrected mean improvement of 2.09 points in the Myasthenia Gravis Activities of Daily Living (MG-ADL) score at week 12 (p<0.001).6

Zilucoplan demonstrated a favorable safety and tolerability profile, showing a similar rate of treatment-emergent adverse events (TEAEs) between zilucoplan (76.7%) and placebo (70.5%). The most common TEAEs were injection site bruising, headache, and diarrhea. Rates of treatment discontinuation due to a TEAE were low and all patients who completed the 12-week treatment period have entered the ongoing RAISE-XT open-label extension study (NCT04225871).6,7

In the RAISE study, 174 adult patients were randomised to receive daily SC, self-administered doses of placebo (N=88) or zilucoplan 0.3 mg/kg (N=86). Patient demographics and baseline disease characteristics were generally balanced between treatment arms.6

As a complement C5 inhibitor, zilucoplan is a targeted therapy that inhibits key components in the underlying pathophysiology of gMG, addressing the underlying mechanism of neuromuscular junction damage.8,9

UCB anticipates making regulatory filings for zilucoplan in gMG in Great Britain, Japan, and rest of the world from Q3 2022 onwards. 

Alongside zilucoplan, UCB is also investigating rozanolixizumab, a SC-administered, humanized monoclonal antibody that specifically binds, with high affinity, to human neonatal Fc receptor (FcRn), as a potential treatment for gMG. UCB anticipates filing regulatory submissions for rozanolixizumab later this year. 

About the zilucoplan RAISE study 6,7

The RAISE study (NCT04115293) is a multi-center, Phase 3, randomized, double-blind, placebo-controlled study to confirm the efficacy, safety, and tolerability of zilucoplan in patients with AChR-Ab+ gMG. Patients were randomized in a 1:1 ratio to receive daily subcutaneous (SC) doses of 0.3 mg/kg zilucoplan or placebo for 12 weeks.

The primary endpoint for the RAISE study is change from baseline to Week 12 in the Myasthenia Gravis-Activities of Daily Living (MG-ADL) score. Secondary endpoints include change in the Quantitative Myasthenia Gravis (QMG) score, the Myasthenia Gravis Composite (MGC) and the Myasthenia Gravis Quality of Life 15 revised (MG-QoL15r) score from baseline to Week 12,  time to rescue therapy, the proportion with minimal symptom expression (MSE) (defined as MG-ADL of 0 or 1), the proportion with a ≥3-point reduction in MG-ADL and the proportion with a ≥5-point reduction in QMG without rescue therapy, all measured at Week 12. The secondary safety endpoint is incidence of TEAEs. Patients who completed the 12 week RAISE trial had the possibility to enter the open label extension study, RAISE-XT. 

For more information about the trial visit https://clinicaltrials.gov/ct2/show/NCT04115293


References:

  1. US Food and Drug Administration https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=699319. Accessed October 2022
  2. Data on file.
  3. Hansen JS, et al. Mortality in myasthenia gravis: A nationwide population-based follow-up study in Denmark. Muscle Nerve. 2016;53:73-77.
  4. Myasthenia Gravis Foundation of America. Clinical Overview of MG. https://myasthenia.org/Professionals/Clinical-Overview-of-MG. Accessed August 2022 
  5. Salari N, et al. Global prevalence of myasthenia gravis and the effectiveness of common drugs in its treatment: a systematic review and meta-analysis. J Transl Med 19, 516 (2021). https://doi.org/10.1186/s12967-021-03185-7. Accessed September 2022.
  6. Vu T, et al. Efficacy and safety of zilucoplan in myasthenia gravis: Responder analysis from the randomized Phase 3 RAISE trial. Poster 200, AANEM 2022.
  7. Weiss MD, et al, Quality of life outcomes in RAISE: A double-blind randomized, placebo-controlled study of zilucoplan in gMG. Oral presentation. MGFA Scientific Session, AANEM 2022.
  8. Tannemaat et al. Emerging therapies for autoimmune myasthenia gravis: Towards treatment without corticosteroids. Neuromuscul Disord. 2020;30(2):111-119
  9. Howard J, et al. Clinical Effects of the Self-administered Subcutaneous Complement Inhibitor Zilucoplan in Patients With Moderate to Severe Generalized Myasthenia Gravis: Results of a Phase 2 Randomized, Double-Blind, Placebo-Controlled, Multicenter Clinical Trial. JAMA Neurol 2022 1;77(5)
  10. ClinicalTrials.gov. 2022. A Study to Test Efficacy and Safety of Rozanolixizumab in Adult Patients With Generalized Myasthenia Gravis. https://clinicaltrials.gov/ct2/show/NCT03971422. Accesed October 2022 
  11. Chen J, et al. Incidence, mortality, and economic burden of myasthenia gravis in China: A nationwide population-based study. Lancet Reg Health West Pac: 2020;5:100063.
  12. National institute of Neurological Disorders and Stroke. 2022. Myasthenia Gravis Fact Sheet. https://www.ninds.nih.gov/myasthenia-gravis-fact-sheet. Accessed October 2022.
  13. Dong D, et al. Gender differences in quality of life among patients with myasthenia gravis in China. Health and Quality of Life Outcomes 2020 18;296
  14. Myasthenia Gravis Foundation of America. MG Quick Facts. https://myasthenia.org/MG-Education/MG-Quick-Facts Accessed October 2022
  15. Smith B, et al. Generation and characterization of a high affinity anti-human FcRn antibody, rozanolixizumab, and the effects of different molecular formats on the reduction of plasma IgG concentration. MAbs. 2018;10:1111-30.
  16. Kiessling P, et al. The FcRn inhibitor rozanolixizumab reduces human serum IgG concentration: A randomized phase 1 study. Sci Transl Med. 2017;9(414:eaan1208).
  17. US Food and Drug Administration https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=669918. Accessed August 2022
  18. European Medicines Agency, EU/3/20/2272: Orphan designation for the treatment of myasthenia gravis https://www.ema.europa.eu/en/medicines/human/orphan-designations/eu3202272. Accessed August 2022 

Upstaza™ gene therapy granted marketing authorisation for AADC deficiency by MHRA

  • First gene therapy infused directly into the brain for the treatment of AADC deficiency
  • MHRA authorisation follows recent European Union authorisation
  • AADC deficiency is a rare, fatal disorder that arrests motor development causing severe disability

PTC Therapeutics, Inc. announced on 17th November that Upstaza™ (eladocagene exuparvovec) was granted authorisation by the Medicines and Healthcare Products Regulatory Agency (MHRA) in Great Britain. Upstaza is the first and only approved disease-modifying treatment for aromatic L-amino acid decarboxylase (AADC) deficiency and the first marketed gene therapy directly infused into the brain. It is approved for patients 18 months and older.

“We are thrilled with the MHRA’s rapid authorisation of Upstaza,” said Stuart W. Peltz, Ph.D., Chief Executive Officer, PTC Therapeutics. “Patients in the UK with AADC deficiency are one step closer to having access to a much-needed disease modifying therapy. This is another milestone towards our commitment to advance innovative treatments and improve outcomes for people living with rare diseases.”

During Upstaza clinical studies, patients went from not achieving any developmental motor milestones to demonstrating a mastery of clinically meaningful motor skills, including the ability to ambulate independently. Milestone achievements including cognitive and language acquisition occurred from as early as three months following treatment, with clinically significant improvements shown to continue up to ten years after treatment. Upstaza also reduced symptoms that cause potentially life-threatening and morbid complications.

“The approval of an AADC deficiency gene therapy in the UK will provide the opportunity to transform the prognosis for those born and living with this disease, and we are hopeful for access in the coming months. Without treatment, most children born with AADC deficiency will have difficulty with their development and many of the symptoms can be distressing and life-threatening. The impact on those living with AADC and their communities is significant, with children facing frequent hospitalisations, emergency visits and requiring a multi-disciplinary team of highly trained specialists,” stated Kirsty Hoyle, CEO, Metabolic Support UK

Upstaza has marketing authorisation in all 27 European Union member states, as well as Iceland, Norway, Liechtenstein, and Northern Ireland.  

Patients in the UK with AADC deficiency are one step closer to having access to a much-needed disease modifying therapy. This is another milestone towards our commitment to advance innovative treatments and improve outcomes for people living with rare diseases.

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

References:

  1. Tai CH, et al. Long-term efficacy and safety of eladocagene exuparvovec in patients with AADC deficiency. Mol Ther. 2022;30(2):509-518.
  2. Chien et al. AGIL-AADC gene therapy results in sustained improvements in motor and developmental milestones through 5 years in children with AADC deficiency. Poster presented at the 48th Annual Meeting of the Child Neurology Society, Charlotte, NC, USA, Oct 23-26, 2019.
  3. Chien YH, et al. Efficacy and safety of AAV2 gene therapy in children with aromatic L-amino acid decarboxylase deficiency: an open-label, phase 1/2 trial. Lancet

About Upstaza™ (eladocagene exuparvovec)

Upstaza is a one-time gene replacement therapy indicated for the treatment of patients aged 18 months and older with a clinical, molecular, and genetically confirmed diagnosis of aromatic L‑amino acid decarboxylase (AADC) deficiency with a severe phenotype. It is a recombinant adeno-associated virus serotype 2 (AAV2)-based gene therapy, containing the human DDC gene.1 It is designed to correct the underlying genetic defect, by delivering a functioning DDC gene directly into the putamen, increasing the AADC enzyme and restoring dopamine production.2,3

The efficacy and safety profile of Upstaza has been demonstrated across clinical trials and compassionate use programmes.1 The first patient was dosed in 2010. In clinical trials, Upstaza demonstrated transformational neurological improvements. The most common side effects were initial insomnia, irritability and dyskinesia.

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

About aromatic L-amino acid decarboxylase (AADC) deficiency

AADC deficiency is a fatal, rare genetic disorder that typically causes severe disability and suffering from the first months of life, affecting every aspect of life – physical, mental and behavioural. The suffering of children with AADC deficiency may be exacerbated by: episodes of distressing seizure-like oculogyric crises causing the eyes to roll up in the head, frequent vomiting, behavioural problems, and difficulty sleeping.

The lives of affected children are severely impacted and shortened. Ongoing physical, occupational and speech therapy, and interventions, including surgery, also are often required to manage potentially life-threatening complications such as infections, severe feeding and breathing problems.

About PTC Therapeutics, Inc.

PTC is a science-driven, global biopharmaceutical company focused on the discovery, development and commercialization of clinically differentiated medicines that provide benefits to patients with rare disorders. PTC’s ability to innovate to identify new therapies and to globally commercialise products is the foundation that drives investment in a robust and diversified pipeline of transformative medicines. PTC’s mission is to provide access to best-in-class treatments for patients who have little to no treatment options.

First autopsy-confirmed results for identifying Alzheimer’s in presence of other co-morbid pathologies using DISCERN test

SYNAPS Dx (SDx), a privately held company focused on the research, development and commercialisation of a diagnostic test for Alzheimer’s disease (AD), is pleased to announce the publication of “Morphometric imaging biomarker identifies Alzheimer’s disease even among mixed dementia patients” in Scientific Reports.

Up until now, there have been no autopsy-validated tests shown to accurately identify AD in the presence of mixed dementia, or dementia from one or more co-existing causes, affecting over half of patients diagnosed with AD. We are pleased to share this groundbreaking data showing that the MI biomarker demonstrated specificity and sensitivity of 100% (p<.001) when compared to the NIH Gold Standard criteria for AD in distinguishing AD from non-AD patients, even in the presence of other co-morbid pathologies.

Dr. Daniel Alkon, chief scientific advisor, SDx and corresponding author of the paper.

Dr. Alkon further explains that DISCERN™ is a CLIA-certified diagnostic skin test comprised of three assays that assess several factors related to synaptic and neuronal loss that impact cognitive loss, as well as regulators of amyloid plaque and neurofibrillary tangles in the brain. The test is autopsy-validated to inform a definitive diagnosis of AD, even in people recently diagnosed with dementia. The DISCERN AD biomarkers also depend on factors that regulate amyloid plaque and tau formation, hallmarks of AD at autopsy.

“DISCERN is an important breakthrough for the AD community because there are currently no other autopsy-validated tests that are highly sensitive and highly specific for identifying AD in people recently diagnosed with dementia or mixed-dementia,” says Frank Amato, CEO and president, SDx. “With expected FDA-approved treatments for AD on the horizon, in addition to determining the presence of amyloid plaques consistent with AD, patients will likely need an accurate AD diagnosis to determine if amyloid targeted drugs are appropriate for them.”

Amato explains that currently, most patients with dementia are managed in primary care where due to the lack of availability of diagnostic tools, more than half are misdiagnosed.

“While blood biomarkers have the potential to help clinicians screen for the presence of amyloid plaque or tau, hallmarks of AD, they do not diagnose mild cognitive impairment (MCI) or early AD dementia with high accuracy,” Dr. Alkon continues. “Well-defined cohorts such as the oldest old individuals can be entirely cognitively normal – i.e. not at all demented – but have abundant amyloid plaques and tau tangles at autopsy.”

“With use of the DISCERN test, which relates to loss of synaptic networks as well as amyloid and tau, primary care clinicians have indicated a greater confidence in the diagnosis of AD, potentially avoiding unnecessary, invasive and expensive diagnostic procedures and identifying patients with AD dementia who are appropriate candidates for treatment,” says Dr. Alkon.

About SYNAPS Dx
SYNAPS Dx is a privately held company focused on the research, development and commercialisation of a diagnostic test for Alzheimer’s disease (AD). The Company offers DISCERN™, the first highly accurate, minimally invasive test supporting a clinician’s definitive diagnosis of AD versus other forms of dementia, even in people recently diagnosed with dementia. SYNAPS Dx’s laboratory is certified under the Clinical Laboratory Improvement Amendments (CLIA) as qualified to perform high complexity clinical laboratory testing. Physicians and patients seeking more information can visit https://discerntest.com/. For more information on the Company, visit https://www.synapsdx.com/. Contact: info@synapsdx.com.