Author: Rachael Hansford

Professor Anna Williams and Professor Tilo Kunath appointed as Co-Directors of the Centre for Regenerative Medicine

Posted on November 7, 2024 by - Awards & Appointments

Congratulations to Professor Anna Williams and Professor Tilo Kunath who have been appointed as Co-Directors of the Centre for Regenerative Medicine. Professor Williams is a Professor of Regenerative Neurology and Honorary Consultant Neurologist and Professor Kunath is a Chair of Regenerative Neurobiology. Both new Co-Directors have been Principal Investigators in the Centre from its very start in 2008, moving into what is now IRR North in 2011.

Professor Williams’ research focuses on how to keep myelin and oligodendrocytes healthy for good neuronal function in brain and spinal cord.

Professor Kunath’s research focuses on using pluripotent stem cells to model and treat Parkinson’s disease.

The Centre for Regenerative Medicine was formed in 2008 with funding from the Medical Research Council. Its founding Director was Professor Sir Ian Wilmut who was succeeded by Professor Charles ffrench-Constant and then Professor Forbes.

Further information can be found here https://lnkd.in/eYhQfAEf

Professor Anna Williams and Professor Tilo Kunath

‘Access to Health’ to improve stroke care in Africa

Posted on October 28, 2024 by - Stroke

New initiative from Merz Therapeutics and World Stroke Organization

  • Official launch of the “Access to Health” initiative announced at the World Stroke Congress by WSO President, Dr. Sheila Martins
  • Partnership aims to reduce healthcare disparities with pilot projects in Nigeria and Tanzania
  • Project leaders and healthcare professionals convene to discuss next steps and project execution

October 24th, 2024: at the annual World Stroke Congress in Abu Dhabi, the President of the World Stroke Organization (WSO), Dr. Sheila Martins, officially announced a partnership with Merz Therapeutics to launch the ‘Access to Health’ initiative. This project, focusing on addressing healthcare disparities in low- and middle-income countries (LMICs), will begin with two pilot projects in Nigeria and Tanzania.

During the event, project leaders from around the world gathered to discuss next steps and the strategic direction of this innovative partnership. “We are incredibly proud to be part of a mission that can make a tangible difference in the lives of stroke survivors in underserved communities,” said Stefan König, CEO of Merz Therapeutics. “Our collaboration with the World Stroke Organization will enable us to expand access to much-needed stroke care in regions where healthcare infrastructure is yet limited.”

The initiative aims to tackle the critical issues facing stroke care in these regions, where the incidence of stroke is high, particularly among younger populations. Stroke cases in Sub-Saharan Africa are projected to rise dramatically, with an annual incidence rate of 316 cases per 100,000 people and a 3-year fatality rate exceeding 80%. Limited public awareness, inadequate rehabilitation facilities, and a shortage of healthcare professionals further exacerbate the crisis1.

Pilot Programmes in Nigeria and Tanzania

In Nigeria, the initiative will focus on building capacity in stroke care by enhancing the education and training of neurologists and healthcare professionals. This will include the development of comprehensive educational modules designed to improve post-stroke rehabilitation programs. The goal is to expand the workforce’s ability to provide state-of-the-art stroke management and rehabilitation.

In Tanzania, the initiative will concentrate on improving patient access to stroke care services in low-resource settings. Building on the existing efforts led by the WSO, Merz Therapeutics will offer strategic support to further develop stroke care infrastructure, specifically through the support of stroke units in hospitals. Merz Therapeutics aims to improve patient outcomes by consulting local healthcare providers to enable comprehensive and multidisciplinary care for underserved communities.

Creating Sustainable Healthcare Solutions

Launched in 2023, the Access to Health initiative is part of Merz Therapeutics’ broader strategy to reduce healthcare disparities in LMICs through healthcare professional training, patient education, strategic partnerships, and employee volunteering. By collaborating with the WSO, Merz Therapeutics aims to establish scalable healthcare models that can be replicated globally, ensuring that everyone, regardless of geographic or economic barriers, has access to high-quality medical care.

Our long-term goal is to create sustainable, scalable healthcare improvements that can transform stroke care in these regions and beyond. This initiative embodies our commitment to making healthcare more equitable and accessible for all.
Stefan Albrecht, Chief Scientific and Medical Officer of Merz Therapeutics

References

1Akinyemi, R. O., Ovbiagele, B., Adeniji, O. A., Sarfo, F. S., Abd-Allah, F., Adoukonou, T., Ogah, O. S., Naidoo, P., Damasceno, A., Walker, R. W., Ogunniyi, A., Kalaria, R. N., & Owolabi, M. O. (2021). Stroke in Africa: profile, progress, prospects and priorities. Nature reviews. Neurology, 17(10), 634–656. https://doi.org/10.1038/s41582-021-00542-4

New research in glioblastoma

Posted on October 26, 2024 by - Brain tumours

Merck & Co is buying Yale spinout Modifi Biosciences, a deal that includes a preclinical asset designed to take on glioblastoma (GBM).

This could “change the whole landscape,” said Ranjit Bindra, M.D., Ph.D., Modifi co-founder and physician-scientist at the Yale School of Medicine.

GBM is the most common type of brain cancer and is a devastating disease, with a five-year survival rate of around 5%.

Modifi’s main asset, MOD-246, is a small molecule. Bindra noticed that some patients had cancers that were resistant to the chemotherapy drug temozolomide (TMZ). TMZ is used when the cancer cells have a nonfunctional version of the DNA repair protein called O6-methylguanine methyltransferase (MGMT), which occurs in about half of GBM cases. However, even when his patients had nonfunctional MGMT, TMZ sometimes didn’t work.

Bindra and colleagues discovered that TMZ kills cancer cells by adding methyl groups to the cells’ DNA. Normally, MGMT would remove these methyl groups, but, without it, the barrage of DNA modification activates a separate DNA repair pathway called mismatch repair (MMR). MMR detects all of the methyl groups and thinks the genome is damaged, so it shuts down replication and kills the cell.

TMZ exploits a cancer’s deficiency in one DNA repair pathway by using another, but it is ineffective if the cancer lacks a functional MMR pathway. To overcome this, researchers, including Seth Herzon, Ph.D., and Kingson Lin, M.D., Ph.D., developed a TMZ-based drug targeting MGMT directly, bypassing the need for MMR. This drug adds fluoroethyl groups to cancer DNA, causing cross-linking that blocks replication. They launched Modifi in 2021.

Merck and Modifi are now conducting IND-enabling studies for MOD-246, aiming to start clinic trials next year (2025).

MHRA approves donanemab…

Posted on October 24, 2024 by - Alzheimer's Disease, Dementia

…but NICE says it does not demonstrate value for the NHS

The Medicines and Healthcare products Regulatory Agency (MHRA) has granted marketing authorisation for donanemab, an injection for intravenous infusion every four weeks to treat mild cognitive impairment and mild dementia due to Alzheimer’s disease in eligible adults in Great Britain. Eligible patients are limited to apolipoprotein E ε4 (ApoE ε4) heterozygotes or non-carriers, which is a requirement for the class of currently approved amyloid-targeting therapies in Great Britain. Donanemab is the only amyloid plaque-targeting therapy with evidence to support stopping therapy when amyloid plaques are removed. Great Britain is the third major market to approve donanemab, marketed as Kisunla.

I believe we can improve the standard of care for people living with Alzheimer’s disease. Despite years of medical research, until recently, there has been little progress in treatment options for this disease. The authorisation of donanemab for eligible adults is welcome news. Great Britain now needs to rapidly increase National Health Service (NHS) capacity and expertise in diagnostics and treatment facilities to enhance the management of Alzheimer’s disease for the benefit of people today and tomorrow.

Professor Cath Mummery, Consultant Neurologist at University College London Hospitals NHS Foundation Trust and Chair of the NIHR Dementia Translational Research Collaboration.

However, the costs of providing donanemab, including regular infusions and intensive monitoring for serious side effects, balanced against the relatively small benefit it provides to patients, means it cannot currently be considered good value for the taxpayer, according to NICE.

The clinical trial evidence suggests that the monthly injection can slow Alzheimer’s disease progression by 4 to 7 months. However, there are significant uncertainties about how much benefit donanemab provides, and how long this lasts after stopping treatment.

There are also significant health risks associated with the treatment. A third of donanemab recipients experienced amyloid-related imaging abnormalities (ARIA) caused by brain swelling and bleeding.

NICE has asked the company and NHS England to provide additional information to address areas of uncertainty in the evidence.

The consultation on the draft NICE guidance on donanemab will close on 20 November 2024. The independent committee will consider all responses, including any additional analyses, at a second committee meeting before producing its final recommendations.

View the draft guidance and comment here.

Fast track approval in Fabry disease?

Posted on October 24, 2024 by - Research

Sangamo Therapeutics announces alignment with FDA on Accelerated Approval Pathway for ST-920 in Fabry Disease: BLA submission expected in 2025

– U.S. Food and Drug Administration (FDA) provides a clear regulatory pathway to Accelerated Approval for isaralgagene civaparvovec using data from ongoing Phase 1/2 STAAR study, avoiding requirement for additional registrational study and accelerating estimated time to potential approval by approximately three years.

– FDA confirms that estimated glomerular filtration rate (eGFR) slope data at one year across all Phase 1/2 patients can serve as primary basis for approval under Accelerated Approval pathway.

– Data to support Accelerated Approval pathway available in first half of 2025, with a potential Biologics License Application (BLA) submission expected in the second half of 2025.

22nd October 2025: Sangamo Therapeutics, Inc, a genomic medicine company, has announced the outcome of a recent successful interaction with the U.S. FDA, providing a clear regulatory pathway to Accelerated Approval for isaralgagene civaparvovec, or ST-920, its wholly owned gene therapy product candidate for the treatment of Fabry disease.

The FDA has agreed in a Type B interaction that data from the ongoing Phase 1/2 STAAR study can serve as the primary basis for approval under the Accelerated Approval Program, using eGFR slope at 52 weeks across all patients as an intermediate clinical endpoint. The complete dataset to support an Accelerated Approval pathway will be available in the first half of 2025. This approach unlocks a potential BLA submission in the second half of 2025, three years ahead of previous estimates, and avoids the requirement for an additional registrational study to establish clinical efficacy.

Sangamo engaged with the FDA on alternative pathways to potential approval following analysis of clinical data from the Phase 1/2 STAAR study showing encouraging safety and efficacy data, including promising preliminary evidence of improved kidney function. Renal manifestations, such as proteinuria or a decreased glomerular filtration rate, occur early in life in almost all male, and in many female, patients with Fabry disease, and can lead to end-stage renal disease and early death. In the 18 male and female patients treated with isaralgagene civaparvovec with more than one year of follow-up data, statistically significant improvements were observed in both mean and median eGFR levels, resulting in a positive annualised eGFR slope. Based on these latest data, the FDA agreed that eGFR slope at 52 weeks can serve as an intermediate clinical endpoint to support a potential Accelerated Approval. The FDA also advised that eGFR slope at 104 weeks may be assessed to verify clinical benefit.

Fabry is a debilitating disease, for which there is a serious unmet medical need. I strongly believe in the potential for ST-920 to alleviate many manifestations of Fabry disease and am delighted to have a clear regulatory pathway that could bring this treatment to patients significantly sooner than originally anticipated

Sandy Macrae, Chief Executive Officer of Sangamo

Dosing was completed in the Phase 1/2 STAAR study in April 2024, with a total of 33 patients dosed. The longest treated patient recently achieved four years of follow-up. The 18th and final patient who started the study on Enzyme Replacement Therapy (ERT) was successfully withdrawn from ERT in September 2024, and all 18 patients remain off ERT as of today. The 52-week eGFR slope data from all enrolled patients in the Phase 1/2 STAAR study will be available in the first half of 2025. A potential BLA submission is anticipated in the second half of 2025.

Bepranemab Phase 2a study

Posted on October 22, 2024 by - Alzheimer's Disease, Dementia

Results accepted for Late-Breaking Presentation at Clinical Trials on Alzheimer’s Disease (CTAD) 2024 Meeting

  • Bepranemab – an investigational anti-tau antibody – targeting the mid-region of the tau protein is being studied to assess its potential to delay Alzheimer’s disease progression1 
  • Late-breaking Phase 2a study TOGETHER (AH0003) results include all relevant clinical and imaging data1
  • Late-breaking symposium will take place on 31 October 20242
  • UCB has regained all global rights to bepranemab from Roche/Genentech

22nd October 2024: UCB today announced that the results of its double-blind TOGETHER (AH0003) Phase 2a study of bepranemab – an investigational anti-tau antibody – in people living with prodromal to mild Alzheimer’s Disease (AD), have been accepted for presentation in a late-breaking symposium at the 2024 Clinical Trials on Alzheimer’s Disease (CTAD) Meeting.2 The CTAD meeting will take place in Madrid, Spain, October 29 – November 1, 2024.

The presentation will highlight primary and key secondary results from the Phase 2a study, including clinical, safety, and imaging endpoints.

“We are pleased to have our innovative research programme recognised by the CTAD committee and look forward to sharing the encouraging results of the TOGETHER study with the scientific community. These new data represent an important step in building a rigorous body of evidence evaluating bepranemab as an investigational treatment option, for people living with early Alzheimer’s disease,” said Alistair Henry, Chief Scientific Officer, UCB.

TOGETHER is a Phase 2a, global, multicenter, participant- and investigator-blind, placebo-controlled, parallel-group study designed to investigate the efficacy, safety and tolerability of bepranemab (two dose levels) – administered intravenously every 4 weeks – versus placebo in participants with prodromal (40% of study population) or mild (60% of study population) Alzheimer’s disease over an 80-week treatment period, followed by a 48-week open-label extension period, and a 16-week safety follow-up period.1

Details of the late-breaking symposium:

  • Title: Results from TOGETHER, a double-blind, placebo-controlled Phase 2 study evaluating efficacy, safety and tolerability of bepranemab in prodromal–mild Alzheimer’s disease
  • Presenters: Martin Citron, PhD (UCB Pharma); Matthew E Barton, PhD (UCB Pharma); Randall J Bateman, MD (Washington University School of Medicine, St Louis, MO, USA)
  • Date/Time: October 31, 5:10pm CET

UCB also announced today that the company has regained all global rights to bepranemab following termination of a Collaboration Agreement with Genentech, a member of the Roche Group, and Roche. In July 2020, UCB entered a worldwide, exclusive license agreement with Roche and Genentech, for the global development, manufacturing, and commercialization of bepranemab in Alzheimer’s disease.3

For more information, visit https://www.ucb.com/clinical-studies/Clinical-Trials?studyId=AH0003

This release discusses investigational uses of an agent in development and is not intended to convey conclusions about efficacy or safety. There is no guarantee that any investigational uses of such product will successfully complete clinical development or gain health authority approval.

About bepranemab

Bepranemab is a recombinant, humanised, full-length immunoglobulin G4 monoclonal antibody (mAb) that specifically targets human tau protein.4,5 Bepranemab targets a central region of tau (amino acids 235–250), near to the microtubule binding region (MTBR). 4,6 The rationale of this approach is that a mid-region antibody will more potently interfere with cell-to-cell propagation of pathogenic, aggregated tau than antibodies that target other regions of tau (ie., the N-terminus).4,6,7

References:

  1. https://www.ucb.com/clinical-studies/Clinical-Trials?studyId=AH0003. Accessed October 2024.
  2. https://www.ctad-alzheimer.com/files/files/PROGRAM_CTAD2024_WEB%20October%2014.pdf. Accessed October 2024.
  3. https://www.ucb.com/stories-media/Press-Releases/article/UCB-enters-into-collaboration-with-Roche-to-develop-antibody-treatment-for-people-living-with-Alzheimer-s-Disease. Accessed October 2024.
  4. Courade JP, et al. Epitope determines efficacy of therapeutic anti-Tau antibodies in a functional assay with human Alzheimer Tau. Acta Neuropathol. 2018;136(5):729–745.
  5. Ewen C, et al. Bepranemab: an overview of the Phase I/IB clinical study program. Presentation at Tau2024, March 25-26, 2024, Washington, D.C, USA.
  6. Albert M, et al. Prevention of tau seeding and propagation by immunotherapy with a central tau epitope antibody. Brain. 2019;142(6):1736–1750.
  7. Alzforum – Networking for a cure. https://www.alzforum.org/therapeutics/bepranemab. Accessed October 2024.

Oditrasertib in multiple sclerosis – phase 2 trial stopped

Posted on October 21, 2024 by - Multiple Sclerosis

Sanofi has stopped a phase 2 trial of Denali Therapeutics-partnered oditrasertib in multiple sclerosis. The RIPK1 inhibitor was removed from the list of active studies after it failed to meet its primary and secondary endpoints.

The belief was that inhibiting the kinase may stop tissue damage and neuronal death by disrupting the production of cytokines and other proinflammatory factors, but Sanofi has failed to prove this in the clinic.

The study was comparing the effect of oditrasertib, also known as SAR443820, and placebo on serum neurofilament levels. Neurofilament light chain (NfL) is a neurodegenerative disease biomarker. A drop in NfL could reflect a reduction in axonal damage or neuronal degeneration, events that cause the release of the biomarker.

Oditrasertib failed to cause a positive change in NfL compared to placebo.

Lundbeck enhances neuroscience pipeline

Posted on October 20, 2024 by - Epilepsy

Deal to acquire Longboard Pharmaceuticals gives access to Bexicaserin for Dravet Syndrome

October 14 2024: H. Lundbeck A/S and Longboard Pharmaceuticals, Inc have announced an agreement for Lundbeck to acquire Longboard. Longboard is a clinical-stage biopharmaceutical company focused on developing novel, transformative medicines for neurological diseases.

Through the acquisition of Longboard, Lundbeck gains access to bexicaserin, a novel 5-HT2C agonist in development for the treatment of seizures associated with DEEs, including Dravet syndrome, Lennox-Gastaut syndrome, and other rare epilepsies. This aligns with Lundbeck’s expertise in delivering innovative treatments and re-establishes scientific and commercial leadership in rare epilepsies.

Bexicaserin has entered a global phase III trial (DEEp SEA Study) evaluating bexicaserin for the treatment of seizures associated with Dravet syndrome in participants two years of age and older. The DEEp SEA Study is part of a broader DEEp Programme (DEEp SEA, DEEp OCEAN and DEEp OLE) which is planned to take place across ~80 sites globally and include ~480 participants with a range of DEEs. Bexicaserin has received Breakthrough Therapy Designation (BTD) from the U.S. FDA and is set to become a cornerstone of Lundbeck’s new neuro-rare disease franchise. Recent nine-month open-label data further supports the de-risked nature of its 5-HT2C mode-of-action, highlighting its superior target product profile.

About the DEEp SEA Study

The DEEp SEA Study (LP352-302) is a global phase III double-blind, placebo-controlled clinical trial to evaluate the efficacy of bexicaserin in Dravet syndrome as assessed by countable motor seizures in ~160 participants between the ages of two and 65 years old. An important secondary objective is to evaluate the safety and tolerability of bexicaserin. Following a 5-week screening period and baseline evaluations, study participants initiate dose titration over a 3-week period and subsequently continue on the highest tolerated dose throughout the maintenance period of 12-weeks. Following the maintenance period, eligible participants will be given the opportunity to enroll in the 52-week DEEp Open-Label Extension (DEEp OLE Study LP352-303). The phase III DEEp SEA Study is part of the broader DEEp Program which will take place across ~80 sites globally and include ~480 participants with a range of Developmental and Epileptic Encephalopathies (DEEs).

About Developmental and Epileptic Encephalopathies (DEEs)

Epilepsy is the third leading contributor to the global burden of neurological disorders and affects 65 million people worldwide. DEEs are a group of severe early-childhood onset epilepsies characterized by refractory seizures and developmental delay and/or regression. These diseases are often progressive and commonly show resistance to treatment. DEEs encompass a diverse range of over 25 syndromes, of which only four currently have FDA-approved therapies with partial treatment responses. Consequently, there is a remaining significant unmet need to find therapies that efficiently act across the DEE spectra. Some common epilepsy syndromes that are DEEs include:

  • Dravet syndrome
  • Lennox-Gastaut syndrome
  • Tuberous sclerosis complex
  • CDKL5 deficiency disorder
  • Early infantile epileptic encephalopathy, including Ohtahara syndrome and early myoclonic encephalopathy
  • Infantile epileptic spasms syndrome, including West syndrome
  • Febrile infection-related epilepsy syndrome
  • Epilepsy of infancy with migrating focal seizures
  • Epilepsy with myoclonic-atonic seizures, otherwise known as myoclonic-atonic epilepsy (MAE) or Doose syndrome.
  • Landau-Kleffner syndrome
  • Developmental and epileptic encephalopathy with spike and wave activation in sleep (DEE-SWAS)

Epilepsy drug may treat obstructive sleep apnoea

Posted on October 19, 2024 by - Epilepsy, Sleep

10 September 2024: Patients taking sulthiame (brand name Ospolot), a drug currently in use for epilepsy, experienced a reduction in their symptoms of obstructive sleep apnoea (OSA) according to results of a clinical trial presented at the European Respiratory Society (ERS) Congress in Vienna Austria [1].

Patients with OSA often snore loudly, their breathing starts and stops during the night, and they may wake up several times. Not only does this cause tiredness, but it can also increase the risk of high blood pressure, stroke, heart disease and type 2 diabetes. OSA is very common, but many people do not realise they have the condition.

The new research was presented by Professor Jan Hedner from Sahlgrenska University Hospital and the University of Gothenburg in Sweden. He said: “The standard treatment for obstructive sleep apnoea is sleeping with a machine that blows air through a face mask to keep the airways open. Unfortunately, many people find these machines hard to use over the long term, so there is a need to find alternative treatments. We also a need better understanding of the underlying mechanisms in OSA to help clinicians give more personalised treatment.”

The trial was a double-blind, randomised, placebo-controlled trial. It involved 298 people with OSA being treated at 28 different centres in Spain, France, Belgium, Germany and the Czech Republic. All the patients could not tolerate or refused to use continuous positive airway pressure (CPAP) machines or mouthpieces designed to keep the airways open.

The patients were assessed with polysomnography at the start of the trial, and after four weeks and 12 weeks in the study. Polysomnography measures breathing, levels of oxygen in the blood, heart rhythm, eye movements, brain and muscle activity during a night of sleep.

The patients were divided into four groups: 74 people took 100 mg of sulthiame daily, 74 took 200 mg, 75 took 300 mg and the remaining 75 took a placebo (dummy pill). Sulthiame is a drug that targets the respiratory system by inhibiting an enzyme called carbonic anhydrase and stimulating the upper airway muscles.

Professor Hedner said:

People taking sulthiame in the trial had a reduction in OSA symptoms such as stopping breathing during the night and feeling sleepy during the day. Their average levels of oxygen in the blood were also improved with the treatment. This suggests that sulthiame could be an effective treatment for OSA, especially for those who find they cannot use the existing mechanical treatments. Although sulthiame is already available as a treatment for childhood epilepsy, we still need to carry out a phase III study to confirm the beneficial respiratory effects of this drug in a larger group of patients with OSA.”

References

[1] Abstract no: OA5433 “Late Breaking Abstract – A randomized, double-blind, placebo controlled, dose-finding trial of sulthiame in obstructive sleep apnea”, by Jan Hedner et al; Presented in session, “Emerging insights in prognostic aspects and positive airway pressure treatment for obstructive sleep apnoea” at 14:15–15:30 CEST on Tuesday 10 September 2024. [https://live.ersnet.org/programme/session/93028]

Read more: Positive study results in 298 patients with obstructive sleep apnea (OSA) – Desitin Arzneimittel GmbH (desitinpharma.com)