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Author: Jean-Claude Muller, 穆卓Executive Editor at BtoBioInnovation  jcm9144@gmail.com

SPECIAL REPORT 24.05 

Stroke: An Update

This report is an update from the paper published on February 28, 2022.

Stroke ranks as the third cause of death in the world after ischaemic heart disease and the cumulative cancer diseases and the first cause of women’s death. Each year, about 20 million strokes occur in the world causing a total of 7.2 million deaths. Stroke is a global epidemic which affects all types of countries, a study published in 2009 stated that about 85% of all stroke deaths occur in low-and middle-income countries.  Age, atherosclerosis, and high blood pressure are recognised as the most relevant risk factors associated with stroke. With a fast-growing ageing population around the globe, the number of persons at risk is expected to increase by as much as 20% in the next decades.

The economic and societal burden of stroke is extremely high with direct and indirect costs estimated at more than €60 billion in the European Union and at $103 billion in the United States

Three months after a stroke, 17% of patients have died, 54% still have moderate to severe disability and only 29% went back to normal living. Disability induced by stroke often requires adapted assistance for daily care over several months. The key word for stroke recovery is undisputedly speed to treatment access.  The sooner signs of onset of stroke are recognised and treated the better the overall outcome will be for a given patient.

There are two types of strokes:

• Ischaemic stroke is caused by a clot, often called thrombus, that obstructs a cerebral artery and inhibits the blood flow to a given region of the brain. The main causes of ischaemic stroke are due to atherosclerosis and atrial fibrillation.
• Haemorrhagic stroke is caused by a blood vessel that ruptures and subsequently prevents blood flow to part of the brain. The main underlying cause of haemorrhagic stroke is high blood pressure. The Black Women Health Study showed that women who develop hypertension before age 45 have twice the risk of suffering a stroke.

Whatever occurs, in all these cases, brain cells close to the injured area are being oxygen deprived and begin to die or are being severely damaged.

70 to 80% of all strokes are of the ischaemic type. The primary goal for the acute treatment of ischaemic stroke patients its to restore as rapidly as possible blood flow to the injured brain area to protect healthy tissues and help damaged area to recover. The longer brain tissues are deprived of oxygen and nutrients the greater patients are at risk of a fatal issue or of a permanent brain damage followed by neurologic deterioration characterised by a sudden onset and quick peak of transient and often permanent neurological deficits.  Acute treatments for ischaemic stroke include thrombolysis such as alteplase, a tissue Plasminogen Activator (t-PA), the gold standard thrombolytic agent sold by Roche, Boehringer Ingelheim, and Pfizer and drug therapies to break down the thrombus and inhibit platelet aggregation around the occlusion. The major risk with these agents is the occurrence of intracerebral haemorrhages (ICH).The current interventional treatment, called mechanical thrombectomy, consists of a procedure aimed at physically removing the clot.  In a result published in JAMA researchers led by Johannes Kaesmacher (1), from the University Hospital Bern in Switzerland, showed that associating thrombolysis plus thrombectomy versus thrombectomy alone was beneficial at 90 days if administration of thrombolysis was performed within 2hours 20 minutes.

Acute haemorrhagic stroke affects around 28% of all yearly strokes but 44% of all stroke-related deaths. Researchers from King College London (2) have predicted that in the UK, the increase in deaths related to intracerebral haemorrhage (ICH) in people aged 70 to 95 and over is estimated to be 59.4% by 2050. This stroke subtype is a condition where haematoma is formed within the brain parenchyma with or without blood extension into the ventricles. There is currently no approved treatment available for this form of stroke.  Consequentl, 75% of acute haemorrhagic stroke patients die or suffer from severe disability. In the MISTIE III trial published in 2019 by Hanley et al. (3), the authors also showed that there was a strong relationship between the volume of haematoma evacuated with the use of alteplase, and the level of handicap one year after treatment.

To reduce the burden of stroke and address its long-term consequences, the European Stroke Organisation (ESO) and the Stroke Alliance for Europe (SAFE) published the Stroke Action Plan 2018-2030 (4 and 5) with the objectives to decrease first month-case fatality rates to less than 25% and increasing the rate of good functional outcomes to more than 50%.

Right now, most innovations occur in the acute management of the condition and unfortunately very little in the treatment of the different phases of stroke recovery which can last several years. Since many years the main treatment of long-lasting stroke conditions are aspirin and platelet aggregation inhibition with drugs such as clopidogrel, associated with continuous care. Because of the high plasticity of the brain, intense physical rehabilitation, dedicated daily care and, as shown recently, regular vagal nerve stimulation can nevertheless still lead to improvement on physical function with benefits at one year.

Two French start-up companies are currently trying to bring new solutions to treat the acute phase of the two types of strokes.

Acticor, a Euronext traded company based in Paris, is developing glenzocimab, a monoclonal antibody which targets glycoprotein VI (GP VI), a platelet membrane protein which belongs to the immunoglobulin superfamily. Glycoprotein VI is expressed exclusively by platelets and is a key receptor for binding fibrin, fibrinogen, and collagen. Interactions between GP VI and its different ligands trigger platelet activation leading to aggregation, additional platelets recruitment and clot formation. Inhibiting GP VI is considered as an attractive antithrombotic strategy without the risk of major bleeding. Acticor has several ongoing clinical trials to study the efficacy and safety of glenzocimab. ACTIMIS, an add-on therapy to standard of care and ACTISAVE, an add-on therapy to thrombolysis. On January 23, 2024, Acticor has published results from the ACTIMIS’ clinical study in The Lancet Neurology Journal (7). In 106 patients randomly assigned to glenzocimab at 1,000 mg (n=53) or placebo (n=53) the outcomes were impressive. Patients treated with glenzocimab had a reduction of 50% of non-symptomatic haemorragic transformation with no patients with an intracranial haemorrhage versus five in the placebo group. All cause of deaths were lower with glenzocimab (four patients) than with placebo (11 patients). On February 7, Acticor and the University of Birminghan in the UK have announced the launch of LIBERATE, a phase 2b clinical study aimed at evaluating the tolerance and activity of glenzocimab in 200 myocardial infarcted patients with elevated segment ST (STEMI).

Op2Lysis, based in Caen (France) and in Liège (Belgium) is developing O2L-001, a nanoparticule formulation of an engineered alteplase, OptPA, which is an effective and safe treatment to remove intracerebral haematoma (ICH) and reduce disability and death. O2L-001 is locally injected in the brain, through micro-invasive surgery via a catheter at the core of the haematoma. O2L-001 is used via a unique injection, it has a better thrombolytic effect than alteplase, and is expected to induce less side effects. The product is in late-stage preclinical development. In late 2021, the US Food and Drug Administration has granted Orphan Drug Designation to 02L-001 for the treatment of intracerebral haemorrhage. The company has recently been awarded funding by the European Innovation Council (ECI) and is currently actively involved in raising funds to launch its clinical trial. On October 9, 2023, Op2Lysis has been nominated for the Prix Gallien USA 2023 in the Best StartUp category.

References.

1. Johaness Kaesmacher et al., JAMA 2024 Feb 7:e240589.  Published Online  https://Doi 10.1001/jama.2024.0589. 
2. Hatem A. Wafa, Iain Marshall, Charles D. A. Wolfe, Wanqing Xie, Catherine O. Johnson, Roland Veltkamp, and Yanzhong Wang, on behalf of the PRESTIGE-AF consortiumThe Lancet Regional Health – Europe 2024;38: 100842 Published Online xxx https://doi.org/10. 1016/j.lanepe.2024. 10084
3.  Hanley DF, Thompson RE, Rosenblim M. et al. Efficacy and safety of minimally invasive surgery with thrombolysis in intracerebral haemorrgage evacuation (MISTIE III) a randomized, controlled, open-label, blinded endpoint phase 3 trial . Lancet, 2019 published February 7. http:///dx.doi.org/10.1016/S0140-6736 (19)30195-3
4. https://actionplan.eso-stroke.org/
5. https://actionplan.eso-stroke.org/wp-content/uploads/2021/04/SAP-E-Scientific-Publication.pdf
6. See also further results presented at the International Stroke Conference 2024, held on February 7-9 in Phoenix, Arizona.*
7. The Lancet Neurology. Published:February, 2024DOI:https://doi.org/10.1016/S1474-4422(23)00427-1

Paris, February 28, 2024

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