EP-4741007-A2 - METHOD OF TREATING OR PREVENTING AN ADVERSE SECONDARY NEUROLOGICAL OUTCOME FOLLOWING A HAEMORRHAGIC STROKE

Abstract

The present disclosure relates generally to methods of treating or preventing an adverse secondary neurological outcome in a subject following a haemorrhagic stroke accompanied by extravascular erythrolysis and release of cell-free heme and/or cell-free haemoglobin (Hb) into a cerebral spinal fluid (CSF), the method comprising exposing the CSF of a subject in need thereof to a therapeutically effective amount of hemopexin (Hx) and for a period of time sufficient to allow the Hx to form a complex with, and thereby neutralise, the cell-free heme and, optionally, exposing the CSF of the subject to a therapeutically effective amount of haptoglobin (Hp) and for a period of time sufficient to allow the Hp to form a complex with, and thereby neutralise, the cell-free Hb.

Inventors

• The designation of the inventor has not yet been filed

Assignees

• CSL Behring AG
• Universität Zürich

Dates

Publication Date

20260513

Application Date

20220131

Claims (9)

1. An in vitro method of determining whether a subject is at risk of developing an adverse secondary neurological outcome following a haemorrhagic stroke accompanied by extravascular erythrolysis and release of cell-free heme and/or cell-free haemoglobin (Hb) into a cerebral spinal fluid (CSF), the method comprising (i) measuring in a CSF sample, obtained from the subject following the haemorrhagic stroke, the amount of cell-free Hb; and (ii) comparing the amount of cell-free Hb in the CSF sample determined in step (i) with a reference value, wherein the subject's risk of developing an adverse secondary neurological outcome is determined based on the comparison in step (ii).
2. The method of claim 1, wherein the subject is determined to be at risk of developing adverse secondary neurological outcome where the amount of cell-free Hb in the CSF sample determined in step (ii) is at least about 7 µM.
3. The method of claim 1, wherein the adverse secondary neurological outcome is angiographic vasospasm and the subject is determined to be at risk of developing angiographic vasospasm where the amount of cell-free Hb in the CSF sample determined in step (ii) is at least about 7 µM.
4. The method of claim 1, wherein the adverse secondary neurological outcome is delayed cerebral ischemia and the subject is determined to be at risk of developing delayed cerebral ischemia where the amount of cell-free Hb in the CSF sample determined in step (ii) is at least about 3 µM.
5. The method of claim 1, wherein the adverse secondary neurological outcome is delayed ischemic neurological deficit and the subject is determined to be at risk of developing delayed ischemic neurological deficit where the amount of cell-free Hb in the CSF sample determined in step (ii) is at least about 7 µM.
6. The method of claim 1, wherein the cell-free haemoglobin is oxyhemoglobin (oxyHb) or methemoglobin (metHb).
7. The method of claim 6, wherein the cell-free hemoglobin is oxyHb.
8. The method of claim 6, wherein the cell-free hemoglobin is metHb.
9. Hemopexin (Hx) for use in the treatment of a subject being at risk of an adverse secondary neurological outcome following a haemorrhagic stroke, wherein said subject is determined to be at risk of developing an adverse secondary neurological outcome following a haemorrhagic stroke according to the method of any one of claims 1-8, wherein the administration of Hx is for a period of time sufficient to allow the Hx to form a complex with, and thereby neutralise, the cell-free heme.

Description

TECHNICAL FIELD The present invention relates generally to methods and compositions for treating and/or preventing an adverse secondary neurological outcome in a subject following a haemorrhagic stroke into a cerebral spinal fluid (CSF) compartment, in particular following subarachnoid hemorrhage (SAH). BACKGROUND All references, including any patents or patent application, cited in this specification are hereby incorporated by reference to enable full understanding of the invention. Nevertheless, such references are not to be read as constituting an admission that any of these documents forms part of the common general knowledge in the art, in Australia or in any other country. Haemorrhagic stroke involves the rupture of a blood vessel in or on the surface of the brain with bleeding into the surrounding tissue. Examples of haemorrhagic stroke include i) intracerebral haemorrhage (herein referred to as ICH) which involves a blood vessel in the brain bursting; ii) intraventricular haemorrhage (herein referred to as IVH) which is bleeding into the brains ventricular system; and iii) subarachnoid haemorrhage (herein referred to as SAH) which involves bleeding in the space between the brain and the tissue covering the brain known as the subarachnoid space. Most often SAH is caused by a burst aneurysm (herein referred to as aSAH). Other causes of SAH include head injury, bleeding disorders and the use of blood thinners. Aneurysmal subarachnoid hemorrhage (aSAH) is the most common cause of SAH and is associated with the highest rates of mortality and long-term neurological disabilities. Despite advances in aneurysm repair and neurointensive care, the median in-hospital case fatality rate in Europe is 44.4% and 32.2% in the United States. 35% of the survivors report a poor overall quality of life 1 year after the bleeding event with 83-94% not able to return to work. The estimated incidence of aSAH from a ruptured intracranial aneurysm in the U.S. is 1 case per 10,000 persons, yielding approximately 27,000 new cases each year. Additionally, aSAH is more common in women than in men (2:1); the peak incidence is in persons 55 to 60 years old. Besides early brain injury within the first 72 hours (Sehba et al., 2012), patient outcomes after aSAH are determined by delayed secondary brain injury, which occurs between day 4 to 10 after aneurysm rupture (Macdonald, 2014). Delayed secondary brain injury is assumed to be multifactorial involving macro- and microvascular dysfunction, neuroinflammation, neuronal apoptosis, and pathological electrical activity of the brain (Macdonald, 2014). Two-thirds of patients after aSAH develop angiographic vasospasms of large cerebral arteries (aVSP) (Dorsch and King, 1994). Delayed cerebral ischemia (DCI) with radiologic demarcation of ischemic brain areas and clinically evident delayed ischemic neurologic deficits (DIND) are found in one-third of patients (Rowland et al., 2012). The occurrence of at least one of these secondary manifestations defines subarachnoid hemorrhage related secondary brain injury (SAH-SBI). The lag-time between aneurysm rupture and the onset of SAH-SBI provides a window of opportunity for preventative and therapeutic interventions, defining an unmet need for identifying patients at high risk for SAH-SBI as well as new drug targets. So far, the only preventative intervention that has been shown to moderately improve neurological outcomes after aSAH is oral nimodipine (Class I, Level A) (Diringer et al., 2011; Connolly et al., 2012). In symptomatic patients, therapeutic options are currently limited to rescue therapies with induction of systemic arterial hypertension and, in selected patients, mechanical or chemical angioplasty to resolve aVSP (Diringer et al., 2011; Connolly et al., 2012). Hence, there is an urgent and unmet need for specific therapies to treat and / or prevent SAH-SBI in patients following aSAH. Despite enormous research efforts, there is still no clinically established biomarker for reliable monitoring of SAH-SBI. Although widely used, clinical scores (Hunt and Hess, 1968; Teasdale et al., 1988), radiological scores (Fisher et al., 1980; Frontera et al., 2006; Wilson et al. , 2012), and day-to-day assessment with transcranial doppler sonography (TCD) (Diringer et al., 2011; Connolly et al., 2012) show a limited accuracy for the detection of patients at risk (de Rooij et al., 2013). Cell-free hemoglobin (Hb) accumulates in patient-CSF and has been considered as an upstream driver of SAH-SBI (Pluta et al., 2009; Hugelshofer et al., 2019; Buehler et al., 2020). Data from a small pilot study with daily CSF spectrophotometry in 18 patients indicated that patients with a high cumulative CSF-Hb exposure over two weeks after aneurysm rupture may have an increased risk to develop SAH-SBI (Hugelshofer et al., 2018). However, so far no correlation between the concentration of cell-free Hb in the patient's CSF (CSF-Hb) and the incidence of subarachnoid hae