Pharmaceutical
Division

CNS Program – Arterial Ischaemic Stroke (AIS)

Scientific progress has demonstrated the ability of melanocortins as hormonal therapy to exert a positive effect on the central nervous system (CNS).

Melanocortins, including analogues of the naturally occurring alpha-melanocyte stimulating hormone (α-MSH), bind to melanocortin receptors (MC1R through MC5R) on cells throughout the body and exert their effects.

Advanced knowledge on the expression of MC1R and MC4R in the brain has enabled afamelanotide and derivative molecules to be used for specific disorders affecting brain function.

NEUROPROTECTION

The concept of neuroprotection offered by afamelanotide, an α-MSH analogue, and other hormones of the melanocortins family.

Afamelanotide is known to act as a potent anti-oxidative hormone. The drug possesses further therapeutic benefits, causing dilation of vessels, reduction of fluid formation, protection of nerve and brain tissue, and restoration of the Blood Brain Barrier (BBB; a critical barrier to protect the brain in the case of trauma and infections).

The BBB is a highly selective structure formed around the cells of blood vessels in the brain to protect it from pathogens (toxins) and other substances that can damage neurons, the principal cells of the brain. The BBB consists of various cells, but the barrier function comes mainly from astrocytes (end-feet) which wrap around the cells of blood vessels (endothelial cells).

In the event of damage (trauma) and diseases of the brain, such as stroke, the BBB becomes disrupted and rapidly starts to leak various toxins outside the circulation (extra-cellular space) affecting neuronal networks, and therefore the primary functions of these cells, conduction of signals.

In its healthy state, the BBB allows the diffusion of oxygen, water and glucose.

Melanocortins, including afamelanotide, are shown to protect critical brain cells, as well as the BBB in experimental and under pathological conditions.

Stroke (AIS)

Stroke is the second most common cause of death and a leading cause of disability worldwide, yet many stroke patients are ineligible for the current standard of care (clot removal and clot dissolution).

Acute stroke most frequently occurs unexpectedly and without warning. There are two main reasons for AIS: a severe constriction of a blood vessel, and a clot lodged within the vessel. This causes an immediate lack of oxygen and glucose supply, leading to partial death of brain tissue. A stroke patient may lose sudden consciousness, and typically will experience loss of movement of one side of the body (such as the arms, legs or face).

Following a stroke, family and bystanders usually ensure that the patient is immediately transported to an emergency department of a hospital, where a brain scan (computed tomographic angiography; CTA) needs to confirm the diagnosis. Partial or full recovery of the patient depends on the size of the infarct (dead brain tissue) incurred, speed of treatment offered, and underlying general health.

A stroke affects the brain instantly, as blood flow stagnates or comes to a complete standstill due to the clot within the vessel. The lack of oxygen supply to the brain is called ischemia, and in general three zones of oxygen depletion are distinguished within the brain. The outer zone is called the oligemic zone, the middle zone the penumbra and the centre the ischaemic core (dead brain tissue).

The immediate objective is to restore the penumbra and oligemic areas of the brain which are found around the lodged clot within the brain vessel.

For more scientific detail, see Scientific Communiqué VII (November 2020) – The Cerebral Vascular System.

Unfortunately, the majority of stroke patients do not benefit from standard therapy (clot removal or clot dissolution) because the treatment is not offered within the internationally accepted critical treatment window of four and a half hours, or because the clot is lodged in the higher regions of the brain (M2 branch and higher).

CLINUVEL’s CUV801 pilot study focusses on arterial ischaemic stroke (AIS) as the first CNS indication for afamelanotide.

More than two decades of safety data captured in clinical trials, special access programs and post-authorisation use of SCENESSE^® provide justification for expanding the use of the drug to evaluate its therapeutic benefit for patients with acute conditions.

The pilot AIS study, CUV801, is evaluating the safety of afamelanotide in six adult patients suffering acute strokes but who are ineligible for current standard of care due to the location of the clot (M2 levels and higher). The primary objective of the study is to assess the safety of afamelanotide in these patients, while the secondary objective is to assess whether the therapy affects the size of the penumbra (brain tissue at risk of cell dying off), by increasing blood flow, restoring oxygen supply to the brain, and reducing the amount of cerebral oedema (fluid) which is seen as a result of the stroke.

In general, CLINUVEL is interested in providing a therapeutic solution to those stroke patients who are not selected for standard clot removal or dissolution therapy.

During the CUV801 study, patients are assessed on parameters such as the amount of blood reaching the affected area of the brain, the size of the oligemic zone and penumbra (oxygen deprived zone at risk) and ischaemic core (infarct, dead brain area).

A qualitative and quantitative comparison will be made between brain scans, comprising images generated by CTA and magnetic resonance imaging (MRI) taken at various timepoints during the three month study.

As the clinical study progresses, patients’ neurological function (movement and mental activity of learning and understanding) are being assessed through standardised clinical observations and questionnaires. Since most stroke patients spend the first two weeks in a hospital or rehabilitation centre, patients will be evaluated and monitored while they remain hospitalized.

The university hospital in Melbourne conducting CUV801 is currently screening stroke patients for inclusion in this study.