GB2568291A

GB2568291A - New use

Info

Publication number: GB2568291A
Application number: GB1718676.8A
Authority: GB
Inventors: Crisby Milita
Original assignee: Individual
Current assignee: Individual
Priority date: 2017-11-13
Filing date: 2017-11-13
Publication date: 2019-05-15
Also published as: GB201718676D0

Abstract

Hydroxychloroquine, or a pharmaceutically acceptable salt thereof, for use in the treatment of mild cognitive impairment is provided. Hydroxychloroquine, or a pharmaceutically acceptable salt thereof, for use in preventing, and/or reducing the risk of the onset of dementia, preferably wherein the dementia is Alzheimer’s disease is also outlined. A method of treatment of mild cognitive impairment, of reducing the risk of the onset of dementia in a patient with mild cognitive impairment, and/or of prevention of the onset of dementia in a patient with mild cognitive impairment, which method comprises: (a) measuring the patient’s plasma level, or cerebrospinal fluid level, of one or more biomarker(s) of dementia; (b) determining whether the level of that biomarker in the relevant fluid is above or below (as appropriate) a relevant minimum or maximum (as appropriate) normal value; and (c) if so, administering hydroxychloroquine, or a pharmaceutically acceptable salt thereof, to the patient for a time and at an appropriate dosage to increase or reduce (as appropriate) the level of that biomarker to above or below (as appropriate) the relevant normal value, is outlined. Preferably the dementia is Alzheimer’s disease and the biomarker is beta-amyloid protein as measured in the patient’s cerebrospinal fluid and the level of β-amyloid measured prior to administration is below a minimum normal value.

Description

NEW USE

Field of the Invention

This invention relates to a new use of a known pharmaceutically-active compound.

Prior Art and Background

The listing or discussion of an apparently prior-published document in this specification should not necessarily be taken as an acknowledgement that the document is part of the state of the art or common general knowledge.

Neurological disorders, which are characterized by one or more structural, biochemical and/or electrical abnormalities in the brain, spinal cord and/or other part of the nervous system have been estimated by the World Health Organization to affect as many as one billion people worldwide.

Neurodegenerative processes that lead to the such disorders typically involve a loss of structure and/or function (including death) of neurons, and may take place in many different levels of molecular and/or systemic neuronal circuitry. Such processes often lead to dementia.

The clinical term “dementia” is an umbrella term for the syndrome defined by a group of symptoms, including impaired thinking and memory, disturbances with language, psychological and psychiatric changes and the like (see, for example, Burns and lliffe, BMJ, 338, 405 (2009)).

The World Alzheimer Report 2010 (The Global Impact of Dementia, Wimo and Prince, Alzheimer’s Disease International) estimates that 35.6 million people worldwide were living with dementia in 2010. It is estimated that this number will nearly double to 65.7 million by 2030 and increase to 115.4 million by 2050. The incidence is highest in Asian countries.

Alzheimer’s disease (AD) is the most common form of dementia. Other types of dementia include vascular dementia, frontotemporal lobe dementia, mixed dementia (vascular dementia and AD), as well as dementia due to Parkinson’s Disease, Huntington’s Disease, HIV infection and/or Creutzfeldt-Jakob disease, and/or with Lewy Bodies.

There is presently no cure for AD, which is known to worsen as it progresses and eventually leads to death. AD is often diagnosed in the elderly, although early-onset of AD is not uncommon.

Diagnosis of AD is typically confirmed by tests that evaluate cognitive functions and/or daily living activity, brain imaging, such as computerized tomography (CT-scans) and magnetic resonance imaging (MRI), and/or biomarkers in cerebrospinal fluid (CSF; vide infra). The disease is thought to be associated with amyloid plaques and tangles due to deposition of tau protein in the brain (see, for example, Tiraboschi et al, Neurology, 62, 1984 (2004)).

Later symptoms include longer-term memory loss, confusion, behavioural changes such as irritability and/or aggression, and hallucinations. Further decline results in inability to recognise family and friends. Eventually, various physical functions such as gait and balance are affected, with the end result typically being death. Life expectancy following diagnosis is approximately seven years, and fewer than 3% of individuals live more than 14 years after diagnosis.

One of the worst facets of AD is its degenerative nature, which means the sufferer becomes increasingly reliant on caregivers for assistance. This role is often filled by a spouse or a close relative, which usually places an enormous physical, psychological social and/or economic burden on such an individual. Thus, in addition to its primary healthcare treatment requirement, AD presents a significant burden on society. Increasing prevalence of the disease and an ageing population will only add to the disease burden in the coming years.

Despite considerable research in the area over many years, including literally thousands of clinical trials, there is no known cure for AD, and available treatments offer relatively small symptomatic relief in mild to moderate stages of AD. Currently-available medicines include the acetylcholinesterase inhibitors (rivastigmine, galantamine, and donepezil), and the NMDA receptor antagonist, memantine. Nothing has been shown clearly to delay or halt the progression of AD. Therefore, disease-modifying treatment for AD represents a huge unmet clinical need.

The term ’’mild coginitive impairment” (MCI) was first introduced by Reisberg et al in 1982 (see Am. J. Psychiatry, 139 1138 (1982)) to describe the intermediate stage between normal cognition and dementia. It is a disorder characterized by impairment of memory, learning difficulties, a reduced ability to concentrate on a task for more than brief periods, a marked feeling (often) of mental fatigue when mental tasks are attempted, and/or new learning found to be subjectively difficult even when objectively successful.

The concept was further refined in 1999, when MCI was defined as a state where individuals have subjective and objective memory impairment that is inconsistent with age, which do not interfere with normal physical functioning and performance in non-memory cognitive domains.

Although MCI may increase the risk of later progression to dementia (whether caused by Alzheimer's disease or other neurological conditions), rates of deterioration in patients with MCI vary.

The aforementioned AD drugs are not approved for the treatment of MCI. Their side-effects are thought to outweigh any potential benefits that a patient may get from such treatment. There is therefore a clear unmet clinical need for an effective treatment of MCI which could prevent the onset of dementia, including AD.

The antimalarial drug hydroxychloroquine is sold under the brand name Plaquenil®. It is also used to treat conditions, such as systemic lupus erythematosus, rheumatic disorders like rheumatoid arthritis, sarcoidosis and post-Lyme arthritis following Lyme disease. It is administered perorally.

A study by van Gool et al in The Lancet, 358, 455 (2011) reported a double-blind, parallelgroup study, in which hydroxychloroquine at 200 mg and 400 mg doses was tested against placebo in 168 patients with mild AD. The study showed treatment with hydroxychloroquine for 18 months did not slow the rate of decline in AD compared to placebo.

It is therefore highly surprising that we have now found that hydroxychloroquine has a positive effect in the clinic on MCI. Hydroxychloroquine is therefore expected to be useful in the treatment of MCI and prevention of the onset of dementia and/or AD.

Disclosure of the Invention

According to a first aspect of the invention there is provided hydroxychloroquine, or a pharmaceutically-acceptable salt thereof, packaged and presented for use in a method of treating MCI. Such a method comprises administering a pharmaceutically-effective amount of hydroxychloroquine, or a pharmaceutically-acceptable salt thereof, to a patient in need of such treatment.

The term “MCI” will be well known to those skilled in the art to include the terms “mild neurocognitive disorder”, “incipient/prodromal dementia”, or “isolated memory impairment”, as well as any condition that may be characterised as the intermediate stage between normal cognition and dementia. The term thus includes amnestic MCI, where memory loss is the predominant symptom (often associated with Alzheimer’s pathology), non-amnestic single MCI and multiple-domain MCI, and may also be defined as one or more of the following:

(a) noticeable cognitive decline from a previous level of performance in one or more cognitive domains (as identified in one or more standard cognitive tests), raised by the patient or an informant or observations made by a clinician, wherein the cognitive impairment does not interfere with independence of activities of daily living (see The Diagnostic and Statistical Manual of Mental Disorders, 5^th edition (2013));

(b) a subjective memory complaint either from the patient or reliable informant, and/or an objective memory impairment (as determined in a standard cognitive test), whilst exhibiting normal cognitive function and preserved activities of daily living (Mayo Clinic); and/or (c) concern regarding a change in cognition from the patient, an informant or a clinician, characterized by impairment in one or more cognitive domains, with preservation of independence in functional abilities (The National Institute on Aging and the Alzheimer's Association (NIA-AA) working group on MCI; see Albert et al, Alzheimer’s Dement., 7, 270 (2011)).

In all of the above definitions, it is stated that the patient does not have dementia, such as AD. Also, in at least definition (a) above, the cognitive symptoms are stated not to be due to delerium.

Patients with MCI do not suffer from cognitive impairment that has a severe effect on their daily living activities, and therefore are not classified as having dementia. For the avoidance of doubt, in the context of the present invention therefore, the terms “treatment”, “therapy” and “therapy method” include the therapeutic (i.e. disease-modifying) treatment of patients with MCI, as well as prevention of the onset of dementia, irrespective of the pathology of the relevant condition (as discussed herein). “Patients” include human patients.

Pharmaceutically-acceptable salts of hydroxychloroquine that may be mentioned include acid and base addition salts, such as, but not limited to, sulfate salts.

Salts may be formed by conventional means, for example by reaction of hydroxychloroquine with one or more equivalents of an appropriate acid or base, optionally in a solvent, or in a medium in which the salt is insoluble, followed by removal of said solvent, or said medium, using standard techniques (e.g. in vacuo, by freeze-drying or by filtration). Salts may also be prepared by exchanging a counter-ion of active ingredient in the form of a salt with another counter-ion, for example using a suitable ion exchange resin.

According to a further aspect of the invention there is provided a method of treating a MCI in a patient by (packaging, presenting and/or) administering hydroxychloroquine, or a pharmaceutically-acceptable salt thereof, at a sufficient, pharmaceutically-effective dose to treat MCI, as well as a method of reducing the risk, and/or preventing the onset, of dementia (e.g. AD) in a patient by (packaging, presenting and/or) administering hydroxychloroquine, or a pharmaceutically-acceptable salt thereof, at a sufficient, pharmaceutically-effective dose.

Hydroxychloroquine may be of use in the relief of symptoms of MCI, including those mentioned hereinbefore, such as cognitive impairment.

According to a further aspect of the invention there is provided a method of relieving one or more symptom of MCI in a patient suffering from MCI, which method comprises administering hydroxychloroquine, or a pharmaceutically-acceptable salt thereof, to such a patient.

We have found, surprisingly, that hydroxychloroquine is capable of ameliorating the symptoms and modifying/abrogating the progression of MCI, without giving rise to significant adverse side effects, potentially reducing neuronal death and preventing the onset of dementia, irrespective of the underlying pathology of the condition. As described hereinafter, however, we have also found that hydroxychloroquine is capable of returning to normal levels at least one key marker of dementia associated with AD, namely β-amyloid protein (also known as amyloid-beta, Abeta and Αβ) in CSF. Hydroxychloroquine is therefore particularly capable of treating amnestic MCI and/or MCI with underlying

Alzheimer’s pathology, and/or of reducing the risk, and/or preventing the onset, of AD in a patient having amnestic MCI and/or MCI with underlying Alzheimer’s pathology.

In this respect, biological markers of the onset, or potential onset, of dementia (and/or a pre-dementia MCI state) that may be measured to detect that hydroxychloroquine is successfully treating MCI, and so preventing the onset of dementia, include markers of the amyloid cascade (alpha, beta and gamma secretases activity), amyloid beta production and clearance, formation and accumulation ot tau protein tangles and tau phosphorylation, neurofilaments and triggering receptor expressed on myeloid cells 2 (TREM-2); antiphospholipid antibody pathway markers; nuclear factor (erythroid-derived 2)-like 2-kelchlike ECH-associated protein 1 (Nrf2-Keap1) pathway markers; inflammatory cascade/pathway markers, such as immumoglobulins(e.g. IgG), interleukin-1-beta(IL-1p), tumour necrosis factor alpha (TNF-α), interleukin-1 (IL-6), chemokines, macrophages, autophagy pathway; markers of insulin resistance and glucose metabolism, apoptosis/cell death pathway markers, epigenetics markers, markers of modification of gut bacteria; PI3 kinase/AKT/GSK-beta pathway markers, M-TOR pathway markers and/or telomerase activity markers, as well as markers of chemotaxis of polymorphonuclear leukocytes, major histocompatibilty complex (MHC) class II, protein processing, receptor recycling, protein secretion, and/or modulation of lysosomal enzymes (lysosomotropism).

As described hereinafter, we have also found that hydroxychloroquine is capable of providing improvements in certain psychological, such as neuropsychiatric inventory (NPI), tests.

In this respect, psychological tests that can be used to determine that hydroxychloroquine is successfully treating MCI, and so preventing the onset of dementia, include Mini-Mental State Examinations (MMSEs) and NPI tests, such as tests of episodic memory, working memory and Rey Auditory Verbal Learning Tests (RAVLTs), executive function, visuospatial memory, Boston Naming Test, etc..

According to a further aspect of the invention there is provided a method of treatment of MCI, of reducing the risk of the onset of dementia in a patient with MCI, and/or of prevention of the onset of dementia in a patient with MCI, which method comprises:

(a) measuring that patient’s plasma level, or CSF level, of one or more of the abovementioned biomarkers;

(b) determining whether the level of that biomarker in the relevant fluid is above or below (as appropriate) a relevant minimum or maximum (as appropriate) “normal” value (which will be well known to, and/or easily determined by, the person skilled in the art); and (c) if so, administering hydroxychloroquine, or a pharmaceutically acceptable salt thereof, to that patient for a time and at an appropriate dosage to increase or reduce (as appropriate) the level of that biomarker, for example to above or below (as appropriate) the relevant minimum or maximum normal value (and, if necessary or appropriate, continuing with said administering of hydroxychloroquine or salt thereof thereafter).

For example, there is provided a method of treatment of MCI (e.g. amnestic MCI/MCI with Alzheimer’s pathology), of reducing the risk of the onset of dementia (e.g. AD) in a patient with MCI, and/or of prevention of the onset of dementia (e.g. AD) in a patient with MCI, which method comprises:

(a) measuring that patient’s CSF level of β-amyloid;

(b) determining whether the level of β-amyloid in that fluid is below a minimum “normal” value (e.g. about 550 ng/L, or about 700 ng/ml_); and (c) if so, administering hydroxychloroquine, or a pharmaceutically acceptable salt thereof, to that patient for a time and at an appropriate dosage to increase the level of β-amyloid above the minimum normal value (e.g. about 550 ng/L, or about 700 ng/mL) (and, if necessary or appropriate, continuing with said administering of hydroxychloroquine or salt thereof thereafter).

“Normal” values as hereinbefore employed means any level of a marker that is accepted within the relevant field as a meaningful threshold, which the skilled person will appreciate may vary over time.

Alternatively, according to a further aspect of the invention there is provided a method of treatment of MCI, of reducing the risk of the onset of dementia in a patient with MCI, and/or of prevention of the onset of dementia in a patient with MCI, which method comprises:

(a) conducting a relevant neuropsychological inventory test or other cognitive measure on that patient to determine whether that patient has the cognitive impairment that may be associated with MCI; and (b) if so, administering hydroxychloroquine, or a pharmaceutically acceptable salt thereof, to that patient for a time and at an appropriate dosage until the cognitive performance in the same test shows a degree of measurable improvement (and, if necessary or appropriate, continuing with said administering of hydroxychloroquine or salt thereof thereafter).

In the uses and methods described herein, hydroxychloroquine is preferably administered locally or systemically, for example orally (preferably), intravenously or intraarterially (including by intravascular or other perivascular devices/dosage forms (e.g. stents)), intramuscularly, cutaneously, subcutaneously, transmucosally (e.g. sublingually or buccally), rectally, transdermally, nasally, pulmonarily (e.g. by inhalation, tracheally or bronchially), topically, or by any other parenteral route, in the form of a pharmaceutical preparation comprising the compound in a pharmaceutically acceptable dosage form. Preferred modes of delivery include oral (particularly).

In packaging and presenting it for use in the treatment of MCI, hydroxychloroquine will generally be administered in the form of one or more pharmaceutical formulations in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, which may be selected with due regard to the intended route of administration and standard pharmaceutical practice. Such pharmaceutically acceptable carriers may be chemically inert to the active compound and may have no detrimental side effects or toxicity under the conditions of use. Such pharmaceutically acceptable carriers may also impart an immediate, or a modified (e.g. delayed and/or, preferably, extended), release of hydroxychloroquine.

Suitable pharmaceutical formulations may be commercially available or otherwise may be made by combining hydroxychloroquine or salt thereof with conventional pharmaceutical additives and/or excipients used in the art for the preparation of pharmaceutical formulations, and thereafter incorporated into various kinds of pharmaceutical preparations and/or dosage forms using standard techniques (see, for example, Lachman eta/, “The Theory and Practice of Industrial Pharmacy', Lea & Febiger, 3^rd edition (1986); “Remington: The Science and Practice of Pharmacy”, Troy (ed.), University of the Sciences in Philadelphia, 21^st edition (2006); and/or “Aulton’s Pharmaceutics: The Design and Manufacture of Medicines”, Aulton and Taylor (eds.), Elsevier, 4^th edition, 2013), and the documents referred to therein, the relevant disclosures in all of which documents are hereby incorporated by reference. Otherwise, the preparation of suitable formulations may be achieved non-inventively by the skilled person using routine techniques.

The amount of hydroxychloroquine or salt thereof in the formulation will depend on the severity of the condition, and on the patient, to be treated, but may be determined noninventively by the skilled person.

Depending on the patient to be treated, as well as the route of administration, hydroxychloroquine or salt thereof may be administered at varying therapeutically effective doses to a patient in need thereof.

However, the dose administered to a human, in the context of the present invention should be sufficient to effect a therapeutic response over a reasonable timeframe. One skilled in the art will recognize that the selection of the exact dose and composition and the most appropriate delivery regimen will also be influenced by inter alia the pharmacological properties of the formulation, the nature and severity of the condition being treated, and the physical condition and mental acuity of the recipient, as well as the age, condition, body weight, sex and response of the patient to be treated, and the stage/severity of the disease, as well as genetic differences between patients.

Administration of hydroxychloroquine or salt thereof may be continuous or intermittent (e.g. by bolus injection). The dosage may also be determined by the timing and frequency of administration.

Suitable doses of hydroxychloroquine or salt thereof are therefore in the range of about 0.1 and about 50.0 mg, including between about 0.5 (e.g. about 1) and about 30 (e.g. about 20) mg, for example between about 1.5 (e.g. about 2) and about 15 (e.g. about 10) mg of the compound per kilogram of the patient's total body weight per day.

Suitable individual daily doses may be between (i.e. at least) about 50 mg, preferably about 62.5 mg, more preferably about 75 mg, more preferably about 100 mg, more preferably about 125 mg, for example about 150 mg, such as about 175 mg, and (i.e. no more than) about 1,000 mg, preferably about 850 mg, more preferably about 750 mg, for example about 600 mg, such as about 500 mg, per unit dosage form. Suitable individual daily doses may further be between about 200 mg (e.g. about 250 mg) and about 450 mg, such as between about 300 mg and about 400 mg (e.g. about 350 mg), per unit dosage form.

In any event, the medical practitioner/physician, or other skilled person, will be able to determine routinely the actual dosage, which will be most suitable for an individual patient. The above-mentioned dosages are exemplary of the average case; there can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.

Wherever the word “about” is employed herein, for example in the context of amounts (e.g. doses of active ingredients), it will be appreciated that such variables are approximate and as such may vary by ±15%, such as ±10%, for example ±5% and preferably ±2% (e.g. ±1%) from the numbers specified herein.

The uses/methods described herein may have the advantage that, in the treatment of MCI, they may be more convenient for the physician and/or patient than, be more efficacious than, be less toxic than, have a broader range of activity than, be more potent than, produce fewer side effects than, or that it may have other useful pharmacological properties over, any similar methods (treatments) that may be described in the prior art.

The invention is illustrated, but in no way limited, by the following example.

Example

A Reversible Case of MCI and CSF β-Amyloid Levels

A 65 year-old Swedish female, former smoker with a clinical history of cardiovascular disease (myocardial infarction in 2005), depression and anxiety disorders and (since 1970) Sjogrens syndrome, sarcoidosis, hypothyreoidism and osteoporosis was, in 2013, diagnosed with amnestic MCI.

Her concomittant medications included low dose citaprolam, L-thyroxine (Levaxin®; 75 pg once daily), aspirin (Trombyl®; 75 mg once daily), cyanocobalamin (synthetic vitmain B12; Behepan®; 1 mg once daily); and escialopram (Cipralex® ; 5 mg once daily).

In June of 2015 the patient was prescribed a 200 mg daily dose of hydroxychloroquine to treat her sarcoidosis. This dose was increased to 400 mg (200 mg bid) in May of 2016.

In December of 2016, her Mini-Mental State Examination (MMSE) score was 30/30 (normal). In 2013, an equivalent test score was 29/30. Neuropsychiatric inventory tests conducted in 2017 showed that tests of working memory and Rey Auditory Verbal Learning Test(RAVLT) values were normal. In 2013 and 2015, equivalent tests of working memory and RAVLT were pathological. The patient also noticed subjectively that her memory had improved.

A CSF analysis conducted in 2013 revealed an abnormal level of β-amyloid (457 ng/L). In a CSF analysis conducted in 2017, a β-amyloid level of 952 ng/L was measured (normal values are >550 ng/L). Accordingly, β-amyloid protein in the CSF that was pathological in 2013 had also returned to normal levels. (Other markers were measured, including phospho-tau and tau (both tests), and neurofilament, CSF-IgG, P and CSF Albumin, CSF/plasma Albumin (2017 test). All of these were within normal ranges when 5 measured.)

Claims

1. Hydroxychloroquine, or a pharmaceutically acceptable salt thereof, for use in the treatment of mild cognitive impairment.

2. Hydroxychloroquine, or a pharmaceutically acceptable salt thereof, for use in preventing, and/or reducing the risk of, the onset of dementia.

3. The use of hydroxychloroquine, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of mild cognitive impairment.

4. The use of hydroxychloroquine, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for preventing, and/or reducing the risk of, the onset of dementia.

5. A method of treatment of mild cognitive impairment, which method comprises the administration of hydroxychloroquine, or a pharmaceutically acceptable salt thereof, to a patient in need of such treatment.

6. A method of preventing, and/or reducing the risk of, the onset of dementia, which method comprises the administration of hydroxychloroquine, or a pharmaceutically acceptable salt thereof, to a patient in need of such treatment.

7. A compound for use as claimed in Claim 2, a use as claimed in Claim 4, or a method as claimed in Claim 6, wherein the dementia comprises Alzheimer’s Disease.

8. A method of treatment of mild cognitive impairment, of reducing the risk of the onset of dementia in a patient with mild cognitive impairment, and/or of prevention of the onset of dementia in a patient with mild cognitive impairment, which method comprises:

(a) measuring that patient’s plasma level, or cerebrospinal fluid level, of one or more biomarker of dementia;

(b) determining whether the level of that biomarker in the relevant fluid is above or below (as appropriate) a relevant minimum or maximum (as appropriate) normal value; and (c) if so, administering hydroxychloroquine, or a pharmaceutically acceptable salt thereof, to that patient for a time and at an appropriate dosage to increase or reduce (as appropriate) the level of that biomarker to above or below (as appropriate) the relevant normal value.

9. A method as claimed in Claim 8, wherein the dementia is Alzheimer’s Disease, the

5 biomarker is β-amyloid protein, as measured in the patient’s cerebrospinal fluid, and the level of β-amyloid measured prior to administration is below a minimum normal value.