WO2015001357A2

WO2015001357A2 - Drug combination and its use in therapy

Info

Publication number: WO2015001357A2
Application number: PCT/GB2014/052047
Authority: WO
Inventors: Peter Richardson; Bruce Campbell
Original assignee: Proximagen Ltd
Current assignee: BenevolentAI Cambridge Ltd
Priority date: 2013-07-05
Filing date: 2014-07-04
Publication date: 2015-01-08
Anticipated expiration: 2016-01-05
Also published as: GB201312131D0; WO2015001357A3

Abstract

A product comprising: (i) (2R)-Methyl-1-{3-[2-(3-pyridinyloxy)ethoxy]-2-pyrazinyl}piperazine or vabicaserin, and (ii) methylphenidate as a combined preparation for simultaneous, sequential or separate use in treating over-weight or obesity.

Description

DRUG COMBINATION AND ITS USE IN THERAPY

Field of the Invention

This invention relates to a drug combination, its composition and its use in the treatment of over-weight or obesity.

Background of the Invention

Over-weight and obesity are growing problems in the world population, especially in North America and Europe. Obesity is now recognized as a chronic disease and a critical global health issue (Fiegal et al, 1998, Int. J. Obesity 22:39-47, Mokdad et al, 1999, JAMA 282:1519-1522; Halford, 2006, Appetite, 46, 6-10). The "identifiable signs and symptoms" of obesity include an excess accumulation of fat or adipose tissue, an increase in the size or number of fat cells (adipocyte differentiation), insulin resistance, increased glucose levels (hyperglycemia), increased blood pressure, elevated cholesterol and triglyceride levels and decreased levels of high-density lipoprotein. Obesity is associated with a number of comorbidities including a significantly elevated risk for type 2 diabetes, coronary heart disease, stroke, hypertension, various types of cancer and numerous other major illnesses, and overall mortality from all causes (Must et al, 1999, JAMA 282:1523-1529, Calle et al, 1999, N. Engl. J. Med. 341 :1097- 1 105).

Therefore there is a growing unmet medical need for new medications useful for treating over-weight or obesity.

There are few safe current treatments available, although anorectic drugs such as phentermine and sibutramine have been reported to reduce appetite, and although widely used have the side effect of raising blood pressure which severely restricts their use in obese patients, many of whom already suffer from hypertension. In addition these agents have other side effects including tachycardia (increased heart rate), pulmonary hypertension and heart valve damage. Summary of the Invention

In preliminary experimental studies it has been surprisingly found that a combination of a 5HT₂c agonist of formula (I) or vabicaserin and methylphenidate shows a synergistic effect in reducing appetite in a suitable animal model. The preliminary studies indicate that the effect of the 5HT₂c agonist of formula (I) combined with methylphenidate is surprisingly potent and greater than the sum of the individual drugs, suggesting that the combination has a substantially improved effect in reducing appetite, and therefore in the treatment of obesity. One advantage of lowering the minimum effective dose of the 5HT₂c agonist is that there is a reduced risk of the side effects seen with other anorectic drugs such as phentermine and sibutramine.

Consequently, a considerably reduced dose of both drugs can be given for an equivalent effect for each individual drug, thus reducing side-effects and drug burden.

It is well known that obese patients are at increased risk of hypertension, and it is acknowledged that the obese patient population includes a sub-group which suffers from both obesity and hypertension. In a further aspect of the invention, preliminary studies indicate that obese hypertensive patients treated with a compound of formula (I) or vabicaserin and methylphenidate will experience a reduction in blood pressure which is greater than would be expected from weight loss alone. It is expected that within 14 days of starting treatment patients will experience an initial reduction in blood pressure. It is predicted that this unexpected initial reduction in blood pressure will then be followed by a more gradual reduction as a consequence of weight loss. It is known also that methylphenidate has the effect of increasing blood pressure. This increase in blood pressure is especially hazardous in patients already suffering from hypertension. However obese hypertensive patients who experience an increase in blood pressure when treated with methylphenidate are expected to experience a lesser increase in blood pressure, or even a reduction in blood pressure, when treated with a combination of a compound of formula (I) or vabicaserin and methylphenidate. For the above reasons the claimed combination is expected to be useful for treatment of over-weight or obesity in patients suffering from hypertension. It is expected that the initial reduction in systolic blood pressure will be about 1 to 20 mmHg, preferably from 3 to 15 mmHg such as from 5 to 12 mmHg, from 5 to 10 mmHg, or from 7 to 9 mmHg. In an embodiment the initial reduction in blood pressure is at least 8mmHg. It is expected that the initial reduction in blood pressure will occur within 14 days of commencing treatment It is expected that this surprising initial (acute) reduction in blood pressure will then be followed by a more gradual reduction as a consequence of weight loss. It is expected that within 14 days of starting treatment with the claimed combination of PRX933 or vabicaserin and methylphenidate patients will experience an initial reduction in blood pressure wherein the patient's systolic blood pressure is reduced by greater than 3mmHg within 14 days of starting treatment. In an embodiment the patient's blood pressure is reduced by greater than 4mmHg within 14 days of starting treatment. In an embodiment the patient's blood pressure is reduced by greater than 5mmHg within 14 days of starting treatment. In an embodiment the patient's blood pressure is reduced by greater than 6mmHg within 14 days of starting treatment.

Suitable 5HT₂c agonists of formula (I) for use in the present invention are disclosed in WO00/76984, where they are defined in claims 1 to 41 .

In an embodiment of the invention the compound of formula (I) is (2R)-

Methyl-1 -{3-[2-(3-pyridinyloxy)ethoxy]-2-pyrazinyl}piperazine, also known as P following structure:

and pharmaceutically acceptable salts thereof. In an embodiment the pharmaceutically acceptable salt is the L-malate. The synthesis and medical use of PRX933, and salt forms thereof, is disclosed in WO00/76984 (PCT/SEOO/01017) and WO2004/000829 (PCT/SE2003/001043). The content of both documents is hereby incorporated by reference. In an alternative embodiment the 5HT₂c agonist is vabicaserin (9aR,12aS)- 4,5,6,7,9,93,10,1 1 , 12,12a-decahydrocyclopenta[c][1 ,4]diazepino[6,7,1 - ij]quinoline), which has the following structural formula:

All pharmaceutically acceptable salt forms of vabicaserin are suitable for use in the present invention. Accordingly, the present invention makes available a product comprising a compound of formula (I) or vabicaserin and methylphenidate as a combined preparation for simultaneous, sequential or separate use in treating over-weight or obesity.

In another embodiment, the present invention makes available a compound of formula (I) or vabicaserin for use in treating over-weight or obesity wherein methylphenidate is administered simultaneously, separately or sequentially with the compound of formula (I) or vabicaserin.

In another embodiment, the present invention makes available a method of preventing or treating over-weight or obesity, comprising administering to a human or animal subject in need thereof a compound of formula (I) or vabicaserin and methylphenidate in sufficient amounts to provide a therapeutic effect. Description of the Invention

As used herein, the terms "over-weight" and "obesity" are taken to mean the medical condition in which excess body fat has accumulated to the extent that it may have an adverse effect on health, leading to reduced life expectancy and/or increased health problems. Body mass index (BMI), a measurement which compares weight and height, defines people as "over-weight" (pre-obese) if their BMI is between 25 and 30 kg/m², and "obese" when it is greater than 30 kg/m². As used herein, the term "hypertension" is taken to mean a persistently elevated blood pressure i.e. systolic blood pressure greater than 140mmHg and diastolic blood pressure greater than 90mmHg.

Any suitable form of the 5HT₂c agonist and methylphenidate can be used. These include salts, prodrugs and active metabolites. Suitable dose ranges for the 5HT₂c agonist or methylphenidate are known in the art, although the synergistic effect of the combination means that the effective dose may be reduced.

The dose of methylphenidate that is administered with the 5HT_2C agonist will of course depend on the usual factors, including its potency, but is preferably at least 0.01 , e.g. at least 0.02, and may be up to 1 .5 mg/ kg/day. In an embodiment the dose of methylphenidate is from 0.01 to 1 mg/kg/day. In another embodiment the dose is from 0.01 to 0.2 mg/kg/day. In another embodiment the dose is from 0.05 to 0.22 mg/kg/day. In another embodiment the dose is from 0.1 to 0.5 mg/kg/day.

The dose of the 5HT₂c agonist that is administered with methylphenidate will of course depend on the usual factors, including its potency, but is preferably at least 0.01 , e.g. at least 0.02, and may be up to 0.5 mg/ kg/day. In an embodiment the dose of the 5HT_2C agonist is from 0.01 to 0.3 mg/kg/day. In another embodiment the dose is from 0.01 to 0.2 mg/kg/day. In another embodiment the dose is from 0.05 to 0.2 mg/kg/day. In another embodiment the dose is from 0.1 to 0.5 mg/kg/day.

The compounds of the invention may be administered by any available route, such as via the oral, inhaled, intranasal, sublingual, intravenous, rectal, dermal, and vaginal routes. The oral route is the preferred route of administration.

The compounds of the invention are preferably formulated as combinations to be administered orally, for example as tablets, troches, lozenges, aqueous or oral suspensions, dispersible powders or granules. Preferred pharmaceutical compositions of the invention are tablets and capsules. Liquid dispersions for oral administration may be syrups, emulsions and suspensions. More preferably, the pharmaceutical composition of the combination is a pressed tablet or capsule with conventional excipients, examples of which are given below. These may be immediate release or modified, sustained or controlled release preparations.

Compositions of the combination intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavouring agents, colouring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the combined active ingredients in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may include but are not restricted to, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example corn starch or alginic acid; binding agents, for example starch gelatin, acacia, microcrystalline cellulose or polyvinyl pyrrolidone; and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate, or glyceryl distearate may be employed.

Aqueous suspensions may contain the combined active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long- chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids, for example polyoxyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl or n- propyl p-hydroxybenzoate, one or more colouring agents, one or more flavouring agents, and one or more sweetening agents, such as sucrose or saccharin. Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, polyoxyethylene hydrogenated castor oil, fatty acids such as oleic acid, or in a mineral oil such as liquid paraffin or in other surfactants or detergents. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those set forth above, and flavouring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the combined active ingredients in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable sweetening, flavouring and colouring agents may also be present.

The combined pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin, or mixtures of these. Suitable emulsifying agents may be naturally occurring gums, for example gum acacia or gum tragacanth, naturally occurring phosphatides, for example soya bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavouring agents.

Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, flavouring and colouring agents.

Suspensions and emulsions may contain a carrier, for example a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol.

In a preferred embodiment, the 5HT₂c agonist of formula (I) or vabicaserin in combination with methylphenidate is to be administered via the oral route. Combined compositions according to the invention may be produced using conventional formulation techniques. In particular, spray-drying may be used to produce microparticles comprising the active agent dispersed or suspended within a material that provides the controlled release properties.

The process of milling, for example jet milling, may also be used to formulate the therapeutic composition. The manufacture of fine particles by milling can be achieved using conventional techniques. The term "milling" is used herein to refer to any mechanical process which applies sufficient force to the particles of active material to break or grind the particles down into fine particles. Various milling devices and conditions are suitable for use in the production of the compositions of the invention. The selection of appropriate milling conditions, for example, intensity of milling and duration, to provide the required degree of force, will be within the ability of the skilled person. Ball milling is a preferred method. Alternatively, a high pressure homogeniser may be used, in which a fluid containing the particles is forced through a valve at high pressure, producing conditions of high shear and turbulence. Shear forces on the particles, impacts between the particles and machine surfaces or other particles, and cavitation due to acceleration of the fluid, may all contribute to the fracture of the particles. Suitable homogenisers include the EmulsiFlex high pressure homogeniser, the Niro Soavi high pressure homogeniser and the Microfluidics Microfluidiser. The milling process can be used to provide the microparticles with mass median aerodynamic diameters as specified above. If hygroscopic, the active agent may be milled with a hydrophobic material, as stated above.

If it is required, the microparticles produced by the milling step can then be formulated with an additional excipient. This may be achieved by a spray- drying process, e.g. co-spray-drying. In this embodiment, the particles are suspended in a solvent and co-spray-dried with a solution or suspension of the additional excipient. Preferred additional excipients include polysaccharides. Additional pharmaceutically effective excipients may also be used.

Compositions of the combination intended for inhaled, topical, intranasal, intravenous, sublingual, rectal and vaginal use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions. Therapy according to the invention may be conducted in generally known manner, depending on various factors, such as the sex, age or condition of the patient, and the existence or otherwise of one or more concomitant therapies. The patient population may be important.

The present invention is based at least in part on the following studies. Study 1

The preliminary experimental studies indicate that combinations of (i) (2R)-Methyl-1 -{3-[2-(3-pyridinyloxy)ethoxy]-2-pyrazinyl}piperazine and (ii) methylphenidate have significantly improved efficacy in appetite control in animals when compared to (2R)-Methyl-1 -{3-[2-(3-pyridinyloxy)ethoxy]-2- pyrazinyl}piperazine monotherapy and methylphenidate monotherapy. (2R)-Methyl-1 -{3-[2-(3-pyridinyloxy)ethoxy]-2-pyrazinyl}piperazine (6 mg p.o.) was dosed over a 6h period to a group of 9 normal weight rats fed ad libitum. Methylphenidate (10mg p.o.) was dosed over a 6h period to a separate group of 9 normal weight rats fed ad libitum. Neither dose levels had a significant effect on food intake over a 6h period. However when (2R)-Methyl-1 -{3-[2-(3- pyridinyloxy)ethoxy]-2-pyrazinyl}piperazine (6 mg p.o.) and methylphenidate (10mg p.o.) were dosed in combination a significant (p<0.01 ) 33.1 ± 1 1 .3% reduction in food intake over the same time period was observed.

Study 2

The preliminary clinical studies in obese and overweight patients indicate that dosing with (2R)-Methyl-1 -{3-[2-(3-pyridinyloxy)ethoxy]-2-pyrazinyl}piperazine caused a surprising initial reduction in blood pressure within 14 days which was independent of the weight reduction. The surprising initial (acute) reduction in blood pressure was followed by a second reduction in blood pressure consequent on a reduction in weight. The initial reduction in blood pressure attributable to (2R)-Methyl-1 -{3-[2-(3-pyridinyloxy)ethoxy]-2-pyrazinyl}piperazine is expected to counteract the increase in blood pressure caused by dosing methylphenidate. Figure 1 shows a graph of the change in supine systolic blood pressure in patients taking (2R)-Methyl-1 -{3-[2-(3-pyridinyloxy)ethoxy]-2- pyrazinyl}piperazine. The reduction in blood pressure after 2 weeks (filled bars) and 8 weeks (hatched bars) dosing is plotted against Cmax. Asterisks indicate significantly (P<0.05) different from placebo (t test).

Claims

1 . A product comprising:

(i) (2R)-Methyl-1 -{3-[2-(3-pyridinyloxy)ethoxy]-2-pyrazinyl}piperazine or vabicaserin, and

(ii) methylphenidate

as a combined preparation for simultaneous, sequential or separate use in treating over-weight or obesity.

2. (2R)-Methyl-1 -{3-[2-(3-pyridinyloxy)ethoxy]-2-pyrazinyl}piperazine or vabicaserin for use in treating over-weight or obesity wherein methylphenidate is administered simultaneously, separately or sequentially with (2R)-Methyl-1 -{3-[2- (3-pyridinyloxy)ethoxy]-2-pyrazinyl}piperazine or vabicaserin.

3. A method of preventing or treating over-weight or obesity, comprising administering to a human or animal subject in need thereof (2R)-Methyl-1 -{3-[2-

(3-pyridinyloxy)ethoxy]-2-pyrazinyl}piperazine or vabicaserin and methylphenidate in sufficient amounts to provide a therapeutic effect.

4. A product according to claim 1 , or a compound according to claim 2, or a method according to claim 3 wherein the treatment for over-weight or obesity is administered to a patient suffering from hypertension.

5. A product according to claim 1 , or a compound according to claim 2, or a method according to claim 3 wherein the treatment for over-weight or obesity is administered to a patient suffering from diabetes.

6. A product, compound, or method according to any one of claims 1 to 5 wherein the patient's blood pressure is reduced by greater than 3mmHg within 14 days of starting treatment.

7. A product, compound, or method according to claim 6 wherein the patient's systolic blood pressure is reduced by greater than 3mmHg within 14 days of starting treatment.

8. A product, compound, or method according to any one of claims 1 to 7 comprising (2R)-Methyl-1 -{3-[2-(3-pyridinyloxy)ethoxy]-2-pyrazinyl}piperazine or a pharmaceutically acceptable salt thereof.

9. A product, compound, or method according to claim 8 wherein the pharmaceutically acceptable salt is the L-Malate salt.