WO2014140631A1

WO2014140631A1 - Prx933 (prx-00933), a 5ht2c agonist, for use in the treatment of hypertension

Info

Publication number: WO2014140631A1
Application number: PCT/GB2014/050811
Authority: WO
Inventors: Peter Richardson
Original assignee: Proximagen Limited
Priority date: 2013-03-15
Filing date: 2014-03-14
Publication date: 2014-09-18
Also published as: GB201304811D0

Abstract

The use of PRX933 for the acute treatment of hypertension.

Description

RX-00933), A 5HT2C AGONIST, FOR USE IN THE TREATMENT

OF HYPERTENSION

Field of the Invention

This invention relates to the use of PRX933 for treatment of hypertension, and to pharmaceutical compositions comprising the same, and to kits and packages comprising the same, and to novel dosage regimes.

Background of the Invention

Hypertension, which is defined as a systolic/diastolic blood pressure greater than 140/90 mmHg, is a dangerous condition. Elevated blood pressure is an important risk factor for cardiovascular incidents such as angina pectoris, myocardial infarction, heart failure, cerebral infarction, cerebral haemorrhage and subarachnoid haemorrhage. The benefits accruing as a result of aggressive control of blood pressure have been clearly demonstrated in clinical trials (reviewed by Cooper-deHoff et al., 201 1 ). Typical therapeutics include diuretics, calcium channel blockers, angiotensin receptor antagonists, adrenoceptor antagonists, vasodilators and angiotensin converting enzyme inhibitors. All of these therapeutics have their own side effects and clinical treatment is largely based on finding the drug and mechanism that each patient can tolerate. In patients with obesity and/or diabetes hypertension is a common issue, and tends to poorly controlled, since less than 30% of patients with hypertension achieve adequate control (Wolf-Maier et al., 2004; Paulis and Unger, 2010). Type 3 or morbid obesity (BMI>40kg/m²) is particularly associated with hypertension, diabetes and increased risk of death. The patients are obliged to take multiple anti-hypertensive therapies in order to control the blood pressure (Bramlage et al., 2004; McTigue et al., 2006) Taking into account the worldwide increase in obesity and Type 2 diabetes, there is an urgent need for therapeutics which can both assist weight reduction while also reducing blood pressure. It is estimated that overall 72% of those over 65 years of age have hypertension (Centre for Disease Control, http://www.cdc.gOv/mmwr/preview/mmwrhtml/su6203a24.htm#Tab).

In overweight or obese patients, weight loss is a prudent long term strategy to reduce blood pressure. However the blood pressure reduction following weight loss is typically modest. It is generally acknowledged (The Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults: The Evidence Report. NIH PUBLICATION NO. 98-4083 1998) that a reduction in bodyweight of 5 kg will be accompanied by a reduction in blood pressure of around 3.5 mm Hg. However the process of reducing body weight in many people is slow, unreliable and readily reversible, even when pharmaceutical drugs are used to aid the process. Most known pharmaceutical weight-loss drugs such as fenfluramine and phentermine are associated with an increase in blood pressure. Some recently developed weight-loss drugs such as lorcaserin are associated with a small reduction in blood pressure, that reduction resulting from weight loss. However this reduction in blood pressure arising from weight loss is slow, taking around 26 to 52 weeks, which leaves the patient at high risk of a hypertension associated crises (including stroke and myocardial infarction) during this dosing period. An unmet medical need therefore exists for a hypertension treatment which results in a more rapid reduction in blood pressure than is expected from weight loss alone.

This rapid reduction in blood pressure will be particularly useful in patients with high systolic pressures (e.g. >180mmHg), and in those who are resistant to current anti-hypertensives (approximately 10% of all hypertensives, Pimenta and Calhoun, Circulation. 2012 April 3; 125(13): 1594-1596).

In three recent clinical trials the 5HT_2C agonist Lorcaserin was investigated for treatment of obesity in obese and diabetic obese patients. Over the 52 week trial period in patients with diabetes an average bodyweight reduction of 5.6 kg was observed (O'Neil PM, Smith SR, Weissman NJ, Fidler MC, Sanchez M, Zhang J, Raether B, Anderson CM, Shanahan WR. Obesity (Silver Spring). 2012 Jul;20(7):1426-36). However this was associated with an average reduction in systolic blood pressure of only 1 .4mm Hg, even after 52 weeks dosing, which is less than the modest 3.5mmHg expected from weight loss alone and unlikely to be of significant clinical benefit.

Summary of the Invention

It has been found that treatment of obese hypertensive patients with the 5HT₂c agonist PRX933 causes a surprising reduction in blood pressure, greater than that attributable to the weight loss and much greater and faster than that seen with the 5HT₂c agonist Lorcaserin. 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. Human clinical trial data demonstrates that treatment of an obese patient population with PRX933 over an 8 week period results in a reduction of bodyweight of 3kg and a reduction in blood pressure of approximately 9mm Hg. There are two components to this antihypertensive effect: an initial rapid phase which was complete within around 2 weeks, and a later slower phase which could be accounted for by the reduction in body weight.

Thus, clinical studies in obese and overweight patients indicate that dosing with PRX933 ((2R)-Methyl-1 -{3-[2-(3-pyridinyloxy)ethoxy]-2-pyrazinyl}piperazine) causes an initial reduction in blood pressure within 14 days followed by a second reduction in blood pressure consequent on a reduction in weight.

In an embodiment, the present invention makes available PRX933 for use in the treatment of hypertension, or the use of PRX933 in the manufacture of a medicament for treatment of hypertension, in a patient wherein the patient's 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. In an embodiment the patient's blood pressure is reduced by greater than 3mmHg within 7 days of starting treatment. In an embodiment the patient's blood pressure is reduced by greater than 4mmHg within 7 days of starting treatment. In an embodiment the patient's blood pressure is reduced by greater than 5mmHg within 7 days of starting treatment. In an embodiment the patient's blood pressure is reduced by greater than 3mmHg within 6 days of starting treatment. In an embodiment the patient's blood pressure is reduced by greater than 3mmHg within 30 days of starting treatment. In an embodiment the patient's blood pressure is reduced by greater than 4mmHg within 30 days of starting treatment. In an embodiment the patient's blood pressure is reduced by greater than 5mmHg within 30 days of starting treatment. In an embodiment the patient's blood pressure is reduced by greater than 6mmHg within 30 days of starting treatment.

In an embodiment, the present invention makes available a method of treatment of hypertension, comprising administering to a patient suffering from hypertension an effective amount of PRX933 wherein the patient's 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. In an embodiment the patient's blood pressure is reduced by greater than 3mmHg within 7 days of starting treatment. In an embodiment the patient's blood pressure is reduced by greater than 4mmHg within 7 days of starting treatment. In an embodiment the patient's blood pressure is reduced by greater than 5mmHg within 7 days of starting treatment. In an embodiment the patient's blood pressure is reduced by greater than 3mmHg within 6 days of starting treatment. In an embodiment the patient's blood pressure is reduced by greater than 3mmHg within 30 days of starting treatment. In an embodiment the patient's blood pressure is reduced by greater than 4mmHg within 30 days of starting treatment. In an embodiment the patient's blood pressure is reduced by greater than 5mmHg within 30 days of starting treatment. In an embodiment the patient's blood pressure is reduced by greater than 6mmHg within 30 days of starting treatment.

In an embodiment, the reduction in blood pressure is a reduction in the patient's systolic blood pressure.

In an embodiment, the present invention makes available a pharmaceutical composition comprising PRX933 and at least one suitable excipient for use in treatment of hypertension.

In an embodiment, PRX933 is useful in the treatment of, and in methods for treatment of, and in compositions for treatment of over-weight or obese patients suffering from hypertension.

In an embodiment the reduction in blood pressure obtained by the uses of PRX933, and the methods of use of PRX933 and the compositions comprising PRX933 as disclosed herein is greater than 3mmHg, or greater than 4mmHg, or greater than 5mmHg, or greater than 6mmHg.

In an embodiment PRX933 is useful for acute treatment of hypertension wherein the duration of dosing is 7 or fewer days, 14 or fewer days, or 30 or fewer days. In an embodiment the reduction in blood pressure is greater than 3mmHg, or greater than 4mmHg, or greater than 5mmHg, or greater than 6mmHg. In an embodiment, the reduction in blood pressure is a reduction in the patient's systolic blood pressure. In an embodiment the patient's blood pressure is reduced by greater than 4mmHg within 14 days of starting dosing. In an embodiment the patient's blood pressure is reduced by greater than 5mmHg within 14 days of starting dosing. In an embodiment the patient's blood pressure is reduced by greater than 6mmHg within 14 days of starting dosing. In an embodiment the patient's blood pressure is reduced by greater than 3mmHg within 7 days of starting dosing. In an embodiment the patient's blood pressure is reduced by greater than 4mmHg within 7 days of starting dosing. In an embodiment the patient's blood pressure is reduced by greater than 5mmHg within 7 days of starting dosing. In an embodiment the patient's blood pressure is reduced by greater than 3mmHg within 6 days of starting dosing. In an embodiment the patient's blood pressure is reduced by greater than 3mmHg within 30 days of starting dosing. In an embodiment the patient's blood pressure is reduced by greater than 4mmHg within 30 days of starting dosing. In an embodiment the patient's blood pressure is reduced by greater than 5mmHg within 30 days of starting dosing. In an embodiment the patient's blood pressure is reduced by greater than 6mmHg within 30 days of starting dosing.

In an embodiment the dose of PRX933 that is administered is from 0.01 to 0.3 mg/kg/day, or from 0.01 to 0.2 mg/kg/day, or from 0.1 to 0.5 mg/kg/day.

In an embodiment PRX933 is the L-malate salt form.

The present invention makes available a pharmaceutical package, the package comprising:

(a) a plurality of unit dosage forms containing a pharmaceutically effective amount of PRX933; and

(b) a suitable container.

(c) a label directing administration of the unit dosage forms for use in the treatment of hypertension.

In an embodiment the pharmaceutical package comprises 5-31 unit dosage forms, preferably 7-20 unit dosage forms, preferably 7-14 unit dosage forms, most preferably 7 or 14 unit dosage forms. In an embodiment the unit dosage forms are tablets or capsules. In an embodiment PRX933 is administered once or twice daily.

In an embodiment sufficient unit dosage forms are present for administration for a period of 7-31 consecutive days, preferably 7-14 days, preferably 7 or 14 days.

In an embodiment the package is selected from a bag, a box, a foil packet and a blister sealed package.

In an embodiment the package of the present invention contains sufficient unit dosage forms for at least one week's patient dosing, preferably 1 -4 week's patient dosing, preferably 1 -2 week's patient dosing, most preferably 1 or 2 week's patient dosing.

In an embodiment the pharmaceutical package contains unit doses, wherein each unit dose is present in an amount of about 0.001 mg to about 20 mg, preferably 0.01 mg to about 5 mg, preferably about 0.05 mg to about 1 mg, preferably about 0.1 mg to about 0.5 mg.

In an embodiment, the package is used for the acute treatment of hypertension. In an embodiment the package is used for the acute treatment of hypertension in an obese patient. In an embodiment the package is used for the acute treatment of hypertension in a patient suffering from acute or chronic hypertension.

In an embodiment the invention makes available a treatment regimen for the treatment of hypertension, comprising administering to a patient in need thereof an effective amount of PRX933 dosed at least once per day for a period of at least 7 days. In an embodiment the effective amount is dosed at least once per day for a period of at least 14 days. In an embodiment the effective amount is dosed at least once per day for a period of at least 30 days. In an embodiment the effective amount of PRX933 is dosed twice per day. In an embodiment the patient is overweight or obese. In an embodiment the patent has a BMI of from 25 to 30 kg/m². In an embodiment the patent has a BMI of greater than 40 kg/m². In an embodiment of the regimen, the dose of PRX933 that is administered is from 0.01 to 0.3 mg/kg/day, or from 0.01 to 0.2 mg/kg/day or from 0.1 to 0.5 mg/kg/day. In an embodiment of the regimen, PRX933 is dosed as the L-malate salt form. In an embodiment, the present invention makes available a treatment regimen for the treatment of hypertension, comprising administering to a non-obese patient in need thereof an effective amount of PRX933 dosed at least once per day for a period of at least 14 days.

In an embodiment the present invention makes available a method for acute treatment of hypertension, comprising providing to a patient in need thereof a pharmaceutical package, the package comprising:

(a) a plurality of unit dosage forms containing an effective amount of PRX933;

(b) a label directing administration of the dosage forms to the patient for treatment of hypertension.

In an embodiment the label directs administration of one dosage form once per day or twice per day.

In an embodiment the package comprises a sufficient number of dosage forms for a 7-day course of treatment, or a 14-day course of treatment, or a 30-day course of treatment.

In an embodiment PRX933 is present in the dosage forms as the L-malate salt form.

Brief description of the Figure

The invention itself may be better understood by reference to the following detailed description of the invention, which includes reference to Figure 1.

Figure 1 is a graph of the change in supine systolic blood pressure in patients taking PRX933. 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).

Detailed description of the invention

Figure 1 is based on human clinical trial data. This trial was a randomized, double-blind, placebo-controlled, parallel group, multi-center study designed to assess the effect on body weight of PRX.933 compared to placebo, in obese patients during 8 weeks of treatment. The study started with a 2-week single-blind run-in period using placebo, followed by 8 weeks on either active treatment or placebo. The effect on other obesity measures and the safety tolerability and pharmacokinetics of BVT.933 was assessed in five different dosing regimens. 50 patients were to be randomized to each of the 5 active dose groups and 25 to each of two placebo groups. A total of 336 patients were randomized, and 314 continued following the run-in period (ITT population). Of these, 180 were included in the per protocol population. The patients were obese (BMI 30-40 kg/m2) but otherwise healthy patients, female and male, 18 - 65 years of age. Women were non-pregnant, non-lactating, and using adequate contraceptive methods or postmenopausal. During the two week run in phase patients were dosed with 2 placebo capsules ^*tid or ^**bid. During the dosing phase, the doses used were 12 mg daily (4 mg tid); 12.6 mg daily (6.3 mg bid); 18.9 mg daily (6.3 mg tid); 20 mg daily (10 mg bid); 30 mg daily (10 mg tid), or 2 placebo capsules tid or bid. In addition to the pharmacological treatment, the patients were given dietary and exercise advice, starting from the baseline visit. The prescribed caloric level was based on maintenance energy needs minus 2100 kJ (500 kcal). The recommended increase in physical activity corresponded to 20 to 30 minute walk per day.

*Bid = twice per day.

*^*Tid = three times per day.

Figure 1 shows that the maximum reduction in supine systolic blood pressure was seen in the cohort experiencing the highest drug concentrations, i.e. an average of 8.8 mmHg. Of this, 6.6 mmHg was apparent within two weeks of starting dosing, the remaining 2.2 mmHg was associated with an average reduction of body weight of 2.8 kg after a total of 8 weeks dosing. This 2.2mmHg is close to the predicted 2.0 mmHg expected for this amount of weight loss.

Of particular importance is the observation that those patients who experienced less body weight loss than the placebo group still experienced a significant reduction of blood pressure. Thus those patients with Cmax values greater than 150nM who experienced less than 2.0kg of body weight loss (n=1 1 , 26%) showed an average reduction in blood pressure of 6.7mmHg after 8 weeks, significantly greater than the 0.4mmHg predicted for the average weight loss in this group (0.6kg). This is clear evidence that treatment with PRX933 has an unexpected direct effect on blood pressure, separate from that on body weight.

Thus the present invention makes available a treatment for hypertension providing a surprisingly significant reduction in blood pressure within two weeks of starting dosing. This surprising initial reduction in blood pressure is especially useful in the treatment of patients having an urgent need to reduce blood pressure because the need for rapid reduction in blood pressure is not met by existing treatments such as Lorcaserin, phentermine and phenfluramine. In an embodiment, treatment with PRX933 results in a reduction in blood pressure of >3mmHg within two weeks of starting dosing. In an alternative embodiment the reduction in blood pressure results in a reduction in blood pressure of >4mmHg, or >5mmHg or >6mmHg within two weeks of starting dosing.

Definitions

PRX933 ((2R)-Methyl-1 -{3-[2-(3-pyridinyloxy)ethoxy]-2-pyrazinyl}piperazine, has the following structure):

Reference to PRX933 includes all pharmaceutically acceptable salts thereof. In an embodiment the pharmaceutically acceptable salt is the L-malate.

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, and morbidly obese when BMI>40kg/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.

As used herein the term "acute treatment" means treatment for less than 31 days, for example 21 days, 14 days, or 7 days.

The dose of PRX933 that is administered 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 PRX933 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 daily dose may be given as a single dose or in two or more doses, which can be equal doses or unequal doses. In an embodiment the mass of the patient is 60, 70, 80, 90 or 100kg.

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 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 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 active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include, for example: suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as 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 optionally 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, PRX933 is to be administered via the oral route. 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 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.

Kits and Packages

The dosages or compositions for the dosing regimens of the invention can be provided in the form of a kit or package, optionally with the dosages arranged for sequential administration. For example, in the oral form of the composition, the present invention provides a pharmaceutical package which contains a plurality of unit dosage forms, preferably similar or identical dosage units. Said dosage forms may be presented in a synchronized, fixed sequence, wherein the sequence or arrangement of the dosage units corresponds to the stages of daily administration.

In another embodiment, the kit or package includes unit dosages of different strengths, arranged to provide a titration or down-titration as may be suitable.

Thus, for example, the pharmaceutical compositions useful in the invention can be provided in kit form containing 5-31 unit dosage forms, preferably 7-20 unit dosage forms, preferably 7-14 unit dosage forms, most preferably 7 or 14 unit dosage forms. Such unit dosage forms are preferably tablets or capsules.

The unit dose may be a solid or liquid. Preferably the unit dose is a solid, preferably a tablet, preferably a coated tablet.

Administration is preferably once daily or twice daily.

Administration of the unit dosage forms is preferably for a period of 7-31 consecutive days, preferably 7-14 days. The pharmaceutical kits of the invention can further include instructions for administration in accordance with the regimens of the present invention.

The kit or package can also include a container for storing or packaging the components of the kit or package. Suitable containers include, for example, a bag, a box, a foil packet, a blister sealed package, and any other container that would be suitable for use in the present invention. In some embodiments, the kits or packages of the invention are designed in a manner such that they are tamper resistant or the packaging can indicate if tampering has occurred. In a particularly preferred embodiment, the package is a blister pack.

Preferably, the kit or package of the present invention contains sufficient unit dosage forms for at least one week's patient dosing, preferably 1 -4 week's patient dosing, preferably 1 -2 week's patient dosing, most preferably 1 or 2 week's patient dosing.

The unit dose used in the invention can be administered in a unit dose comprising about 0.001 mg to about 50 mg of PRX933, preferably from about 0.001 mg to about 20 mg of PRX933. For example, the composition of the invention can be administered in a unit dose comprising about 0.01 mg to about 5 mg of PRX933, for example about 0.01 mg to about 1 mg of PRX933, for example, about 0.02 mg to about 0.5 mg of PRX933. In an embodiment the dose of PRX933 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 kit or package of the invention will contain a plurality of such unit dosage forms as set out herein. The kit or package of the invention will preferably contain 5-31 unit dosage forms, preferably 7-20 unit dosage forms, preferably 7-14 unit dosage forms, most preferably 7 or 14 unit dosage forms. Such unit dosage forms are preferably tablets or capsules. Such dosage forms are preferably presented in a blister pack or a plastic container.

The present invention is also directed to a method of delivering a pharmaceutical composition for an dosage regimen of the present invention to a patient in need thereof the method comprising (a) registering in a computer readable medium the identity of a physician permitted to prescribe a pharmaceutical composition for an ascending-dose extended cycle regimen; (b) providing the patient with counselling information concerning the risks attendant to the pharmaceutical composition; (c) obtaining informed consent from the patient to receive the pharmaceutical composition despite the attendant risks; (d) registering the patient in a computer readable medium after obtaining their informed consent; and (e) permitting the patient access to the pharmaceutical composition.

"Instructions" for administering the dosage regimen of the invention can comprise printed matter, a pre-recorded media device, or a planner describing the use and/or proper administering of the unit dosage forms.

A "planner" can be, for example, a weekly, a monthly, a multi-monthly, a yearly, or a multi- yearly planner. In some embodiments, a planner can be useful in a clinical or diagnostic setting as a diary to monitor dosage amounts or keep track of dosages administered. One skilled in the art will appreciate the variety of planning tools that would be appropriate for use with the present invention.

The kits or packages of the invention preferably provide sufficient unit dosages containing sufficient pharmaceutical composition of the present invention in order to achieve the antihypertensive effect referred to herein, in particular, the acute reduction in blood pressure. This effect is usually observed within the first two weeks of administration of the pharmaceutical compositions of the invention.

References

Bramlage P., Pittrow D., Wittchen H., Kirch W., Boehler S., Lehnert H., et al. (2004) Hypertension in overweight and obese primary care patients is highly prevalent and poorly controlled. Am J Hypertens 17: 904-910

McTigue K., Larson J., Valoski A., Burke G., Kotchen J., Lewis C, et al. (2006) Mortality and cardiac and vascular outcomes in extremely obese women. JAMA 296: 79-86

Paulis, L and Unger, T (2010) Novel therapeutic targets for hypertension Nature Rev Cardiology 7, 431 -441

Redwood, H. Hypertension, society, and public policy. Eur. Heart J. 9 (Suppl. B), B13-B18 (2007)

Claims

1 . PRX933 for use in the treatment of hypertension in a patient wherein the patient's blood pressure is reduced by greater than 3mmHg within 14 days of starting treatment.

2. A method of treatment of hypertension, comprising administering to a patient suffering from hypertension an effective amount of PRX933 wherein the patient's blood pressure is reduced by greater than 3mmHg within 14 days of starting treatment.

3. A pharmaceutical composition comprising PRX933 and at least one suitable excipient for use in treatment of hypertension as set out in claim 1 , or a method as set out in claim 2.

4. A compound according to claim 1 , or a method according to claim 2, or a pharmaceutical composition according to claim 3, for treatment of hypertension wherein the patient is over-weight or obese.

5. A compound, method or pharmaceutical composition according to any one of claims 1 to 4 wherein the reduction is in the patient's systolic blood pressure.

6. The use of PRX933 for acute treatment of hypertension wherein the duration of dosing is 14 or fewer days.

7. The use according to claim 6 wherein the dose of PRX933 that is administered is from 0.01 to 0.3 mg/kg/day.

8. The use according to claim 6 wherein the dose of PRX933 that is administered is from 0.1 to 0.5 mg/kg/day.

9. A compound, or a pharmaceutical composition, or a method according to any one of claims 1 to 8 wherein PRX933 is the L-malate salt form.

10. A pharmaceutical package, the package comprising: (a) a plurality of unit dosage forms containing a pharmaceutically effective amount of PRX933; and

(b) a suitable container.

1 1 . The pharmaceutical package of claim 10, comprising 5-31 unit dosage forms, preferably 7-20 unit dosage forms, preferably 7-14 unit dosage forms, most preferably 7 or 14 unit dosage forms.

12. The pharmaceutical package of any one of claims 10 or 1 1 , wherein the unit dosage forms are tablets or capsules.

13. The pharmaceutical package of any one of claims 10 to 12, wherein administration is once or twice daily.

14. The pharmaceutical package of any one of claims 10 to 13, wherein sufficient unit dosage forms are present for administration for a period of 7-31 consecutive days, preferably 7-14 days, preferably 7 or 14 days.

15. The pharmaceutical package of any one of claims 10 to 14, wherein the package is selected from a bag, a box, a foil packet and a blister sealed package.

16. The pharmaceutical package of any one of claims 10 to 15, wherein the package of the present invention contains sufficient unit dosage forms for at least one week's patient dosing, preferably 1 -4 week's patient dosing, preferably 1 -2 week's patient dosing, most preferably 1 or 2 week's patient dosing.

17. The pharmaceutical package of any one of claims 10 to 16, wherein each unit dose is present in an amount of about 0.001 mg to about 20 mg, preferably 0.01 mg to about 5 mg, preferably about 0.05 mg to about 1 mg, preferably about 0.1 mg to about 0.5 mg.

18. Use of a package according to any one of claims 10 to 17 for the acute treatment of hypertension. obese.

20. Use of a package according to any of claims 10-19, wherein the patient suffers from acute or chronic hypertension.

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