WO2020049327A1 - Methods and pharmaceutical composition for the treatment of hidradenitis suppurativa in patients in need thereof - Google Patents

Abstract

Hidradenitis suppurativa (HS) is a chronic, inflammatory, recurrent, debilitating, disease of the skin that usually presents after puberty. It features painful, deep-seated, inflamed lesions most commonly in the axillary, inguinal and anogenital regions. The inventors report a successful HS treatment with a calcium channel blocker: verapamil. Compared to biologic agents, verapamil is safer and cheaper. Given its possible role on TNF-α/IL-1, calcium channel blockers thus represent an alternative therapeutic option in mild and moderate HS. Accordingly, the present invention relates to a method of treating Hidradenitis suppurativa in a patient in need thereof comprising administering to the subject a therapeutically effective amount of a calcium-channel blocker.

Description

METHODS AND PHARMACEUTICAL COMPOSITION FOR THE TREATMENT OF HIDRADENITIS SUPPURATIVA IN PATIENTS IN NEED THEREOF

FIELD OF THE INVENTION:

The present invention relates to methods and pharmaceutical composition for the treatment of Hidradenitis suppurativa in patients in need thereof

BACKGROUND OF THE INVENTION:

Hidradenitis suppurativa (HS) is a chronic, inflammatory, recurrent, debilitating, disease of the skin that usually presents after puberty. It features painful, deep-seated, inflamed lesions most commonly in the axillary, inguinal and anogenital regions. The estimated prevalence is 1% to 4% in Europe and 0,5% in USA. Because HS is a painful and distressing disorder and is associated with strong feelings of shame, it reduces patients’ quality of life substantially. Several treatments are available such as topical and oral therapy, surgery and recently TNF-a inhibitors, but the results are mixed. Treatments show indeed an inconstant efficiency, generally moderate and transient. Antibiotics for cutaneous bacterial persistence in affected skin are successful for some patients only. Moreover, systematic use of antibiotic may lead to the development of multi-resistant bacteria. The use of immunosuppressive agents has pointed to a role of the immune system. The pathogenesis of HS is still poorly understood and is probably multifactorial. Smoking, obesity and hormonal influences may be pathogenic factors.

SUMMARY OF THE INVENTION:

The present invention relates to methods and pharmaceutical composition for the treatment of Hidradenitis suppurativa in patients in need thereof. In particular, the present invention is defined by the claims.

DETAILED DESCRIPTION OF THE INVENTION:

The first object of the present invention relates to a method of treating Hidradenitis suppurativa in a patient in need thereof comprising administering to the subject a therapeutically effective amount of a calcium-channel blocker.

As used herein the term‘ Hidradenitis suppurativa” or“HS” has its general meaning in the art and refers to a chronic skin disease characterized by clusters of abscesses and/or cysts that most commonly affects apocrine sweat gland bearing areas. Hidradenitis suppurativa is also called acne inversa or Vemeuil’s disease. In some embodiments, the method of the present invention is particularly suitable for the treatment of mild and moderate HS. As used herein, the term "treatment" or "treat" refer to both prophylactic or preventive treatment as well as curative or disease modifying treatment, including treatment of patient at risk of contracting the disease or suspected to have contracted the disease as well as patients who are ill or have been diagnosed as suffering from a disease or medical condition, and includes suppression of clinical relapse. The treatment may be administered to a subject having a medical disorder or who ultimately may acquire the disorder, in order to prevent, cure, delay the onset of, reduce the severity of, or ameliorate one or more symptoms of a disorder or recurring disorder, or in order to prolong the survival of a subject beyond that expected in the absence of such treatment. By "therapeutic regimen" is meant the pattern of treatment of an illness, e.g., the pattern of dosing used during therapy. A therapeutic regimen may include an induction regimen and a maintenance regimen. The phrase "induction regimen" or "induction period" refers to a therapeutic regimen (or the portion of a therapeutic regimen) that is used for the initial treatment of a disease. The general goal of an induction regimen is to provide a high level of drug to a patient during the initial period of a treatment regimen. An induction regimen may employ (in part or in whole) a "loading regimen", which may include administering a greater dose of the drug than a physician would employ during a maintenance regimen, administering a drug more frequently than a physician would administer the drug during a maintenance regimen, or both. The phrase "maintenance regimen" or "maintenance period" refers to a therapeutic regimen (or the portion of a therapeutic regimen) that is used for the maintenance of a patient during treatment of an illness, e.g., to keep the patient in remission for long periods of time (months or years). A maintenance regimen may employ continuous therapy (e.g., administering a drug at a regular intervals, e.g., weekly, monthly, yearly, etc.) or intermittent therapy (e.g., interrupted treatment, intermittent treatment, treatment at relapse, or treatment upon achievement of a particular predetermined criteria [e.g., disease manifestation, etc.]).

As used herein, the term“calcium-channel blocker” has its general meaning in the art and refers to one of a class of pharmacological agents, also known as calcium antagonists, which inhibit the transmembrane flux of calcium (Ca2+) ions.“Calcium channel blockers” are also known as calcium ion influx inhibitors, slow channel blockers, calcium ion antagonists, and calcium channel antagonist drugs. In some embodiments, the calcium-channel blocker of the present invention is a L-type voltage-dependent calcium channel blocker. L-type calcium channels are characterized as Cavl .1 , Cavl .2, Cavl .3, and Cavl .4. In some embodiments, the calcium channel blocker exhibits IC50 values of about 1 mM or less. In some embodiments, the calcium channel blocker exhibits IC50 values of about 0.9 mM, 0.8 mM, 0.7 mM, 0.6 mM, 0.5 mM, 0.4 mM, 0.3 mM, 0.2 mM, or 0.1 mM or less. One class of L-type calcium channel blocker includes dihydropyridines. Dihydropyridines include, but are not limited to, amlodipine, aranidipine, azelnidipine, bamidipine, benidipine, cilnidipine, clevidipine, efonidipine, felodipine, isradipine, lacidipine, lercanidipine, manidipine, nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine, nitrendipine, and pranidipine. A particular L- type calcium channel blocker of interest is nifedipine. Another class of L-type calcium channel blocker includes phenylalkylamines. Phenylalkylamines include, but are not limited to, verapamil and gallopamil. A particular L-type calcium channel blocker of interest is verapamil. Another class of L-type calcium channel blocker includes benzothiazepines. Benzothiazepines include, but are not limited to, diltiazem, which is of particular interest.

In a preferred embodiments, the calcium channel blocker of the present invention is verapamil. As used herein, the term“verapamil” has its general meaning in the art and refers to (2-(3,4-dimethoxyphenyl)-5-{[2-(3,4-dimethoxyphenyl)ethyl]-(methyl)amino}-2-prop-2- ylpentanenitrile). The term includes the stereoisomers, derivatives, metabolites, salts, solvates and/or combinations thereof, and may be any of (R)-(+)-verapamil, (S)-(-)-verapamil, a mixture of (R)-(+)-verapamil and (S)-(-)-verapamil, a pharmaceutically acceptable derivative, stereoisomer, metabolite, salt or solvate thereof, or a combination thereof. Verapamil is known to exist in either (R)- or (S)-form. It is well known that pharmacodynamics and pharmacokinetics of the (R)-(+)-verapamil and (S)-(-)-verapamil differs in vivo, with (S)-form more potent than the (R)-form. In some embodiments, verapamil is provided in (R)-form. In some embodiments, verapamil is provided in (S)-form. In some embodiments, verapamil is proved as a mixture of (R)-(+)-verapamil and (S)-(-)-verapamil, for example, about 90% (R)- form and about 10% (S)-form, about 80% (R)-form and about 20% (S)-form, about 70% (R)- form and about 30% (S)-form, about 60% (R)-form and about 40% (S)-form, about 40% (R)- form and about 60% (S)-form, about 30% (R)-form and about 70% (S)-form, about 20% (R)- form and about 80% (S)-form, or about 10% (R)-form and about 90% (S)-form. In some embodiments, verapamil is as a racemic mixture containing approximately equal amount of (R)-(+)-verapamil and (S)-(-)-verapamil, that is, with (R)- and (S)-form being about 50%, respectively.

By a "therapeutically effective amount" is meant a sufficient amount of the calcium channel blocker to treat Hidradenitis suppurativa at a reasonable benefit/risk ratio applicable to any medical treatment. It will be understood that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed, the age, body weight, general health, sex and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific drug employed; and like factors well known in the medical arts. For example, it is well within the skill of the art to start doses of the compound at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. However, the daily dosage of the products may be varied over a wide range from 0.01 to 1,000 mg per adult per day. Typically, the compositions contain 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 250 and 500 mg of the agent for the symptomatic adjustment of the dosage to the subject to be treated. A medicament typically contains from about 0.01 mg to about 500 mg of the agent, preferably from 1 mg to about 100 mg of the agent. An effective amount of the drug is ordinarily supplied at a dosage level from 0.0002 mg/kg to about 20 mg/kg of body weight per day, especially from about 0.001 mg/kg to 7 mg/kg of body weight per day.

Typically the calcium channel blocker of the present invention is combined with pharmaceutically acceptable excipients, and optionally sustained-release matrices, such as biodegradable polymers, to form pharmaceutical compositions. The term "Pharmaceutically" or "pharmaceutically acceptable" refers to molecular entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to a mammal, especially a human, as appropriate. A pharmaceutically acceptable carrier or excipient refers to a non-toxic solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. The carrier can also be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetables oils.

In some embodiments, it may be desirable to administer the calcium channel blocker of the present in a topical formulation. As used herein the term“topical formulation” refers to a formulation that may be applied to skin. Topical formulations can be used for both topical and transdermal administration of substances. As used herein,“topical administration” is used in its conventional sense to mean delivery of a substance, such as a therapeutically active agent, to the skin or a localized region of a subject's body. As used herein,“transdermal administration” refers to administration through the skin. Transdermal administration is often applied where systemic delivery of an active is desired, although it may also be useful for delivering an active to tissues underlying the skin with minimal systemic absorption. Typically, the topical pharmaceutically acceptable carrier is any substantially nontoxic carrier conventionally usable for topical administration of pharmaceuticals in which the calcium channel blocker of the present invention will remain stable and bioavailable when applied directly to skin surfaces. For example, carriers such as those known in the art effective for penetrating the keratin layer of the skin into the stratum corneum may be useful in delivering the calcium channel blocker of the present invention to the area of interest. Such carriers include liposomes. The calcium channel blocker can be dispersed or emulsified in a medium in a conventional manner to form a liquid preparation or mixed with a semi-solid (gel) or solid carrier to form a paste, powder, ointment, cream, lotion or the like. Suitable topical pharmaceutically acceptable carriers include water, buffered saline, petroleum jelly (vaseline), petrolatum, mineral oil, vegetable oil, animal oil, organic and inorganic waxes, such as microcrystalline, paraffin and ozocerite wax, natural polymers, such as xanthanes, gelatin, cellulose, collagen, starch, or gum arabic, synthetic polymers, alcohols, polyols, and the like. The carrier can be a water miscible carrier composition. Such water miscible, topical pharmaceutically acceptable carrier composition can include those made with one or more appropriate ingredients outset of therapy. The topical acceptable carrier will be any substantially non-toxic carrier conventionally usable for topical administration in which the calcium channel blocker will remain stable and bioavailable when applied directly to the skin surface. Suitable cosmetically acceptable carriers are known to those of skill in the art and include, but are not limited to, cosmetically acceptable liquids, creams, oils, lotions, ointments, gels, or solids, such as conventional cosmetic night creams, foundation creams, suntan lotions, sunscreens, hand lotions, make-up and make-up bases, masks and the like. Any suitable carrier or vehicle effective for topical administration to a patient as known in the art may be used, such as, for example, a cream base, creams, liniments, gels, lotions, ointments, foams, solutions, suspensions, emulsions, pastes, aqueous mixtures, sprays, aerosolized mixtures, oils such as Crisco®, soft-soap, as well as any other preparation that is pharmaceutically suitable for topical administration on human and/or animal body surfaces such as skin or mucous membranes. Topical acceptable carriers may be similar or identical in nature to the above described topical pharmaceutically acceptable carriers. It may be desirable to have a delivery system that controls the release of the calcium channel blocker to the skin and adheres to or maintains itself on the skin for an extended period of time to increase the contact time of the calcium channel blocker of the present invention on the skin. Sustained or delayed release of the calcium channel blocker provides a more efficient administration resulting in less frequent and/or decreased dosage of the calcium channel blocker and better patient compliance. Examples of suitable carriers for sustained or delayed release in a moist environment include gelatin, gum arabic, xanthane polymers. Pharmaceutical carriers capable of releasing the calcium channel blocker of the present invention when exposed to any oily, fatty, waxy, or moist environment on the area being treated, include thermoplastic or flexible thermoset resin or elastomer including thermoplastic resins such as polyvinyl halides, polyvinyl esters, polyvinylidene halides and halogenated polyolefins, elastomers such as brasiliensis, polydienes, and halogenated natural and synthetic rubbers, and flexible thermoset resins such as polyurethanes, epoxy resins and the like. Controlled delivery systems are described, for example, in U.S. Pat. No. 5,427,778 which provides gel formulations and viscous solutions for delivery of the calcium channel blocker of the present invention to a skin site. Gels have the advantages of having a high water content to keep the skin moist, the ability to absorb skin exudate, easy application and easy removal by washing. Preferably, the sustained or delayed release carrier is a gel, liposome, microsponge or microsphere. The calcium channel blocker of the present invention can also be administered in combination with other pharmaceutically effective agents including, but not limited to, antibiotics, other skin healing agents, and antioxidants. In some embodiments, the topical formulation of the present invention comprises a penetration enhancer. As used herein,“penetration enhancer” refers to an agent that improves the transport of molecules such as an active agent (e.g., a drug) into or through the skin. Various conditions may occur at different sites in the body either in the skin or below creating a need to target delivery of compounds. Thus, a“penetration enhancer” may be used to assist in the delivery of an active agent directly to the skin or underlying tissue or indirectly to the site of the disease or a symptom thereof through systemic distribution. A penetration enhancer may be a pure substance or may comprise a mixture of different chemical entities.

The invention will be further illustrated by the following figures and examples. However, these examples and figures should not be interpreted in any way as limiting the scope of the present invention.

EXAMPLE:

Introduction:

Hidradenitis suppurativa (HS) is a debilitating chronic inflammatory skin disease characterized by recurrent painful abscesses and sinus tract formation in apocrine sweat glands areas. Several treatments are available such as topical and oral therapy, surgery and recently TNF-a inhibitors, but the results are mixed. We report a case of HS that responded to verapamil.

Case report: A 39-year-old man with a l2-year history of HS presented with inflammatory and painful nodules, draining fistulas with malodorous suppuration, hypertrophic scars (Hurley stage 2) in axillae, groin, buttocks, scalp and beard. According to the Canoui-Poitrine classification, the patient presented the phenotype « gluteal » (2). Histology was consistent with HS: inflammatory infiltrates containing histiocytes and giant cells around apocrine glands, follicular plugging, reduced volume of sebaceous glands and sinus tracts lined by a stratified epithelium. The patient did not have any other skin lesions or any other comorbidities. He was an active smoker and was slightly overweight (BMI=25.6) without metabolic syndrome. No family history of HS was known. Fusidic acid (2008) and isotretinoin (2009-2014) were poorly effective. The Dermatology Life Quality Index (DLQI) score was 27 (with 0 for best to 30 for worst quality of life). For 2.5 years, the patient had been suffering from cluster headache. A treatment with SR-verapamil (240 mgx3/day) began in 2014, two months after the discontinuation of isotretinoin. No other treatment was given, except SC sumatriptan in case of severe attack. The patient, always an active smoker, noticed a reduction in pain and lesions in the 2 months following verapamil initiation. In 2015, when verapamil was stopped, the painful nodules and suppuration recurred within 1.5 months. The patient resumed taking verapamil as before and a remission occurred (DLQI=6). After a two-month treatment with verapamil, an improvement in the quality of life was shown in the following domains: daily activities, work, leisure and personal relationship (except sexual relation). No adverse drug reaction (ADR) occurred during the observation period.

Conclusion:

HS, also named“Vemeuil’s disease” or acnea inversa, is a chronic inflammatory skin disease (prevalence 0.25%-5%), with a major impact on the quality of life. HS is sometimes associated with Crohn’s disease, arthropathy, metabolic syndrome and migraine (1). The pathogenesis is not still understood; genetic predisposition, bacterial infection, hormones, obesity and smoking play a role. Recently, an immune response dysfunction has been identified, involving pro-inflammatory cytokines such as tumor necrosis factor-a (TNF-a), interleukin (IL)-lp, IL-10, IL-12/23 and IL-17 (3). In patients with Hurley stages 2 and 3, elevated serum levels of TNF-a, IL- 1 b and IL-10 have been measured (4). Several clinical trials with biologic agents such as anti-TNF-a (adalimumab), anti-ILl (anakinra), anti-IL23 (ustekinumab) showed an improvement in patients with HS (3). In 2015, adalimumab was the first TNF-a inhibitor approved for moderate to severe HS. Nevertheless, patients given biologic therapies are at increased risk of infections, malignancies, and hypersensitivity reactions (5). Verapamil is an L-type voltage-dependent calcium channel blocker (CCB), belonging to the phenylalkylamine group, used in the treatment of hypertension, angina pectoris, arrhythmia and migraine. Induced ADRs severity is modest: hypotension, dizziness, flushing, edema, asthenia, constipation, and gingival hyperplasia. Verapamil and other CCBs have a wide spectrum of skin actions. Verapamil inhibits the growth and proliferation of fibroblasts, the synthesis of extracellular matrix proteins (collagen, fibronectin, proteoglycans), and reduces cytokines (IL-6, VEGF and TGF-bl) often elevated in keloids; so the intralesional injection of verapamil is a therapeutic option to treat keloid scars and other fibrosing diseases (e.g. Peyronie’s disease) (6-8). Recently, verapamil has been shown to inhibit TNF-a-induced activation of NF-kB signaling both in vitro and in arthritis mice models, and to suppress IF- 1 b and TNF-a production by human peripheral blood mononuclear cells (9-10). So, we hypothesize that verapamil inhibits the inflammatory process through the TNF-a/IF-l pathway involved in the HS physiopathology. In our case, both the HS relapse after the verapamil dechallenge and the regression after the verapamil rechallenge suggest a positive effect of verapamil on HS.

To the best of our knowledge, this is the first report of a successful HS treatment with verapamil. Compared to biologic agents, verapamil is safer and cheaper. Given its possible role on TNF-a/IF-l, verapamil may represent an alternative therapeutic option in mild and moderate HS.

REFERENCES:

Throughout this application, various references describe the state of the art to which this invention pertains. The disclosures of these references are hereby incorporated by reference into the present disclosure.

1. Zouboulis CC, Desai N, Emtestam F et al. European Sl guideline for the treatment of hidradenitis suppurativa/acne inversa. J Eur Acad Dermatol Venereol 2015; 29:619-44.

2. Canoui-Poitrine F, Fe Thuaut A, Revuz JE et al. Identification of three hidradenitis suppurativa phenotypes: latent class analysis of a cross-sectional study. J Invest Dermatol 2013;133: 1506-11.

3. Hoffman FK, Ghias MH, Fowes MA. Pathophysiology of hidradenitis suppurativa. Semin Cutan Med Surg 2017; 36:47-54.

4. van der Zee HH, de Ruiter F, van den Broecke DG et al. Elevated levels of tumour necrosis factor (TNF)-a, interleukin (IF)- 1 b and IF- 10 in hidradenitis suppurativa skin: a rationale for targeting TNF-a and IF- 1 b. Br J Dermatol 2011; 164: 1292-8. 5. Badavanis G, Pasmatzi E, Monastirli A et al. Biologic agents in systemic dermatotherapy: cutaneous and systemic side effects. Curr Drug Saf 2017 May 18. doi: 10.2174/1574886312666170518124014

6. Berman B, Maderal A, Raphael B. Keloids and Hypertrophic Scars: Pathophysiology, Classification, and Treatment. Dermatol Surg 20l7;43 Suppl 1 :S3-S 18

7. DAndrea F, Brongo S, Ferraro G, Baroni A, Prevention and treatment of keloids with intralesional verapamil, Dermatology 2002; 204:60-2.

8. Favilla V, Russo GI, Zucchi A et al. Evaluation of intralesional injection of hyaluronic acid compared with verapamil in Peyronie's disease: preliminary results from a prospective, double-blinded, randomized study. Andrology 2017; 5:771-775.

9. Matsumori A, Nishio R, Nose Y. Calcium channel blockers differentially modulate cytokine production by peripheral blood mononuclear cells. Circ J 2010; 74:567-71.

10. Wang W, Fi Z, Meng Q, Zhang P et al. Chronic Calcium Channel Inhibitor Verapamil Antagonizes TNF-a-Mediated Inflammatory Reaction and Protects Against Inflammatory Arthritis in Mice. Inflammation 2016; 39:1624-34.

Claims

CLAIMS:

1. A method of treating Hidradenitis suppurativa in a patient in need thereof comprising administering to the subject a therapeutically effective amount of a calcium-channel blocker.

2. The method of claim 1 wherein the patient suffers from mild and moderate Hidradenitis suppurativa.

3. The method of claim 1 wherein the calcium channel blocker is a L-type voltage- dependent calcium channel blocker.

4. The method of claim 1 wherein the calcium channel blocker is selected among dihydropyridines.

5. The method of claim 1 wherein the calcium channel blocker is selected from the group consisting of amlodipine, aranidipine, azelnidipine, bamidipine, benidipine, cilnidipine, clevidipine, efonidipine, felodipine, isradipine, lacidipine, lercanidipine, manidipine, nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine, nitrendipine, and pranidipine.

6. The method of claim 1 wherein the calcium channel blocker is selected among pheny lalky lamines .

7. The method of claim 1 wherein the calcium channel blocker is selected from the group consisting of verapamil and gallopamil.

8. The method of claim 1 wherein e calcium channel blocker is selected from the group consisting of benzothiazepines, such as diltiazem.

9. The method of claim 1 wherein the calcium channel blocker is verapamil

10. The method of claim 1 wherein the calcium channel blocker is administered to the patient via a topical formulation.