WO2019130215A1

WO2019130215A1 - Cannabis compositions for the treatment of inflammatory skin disorders

Info

Publication number: WO2019130215A1
Application number: PCT/IB2018/060616
Authority: WO
Inventors: Sid TAUBENFELD
Original assignee: To Pharmaceuticals Llc; Reinhold Cohn And Partners
Priority date: 2017-12-27
Filing date: 2018-12-26
Publication date: 2019-07-04

Abstract

The invention relates to therapeutic products and methods applicable to the treatment of Hidradenitis Suppurativa (HS) and related conditions, said products and methods using CBD and THC compositions wherein the cannabinoids are present in specific proportions across specific ranges of concentrations and amounts, with particular emphasis on cannabis-based compositions.

Description

CANNABIS COMPOSITIONS FOR THE TREATMENT OF

INFLAMMATORY SKIN DISORDERS

TECHNOLOGICAL LIELD

The present invention generally relates to therapeutic products and methods applicable to the treatment of chronic inflammatory skin conditions, and to Hidradenitis Suppurativa (HS) in particular.

BACKGROUND

Clinical value of cannabis is well documented in the medical literature. Cannabinoids, the active ingredients of cannabis, are present in significantly higher concentrations in resin- producing pistillate inflorescences of cannabis plants. Various types of cannabis, such as C. Sativa, C. Indica and C. Ruderalis, may contain more than 100 different types of cannabinoids in distinct concentrations and proportions. The two predominant types, the tetrahydrocannabinol (THC) and cannabidiol (CBD), have been related to a number of clinically beneficial effects attributed to their analgesic, antiemetic, antioxidative, neuroprotective and anti-inflammatory activities in mammals and humans.

The mammalian endocannabinoid system is a signal transduction system acting predominantly in the brain, and also in the peripheral tissues. Several cannabinoid receptors have been identified so far, the most prominent being the cannabinoid receptors types 1 and 2 (CBi and CB2). The endocannabinoid system has been implicated in maintenance of homeostasis of the normal mammalian physiology, including systems of movement control, pain, appetite, memory, immunity and inflammation, among others. This underlies the notion of high therapeutic potential of exogenous cannabinoids and cannabis-based medicines, and the likelihood of their broad clinical applications. However, a rationalized use of cannabinoids still imposes significant challenges due to lack of significant controlled clinical trials.

A number of oral formulations of cannabinoids are commercially available today by prescription for specific indications. Marinol capsules containing dronabinol, a synthetic D⁹- THC isoform, in oil were approved in certain countries as an antiemetic in cancer patients under chemotherapy and in patients with AIDS, and Cesamet capsules with a synthetic THC analog - as a Marinol substitute. Additional formulations such as Namisol and Arvisol tablets with pure THC and pure CBD, respectively, are now under clinical trial for various indications. More recently, orphan cannabis-derived compositions such as Sativex have been approved for spasticity in multiple sclerosis and Epidolex - for rare forms of epilepsy. The instant invention is relevant to a group of inflammatory conditions collectively referred to as chronic inflammatory skin disorders. In particular the invention is relevant to a condition referred to as Hidradenitis Suppurativa (HS) manifested by recurrent inflammations within and around hair follicles, and around epocrine sweat glands, most commonly in the axillae, inguinal and anogenital regions. A part from significant discomfort and pain, HS patients also suffer from psychological problems and are more prone to other health complications. The current treatment options for HS are limited and mainly include antibiotics, and more recently - biological drugs, but with only 40% documented efficiency.

Potential use of cannabinoids for HS has been referred to in WO2017/055846 together with other inflammatory skin conditions, suggesting specifically CBD and CBD derivatives, and HCV (tetrahydrocannabivarin). The US patents 8,895,536 and US 8,895,537 suggested a broad group of anti-inflammatory compounds stimulating PPARs (peroxisome proliferator).

Hidradenitis Suppurativa (also known as VerneuiTs disease or acne inversa) is a relatively common highly distressing, and at times debilitating, disorder with an incidence of about 4% (although it may be more common as its diagnosis is often overlooked). HS is manifested by the onset of inflammatory lesions, deep and painful, in areas of the skin with apocrine sweat glands abundant in hair follicles, such as in the axillae, groins and external genitals. It is marked by periods of inflammation with occasional secondary infections and intermittent remissions that can last several years.

The etiology of HS is unknown. The disease affects more women than men with a female-to-male predominance of about 4:1, and almost always occurs after puberty and before age 40. All these have led to notion of a hormonal component to HS pathogenesis. There is also a genetic component revealed in families with autosomal dominant inheritance of HS.

Because of painful chronic inflammations and secondary infections (mainly by Staphylococcus aureus ) necessitating constant management and treatment, HS is perceived as a severe reduction in the quality of life. HS has been also related to accompanying illnesses, such as metabolic syndrome, joint inflammation, inflammatory bowel disease, and depression. The latter is significantly higher in HS compared to other skin disorders. There are also reports on a higher level of fatigue and sexual dysfunction.

There is no effective cure for HS. Several treatment options of limited efficacy consist of oral antibiotics, steroids, retinoids, immunosuppressants (including biological therapies), and surgery to remove sweat glands. Treatments addressing possible hormonal etiology of HS use oral contraceptives agents with a high estrogen-to-progesterone ratio. Overall, HS remains a challenging disease for patients and physicians, both in terms of etiology and treatment. REFERENCES

[1] WO2017/055846

[2] US 8,895,536

[2] US 8,895,537

[4] WO16103254

GENERAL DESCRIPTION

The present invention addresses the above needs in providing a targeted therapeutic solution for HS, considering specific clinical symptoms, as well as immediate and long-term HS presentations and consequences. The inventors have presently shown that certain cannabinoid compositions comprising specific THC and CBD amounts and ratios are effective for treating or alleviating HS, including inflammatory and nociceptive symptoms, and potentially preventing HS recurrence. Examples of such compositions are presently disclosed along with their therapeutic applications as revealed in a carefully monitored clinical study of patients with moderate to severe HS.

More specifically, the present disclosure exemplifies a phyto-derived material from a cannabis strain having substantially balanced or equal ratio of THC:CBD, also referred to herein as a strain containing THC and CBD in approximately equal proportions. An exemplary member of this group is represented by the strain referred to herein as 'Midnight' generally described in US Plant Patent Application No. 2014/0245495 (US Continuation Application No. 2017/295742).

Another example serves a phyto-derived material from a cannabis strain substantially enriched in CBD with an exemplary member referred to herein as 'Avidekell described in US Plant Patent Application No. 2014/259228 (US Continuation Application No. 2017/290286).

More specifically, Avidekel herein encompasses a group of variants descended from an original Avidekel strain or cultivar characterized as having a particularly high content of CBD and low THC, starting from CBD:THC ratio of about 4:1 or more (w/w).

In other words, an Avidekel strain can comprise CBD as high as 15-20% or more than 20% (w/w), and THC - as low as 1-4% or less than 1% (w/w).

Avidekel can be further defined as a cannabis strain comprising CBD up to at least 15%, 16%, 17%, 18%, 19%, 20% or more, and THC up to 4%, 3%, 2%, 1%, 0.5% or less. According to the invention, the phyto-derived material from Midnight and Avidekel can be provided in a form of a crude dried plant material suitable for smoking or as an oil extract for oral administration. The latter type has been tested in the presently described clinical trial.

Two dosing forms of Midnight oil have been developed for the purpose of low and high dosing regimens:

a. a low dosage form, wherein one drop of an olive oil extract of Midnight (approximately 0.04 ml) comprises a relative content of CBD or THC of approximately 3% (w/w) and a total content of approximately 1.2 mg CBD and 1.2 mg THC, or about 2.4 mg of both cannabinoids; and

b. a high dosage form, wherein one drop of Midnight oil comprises a relative content of CBD or THC of approximately 15% (w/w) and a total content of approximately 6 mg CBD and 6 mg THC, or about 12 mg of both cannabinoids.

The Avidekel oil extract has been provided in a single dosage form characteristically comprising CBD in the range of 16-20% and THC 1-4% (w/w). To evaluate safety and efficacy of the above THC/CBD oral forms the inventors have initiated a phase II, randomized, double blind, placebo-controlled, two-arm study including 40 adult male and female patients with moderate to severe symptoms of HS. Patients have been randomly assigned to receive a placebo (olive oil) or the compositions of the invention, specifically a Midnight oil extract provided as low or high dosage forms, or Avidekel oil extract. In this study the cannabis-based medicine has been administered as a combination therapy, i.e., together with conventional HS therapies such as Humira (adalimumab), a tumor necrosis factor (TNF) for reducing inflammation. Study exclusion criteria related to risk of cross-drug interaction (see Detailed Description further below).

Drug safety and efficacy have been evaluated using high quality assessment criteria, including three independent standardized clinical scales: HiSCR (HS Clinical Response); HS- PGA (HS Global Assessment); Hurly clinical staging (HS severity scale); and DLQI (Dermatology Life Quality Index). Clinical evaluation also included laboratory analyses, e.g., serum chemistry and hematological testing. Drug efficacy (6 weeks follow up) and safety (12 months follow up) have been evaluated at primary and secondary endpoints with regard to any changes in the severity of HS symptoms, general quality of life, number and severity of reported adverse events or dosing of concurrent medications. The success rate has been established using a number of high-fidelity statistical methods comparing between the treatment and control groups. A detailed description of the study is provided further below. Apart from establishing applicability of the THC/CBD compositions of the invention to HS, and to adverse reactions induced by conventional HS medicines, this study has further provided tools for establishing therapeutically effective doses and regimens using said compositions for maximization of beneficial clinical outcomes, and avoidance of side effects and cross-drug interaction. In other words, this study has provided an exemplary framework for applying THC/CBD compositions of the invention in a rationalized manner using Midnight and Avidekel extracts in specific dosage form to achieve more effective and safe treatment of HS. It is further conceived that the presently proposed methods, compositions and dosage forms of the invention could be successfully applied as a monotherapy for the treatment of HS, and prevention of HS recurrence, in female and male patients.

In the broadest sense the present invention is meant to provide compositions comprising CBD and THC in specific proportions or ratios with proven benefits and efficacy for treating, alleviated or reducing at least one symptom of HS, or preventing a recurrence of a symptom of HS.

It is one of the important aspects the invention to provide for the above purpose oral pharmaceutical compositions comprising CBD and THC in approximately equal proportions (w/w). It should be noted that the two main cannabinoids comprised in the compositions of the invention can be synthetic, semisynthetic or phyto-derived. An essential feature of this type of compositions is their relative content or ratio of CBD:THC is of at least about 1:1 or more in favor of CBD, which is maintained across specific range of concentrations and amounts of these two actives.

With respect to the compositions of enriched in CBD, in specific embodiments this type of compositions of the invention can comprise CBD:THC ratio of at least about 4:1 or more in favor of CBD (w/w), or more specifically up to about 16-20% CBD and 1-4% THC or even lower THC (w/w).

In one of its aspects the invention provides this type of compositions as cannabis- based compositions, namely in a form of a phyto-derived material such as crude dry material or an oil extract. A phyto-derived material can include additional types of cannabinoids, although at much lesser concentrations and proportions, which can potentially contribute to their clinical effects. Present examples of such compositions include olive oil extracts obtained from the cannabis strains Midnight and Avidekel.

According to the invention the above compositions, and therapeutic methods using thereof, can be applied as monotherapies for HS or in combination with conventional therapies for HS, thus potentially mitigating their adverse effects and leading to a reduced intake of conventional medicines. Sublingual administration of cannabis-based compositions has been presently demonstrated. Cannabis-based compositions can be also administered in many other oral forms, including those adapted for smoking, inhalation, vaporization.

It should be appreciated that compositions and methods of the invention, using cannabis-derived or purified cannabinoids, can be also applied for HS as topical treatments, including a transdermal patch, administered together or apart from the oral dosage forms.

The invention further provides oral dosage forms of cannabis-based compositions of the invention that have been found especially useful for a controlled and rationalized treatment of HS. Of particular interest in this connection are low (3%) and high dosage (15%) forms of Midnight oil extracts, which have been implemented under structured and controlled regimen to achieve personalized therapeutically effective dosing of actives for optimization of treatment.

Ultimately, the invention provides uses of the presently developed THC and CBD compositions in the manufacture/ preparation of a medicament for treating, alleviating or reducing HS symptoms, or preventing recurrence of a symptom of HS.

DESCRIPTION OF SPECIFIC EMBODIMENTS

Before the present methods are described, it is to be understood that this invention is not limited to particular methods, and experimental conditions described, as such methods and conditions may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.

Tetrahydrocannabinol (THC) refers herein to a class of psychoactive cannabinoids characterized by high affinity to CB1 and CB2 receptors, having a molecular formula C21H30O2, an average mass of approximately 314.46 Da, and a general structure of Formula I.

Formula I Cannabidiol (CBD) refers herein to a class of non-psychoactive cannabinoids with a low affinity to CB1 and CB2 receptors, having a formula C21H30O2, an average mass of approximately 314.46 Da, and a general structure of Formula II.

Formula II

The terms THC and CBD herein further refer to isomers, derivatives, or precursors of these molecules, such as (-)-trans-A9-tetrahydrocannabinol (A9-THC), A8-THC, and D9- CBD, and further to THC and CBD derived from their respective 2-carboxylic acids (2- COOH), THC-A and CBD-A.

In the broadest sense, the terms THC and CBD herein refer to a synthetic or semi synthetic or a natural cannabinoid (i.e. purified or extracted from a cannabis plant). THC responsible for the psychoactive ('high') effect of cannabis and is known to relieve pain. CBD has no psychoactive effects and moderates the euphoric effect of THC, it is known to reduce inflammation and nausea.

Cannabis-based and cannabis-derived, these terms herein are interchangeable and signify a composition or a constituent thereof purified or extracted from a cannabis plant There are number of methods for producing extracts or a concentrated cannabis-derived material, e.g., filtration, maceration, infusion, percolation, decoction in various solvents, Soxhlet extraction, microwave- and ultrasound-assisted extractions and other methods. Certain oil extracts from the strains Avidekel and Midnight are presently exemplified.

Therapeutic agent denotes here a broad range of agents drugs from the groups of anti inflammatory, anti-nociceptive, antibiotic, antiemetic, anti-diarrheal drugs, or combinations thereof. In numerous embodiments one or more therapeutic agents are added to the compositions and methods of the invention. In certain embodiments under therapeutic agent is meant concurrent drugs used as convention treatments in HS, such as topical cleansing agents, non-steroidal anti-inflammatory drugs, antibiotics, oral contraceptives with a high estrogen- to-progesterone ratio, oral retinoids, corticosteroids and immunosuppressants such as oral cyclosporine, tri-amcinolone (Aristocort) and Sandimmune, with biological drugs such as adalimumah (Humira) as more recent options.

The terms therapeutic dose or therapeutically effective dose, which herein are interchangeable, relate to doses of a composition of the invention, in any dosage form, that can produce improvement of at least one symptom of HS according to clinically accepted criteria, as exemplified in the present clinical trial. Such improvement can be also evaluated according to clinical severity scales, as at least 5%, 10%, 15%, 20% improvement, for example, or at least 25%, or at least 50%, or at least 75%, or at least 100% improvement. The improvement can involve an improvement in more than one symptom, in terms of severity, frequency or recurrence and use of concurrent medication, etc.

Therapeutically effective amount (also pharmacologically or pharmaceutically or physiologically effective amount) herein denotes an amount of active agent needed to provide a desired level physiological response. The precise amount depends on numerous factors, e.g. type of an agent, activity of a composition, intended patient use (e.g. number of doses per day), patient considerations, and others. An effective amount of an agent can be administered in one administration, or through multiple administrations. It is understood that the effective amount can be the result of empirical and/or individualized (case-by-case) determination on the part of the treating health care professional and/or individual.

Approximately or about, these terms herein are interchangeable, denote up to ± 10% deviation from a respective measurement, or 9%, 8%, 7%, 6%, 5% or less a deviation thereof.

In one of its aspects the invention provides an oral pharmaceutical composition comprising THC and CBD in approximately equal proportions for use in treating, alleviating or reducing at least one symptom of HS, or preventing a recurrence of a symptom of HS.

It is yet another aspect to provide an oral cannabis-based composition comprising THC and CBD in approximately equal proportions for use in treating, alleviating or reducing at least one symptom of HS, or preventing a recurrence of a symptom of HS.

Under equal proportions is meant that the composition comprises THC and CBD at a ratio of approximately 1:1 (w/w), including a measurement error of about ±5%. Equal proportion of THC and CBD is maintained through various THC and CBD concentrations and amounts comprised in compositions of the invention.

For example, in certain embodiments the compositions of the invention can comprise a relative content or a concentration of THC or CBD in the range of approximately 1-20%, 1-15%, 1-10%, 1-5%, 1-2.5% or less (w/w). In specific embodiments, the compositions can comprise a relative content of THC or CBD of approximately 3% or 15% each (w/w), as a low and high dose forms, respectively (see Tables 1 and 2). Applicability of such compositions has been presently exemplified.

In numerous embodiments, the compositions of the invention comprise a total content THC and CBD in the range of approximately 1-1000 mg, 1-500 mg, 1-250 mg, 1-200 mg, 1-150 mg, 1-100 mg, 1-50 mg, 1-25 mg or less.

In certain embodiments, the composition can comprise a total content THC and CBD in the range of approximately 2.4-24 mg and 12-120 mg as low and high dose forms, respectively, with a maximum dose of 10 drops for each form (see Examples E: Dose and Mode of Administration, and Table 4).

In numerous embodiments the compositions of the invention are in a dosage form of oil extracts or dry plant material. In certain embodiments, such compositions can be derived from a cannabis strain herein designated Midnight. Certain high and low dose oil extracts of Midnight cannabis strain have been presently exemplified. Oil extracts are particularly useful for oral administration. Dry plant material is useful for consuming via smoking. Smoking is considered the most rapid method to achieve high bioavailability and high blood concertation of any type of a cannabinoid. Smoking, however, is not suitable for many patients.

The THC (A⁹-THC) bioavailability averages 30% when consumed by smoking. The onset of the effect begins up to half an hour to two hours after consumption with duration that can last up to 12 hours (Grotenhermen 2003, Clin Pharmacokinet, 42, 327-360). In part, this is caused by early metabolism in the liver. Once absorbed, cannabinoids are distributed throughout the body at variable rates depending on the circulation. Since cannabinoids are lipophilic, they are stored in fatty tissue and reach maximum concentrations within 4-5 days. They are then released into other body tissues, including the brain. Due to their lengthy presence in fat, the half-life of A⁹-THC, for example, is about 7 days, and the complete disappearance of a single consumption can take up to 30 days (Maykut 1985, Progress in Neuropsychopharmacology and Biological Psychiatry, 9, 209-238).

CBD's bioavailability ranges from 13% to 19% when taken orally. A prolonged daily dose of 10 mg per kg of CBD taken orally leads to a concentration of 5.9-11.2 ng/mL in plasma (Consroe et al 1991, Pharmacol Biochem Behav, 40, 517-522) and easily passes the blood-brain barrier. The half-life of CBD is around 9 hours and is excreted in the urine (Samara et al 1990, Biopharm Drug Dispos, 11, 785-795). CBD exhibits a very low toxicity level in humans. LD50 was not found when given orally, or was estimated as high as 4,240-10,600 mg per kg (Rosenkrantz et al 1981, Toxicol Appl Pharmacol, 58, 118-131). Of particular relevance to the invention is expertise with clinical diagnosis of HS and assessment of changes in HS condition and related phenotypes. Clinical diagnosis of HS and specific presentations of symptoms are established according to one or more known clinical standards, a number of them have been presently exemplified.

Hidr adenitis Suppurativa Clinical Response (HiSCR)

HiSCR is defined by the status of three types of lesions (defining criteria): abscesses (fluctuant, with or without drainage, tender or painful), inflammatory nodules (tender, erythematous, pyogenic granuloma lesion) and draining fistulas (sinus tracts, with communications to skin surface, draining purulent fluid). The proposed definition of responders to treatment (HiSCR achievers) according to Kimball et al 2014 (in Br J Dermatol, 171, 1434-42) is:

• At least a 50% reduction in abscesses and inflammatory nodules (AN)

• No increase in the number of abscesses

• No increase in the number of draining fistulas from baseline

Hidr adenitis Suppurativa Physician global assessment (HS-PGA)

HS-PGA as a HiSCR is an HS severity index used in clinical trials. HS-PGA has clear guidance for disease severity scoring and is relatively easy to use. The HiSCR score was found to have a better resolution for HS severity determination. Due to extensive clinical heterogeneity especially among patients in the most severe category, some patients have been shown to experience clinically important improvement but not gain a meaningful reduction in the respective HS-PGA score. The HS-PGA scoring is as follows:

• Clear (score = 0): 0 abscesses, 0 draining fistulas, 0 inflammatory nodules, and 0 noninflammatory nodules

• Minimal (score = 1): 0 abscesses, 0 draining fistulas, 0 inflammatory nodules, and presence of noninflammatory nodules

• Mild (score = 2): 0 abscesses, 0 draining fistulas, and 1-4 inflammatory nodules; or 1 abscess or draining fistula and 0 inflammatory nodules.

• Moderate (score = 3): 0 abscesses, 0 draining fistulas, and > 5 inflammatory nodules; or 1 abscess or draining fistula and > 1 inflammatory nodule; or 2-5 abscesses or draining fistulas and < 10 inflammatory nodules.

• Severe (score = 4): 2-5 abscesses or draining fistulas and > 10 inflammatory nodules

• Very severe (score = 5): > 5 abscesses or draining fistulas Hurly clinical staging:

The Hurley stage is yet another scale for the assessment of HS severity. It was originally designed for the selection of an appropriate treatment modality (medical therapy for Hurley stage I, local surgery for stage II, and wide surgical excision for stage III). It was not designed for an accurate assessment of the extent of inflammation within each stage. Hurley classifies patients into three HS severity stages:

1 Single or multiple lesions without sinus tract formation or scarring.

2 Single or multiple, widely separated, recurrent abscesses with tract formation and cicatrization

3 Diffuse or near-diffuse involvement, or multiple interconnected tracts and abscesses across the entire area.

In numerous embodiments the cannabinoid compositions of the invention can be administered as a combination therapy comprising at least one concurrent drug for the treatment of HS. The present examples have demonstrated efficacy and safety of such compositions.

It is further conceived that the cannabinoid compositions of the invention can be administered as a monotherapy for HS

In certain embodiments when being used in combination with other concurrent drugs for HS, the compositions of the invention can be effective for reducing dosing of these drugs, or alleviating or reducing one or more adverse effect thereof.

The compositions of the invention can further comprise at least one additional therapeutic agent.

When considering combination therapies, it is imperative to take into account potential cross-drug interaction. The combination of cannabis and medications usually work well without any interactions. However, there is a cumulative effect for cannabis in conjunction with opiates, alcohol, SSRI anti-depressants and sleep medications. In such cases the dose of the cannabis should be carefully monitored.

Because of the first-pass effect related to cannabis and cannabinoids in the liver (especially when consumed orally), there are certain risks associated with co-administrations of drugs metabolized by the CYP3A4 and CYP2C9 enzymes. Drugs that inhibit these enzymes, such as macrolides (especially clarithromycin and erythromycin), antimycotics (such as ketoconazole, fluconazole, itraconazole, and miconazole), calcium antagonists (especially diltiazem and verapamil), HIV protease inhibitors (especially ritonavir), isoniazid and amiodarone, may increase biological availability of cannabis and increase its side effects. Drugs that inhibit the metabolism of cannabis through these enzymes include: Carbamazepine, Rifampicin, Troglitazone, Rifabutin, Primidone, Phenytoin, Phenobarbital and the herbal plant Hypericum Perforatum. Thus in patients using these medications, there is a likelihood that an increased dose of medical cannabis will be necessary.

Four drugs should be avoided:

Astemizole- second-generation antihistamine drug that has been withdrawn from the market in most countries.

Cisapride- is a gastroprokinetic agent, a drug that increases motility in the upper gastrointestinal tract. It has either been withdrawn from the market or had its indications limited because of side effects.

Pimozide- is an antipsychotic drug of the diphenylbutylpiperidine class. Mainly for treating Tourette syndrome and resistant tics.

Terfenadine- is an antihistamine formerly used for the treatment of allergic conditions. It has been withdrawn from markets worldwide due to the risk of a particular type of disruption of the electrical rhythms of the heart (specifically cardiac arrhythmia caused by QT interval prolongation).

Combining these four drugs with cannabis increases levels of these drugs by decreasing metabolism. Risk of QT interval prolongation (a phenomenon of irregularity in the heart's electrical system).

The use of cannabis in conjunction with other medications should be slow with small dose escalation every two days with attention to side effects.

From yet another point of view the invention to provides a method for treating, alleviating or reducing at least one symptom of HS, or preventing a recurrence of a symptom of HS in a subject in need thereof, the method comprises administering to the subject therapeutically effective amounts of THC and CBD in approximately equal proportions.

In yet another aspect the invention provides a method for treating, alleviating or reducing at least one symptom of HS, or preventing a recurrence of a symptom of HS in a subject in need thereof, the method comprises administering to the subject a therapeutically effective amount of cannabis-based THC and CBD in approximately equal proportions.

In numerous embodiments the methods of the invention apply administering of THC and CBD via an oral route. Oral methods of the invention have been presently exemplified. In yet other embodiments the methods of the invention can apply administering of THC and CBD is via smoking, inhalation, vaporization, especially when said cannabinoids are delivered in the form of cannabis-based compositions of the invention. In numerous embodiments the methods of the invention apply THC and CBD that are administered in the same composition.

Following below are examples of such methods, especially those applying compositions derived from a cannabis strain Midnight in dosage forms as low and high concertations oil extracts.

In numerous embodiments, the methods of the invention use therapeutic doses in the range of approximately 1-1000 mg, 1-500 mg, 1-250 mg, 1-200 mg, 1-150 mg, 1-100 mg, 1-50 mg, 1-25 mg or less.

In certain embodiments, the therapeutic doses are in the range of approximately 2.4-24 mg or 12-120 mg a total content of THC and CBD, as low and high therapeutic doses per administration, respectively.

In still other embodiments, the methods of the invention use therapeutic doses that comprise a relative content of THC or CBD in the range of approximately 1-20%, 1-15%, 1- 10%, 1-5%, 1-2.5% or less (w/w).

In certain embodiments the methods of the invention use therapeutic doses with approximately 3% or 15% (w/w) as a low and high doses, respectively.

The methods of the invention can further comprise administering to the subject at least one concurrent drug for the treatment of HS, said drug being administered simultaneously, before or after the THC and CBD or the composition comprising thereof.

In numerous embodiments such methods using a combination therapy of cannabinoids and other drugs for HS can be applicable for reducing dosing of the concurrent drug and/or reducing at least one adverse effect thereof.

It is yet another important aspect of the invention to provide an oral dosage form comprising a cannabis-derived material comprising THC and CBD in approximately equal proportions for use in treating, alleviating or reducing at least one symptom of HS, or preventing a recurrence of a symptom of HS.

In numerous embodiments the oral dosage form of the invention can comprise a relative content of THC or CBD in the range of approximately 1-20%, 1-15%, 1-10%, 1-5%, 1-2.5% or less (w/w).

In certain embodiments the oral dose form can comprise approximately 3% or 15% (w/w) each one of the cannabinoids, as a low and high dose forms, respectively.

In yet other embodiments the oral form of the invention can comprise a total content of THC and CBD in the range of approximately of 1-20 mg, 1-15 mg, 1-10 mg, 1-5 mg, 1-2.5 mg or less. In certain embodiments the oral dose form can comprise approximately 2.4 mg or 12 mg of both cannabinoids, as a low and high dose forms, respectively.

In numerous embodiments the oral dosage forms can be in the form of an oil extract.

Applicability of the above oral dosage forms of the invention for treatment and particularly for the establishment of rationalized and controlled regimen for treating HS has been presently exemplified. Of a particular value are the oral dosage forms derived from a cannabis strain Midnight.

The oral dosage forms of the invention are particularly applicable to methods for establishing a personalized therapeutically effective daily amount of THC and CBD for treating, alleviating or reducing at least one symptom of HS, or preventing a recurrence of a symptom of HS. Such methods use a titration comprising daily administering to a subject in need thereof at least one drop (n) of an oral dosage form of the invention up to 3 times a day in the course of at least 1-10 weeks.

In certain embodiments the titration period lasts for at least 6 weeks.

In most cases, the titration methods of the invention further comprise increasing the number of drops of the oral dosage form by 1 one (n+l) every 3 days in the course of at least 1 week, and assessing the severity of at least one HS symptom and/or at least one cannabis- related adverse event in said subject (see Table 4).

In certain embodiments a patient would start a titration with the low dosage form of the invention referred to above, and gradually increase the dosing until a noticeable reduction or improvement of at least one symptom of HS is observed.

In further embodiments in absence of a noticeable reduction or improvement, the patient can switch to the high dosage form and continue the titration.

The titration methods can further comprise an assessment of at least one adverse event related to use of a concurrent drug for HS or a dosing of said concurrent drug assessing.

In numerous embodiments the step of increasing the number of drops of the oral dosage form (n+l) can persist for the entire titration period or until it reaches the maximum dose up established the purpose of safety.

The presently exemplified titration methods used a safety threshold of 14 drops, and 10 drops to switch from low to high dosage form.

Further, the step of increasing the number of drops of the oral dosage form (n+l) can persist until an alleviation or a reduction of at least one symptom of HS, or an alleviation or a reduction of at least one adverse event related to use of a concurrent drug for HS, or presence one or more cannabis-related adverse events in said subject. An essential prerequisite of the presently described titration methods is a comprehensive and careful assessment and follow up of clinical symptoms of HS, including related presentations. Classification of symptoms and severity assessment in HS have been already described in detail, including use of bona fide clinical criteria. In this connection the oral dosage forms of the invention are particularly useful not only in terms of efficacy but also in terms of safety to avoid manifestation of potential side effects of cannabis.

The side effects of cannabis are not numerous and most are mild. Cannabis consumption can be accompanied by a feeling of euphoria and may cause two types of side effects, physiological and cognitive. Physiological effects may include dizziness, irregular heartbeat (faster or slower), weakness, lower blood pressure and blood sugar levels, increased appetite, red eyes, tiredness, lack of coordination, lack of balance and dryness in mucous membranes such as the mouth and eyes. Cognitive side effects relate to short-term memory impairment; lose a train of thought and distortions in the perception of time and space. Regular use of large amounts can lead to cognitive impairment, but this effect dissipates when use is ceased. In youth, cognitive impairment could be lasting. The side effects usually dissipate shortly after a reduction of therapeutic dose.

Side effects usually occurring from overdose require special attention. These may include: fainting, significant changes in blood pressure, in pulse, in blood sugar levels, or in respiration rates. A high dose of the product can in some cases, for people that are pre disposed, cause a temporary psychotic attack, anxiety, delusions, or hallucinations (Taylor 1998, J. Am. Pharm. Assoc. 38, 220-227; Wang et al 2008, CMAJ, 178, 1669-1678; Degenhardt et al 2001, Social Psychiatry and Psychiatric Epidemiology, 36, 219-227.).

The following parameters are to be considered during titration of therapeutically effective doses:

• Changes in the activity and severity of HS as assessed by Hidradenitis Suppurativa Severity Index (HSSI) scale. HSSI has a composite score ranging from 0 to 19. The score is obtained by assessing the number of sites involved, percent of body surface involved (the palm of the hand was used to represent 1 % of body surface area), number of erythematous and painful lesions, number of dressing changes during working and leisure hours (which reflects interference in daily activities), and pain as quantified by the visual analog scale (VAS). An HSSI score greater than 8 suffers is related to mild to severe HS.

• Changes in the quality of life as assessed by Dermatology Life Quality Index (DLQI) questionnaires specifically developed for dermatological disorders. The quality of life score on DLQI ranges between 0-30, when a score above 10 considered to impact moderately, and a score above 20 - impact severely on the patient's quality of life. The mean DLQI score in patients with moderate to severe HS disease is above 20. The DLQI scale is as follows:

0-1 No effect,

2-5 Small effect,

6-10 Moderate effect,

11-20 Large effect,

21-30 Extremely large effect, on a patient's quality of life

Assessment of both, DLQI and HSSI can be incorporated in the previously described methods of the invention as a part of a comprehensive profiling of HS symptoms.

It is yet another aspect of the invention to provide certain use aspects. Most prominently to provide use of THC and CBD for the manufacture/ preparation of a composition for treating, alleviating or reducing at least one symptom of HS, or preventing a recurrence of a symptom of HS, said cannabinoids comprised in the composition in approximately equal proportions.

Still further, the invention provides use of cannabis-derived THC and CBD for the manufacture/ preparation of a composition for treating, alleviating or reducing at least one symptom of HS, or preventing a recurrence of a symptom of HS, said cannabinoids comprised in the composition in approximately equal proportions.

In view of more recent findings regarding the applicability of Avidekel oil, the present invention can be further articulated from a broader perspective. Thus it became apparent that according to the invention there is a broader range of compositions for use in treating, alleviating or reducing at least one symptom of HS, or preventing a recurrence of a symptom of HS, as the compositions can comprise CBD:THC in a ratio of at least about 1:1 or more in favor of CBD (w/w).

In certain embodiments the cannabis-based compositions of the invention can comprise CBD:THC of at least about 4:1 or more in favor of CBD (w/w), also referred to herein as CBD enriched compositions of the invention.

In numerous embodiments the CBD enriched compositions of the invention can comprise up to 15-20% CBD and 1-4% THC or even less than 1% THC (w/w), or more specifically, up to at least 15%, 16%, 17%, 18%, 19%, 20% CBD or more, and up to 4%, 3%, 2%, 1%, 0.5% THC or less.

Specifically, the compositions with a CBD:THC ratio of about 1:1, as has been noted, in certain embodiments this type of compositions can be provided in a dose form comprising CBD or THC up to about 3% (w/w), designated herein a low dose form. Yet in other embodiments this type of compositions can be provided in a form comprising CBD or THC up to about 15% (w/w), designated herein a high dose form.

In numerous embodiments the compositions of the invention can be provided in the form of a cannabis-based oil extract or dry plant material adapted for oral or topical administrations.

With respect to the total cannabinoid content or amount, in numerous embodiments the compositions of the invention can comprise up to about 1000-750 mg, 750-500 mg and 500-400 mg, 400-300 mg, 300-200 mg, 200-100 mg, 100-50 mg, 50-40 mg, 40-30 mg, 30-20 mg, 20-10 mg, and also 10, 9, 8, 7, 6, 5, 4, 3, 2, 1 mg CBD and/or THC in a dosage form.

The terms ' total cannabinoid content/amounf refers herein to a quantity of one or two main cannabinoids, CBD and/or THC, per a dosage form or per an administration.

Still on the compositions with CBD: THC ratio of 1:1, in certain embodiments this type of compositions can be provided in a low dosage form comprising a total cannabinoid content in range of about 1-3 mg, 3-6 mg, 6-9 mg, 9-12 mg, 12-15 mg, 15-20 mg, 20-25 mg, 25-30 mg, 30-35 mg, 35-40 mg, 40-45 mg and 45-50 mg CBD and/or THC in a dosage form.

In yet other embodiments, this type of compositions can be provided in a high dosage form comprising a total cannabinoid content in range of 10-15 mg, 15-30 mg, 30-60 mg, 60-90 mg, 90-120 mg, 120-150 mg, 150-180 mg, 180-200 mg, and more CBD and/or THC.

In certain embodiments the compositions with the CBD:THC ratio of about 1:1 can be derived from a cannabis strain Midnight.

In other embodiments the compositions, now defined as enriched in CBD or having CBD:THC ratio of at least about 4:1, can be derived from a cannabis strain Avidekel.

Both types of the above compositions have been presently exemplified.

As has been noted, in numerous embodiments the compositions of the invention are provided in a form of an oil extract or dry plant material. The oil extract are particularly useful for oral, topical administrations.

The compositions of the invention can be further adapted to transdermal administration.

In certain embodiments the compositions of the invention can be provided in the form of transdermal patches or incorporated into various transdermal delivery systems by means of known in the art technologies, including first-, second- and more recent third-generation delivery systems.

The transdermal patches can comprises higher concentrations of actives. The terms ' transdermal patch ' or ' transdermal delivery system ' in this context refer to a variety of systems, including first-generation transdermal delivery systems known to be applicable for lipophilic drugs. First-generation transdermal delivery systems are systems where the drug is stored in a reservoir enclosed on one side with an impermeable backing and on the other side - with an adhesive contacting to the skin. This term encompasses systems wherein the drug is dissolved in a liquid or gel-based reservoir, and also systems where the drug is incorporated into a solid polymer matrix.

For example, the transdermal delivery system of the invention can be composed of four layers, including an impermeable backing membrane, a drug reservoir, a semi-permeable membrane that may serve as a rate-limiting barrier, and an adhesive layer. These particular systems can permit the use of liquid chemical enhancers, such as ethanol.

Further, transdermal delivery systems can have three layers, by eliminating the semi- permeable membrane, or just two layers, by incorporating the drug directly into the adhesive.

Another type of transdermal delivery systems employs second-generation delivery systems, i.e., those using chemical enhancers, non-cavitational ultrasound and iontophoresis.

The most recent type of transdermal delivery systems are third-generation delivery systems, i.e., target their effects to skin’s barrier layer of stratum corneum using microneedles, thermal ablation, microdermabrasion, electroporation and cavitational ultrasound.

In numerous embodiments of the compositions of the invention can incorporated into delivery systems permitting controlled or suspended release of actives. These types of systems have been subject to intensive R&D, yielding first-, second- and third-generation delivery systems, including so-called 'smart' polymers and hydrogels to make systems that are triggered by changes in environmental factors, such as pH, temperature, or glucose.

Controlled drug delivery systems are applicable to oral and transdermal forms of the presently disclosed compositions.

Further, in numerous embodiments the compositions of the invention are administered as a combination therapy comprising at least one concurrent drug for the treatment of HS. Drugs that are relevant to this clinical context, and HS in particular, were mentioned above.

Notwithstanding, in certain embodiments the compositions can be administered as a monotherapy for treating, alleviating or reducing one or more symptoms of HS.

In the form of combination therapies, the treating, alleviating or reducing at least one symptom of HS can also comprise reducing dosing of the at least one concurrent drug. In further embodiments the treating, alleviating or reducing at least one symptom of HS with the compositions of the invention can further comprise alleviating or reducing at least one adverse effect of the at least one concurrent drug.

It should be appreciated that in numerous embodiments the compositions of the invention can further comprise at least one additional therapeutic agent. Agents that are relevant to this particular embodiments were previously discussed.

It yet another aspect of the invention to provide methods for treating, alleviating or reducing at least one symptom of HS, or preventing a recurrence of a symptom of HS in a subject in need thereof, said methods comprise administering to the subject a therapeutically effective amount of a cannabis-based composition comprising CBD:THC in a ratio of at least about 1:1 or more in favor of CBD (w/w).

The terms ' therapeutically effective amount', 'treating, alleviating or reducing' as well as determining, assessing or measuring symptoms characteristic of HS have been explained in detail above.

In certain embodiments the methods of the invention apply cannabis-based compositions with CBD:THC ratio of about 1:1 provided in a low dosage form comprising up to 3% CBD or THC (w/w).

Yet in other embodiments the methods of the invention apply this type of compositions (i.e., CBD:THC 1:1) provided in a high dosage form comprising up to 15% CBD or THC (w/w).

In yet other embodiments the methods of the invention apply cannabis-based compositions enriched in CBD or more specifically compositions with CBD:THC ratio of at least about 4:1 or more in favor of CBD (w/w).

This type of methods can be further articulated as methods applying cannabis-based compositions comprising up to 15-20% CBD and 1-4% THC or even less than 1% THC (w/w), or more specifically up to at least 15%, 16%, 17%, 18%, 19%, 20% CBD or more, and up to 4%, 3%, 2%, 1%, 0.5% THC or less.

In numerous embodiments both types of methods the cannabis-based compositions can be applied or administered via an oral route in the form of an oil extract or dry plant material.

In certain embodiments the methods of the invention apply the cannabis-based compositions topically as oil extracts for example, including use of transdermal patches using first-, second- and more recent third-generation delivery systems referred to above.

In terms of therapeutic dose, in numerous embodiments the methods of the invention can comprise administering a total cannabinoid content in the range of about 1000-750 mg, 750-500 mg and 500-400 mg, 400-300 mg, 300-200 mg, 200-100 mg, 100-50 mg, 50-40 mg, 40-30 mg, 30-20 mg, 20-10 mg, and also 10, 9, 8, 7, 6, 5, 4, 3, 2, 1 mg CBD and/or THC per single administration.

In numerous embodiments the methods of the invention involve administering of the cannabis-based compositions are administered via oral or topical routes.

In certain embodiments by the methods of the invention the cannabis-based compositions can be administered via a transdermal route, for example in the form of transdermal patches. Various forms of such patches were previously discussed.

With respect to the oral and topical forms in most cases the methods of the invention involve between 1 and 3 administrations per day.

In specific cases the number of administrations can exceed 3 administrations per day.

In other cases the number of administrations can be between 1 and 3 administrations per week, or 1, 2, 3, 4, administrations per month.

In many embodiments the methods of the invention are applied upon recurrence of a symptom of HS.

In certain embodiments the methods of the invention apply compositions derived from the strain Midnight.

In yet other embodiments the methods of the invention apply compositions derived from the strain Avidekel.

Both such methods have been presently demonstrated.

It should be further appreciated that in numerous embodiments the methods of the invention can further comprise administering to the subject at least one concurrent drug for treating, alleviating or reducing at least one symptom of HS.

Candidate drugs that are relevant to this context were previously discussed. According to the presently disclosed methods said drug being administered simultaneously with the cannabis-based compositions, or in succession - before or after the compositions, under various dose and time regimens.

More importantly, in numerous embodiments the methods of the invention provide treating, alleviating or reducing of at least one symptom of HS that further comprises reducing dosing of said at least one concurrent drug, or alleviating or reducing at least one adverse effect of the concurrent drug.

From yet another point of view the invention provides distinct oral forms that are particularly applicable to the treatment of inflammatory skin conditions and HS in particular. More specifically, the oral dose of the invention can be provided in the following forms: i. An oral dose of an oil extract of the cannabis strain Midnight, the oral dose comprising CBD:THC in a ratio of about 1:1 at a concentration of CBD or THC up to about 3% (w/w), i.e. the low oral dose form of Midnight;

ii. An oral dose of an oil extract of the cannabis strain Midnight, the oral dose comprising CBD:THC in a ratio of about 1:1 at a concentration of CBD or THC up to about 15% (w/w) i.e. the high oral dose form of Midnight; and

iii. An oral dose of an oil extract of the cannabis strain Avidekel, the oral dose comprising CBD: THC in a ratio of at least about 4:1 or more in favor of CBD (w/w) at a concentration of up to about 15-20% CBD and 1-4% THC or less than 1% THC (w/w), the oral dose form of Avidekel.

As has been presently demonstrated, each oil drop is approximately 0.04 ml in volume. The Midnight contains about 1.2 mg CBD and 1.2 mg A⁹-THC for the 3% low-dose oil, and about 6 mg CBD and 6 mg A⁹-THC for the 15% high-dose oil. The Avidekel oil contains approximately 6.54 mg CBD and 1.6 mg A⁹-THC (see Examples A: Investigational Product).

In numerous embodiments the oral dose forms of the invention can be provided as a kit comprising at least one oral dose i-iii as above, or a combination thereof, and instructions for use. The oral dose forms are provided in separate containers or vials with drop applicators, or alternatively, as pre-set forms to provide the optimal therapeutic amount referred to above. There are a number of known in art technologies using gelatin capsules or another packaging material that can be applicable for this purpose.

The instructions accompanying the kit are meant to explain in detail how to apply the oral dose forms of the invention using the titration methods (e.g., increments of n+l doses) time regimens (e.g., increments of every 3 days) and safety thresholds (e.g., max 10 doses before shifting to the next dose form) to achieve treating, alleviating or reducing at least one symptom of HS, or preventing a recurrence of an HS symptom, and also - reducing dosing or at least one adverse effect of at least one concurrent drug.

It is yet another aspect of the invention to provide use of cannabis-derived material for the manufacture/ preparation of a composition for treating, alleviating or reducing at least one symptom of HS, or preventing a recurrence of a symptom of HS, said composition comprises CBD:THC in a ratio of at least about 1:1 or more in favor of CBD (w/w).

The applicability and production of such uses were discussed in detail above. The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the methods and compositions of the invention, and are not intended to limit the scope of what the inventors regard as their invention.

EXAMPLES

A. Investigational Products (IP)

Midnight or Avidekel oils are prepared from resin-producing pistillate inflorescences of the respective cannabis strains and olive oil. The Midnight strain typically contains THC (A⁹-THC ) and CBD in a 1:1 ratio, or close to 1:1 (w/w). The Avidekel strain is considered enriched in CBD, and can contain a CBD:THC ratio of at least 4:1 or more in favor of CBD, or up to 15-20% CBD and 1-4% THC or even less than 1% THC (w/w). The products are analyzed and titrated with pure CBD and olive oil to produce high precision CBD/THC compositions. The two forms, the low and high Midnight oils with 3% or 15% relative content of CBD:THC, are produced by dilutions in olive oil. Examples of such products are demonstrated in Tables 1-3 using quality control analysis by HPLC.

Table 1. Midnight oil 3%(CBD:THC 1:1)

tTHC = 0.877*[THCA] + [THC]

tCBD = 0.877*[CBDA] + [CBD] Table 2. Midnight oil 15%(CBD:THC 1:1)

tTHC = 0.877*[THCA] + [THC]

tCBD = 0.877*[CBDA] + [CBD]

Table 3. Avidekel oil (CBD:THC 4:1)

'Cannabidiol: 2-[(lR,6R)-6-isopropenyl-3-methylcyclohex-2-en-l-yl]-5-pentylbenzene-l,3-diol. 2Tetrahydrocannabinol: (-)-(6aR, 10aR)-6,6,9-Trimethyl-3-pentyl-6a,7,8, 10a-tetrahydro-6H- benzo [c] chromen- 1 -ol .

³Cannabinol: 6,6,9-Trimethyl-3-pentyl-benzo[c] chromen- l-ol.

ND: not determined Each oil drop is approximately 0.04 ml in volume. The Midnight contains about 1.2 mg CBD and 1.2 mg A⁹-THC for the 3% low-dose oil, and about 6 mg CBD and 6 mg D⁹- THC for the 15% high-dose oil. The Avidekel oil contains approximately 6.54 mg CBD and 1.6 mg A⁹-THC.

Study patients have received either low-dose (3%) or high-dose (15%) Midnight oils, starting from the low-dose and switching to high-dose, if necessary, as the study proceeds. Specifically, at the beginning of the study all patients have received the 3% oil, only those reaching 10 drops in the titration period could receive the 15% oil. Another group of patients received Avidekel oil, starting from 1 drop and increasing the number of drops according to clinical outcomes. Patients in the control group has received a placebo oil containing olive oil and chlorophyll.

B. Study population

Male and female >20 years of age with diagnosis of moderate to severe HS for at least 12 months prior to screening. Approximately 40 subjects have been enrolled in this study, 20 patients in the active treatment group and 20 in the control group. Patients has been randomized into experimental and control groups. The duration of study participation has been at least 6 weeks of treatment.

C. Study objective

To evaluate the safety and efficacy of Midnight oil for the treatment of HS.

D. Research Hypothesis

Specific oil-based preparations derived from certain cannabis strains can reduce HS related symptoms in patients suffering from this disorder, including, for example, a reduction in the severity and number of inflammations at relevant sites, and reduction in the level of pain. The presently tested products included oil preparations derived from Midnight and Avidekel strains.

E. Dose and Mode of Administration

Titration Period: An optimal dose (therapeutically effective dose), in terms of number of oil drops, daily administrations and the timing have been established during the titration period (up to 6 weeks) for each study participant. The therapeutically effective dose relates to a balance between maximum impact on symptoms and minimal side effects. Initial and Maximum Dose: The initial dose has been one drop of Midnight or Avidekel oil under the tongue three times a day (morning, noon and evening), for three days. The dose is increased gradually depending on the clinical effects and tolerability to cannabis oil in each patient. Patients experiencing an adverse reaction are tapered down one level to a pre-adverse reaction dose.

With respect to Midnight oil, patient reaching the threshold of ten drops of 3% oil (CBD/THC) per administration have been instructed to adjust to the high-dose oil 15% oil. An example of titration schedule with Midnight oil is provided in Table 4 below.

Table 4. Titration Schedule (demonstrating titration with Midnight oil)

Titration is stopped if any of the following occurs:

• Fainting or lightheadedness as indicated by falling, worsening gait instability, or marked decline in motor function based on staff assessments

• Significant changes in blood pressure

• Significant changes in pulse

• Significant changes in blood sugar levels

• Significant changes in respiration rates

• Investigator decision Concomitant Medications: In all patients cannabis oils have been added to the treatment regime, while carefully monitoring for any changes in the conventional drugs consumption and adverse events. Patients receiving one of: Astemizole, Cisapride, Pimozide or Terfenadine, have been excluded from the study.

F. Study Design

Study schedule is summarized in Table 5 below.

Table 5 Schedule of events

¹ Vital signs - the following parameters will be collected: temperature, pulse, blood pressure, height (only screening visit) and weight

G. Study Endpoints

Efficacy has been evaluated using HSSI. (Time Frame: 6 weeks), whereby a 25% improvement in HSSI score is considered significant. Efficacy further considers changes from baseline in DLQI (Time Frame: From Week 0 to Week 6).

Primary Efficacy Endpoint

Proportion of participants with moderate to severe HS who achieve a clinical response (Time Frame: From Week 0 to Week 6) as evaluated by HiSCR. Clinical response has been defined as a 25% reduction in AN count.

Secondary Efficacy Endpoints

- Proportion of participants with moderate to severe HS who achieve a clinical response (Time Frame: At Week 6) as evaluated by HS-PGA.

- Proportion of participants reporting a reduction in HS associated pain using numeric rating scale to assess the pain level on an 11 -point scale.

Safety Endpoints

Proportion of participants experiencing Adverse Events (AE's) or Serious Adverse Events (SAE's) (Time Frame: Week 3, Week 6, six months and 12 months).

H. Statistics

The data from all the participants has been analyzed as below using SPSS:

I. c² test or t-test for independent groups, as relevant for the variable type, for evaluation of Midnight oil efficacy vs. placebo.

2. McNemar's test or paired sample t-tests, according to the variable type, for evaluation of individual improvement of each of patient, we will conduct. All tests are two-tailed and considered significant when p <0.05.

The study is powered at the 80% level for two-sided alpha = 0.05 to detect a > 25% reduction in abscess and inflammatory nodule count (AN count) in treatment vs. control at week 6, considered clinically significant in HiSCR.

Primary Endpoint Analysis

The specific hypothesis for the primary endpoint analysis has been as follows:

Ho: p2= pi

Hi: p2ypl

where pi is the rate of the primary endpoint (treatment success rate) in treatment arm and p_?. in control arm. The treatment has been considered significantly superior over control group when the Hi hypothesis is accepted at significance level of 5% (p=0.05) in a Z-test procedure (proportions of success are presented as proportions out of available observations along with 95% Confidence intervals).

The analyses have been performed on Intention-to-Treat (ITT) population defined as ail randomized patient-visits. As a part of the secondary analysis the primary endpoint analysis have been repeated on the Per-Protocol (PP) population defined as all patients who received the assigned treatment.

For the dichotomous secondary endpoints, the number and percentage of patients experiencing the outcome, and the exact two-sided 95% confidence interval of the percentage, has been presented for the set of ITT patients.

Continuous variables have been summarized by presenting the number of observations (N), mean, 95% confidence interval of the mean, standard deviation, median, inter-quartile range, minimum and maximum values, using AN OVA repeated measures method for normally distributed variables and Freidman test for variables distributed not normally.

Safety Outcome Measures:

Clinical and laboratory results, include:

• Adverse Events (AEs) - all study visits.

• Serious Adverse Events (SAEs) - entire study duration for the patient.

• Suspected Unexpected Serious Adverse Reaction (SUSARs) Physical Examinations- all study visits.

Vital signs- all study visits.

Serum chemistry and hematology: day 1, week 6, and 12 months. Side effects

In general, the tolerance to cannabis is relatively good, the side effects are usually mild and do not lead to the discontinuation of treatment. In rare cases side effects may manifest as dizziness, dry mouth, nausea, sleepiness, psychoactive effects, headaches, confusion and disorientation, increased appetite, weakness, red/ irritated eyes, decreased memory, decreased concentration, heart palpitations, restlessness, vomiting and fear.

Protocol synopsis is provided in Table 6 below.

Table 6 Protocol synopsis

SPECIFIC EMBODIMENTS OF THE INVENTION

EMBD 1 An oral pharmaceutical composition comprising Tetrahydrocannabinol (THC) and Cannabidiol (CBD) in about equal proportions for use in treating, alleviating or reducing at least one symptom of Hidradenitis Suppurativa (HS), or preventing a recurrence of a symptom of HS.

EMBD 2 An oral cannabis-based composition comprising THC and CBD in about equal proportions for use in beating, alleviating or reducing at least one symptom of HS, or preventing a recurrence of a symptom of HS.

EMBD 3 The composition according to EMBD 1 or 2 comprising a relative content of THC or CBD in the range of about 1-20%, 1-15%, 1-10%, 1-5%, 1-2.5% or less (w/w), optionally of approximately 3% or 15% (w/w) as a low and high dose forms, respectively. EMBD 4 The composition according to EMBD 3 comprising a total content THC and CBD in the range of about 1-500 mg, 1-250 mg, 1-200 mg, 1-150 mg, 1-100 mg, 1-50 mg, 1- 25 mg or less, optionally of in the range of about 2.5-25 mg and 12.5-125 mg, as a low and high dose forms, respectively.

EMBD 5 The composition according to any of EMBDs 2-4 in a dosage form of an oil exbact or a dry plant material.

EMBD 6 The composition according to any of EMBDs 2-5, the composition being derived from a cannabis sbain herein designated Midnight.

EMBD 7 The composition according to any of EMBDs 1-6, the composition being administered as a monotherapy for HS or as a combination therapy comprising at least one concurrent drug for the treatment of HS.

EMBD 8 The composition according to EMBD 7, wherein the treating, alleviating or reducing at least one symptom of HS further comprises reducing dosing of the at least one concurrent drug.

EMBD 9 The composition of EMBD 7 or 8, wherein the treating, alleviating or reducing at least one symptom of HS further comprises alleviating or reducing at least one adverse effect of the at least one concurrent drug.

EMBD 10 The composition of any of the preceding EMBDs, further comprising at least one additional therapeutic agent.

EMBD 11 A method for treating, alleviating or reducing at least one symptom of HS, or preventing a recurrence of a symptom of HS in a subject in need thereof, the method comprises administering to the subject therapeutically effective amounts of THC and CBD in equal proportions. EMBD 12 A method for treating, alleviating or reducing at least one symptom of HS, or preventing a recurrence of a symptom of HS in a subject in need thereof, the method comprises administering to the subject a therapeutically effective amount of cannabis-based THC and CBD in equal proportions.

EMBD 13 The method of EMBD 11 or 12, wherein the therapeutic dose comprises a total content of THC and CBD is in the range of about 1-150 mg, 1-100 mg, 1-50 mg, 1-25 mg or less, optionally of in the range of about 2.5-25 mg and 12.5-125 mg, as low and high therapeutic doses per administration, respectively.

EMBD 14 The method of EMBDs 11-13, wherein the therapeutic dose comprises a relative content of THC or CBD in the range of about 1-20%, 1-15%, 1-10%, 1-5%, 1-2.5% or less (w/w), optionally of about 3% or 15% (w/w) as a low and high doses, respectively. EMBD 15 The method of any of EMBDs 11-14, wherein the THC and CBD are administered in the same composition.

EMBD 16 The method of EMBD 15, wherein the composition is derived from a cannabis strain herein designated Midnight in a dosage form of an oil extract or a dry plant material. EMBD 17 The method of any of EMBDs 11-16, wherein the method further comprises administering to the subject at least one concurrent drug for the treatment of HS, said drug being administered simultaneously, before or after the THC and CBD or the composition comprising thereof.

EMBD 18 The method of EMBD 17, wherein the treating, alleviating or reducing at least one symptom of HS further comprises reducing dosing of the at least one concurrent drug. EMBD 19 The method of EMBD 17 or 18, wherein the treating, alleviating or reducing a symptom of HS further comprises alleviating or reducing at least one adverse effect of the at least one concurrent drug.

EMBD 20 The method of any of EMBDs 11-19, wherein the administering of THC and CBD is via an oral route.

EMBD 21 The method of any of EMBDs 12-20, wherein the administering of THC and CBD is via smoking, inhalation, vaporization.

EMBD 22 An oral dosage form comprising a cannabis-derived material comprising THC and CBD in approximately equal proportions for use in treating, alleviating or reducing at least one symptom of HS, or preventing a recurrence of a symptom of HS.

EMBD 23 The oral dosage form of EMBD 22 comprising a relative content of THC or CBD in the range of about 1-20%, 1-15%, 1-10%, 1-5%, 1-2.5% or less (w/w), optionally of about 3% or 15% (w/w) as a low and high dose forms, respectively. EMBD 24 The oral form of EMBD 23 comprising a total content of THC and CBD in the range of about of 1-20 mg, 1-15 mg, 1-10 mg, 1-5 mg, 1-2.5 mg or less, optionally of about 2.4 mg or 12 mg as a low and high dose forms, respectively.

EMBD 25 The oral dosage form of any of EMBDs 22-24 in a form of an oil extract. EMBD 26 The oral dosage form of any of EMBDs 22-25, wherein cannabis-derived material is derived from a cannabis strain herein designated Midnight.

EMBD 27 A method for personalized dosing of a therapeutically effective daily amount of THC and CBD for treating, alleviating or reducing at least one symptom of HS, or preventing a recurrence of a symptom of HS, said method comprising daily administering to a subject in need thereof at least one drop (n) of an oral dosage form of claims 22-26 up to three times a day in the course of at least 1-10 weeks, optionally at least 6 weeks.

EMBD 28 The method of EMBD 27, wherein the method further comprises increasing the number of drops of the oral dosage form by 1 one (n+l) every 3 days in the course of at least 1 week, and assessing the severity of at least one HS symptom and/or at least one cannabis-related adverse event in said subject.

EMBD 29 The method of EMBD 28, further comprising assessing in the subject at least one adverse event related to use of a concurrent drug for HS or a dosing of said concurrent drug.

EMBD 30 The method of any of EMBDs 28-29, wherein the step of increasing the number of drops of the oral dosage form (n+l) persists for the entire period of said least 1-10 weeks or until the (n+l) is about 20, 19, 18, 17, 15 drops, optionally in the range of 14 or 10 drops.

EMBD 31 The method of EMBD 30, wherein the step of increasing the number of drops of the oral dosage form (n+l) persists until an alleviation or a reduction of at least one symptom of HS, or an alleviation or a reduction of at least one adverse event related to use of a concurrent drug for HS, or presence one or more cannabis-related adverse events in said subject.

EMBD 32 Use of THC and CBD for the manufacture/ preparation of a composition for treating, alleviating or reducing at least one symptom of HS, or preventing a recurrence of a symptom of HS, said cannabinoids comprised in the composition in about equal proportions. EMBD 33 Use of cannabis-derived THC and CBD for the manufacture/ preparation of a composition for treating, alleviating or reducing at least one symptom of HS, or preventing a recurrence of a symptom of HS, said cannabinoids comprised in the composition in about equal proportions.

Claims

CLAIMS:

1. A cannahis-based composition for use in treating, alleviating or reducing at least one symptom of Hidradenitis Suppurativa (HS), or preventing a recurrence of a symptom of HS, the composition comprising CBD:THC in a ratio of at least about 1:1 or more in favor of CBD (w/w).

2. The composition of claim 1 comprising CBD:THC in a ratio of at least about 4:1 or more in favor of CBD (w/w).

3. The composition of claim 1 comprising CBD:THC in a ratio of about 1:1 in a dose form comprising CBD or THC up to about 3% (w/w).

4. The composition of claim 1 comprising CBD:THC in a ratio of about 1:1 in a dose form comprising CBD or THC up to about 15% (w/w).

5. The composition of claim 2 comprising up to about 15-20% CBD and 1-4% THC or less than 1% THC (w/w).

6. The composition of any one of claims 1-5 in a form of an oil extract or dry plant material adapted for oral or topical administrations, optionally for transdermal administration.

7. The composition of any one of claims 1, 3, 4, 6, being derived from a cannabis strain herein designated Midnight.

8. The composition of any of claims 1, 2, 5, 6, being derived from a cannabis strain herein designated Avidekel.

9. The composition of any of claims 1-8, the composition being administered as a monotherapy for treating, alleviating or reducing at least one symptom of HS or as a combination therapy comprising at least one concurrent drug for the treatment of HS.

10. The composition of claim 9, wherein the treating, alleviating or reducing at least one symptom of HS further comprises reducing dosing of the at least one concurrent drug.

11. The composition of claim 9, wherein the treating, alleviating or reducing at least one symptom of HS further comprises alleviating or reducing at least one adverse effect of the at least one concurrent drug.

12. The composition of any of claims 1-11, further comprising at least one additional therapeutic agent.

13. A method for treating, alleviating or reducing at least one symptom of Hidradenitis Suppurativa (HS), or preventing a recurrence of a symptom of HS in a subject in need thereof, the method comprises administering to the subject a therapeutically effective amount of a cannabis-based composition comprising CBD: THC in a ratio of at least about 1:1 or more in favor of CBD (w/w).

14. The method of claim 13, wherein the cannabis-based composition comprises

CBD:THC in a ratio of at least about 4:1 or more in favor of CBD (w/w).

15. The method of claim 13, wherein the cannabis-based composition comprises

CBD:THC in a ratio of about 1:1 in a dose form comprising CBD or THC up to about 3% (w/w).

16. The method of claim 13, wherein the cannabis-based composition comprises

CBD:THC in a ratio of about 1 :1 in a dose form comprising CBD or THC up to about 15% (w/w).

17. The method of claim 14, wherein the cannabis-based composition comprises up to about 15-20% CBD and 1-4% THC or less than 1% THC (w/w).

18. The method of any one of claims 13-17, wherein the cannabis-based composition is administered via oral or topical route, optionally a transderma! route.

19. The method of any one of claims 13, 15, 16, 18, wherein the composition is derived from a cannabis strain herein designated Midnight.

20. The method of any of claims 13, 14, 17, 18, wherein the composition is derived from a cannabis strain herein designated Avidekel.

21. The method of any one of claims 13-20, tire method further comprises administering to the subject at least one concurrent drug for treating, alleviating or reducing at least one symptom of HS, said drug being administered simultaneously, before or after the cannabis- based composition.

22. The method of claim 21, wherein the treating, alleviating or reducing at least one symptom of HS further comprises reducing dosing of the at least one concurrent drug.

23. The method of claim 21, wherein the treating, alleviating or reducing a symptom of HS further comprises alleviating or reducing at least one adverse effect of the at least one concurrent drag.

24. Use of cannabis-derived material for the manufacture/ preparation of a composition for treating, alleviating or reducing at least one symptom of Hidradenitis Suppurativa (HS), or preventing a recurrence of a symptom of HS, said composition comprises CBD:THC in a ratio of at least about 1:1 or more in favor of CBD (w/w).

25. An oral dose of an oil extract of the cannabis strain Midnight, the ora! dose comprising CBD:THC in a ratio of about 1:1 at a concentration of CBD or THC up to about 3% (w/w).

26. An oral dose of an oil extract of the cannabis strain Midnight, the oral dose comprising CBD:THC in a ratio of about 1:1 at a concentration of CBD or THC up to about 15% (w/w).

27. An oral dose of an oil extract of the cannabis strain Avidekei, the oral dose comprising CBD:THC in a ratio of at least about 4:1 or more in favor of CBD (w/w) at a concentration of up to about 15-20% CBD and 1-4% THC or less than 1% THC (w/w ).

28. The oral dose of any one of claims 25-27 for use in treating, alleviating or reducing at least one symptom of Hidradenitis Suppurativa ί 1 IS), or preventing a recurrence of a symptom of HS.

29. The oral dose of claim 28, wherein the treating, alleviating or reducing at least one symptom of HS further comprises reducing dosing or at least one adverse effect of at least one concurrent drug.

30. The composi tion of any one of claims 6-8 in the form of a transdermal patch.

31. A kit comprising at least one oral dose of any one of claims 25-27 or a combination thereof, and instructions for use.