WO2020240550A1 - Cannabidiol for treating type 1 diabetes mellitus - Google Patents

Abstract

The present invention provides a composition comprising cannabidiol (CBD) or an enantiomer, diastereomer, or racemate thereof as a sole cannabinoid, for use together with a standard of care (SoC) medication in the treatment of type 1 diabetes mellitus (T1DM) in a subject in need thereof, or for improving the efficacy of an SoC for treating T1DM, and methods for carrying out the same.

Description

CANNABIDIOL FOR TREATING TYPE 1 DIABETES MELLITUS

FIELD OF INVENTION

[001] This invention is directed to compositions comprising cannabidiol (CBD) for treating Type 1 Diabetes Mellitus (T1DM).

BACKGROUND OF THE INVENTION

[002] Type 1 diabetes mellitus (T1DM) is an autoimmune disease. The disease occurs as a consequence of the organ-specific immune destruction of the insulin-producing b cells in the islets of Langerhans within the pancreas. The b-cells sense glucose and release insulin to maintain physiologic glucose levels within a relatively narrow range. Once those cells are destroyed, patients with T1DM lose blood glucose control, which can result in both acute conditions (for example, ketoacidosis and severe hypoglycemia) and secondary complications (including heart disease, blindness and kidney failure) - even with current insulin replacement therapies. T1DM develops as a consequence of a combination of genetic predisposition, largely unknown environmental factors, and stochastic events. The incidence of T1DM has increased dramatically over the last two decades, especially in children younger than five years old. Those under the age of 18 are most often afflicted, but an equal number of adults over 18 are thought to develop the disease. Because disease onset frequently starts in early childhood, the burden of T1DM is lifelong, with significant economic impact on individuals, families and society.

[003] The precise mechanism underlying T1DM pathogenesis is not yet fully known. Studies in mice have demonstrated that the disease occurs as a consequence of a breakdown in immune regulation, resulting in the expansion of autoreactive CD4+ and CD8+ T cells, autoantibody- producing B lymphocytes, and activation of the innate immune system that collaborate to destroy the insulin-producing b-cells. Genetic mapping and gene -phenotype studies have revealed at least ten genes so far that can be singled out as strong causal candidates. The known functions of these genes indicate the primary etiological pathways of this disease, including HLA class II and I molecules binding to preproinsulin peptides and T cell receptors, T and B cell activation, innate pathogen-viral responses, chemokine and cytokine signaling, and T regulatory and antigen- presenting cell functions.

[004] The standard of care in T1DM is exogenous insulin. Intensive diabetes management with a target HbAlc level < 7.0% is generally recommended because of proven benefits in terms of reduced risks of microvascular complications and cardiovascular disease, but in several surveys only 13-15% of T1DM patients met this target. It is clear that despite significant advances in insulin delivery technologies, continuous glucose monitoring, and closed-loop pump-sensor systems, tight metabolic control remains difficult and even with excellent glycemic control (HbAlc < 6.9%) mortality in those with T1DM is twice that of matched controls.

[005] The concentration of C-peptide in response to a stimulus (mixed-meal or glucagon injection) has been established as a valid and reliable measure of residual b-cell function. The Diabetes Control and Complications Trial established that a stimulated C-peptide concentration >0.2 nmol/L at study entry among subjects with up to a 5-year diabetes duration is associated with favorable metabolic and clinical outcomes over the subsequent 7 years of follow-up (Steffes et al. 2003, Diabetes Care 26(3):832-836). Thus, targeting the autoimmune component of pathophysiology with the aim of preserving even low levels of b-cell activity, is a valid therapeutic goal in T1DM.

[006] Attempts were made to induce remission with non-specific immunosuppressive agents such as cyclosporine, azathioprine and prednisone. These achieved successful reversal to insulin independence, however, the benefits were lost after discontinuation of therapy, leaving the prospect of lifelong immunosuppression and concomitant toxicity, which were unacceptable in this disease. Clinical studies with agents targeting specifically the innate immunity, including the anti-TNFa agent etanercept, anti-IL-1 agents, have been sparse and results have been mixed. Targeting of B -cells provided modest efficacy with significant B-cell depletion, exposing the patients to potential infection risks. Non-myeloablative stem cell therapy has shown success; however, this therapy was also associated with significant side effects.

[007] Cannabis sativa contains over 450 compounds, with at least 70 classified as phytocannabinoids. Two are of particular medical interest. A⁹-Tctrahydrocannabinol (THC) is the main active constituent, with psychoactive and pain-relieving properties. The second molecule of interest is Cannabidiol (CBD), which has lesser affinity for the cannabinoid (CB) receptors and the potential to counteract the negative effects of THC on memory, mood and cognition, but also has an effect on pain modulation. CBD is well tolerated by humans even when taken over extended periods of time and thus has the potential for both clinical research and therapeutic use.

[008] Cannabis has been shown to possess a wide range of potent anti-inflammatory and immunosuppressive properties. Cannabis use in healthy subjects has been associated with a decrease in lymphocyte proliferative response to mitogenic stimulation and IL-2 levels and an increase in IL-10 and transforming growth factor-bΐ levels. In a recent prospective placebo- controlled study, cannabis smoking induced a significant clinical response in patients with refractory Crohn’s disease. CBD possesses strong anti-inflammatory properties. Its administration results in attenuation of clinical disease in animal models of various inflammatory diseases, including multiple sclerosis, rheumatoid arthritis and inflammatory bowel disease. These effects are mediated by T cell attrition and by inhibition of pro -inflammatory cytokine release (tumor necrosis factor-a, INF-g, IL-lb, IL-6, and IL-17) and stimulation of anti-inflammatory cytokine production (IL-4, IL-5, IL-10, and IL- 13). Furthermore, cannabinoids have recently been shown to reduce the capacity of dendritic cells to migrate to secondary lymphoid organs and activate naive T cells.

[009] CBD treatment was shown to significantly reduce the incidence of diabetes in nonobese diabetes mice from an incidence of 86% in non-treated control mice to an incidence of 30% in CBD-treated mice. CBD treatment also resulted in the significant reduction of plasma levels of the pro-inflammatory cytokines, IFN-g and TNF-a. Thl -associated cytokine production of in vitro activated T-cells and peritoneal macrophages was significantly reduced in CBD-treated mice, whereas production of the Th2-associated cytokines, IL-4 and IL-10, was increased when compared to untreated control mice. Histological examination of the pancreatic islets of CBD- treated mice revealed significantly reduced insulitis. These results indicate that CBD can inhibit and delay destructive insulitis and inflammatory Thl -associated cytokine production in NOD mice resulting in a decreased incidence of diabetes possibly through an immunomodulatory mechanism shifting the immune response from Thl to Th2 dominance.

[010] Recently, a study was conducted in which CBD was added to standard Graft-versus host- disease (GVHD) prophylaxis in Forty-eight consecutive adult patients undergoing allogeneic hematopoietic stem cell transplantation (allo-SCT). After a follow-up of 16 months (median 16, range, 7-23), There were no grade 3-4 toxicities attributed to CBD. The cumulative incidences of grade 2-4 and grade 3-4 acute GVHD by day 100 were 12% and 5%, respectively. None of the patients developed acute GVHD while consuming CBD. Compared to 101 historical control subjects given standard GVHD prophylaxis, the hazard ratio of developing grade 2-4 acute GVHD among subjects treated with CBD plus standard GVHD prophylaxis was 0.3 (95% Cl: 0.2-0.6; p¼0.0002). The cumulative incidence of moderate-to-severe chronic GVHD at 1 year was 20%. Relapse rate, non-relapse mortality and overall survival at 1 year were 41%, 11.1% and 68%, respectively.

SUMMARY OF THE INVENTION

[011] According to one aspect, the present application provides a composition comprising cannabidiol (CBD) or an enantiomer, diastereomer, or racemate thereof as a sole cannabinoid, for use together with a standard of care (SoC) medication in the treatment of type 1 diabetes mellitus (T1DM) in a subject in need thereof. [012] According to another aspect, the present application provides a composition comprising cannabidiol (CBD) or an enantiomer, diastereomer, or racemate thereof as a sole cannabinoid, for use in improving the efficacy of a standard of care (SoC) treatment in a subject suffering from type 1 diabetes mellitus (T1DM) and treated with an SoC medication.

[013] According to yet another aspect, the present application provides a method for treating type 1 diabetes mellitus (T1DM), comprising administering to a subject in need thereof a therapeutically effective amount of a composition comprising cannabidiol (CBD) or an enantiomer, diastereomer, or racemate thereof as a sole cannabinoid, together with a standard of care (SoC) medication.

[014] According to still another aspect, the present application provides a method for improving the efficacy of a standard of care (SoC) treatment in a subject suffering from type 1 diabetes mellitus (T1DM) and administered with an SoC medication, said method comprising further administering to said subject a therapeutically effective amount of a composition comprising cannabidiol (CBD) or an enantiomer, diastereomer, or racemate thereof as a sole cannabinoid.

DETAILED DESCRIPTION

[015] The present invention is directed to treating patients suffering from type 1 diabetes mellitus (T1DM) with cannabidiol (CBD) as a sole cannabinoid, in addition to a standard of care (SoC) treatment.

[016] In one aspect, the present invention provides a composition comprising cannabidiol (CBD) or an enantiomer, diastereomer, or racemate thereof as a sole cannabinoid, for use together with a standard of care (SoC) medication in the treatment of type 1 diabetes mellitus (T1DM) in a subject in need thereof.

[017] The term "therapeutically effective amount" as used herein means an amount of said composition that will elicit the biological or medical response of a tissue, system, animal, or human that is being sought. The amount must be effective to achieve the desired therapeutic effect as described above, depending inter alia on the type and severity of the condition to be treated and the treatment regime. The effective amount is typically determined in appropriately designed clinical trials (dose range studies) and the person skilled in the art will know how to properly conduct such trials to determine the effective amount. As generally known, an effective amount depends on a variety of factors including the affinity of the ligand to the receptor, its distribution profile within the body, a variety of pharmacological parameters such as half-life in the body, on undesired side effects, if any, and on factors such as age and gender, etc. [018] The term "treating" or "treatment" as used herein refers to means of obtaining a desired physiological effect. The effect may be therapeutic in terms of partially or completely curing a disease and/or symptoms attributed to the disease. The term also refers to inhibiting the disease, i.e. arresting its development, and preventing deterioration; or ameliorating the disease, i.e. causing regression of the disease.

[019] The phrase "as the sole cannabinoid" as used herein means that the only cannabinoid comprised in composition is CBD.

[020] In some embodiments, the composition of the invention is prepared from substantially pure preparation CBD.

[021] The term "substantially pure" means that the CBD constitutes at least 95% of the weight of the preparation, and that no other active ingredient is present in the preparation in an amount detectable by HPLC.

[022] In some embodiments, the substantially pure CBD preparation contains CBD at at least 96%, at least 97%, at least 98%, or at least 99% of the weight of the preparation.

[023] CBD (2-[6-isopropenyl-3-methylcyclohex-2-en-l-yl]-5-pentylbenzene-l,3-diol), has very low affinity for the cannabinoid CBi and CB2 receptors but is said to act as an indirect antagonist of these receptors. CBD has two stereogenic centers, located at positions 3 and 4 of the cyclohexenyl ring, and may accordingly exist as an enantiomer, i.e., optical isomer, a racemate, i.e., an optically inactive mixture having equal amounts of two enantiomers, a diastereoisomer, or a mixture thereof. The present invention encompasses the use of all such enantiomers, isomers and mixtures thereof. CBD naturally exists as (2-[( //C6//)-6-isopropcnyl-3-mcthylcyclohcx-2-cn- l - yl] -5-pentylbenzene- 1 ,3 -diol) .

[024] For purposes of clarity, the term CBD as used throughout the description and the claims is intended to include enantiomer, diastereomer, or racemate thereof, even when not explicitly stated.

[025] However, in some embodiments, the CBD is the naturally existing enantiomer, (2- [( 1 /C6//)-6-isopropcnyl-3 -methylcyclohex-2-en- 1 -yl] -5-pentylbenzene- 1 ,3 -diol) .

[026] Natural cannabinoids, including CBD may be extracted from the cannabis plant using any suitable extraction or purification method known in the art, such as methods described, for example, in Gaoni and Mechoulam, J. Am. Chem. Soc. 93: 217-224 (1971), or by the method described below in the experimental section. A chemical signature may be made by a mass spectrometer so as to distinguish between a preparation made from an extract and a preparation made from the purified active ingredients.

[027] Alternatively, the CBD may be synthesized following any one of the procedures disclosed in the literature. For example, CBD may be synthesized following any one of the procedures known in the art, e.g., by acid condensation of p-mentha-2,8-dien-l-ol with olivetol. Optically active forms of CBD may be prepared using any one of the methods disclosed in the art, e.g., by resolution of the racemic form by recrystallization techniques; chiral synthesis; extraction with chiral solvents; or chromatographic separation using a chiral stationary phase. A non-limiting example of a method for obtaining optically active materials is transport across chiral membranes, i.e., a technique whereby a racemate is placed in contact with a thin membrane barrier, the concentration or pressure differential causes preferential transport across the membrane barrier, and separation occurs as a result of the non-racemic chiral nature of the membrane that allows only one enantiomer of the racemate to pass through. Chiral chromatography, including simulated moving bed chromatography, can also be used. A wide variety of chiral stationary phases are commercially available.

[028] In some embodiments, the composition does not comprise A⁹-tetrahydrocannabinol (D⁹- THC).

[029] In some embodiments, the composition does not comprise a terpene.

[030] In some embodiments, the composition consists essentially of CBD.

[031] The phrase“consisting essentially of’ used herein with respect to the composition of the present invention means that the CBD is the only active component of the composition. However, inactive agents such as those used in compositions and particularly in pharmaceutical compositions, including carriers, solvents, dispersion media, preservatives, antioxidants, coatings, and isotonic and absorption delaying agents, may be comprised in the composition of the invention. Additionally, it is clarified, that drugs used to treat T1DM are not considered as part of the composition.

[032] In some embodiments, the CBD is formulated as a pharmaceutical composition, further comprising a pharmaceutically acceptable carrier.

[033] The pharmaceutical composition containing CBD of the present invention may be formulated for any suitable administration route as defined below, but is preferably formulated for oral, or sublingual administration, or for inhalation. In some specific embodiments, the pharmaceutical composition of the invention is administered by sublingual administration.

[034] The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" as used herein interchangeably refers to any and all solvents, dispersion media, preservatives, antioxidants, coatings, isotonic and absorption delaying agents, and the like, that are compatible with pharmaceutical administration. According to the present invention, the pharmaceutically acceptable carrier may further comprise ingredients aimed at enhancing the activity of the active agents or modulating the bioavailability thereof. [035] The term "acceptable" with respect to the pharmaceutically acceptable carrier denotes a carrier, excipient, or non-active ingredient that does not produce an adverse, allergic, or other untoward reaction when administered to a mammal or human as appropriate. For human administration, compositions should meet sterility, pyrogenicity, and general safety and purity standards as required by, e.g., the U.S. FDA or the European Medicines Agency (EMA).

[036] The pharmaceutical compositions disclosed herein may be prepared by conventional techniques, e.g., as described in Remington: The Science and Practice of Pharmacy, 19^th Ed., 1995. The compositions can be prepared, e.g., by uniformly and intimately bringing the active agents into association with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the product into the desired formulation. The compositions may be in the form of a liquid (e.g., solution, emulsion, or suspension), gel, cream, solid, semisolid, film, lyophilisate, or aerosol, and may further include pharmaceutically acceptable fillers, carriers, diluents or adjuvants, and other inert ingredients and excipients. In one embodiment, the pharmaceutical composition of the present invention is formulated as nanoparticles.

[037] The pharmaceutical compositions of the present invention may be formulated for any suitable route of administration, e.g., for oral, buccal, sublingual, or parenteral, e.g., intravenous, intraarterial, intramuscular, intraperitoneal, intrathecal, intrapleural, intratracheal, subcutaneous, or topical, administration, as well as for inhalation, but is preferably formulated for oral or sublingual administration, or for inhalation.

[038] The pharmaceutical compositions of the invention, when formulated for oral administration, may be in any suitable form, e.g., tablets, troches, lozenges, aqueous, or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. In certain embodiments, said tablets are in the form of matrix tablets in which the release of a soluble active is controlled by having the active agent diffuse through a gel formed after the swelling of a hydrophilic polymer brought into contact with dissolving liquid {in vitro) or gastro intestinal fluid {in vivo). Many polymers have been described as capable of forming such gel, e.g., derivatives of cellulose, in particular the cellulose ethers such as hydroxypropyl cellulose, hydroxymethyl cellulose, methylcellulose or methyl hydroxypropyl cellulose, and among the different commercial grades of these ethers are those showing fairly high viscosity. In other embodiments, the tablets are formulated as bi- or multi-layer tablets, made up of two or more distinct layers of granulation compressed together with the individual layers lying one on top of another, with each separate layer containing a different active agent. Bilayer tablets have the appearance of a sandwich since the edge of each layer or zone is exposed. [039] Pharmaceutical compositions for oral administration might be formulated so as to inhibit the release of one or both of the active agents in the stomach, i.e., delay the release of one or both of the active agents until at least a portion of the dosage form has traversed the stomach, in order to avoid the acidity of the gastric contents from hydrolyzing the active agent. Particular such compositions are those wherein the active agent is coated by a pH-dependent enteric-coating polymer. Examples of pH-dependent enteric-coating polymer include, without being limited to, Eudragit^® S (poly(methacrylicacid, methylmethacrylate), 1:2), Eudragit^® L 55 (poly (methacrylicacid, ethylacrylate), 1: 1), Kollicoat^® (poly(methacrylicacid, ethylacrylate), 1: 1), hydroxypropyl methylcellulose phthalate (HPMCP), alginates, carboxymethylcellulose, and combinations thereof. The pH-dependent enteric -coating polymer may be present in the composition in an amount from about 10% to about 95% by weight of the entire composition.

[040] In certain embodiments, the invention provides pharmaceutical compositions for oral administration, which is solid and may be in the form of granulate, granules, grains, beads or pellets, mixed and filled into capsules or sachets, or compressed to tablets by conventional methods. In some particular embodiments, the pharmaceutical composition is in the form of a bi- or multilayer tablet, in which each one of the layers comprise one of the active agents, and the layers are optionally separated by an intermediate, inactive layer, e.g., a layer comprising one or more disintegrants.

[041] Another contemplated formulation is depot systems, based on biodegradable polymers. As the polymer degrades, the active agent(s) is slowly released. The most common class of biodegradable polymers is the hydrolytically labile polyesters prepared from lactic acid, glycolic acid, or combinations of these two molecules. Polymers prepared from these individual monomers include poly (D,L-lactide) (PLA), poly (glycolide) (PGA), and the copolymer poly (D,L-lactide- co-glycolide) (PLG).

[042] Pharmaceutical compositions for oral administration may be prepared according to any method known to the art and may further comprise one or more agents selected from sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active agents in admixture with non-toxic pharmaceutically acceptable excipients, which are suitable for the manufacture of tablets. These excipients may be, e.g., inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrating agents, e.g., corn starch or alginic acid; binding agents, e.g., starch, gelatin or acacia; and lubricating agents, e.g., magnesium stearate, stearic acid, or talc. The tablets may be either uncoated or coated utilizing known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated using the techniques described in the US Patent Nos. 4,256,108, 4,166,452 and 4,265,874 to form osmotic therapeutic tablets for control release. The pharmaceutical composition of the invention may also be in the form of oil-in-water emulsion.

[043] Useful dosage forms of the pharmaceutical compositions include orally disintegrating systems including, but not limited to, solid, semi-solid and liquid systems including disintegrating or dissolving tablets, soft or hard capsules, gels, fast dispersing dosage forms, controlled dispersing dosage forms, caplets, films, wafers, ovules, granules, buccal/mucoadhesive patches, powders, freeze dried (lyophilized) wafers, chewable tablets which disintegrate with saliva in the buccal/mouth cavity and combinations thereof. Useful films include, but are not limited to, single layer stand-alone films and dry multiple layer stand-alone films.

[044] The pharmaceutical composition of the invention may comprise one or more pharmaceutically acceptable excipients. For example, a tablet may comprise at least one filler, e.g., lactose, ethylcellulose, microcrystalline cellulose, silicified microcrystalline cellulose; at least one disintegrant, e.g., cross-linked polyvinylpyrrolidinone; at least one binder, e.g., polyvinylpyridone, hydroxypropylmethyl cellulose; at least one surfactant, e.g., sodium laurylsulfate; at least one glidant, e.g., colloidal silicon dioxide; and at least one lubricant, e.g., magnesium stearate.

[045] The pharmaceutical composition of the invention may be in the form of a sterile injectable aqueous or oleagenous suspension, which may be formulated according to the known art using suitable dispersing, wetting or suspending agents. The sterile injectable preparation may also be an injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent. Acceptable vehicles and solvents that may be employed include, without limiting, water, Ringer's solution, polyethylene glycol (PEG), 2-hydroxypropyl- -cyclodextrin (HPCD), a surfactant such as Tween-80, and isotonic sodium chloride solution.

[046] Pharmaceutical compositions according to the invention, when formulated for inhalation, may be in any suitable form, e.g., liquid or fine powder, and may be administered utilizing any suitable device known in the art, such as pressurized metered dose inhalers, liquid nebulizers, dry powder inhalers, sprayers, thermal vaporizers, electrohydrodynamic aerosolizers, and the like.

[047] The pharmaceutical compositions of the invention may be formulated for controlled release of one or more of the active agents. Such compositions may be formulated as controlled -release matrix, e.g., as controlled-release matrix tablets in which the release of a soluble active agent is controlled by having the active agent diffuse through a gel formed after the swelling of a hydrophilic polymer brought into contact with dissolving liquid {in vitro ) or gastro-intestinal fluid {in vivo). Many polymers have been described as capable of forming such gel, e.g., derivatives of cellulose, in particular the cellulose ethers such as hydroxypropyl cellulose, hydroxymethyl cellulose, methylcellulose or methyl hydroxypropyl cellulose, and among the different commercial grades of these ethers are those showing fairly high viscosity. In other configurations, the compositions comprise the active agent formulated for controlled release in microencapsulated dosage form, in which small droplets of the active agent are surrounded by a coating or a membrane to form particles in the range of a few micrometers to a few millimeters.

[048] CBD is insoluble in water but soluble in organic solvents, such as oil. Accordingly, the CBD may be formulated for use in the described methods through use of any organic solvent known to the pharmaceutical arts, including, but not limited to edible oils. When formulated for oral administration, any edible oil can be used in the composition, including medium-chain triglyceride (MCT) oil, and olive oil.

[049] In some embodiments, the composition is formulated as a nutraceutical composition.

[050] The nutraceutical composition may be formulated as a tablet, capsule, pill and powder, or as a liquid such as syrup, or elixir, drink or beverage, and may be prepared by conventional techniques known in the art. Particular such nutraceutical compositions are formulated for oral, buccal or sublingual administration, or for inhalation.

[051] In some embodiments, the daily dose of CBD for treating T1DM in a subject by administering the composition of any of the above embodiments is from about 30 mg to about 600 mg, from about 100 mg to about 600 mg, from about 200 mg to about 450 mg, from about 200 mg to about 300 mg per day, or from about 100 mg to about 300 mg per day. In some embodiments, the daily dose of CBD for treating T1DM in a subject by administering the composition of any of the above embodiments is about 300 mg per day.

[052] In some embodiments, the daily dose of CBD for treating T1DM in a subject by administering the composition of any of the above embodiments is from about 2 mg/kg to about 15 mg/kg, from about 2 mg/kg to about 10 mg/kg, from about 5 mg/kg to about 10 mg/kg. In some embodiments, the daily dose of CBD for treating T1DM in a subject by administering the composition of any of the above embodiments is about 10 mg/kg.

[053] Dosing of the compositions of the invention according to any one of the above embodiments, may be of a single or a plurality of administrations, with course of treatment lasting from several days to several weeks or until cure is effected or diminution of the disease state or symptoms is achieved. [054] Administration of the composition of the invention may be once per day, once every several days such as once every two or three days, twice daily, three times daily, more than three times per day, such as 4, 5, 6 or more times per day, as needed.

[055] In some embodiments, the subject to be treated according to the invention is newly diagnose with T1DM.

[056] The term“newly diagnosed” as used herein refers to a subject that was diagnosed with T1DM a short time prior to start of the treatment, for example within 5, 10, 15, 20, 25, or 30 weeks prior to start of treatment, or within one, two, three, four, five, or six months prior to start of treatment. In some embodiments, the subject has been diagnosed within about 20 weeks (or within about 4.5 months) prior to the start of said treatment. The term“within” as used herein means that the subject may have been diagnosed at any time point that is between start of treatment and the indicated time point in the past (such as 20 weeks prior to the start of treatment), including the end points.

[057] In some embodiments, the subject is between about 5 and about 30 years old at the start of treatment. In some embodiments, the subject is a child at the start of treatment. In some embodiments, the subject is adolescent at the start of treatment. In some embodiments, the subject is an adult. In some embodiments, the subject is 5 to 12 years old at the start of treatment. In some embodiments, the subject is 12 to 18 years old at the start of treatment. In some embodiments, the subject is at least 18 years old.

[058] In some embodiments, the subject is a male subject. In some embodiments, the subject is a female subject.

[059] In some embodiments, the subject has a body mass index (BMI) of at least 18.5 kg/m² at the start of the treatment.

[060] In some embodiments, the subject has one or more islet-specific auto antibodies before the treatment.

[061] In some embodiments, the subject has a non-fasting peak C-peptide > 0.2 nmol/1 during mixed-meal tolerance test (MMTT) before the treatment.

[062] In some embodiments, the daily insulin usage of said subject is < 1 U/kg per day before the treatment.

[063] In some embodiments, the subject does not suffer from pancreatitis before the treatment.

[064] T1DM is a progressive disease, in which the pancreatic beta cells are gradually destroyed, resulting in decreasing levels of endogenous insulin. While insulin administration does not cure diabetes but only replenishes the absent insulin, according to the present invention CBD administration treats diabetes by halting or inhibiting the gradual destruction of beta cells, thereby stopping or inhibiting the decrease in insulin levels. The result is that insulin levels are maintained or increase over time, and the need for exogenous insulin does not increase and possibly decreases.

[065] Accordingly, in some embodiments, treating is manifested in preventing or inhibiting a decrease in endogenous insulin levels relative to insulin levels at the start of treatment. In other words, the insulin level is maintained throughout treatment with the composition of the invention, instead of continuing to decrease.

[066] In some embodiments, treating is manifested in maintaining endogenous insulin levels during treatment by the composition of the invention.

[067] When monitoring insulin levels in a subject, a decrease in pancreatic beta cell function resulting in decreased endogenous insulin levels may start to be measurable after several months to several years, depending on various parameters including age of the patient and severity of the disease (Hao et al., 2016).

[068] Accordingly, in some embodiments, treatment by the composition of the invention as described above results in maintenance (or preventing deterioration) of beta cell function for at least about 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 30, 36, 42, or 48 months from the start of treatment.

[069] Additionally, in some embodiments, treatment by the composition of the invention as described above results in maintenance of endogenous insulin levels (or preventing a decrease thereof) for at least about 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 30, 36, 42, or 48 months from the start of treatment.

[070] Insulin levels may be measured by any acceptable method, including, for example, by measuring levels of C-peptide following a mixed meal tolerance test (MMTT).

[071] In some embodiments, the treating results in at least one outcome selected from the group consisting of: a reduction in the HbAlc levels; an increase in C-peptide levels following an MMTT; a reduction in the number of diabetic ketoacidosis episodes; a reduction in the number of hypoglycemic episodes; a reduction in fasting glucose levels; an increase in % time in 70-180 mg/dL glucose range; and a reduction in daily insulin usage. It is noted that the terms“an increase” or“a reduction” are meant to describe the parameter as measured in the subject following treatment, in comparison to the measurement of the same parameter prior to treatment.

[072] In some embodiments, the treating results in at least one outcome selected from the group consisting of: no increase in the HbAlc levels; no reduction in C-peptide levels following an MMTT; no increase in the number of diabetic ketoacidosis episodes; no increase in the number of hypoglycemic episodes; no increase in fasting glucose levels; no reduction in % time in 70-180 mg/dL glucose range; and no increase in daily insulin usage, for at least about 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 18, 24, 30, 36, 42, or 48 months from the start of treatment. [073] In some embodiments, the treatment more specifically results in at least one outcome selected from the group consisting of an HbAlc level of <7.5%, and daily insulin usage of < 0.5 IU/kg.

[074] In some embodiments, treatment by the composition of the invention results in immune system modulation. Such immune system modulation is manifested in a reduction in levels of autoantibodies directed against pancreatic beta cells, a reduction in levels of T cells directed against pancreatic beta cells, a reduction in pro-inflammatory cytokine levels, an/or increase in anti-inflammatory cytokines levels,

[075] The term "standard of care" (SoC) drug as used herein relates to any drug that is used by standard practice for treating T1DM or any symptom thereof. Such drugs include, for example, insulin, immunosuppressive drugs (e.g. cyclosporin A), anti-CD3 antibodies (e.g. teplizumab and otelixizumab), and anti-CD20 antibodies (rituximab).

[076] In some embodiments, the standard of care (SoC) medication is insulin.

[077] The compositions of the invention including CBD may be used for alleviating adverse events related to T1DM or to treatment thereof, such as allergic reactions to insulin, lipodystrophy, weight gain, hypoglycemia, anxiety, fatigue, damage to the eyes, foot ulcers, kidney failure, stroke heart disease, dizziness, and seizures.

[078] In some embodiments, administering the compositions of the invention enables using lower doses of the SoC drug, thereby reducing side-effects.

[079] In some embodiments, administration of the compositions of the invention for treating T1DM facilitates using sub -therapeutic doses of the presently used drugs, or even eliminates the need for the presently used drugs altogether.

[080] Accordingly, in some embodiments, the SoC drug is administered at a sub-therapeutic dose.

[081] The term "sub-therapeutic dose" as used herein means less than the therapeutic dose of the drug that is needed to produce a therapeutic effect when the drug is used to treat T1DM.

[082] In another aspect, the present invention provides composition comprising cannabidiol (CBD) or an enantiomer, diastereomer, or racemate thereof as a sole cannabinoid, for use in improving the efficacy of a standard of care (SoC) treatment in a subject suffering from type 1 diabetes mellitus (T1DM) and treated with an SoC medication.

[083] The phrase "improving the efficacy" as used herein means that the combined administration of the composition and the SoC medication may result in improved response to the combined treatment compared with the response to the SoC drug alone, such as improvement in any of the parameters measured as an indication for a successful treatment, or any positive effect on symptoms related to the T1DM as described above and in the examples. Improved efficacy may also mean that the SoC drug administered as part of the treatment may be administered at a lower dose or at a lower frequency.

[084] In another related aspect, the present invention provides a method for improving the efficacy of a standard of care (SoC) treatment in a subject suffering from type 1 diabetes mellitus (T1DM) and administered with an SoC medication, said method comprising further administering to said subject a therapeutically effective amount of a composition comprising cannabidiol (CBD) or an enantiomer, diastereomer, or racemate thereof as a sole cannabinoid.

[085] In yet another related aspect, the present invention provides a method for treating type 1 diabetes mellitus (T1DM), comprising administering to a subject in need thereof a therapeutically effective amount of a composition comprising cannabidiol (CBD) or an enantiomer, diastereomer, or racemate thereof as a sole cannabinoid, together with a standard of care (SoC) medication.

[086] Unless otherwise indicated, all numbers expressing, e.g., amounts or concentrations of CBD, or lengths of time, defined above, used in this specification are to be understood as being modified in all instances by the term "about". Accordingly, unless indicated to the contrary, the numerical parameters set forth in this specification are approximations that may vary by up to plus or minus 10% depending upon the desired properties to be obtained by the present invention.

[087] The invention will now be illustrated by the following non-limiting Examples.

EXAMPLES

Methods

Preparation of purified Cannabidiol (CBD, CAS Number: 13956-29-1 )

[088] Cannabis sativa flowers were dried and ground. The ground plant material contained CBD in its acidic form CBDa. Decarboxylation process performed at 140°C turned the CBDa to CBD while releasing CO2 gas. CBD was extracted from the decarboxylated material via supercritical CO2 extraction. The extract was dissolved in ethanol following winterization step at -20°C for 48 hours. The ethanolic winterized extract was filtered to remove waxy constitutes, and the ethanol was evaporated. The dried extract was dissolved in pentane under heat to achieve super saturation and cooled to room temperature. Crystallization took place in two stages: first stage: -20°C, second stage: 4°c. After crystallization, the CBD was dried and milled, and stored in air tight containers, protected from air and light at room temperature.

[089] The CBD was about >95% pure.

Cannabidiol in oil [090] CBD was added to medium-chain triglyceride (MCT) oil in a beaker to a concentration of 250 mg/ml CBD to achieve a concentration of 25 mg CBD per a drop of 0.1 ml. The mixture was stirred with magnetic stirrer for 60 minutes. The solution was then tested for CBD concentration via HPLC. The appropriate number of drops was used to deliver the chosen dose. The solution could also contain a sweetener.

Assessment methods

Mixed Meal Tolerance Test (MMTT) for C-Peptide Level

[091 ] Measurement of C-peptide under standardized conditions (by MMTT) provides a sensitive, widely accepted, and clinically validated assessment of beta-cell function. C-peptide measurement is the most suitable primary outcome for clinical trials of therapies aimed at preserving or improving endogenous insulin secretion in type 1 diabetes patients and is in accordance with regulatory guidelines for such measurements. Available data demonstrate that even relatively modest treatment effects on C-peptide result in clinically meaningful benefits for near term and long-term complications. The level of preserved C-peptide has been positively correlated with improved clinical outcomes. C-peptide is a valid indicator for endogenous insulin secretion. This is assessed best by measurement of C-peptide, which is co-secreted with insulin in a one-to-one molar ratio. Insulin is produced firstly by an earlier form of molecule called pre-insulin. This molecule combines within a connecting peptide, called in short, C-peptide. For every molecule of insulin, there is one molecule of C-peptide in the blood stream. The level of C-peptide is a reliable indicator for the body’ s ability to produce insulin, as opposed to Insulin itself, level of which could be misled by exogenous insulin (from injection).

[092] MMTT instructions to patients: prior to MMTT visits subjects are instructed to: 1. Attend the MMTT visit fasting (no food or drink, with the exception of water, and no smoking after 10 p.m, in the preceding day). 2. Subjects who normally take basal insulin in the morning should withhold their long acting insulin on the morning of the test and bring their basal insulin to the MMTT visit. 3. Participants who are treated with an insulin pump can continue their normal basal injection rate during the test. 4. Not to take any bolus insulin, rapid or short acting insulin, later than 6 hours prior to the MMTT. 5. Remember to bring their bolus insulin to the MMTT visits (to be given after the MMTT). 6. Not to take study drug/placebo on the morning of the MMTT day.

[093] MMTT Procedures: 1. The MMTT is initiated in the morning between 07:00 and 10:00 A.M, after an overnight fast. 2. The capillary glucose value measured at the site before the MMTT must be>70 mg/dl and <200 mg/dl in order to start the test. Otherwise, the MMTT should be re scheduled within up to two weeks. 3. The subject’s body weight is measured before intake of the standardized liquid meal. 4. The amount of the standardized liquid meal (Ensure® or equivalent) is calculated as follow: 6 ml/kg body weight, up to 360 ml or per instructions of the equivalent standardized meal. 5. Subject consumes the standardized liquid meal as quickly as possible and within 5 minutes. 6. Blood samples (7 -point profile) is collected 10 minutes prior to the meal (- 10) at meal start (0), and at 15, 30, 60, 90, 120 minutes after meal start (0-2 hours). The blood samples are assayed for C-peptide and plasma glucose. 7. During the MMTT plasma glucose is monitored using a blood glucose meter at each time point. If the glucose level exceeds 300 mg/dl urine ketones (beta-hydroxybutyrate) will be measured according to SoC at the clinic. If more than +2 ketones will be found in a standard urine kit, the test should be stopped, and the patient treated with the rescue insulin.

Evaluation of Glucose Data

[094] Patients are instructed to monitor their glucose levels (via glucometer, continuous glucose monitoring (CGM) or Flash technology) and insulin doses for 7 days immediately preceding the in-clinic visits. Daily 4-point glucose measurement and basal, boluses and total insulin doses are obtained. Patients with the sensors (CGM/Flash technology) record their glucose levels in the glucose diaries in accordance with the sensor readings at 4 timepoints during the day: before breakfast, before lunch, before supper and before bedtime. Patients with the glucometers only measure their glucose levels at the same 4 timepoints as mentioned above and record the measures in their glucose diaries. 4-point glucose levels and basal, boluses and total insulin doses from the most recent 3 monitoring days with full data available are entered into the electronic case report form (eCRF). For patients who use CGM or Flash technology, mean glucose levels are available. Mean glucose levels across each of the corresponding 7-day monitoring periods are entered into the eCRF, if applicable. Patients who use the CGM or Flash technology, will be also monitored for mean glucose levels and % time in and out (above and below) of the 70-180 mg/dL glucose range across each of the 7-day monitoring periods mentioned above.

Evaluation of Insulin Doses

[095] Patients who do not use insulin pumps are instructed to document in the study diary daily insulin doses during 7 days prior to Baseline, Week 12, Week 24, Week 36, Week 48 (end-of-trial, EOT) and Week 52 (follow-up, FU). Each record should include date, time point (e.g. before breakfast, before lunch etc.), units and type of insulin. In addition, for patients who are treated with insulin pumps, the pump readings is also downloaded during the same visits (Baseline, Week 12, Week 24, Week 36, Week 48 (EOT)), and insulin dose and type are recorded for the 7 days preceding each visit. Insulin data from the most recent 3 monitoring days, prior to each of the corresponding visits, with full data available is entered into the eCRF.

Patients diaries [096] Paper-based glucose and insulin diaries are provided to all patients at Screening Visit 2, Baseline, Week 12, Week 24, Week 36, Week 48 (EOT). The completed diaries are collected on the corresponding subsequent visits. Patients are instructed to monitor their glucose levels (via glucometer or CGM/Flash technology) and insulin doses for 7 days immediately preceding the in clinic visits (Weeks 12, 24, 36, 48 and 52, respectively). Daily 4-point glucose measurement and basal, boluses and total insulin doses are recorded into the diaries. Patients with the sensors (CGM/Flash technology) record their glucose in accordance with the sensor readings at 4 timepoints during the day: before breakfast, before lunch, before supper and before bedtime. Patients with the glucometers only measure their glucose levels at the same 4 timepoints as mentioned above and record the measures in their glucose diaries. For patients who use CGM or Flash technology, mean glucose levels will be available. Mean glucose levels across each of the corresponding 7-day monitoring periods are entered into the eCRF, if applicable. In addition, for patients who use CGM or Flash technology, percent of the time, across each of the corresponding 7-day monitoring periods, in and out (below and above) of 70-180 mg/dF glucose range, are recorded as well.

Blood tests

[097] Blood samples are collected as part of the visit routine for a chemistry panel, and CBC. Samples are analysed at the hospital laboratory. Samples are also obtained for frozen serum collection.

HbAlc

[098] Capillary HbAlc tests are conducted on visits during screening, baseline and at every in clinic visit, according to the hospital’s operating procedures.

Vital signs

[099] Vital signs are assessed at all study in-clinic visits (except Screening Visit 1) and include blood pressure and heart rate, measured after the patient has rested for at least 5 minutes. Significant findings noticed after the start of the study drug, which meet the definition of an AE, must be recorded on the AE CRF.

12 Lead ECG

[0100] Twelve-lead ECG is performed during the Screening period either on Screening Visit 1 or on Screening Visit 2. ECG is assessed by the PI or a local cardiologist. All ECGs with clinically significant interval abnormalities on the machine read, are over-read by a local cardiologist. Any ECG abnormality determined by the Investigator to be clinically significant is noted as an AE on the appropriate CRF page(s). Such abnormalities are closely monitored up to their resolution (if applicable). Physical Examinations

[0101] Physical examination is conducted on Screening Visit 2, Baseline, visits on Weeks 24, 48 and 52, and as deemed necessary by the Investigator. A complete physical examination is conducted and includes an assessment of the head (external), eyes, ears, nose and throat, lungs, cardiovascular system, breast, abdomen, musculoskeletal system, skin, lymph nodes and central nervous system. Significant findings that are present prior to the start of the study drug (or therapy) must be included in the Relevant Medical History/Current Medical Conditions CRF. Height and weight measurements are recorded at all in-clinic visits.

Safety Laboratory Assessments

[0102] All routine clinical laboratory assessments are performed by a local laboratory. Routine laboratory sampling is done under fasting conditions (at least 8 hours) at Screening and on visits. The laboratory evaluations include, but are not limited to: hematology including red blood cell count, hemoglobin (HGB), hematocrit (HCT), white blood cell (WBC) count and differential, platelet count, ESR; blood chemistry including Sodium (Na), Potassium (K), Chloride (Cl), Creatinine, Glucose, Urea, Albumin, Calcium total, Alkaline Phosphatase (ALP), ALT, AST, Total Bilirubin, Direct Bilirubin, LDH, Total Protein, Uric Acid and CRP; and urinalysis; and urinary drug analysis (UDP) for detecting Tetrahydrocannabinol (THC), ecstasy (MDMA), amphetamines (AMP), opiates (OPI), cocaine (COC), benzodiazepines (BZO), methadone (MTD) and oxycodone.

Diabetic ketoacidosis and severe hypoglycemic events

[0103] Diabetic ketoacidosis and severe hypoglycemic events are documented in the patient's CRFs. Reports should include the date, time and severity of each event and any interventions performed.

Columbia-Suicide Severity Rating Scale (C-SSRS)

[0104] The C-SSRS is a semi- structured interview that measures suicide ideation and behavior. The first scale, the severity scale is a 6-point ordinal scale, ranging from 1 (wish to be dead) to 5 (suicidal intent with a plan). Adolescents who denied ideation received a zero. The second subscale, the intensity scale is comprised of five items (i.e., frequency, duration, controllability, deterrents, reasons for ideation), each rated on an ordinal scale (total scores ranging from 2 to 25). These five items are completed only with adolescents who endorse at least one of the severity items. Those without any suicidal ideation are given a scale score of 0 on intensity. The behavior scale is a 5-point nominal scale that investigates interrupted, aborted, and actual suicide attempts; preparatory behavior for a suicide attempt; and non-suicidal self-injurious behavior. Administration time is dependent on the adolescent’s suicidal history ranging from 1 to 2 or 5 to 10 minutes; as indicated above, certain scales may not be required for completion.

Statistics

[0105] A sample size of about 60 subjects was chosen for feasibility. The primary endpoint of change in AUCo-2_h for an MMTT at Week 48 compared to Screening is analyzed using ANCOVA with treatment, age stratification factor (age groups: 5<Age<12; 12<Age<18; Age> 18) and AUCo- 2_h at Screening, as covariates. Last Observation Carried Forward (LOCF) are used to account for missing data. A 95% confidence interval for the difference between the groups id constructed.

Example 1: Effect of cannabidiol (CBD) administration on type 1 diabetes mellitus (T1DM)

Patient inclusion criteria

[0106] Subjects are males or females, aged 5-30 years old, having been diagnosed with type 1 diabetes mellitus (T1DM) up to 20 weeks before the study, having peak C-peptide > 0.2 nmol/1 during mixed-meal tolerance test (MMTT), presence of one or more islet- specific auto antibodies at screening.

[0107] Patients are stratified into the age groups 5-12 years old, 12-18 years old, and > 18 years old.

[0108] Criteria for exclusion from the study were, inter alia, daily insulin usage >lU/kg; history of pancreatitis or of severe or chronic infections or conditions predisposing to chronic infections; diagnosis of malignant neoplasm; known impairment of the immune system, except for T1DM, coeliac disease, alopecia, autoimmune antibodies not considered clinically important (e.g. thyroid antibodies without any clinically important thyroid disease), and vitiligo).

Treatment, dosage regimen and dosage form

Screening period

[0109] During the screening period (up to 8 weeks), patients are interviewed for medical history, concomitant illnesses and concomitant medications; pre-study insulin daily dose is recorded, and MMTT test is performed within 4 weeks prior to the baseline visit; data is downloaded from the patient’s Multi-daily Insulin Injections (MDII) or pump and the glucometer or continuous glucose monitoring (CGM)/Flash technology; a full physical examination is performed, including vital signs, weight and height; a 12-lead ECG is also performed; fasting plasma glucose is obtained; laboratory tests, including urinalysis, complete blood count (CBC), blood chemistry, HbAlc, and samples for cytokine, T cell population and TCR repertoire analyses are obtained. Patients are instructed to monitor their insulin doses and glucose levels via diaries for 7 days immediately preceding the Baseline visit. Columbia-Suicide Severity Rating Scale (C-SSRS) is administered. Baseline visit

[0110] At the baseline visit (week 0 of the study), patients are interviewed for medical history, concomitant illnesses and concomitant medications; baseline insulin daily dose is recorded, vital signs, a full physical examination including weight and height are measured, and any adverse events are recorded; blood test for HbAlc is conducted; data is downloaded from the patient’s MDII or pump and the glucometer or CGM/Flash technology. Patients are instructed to continue monitoring their insulin doses and glucose levels via diaries. C-SSRS is administered.

[0111] All eligible patients are randomly assigned at a 1: 1 ratio into one of two the arms - receiving CBD or placebo as add-on to standard of care (SoC) treatment, and treatment is initiated.

[0112] Patient received 10 mg/Kg/d up to 300 mg/d of BOL-PP-o-05, a CBD formulation of above 95% purity, in the form of medicated drops in medium-chain triglyceride (MCT) oil actuated by a pump and taken by sublingual administration, or placebo (in the same amount, identical to the active formulation in color, taste and smell, but not including CBD), twice a day for 48 weeks. The administration is with food or within half an hour after a meal.

[0113] For the 7 days following baseline, subjects take approximately 1/2 the dose of their study product. After 7 days, barring any special problems, the dose is increased to the full dose, to be taken thereafter.

Treatment period

[0114] During the treatment period, patients have phone or in-clinic visits every 3 months. In the visits, patients are interviewed as above, and insulin daily dose is recorded. In addition, in the in clinic visits, vital signs, weight and height are measured; blood test for HbAlc is conducted; data is downloaded from the patient’s MDII or pump and the glucometer or CGM/Flash technology. C-SSRS is administered. Patients are monitored throughout the study for adverse events, including diabetic ketoacidosis (DKA) and sever hypoglycemia.

[0115] During week 24, a full physical examination, and laboratory tests, including basal C- peptide, CBC, blood chemistry, HbAlc, and samples for cytokine, T cell population and TCR repertoire analyses are performed.

End of treatment

[0116] During the final visit, on week 48, patients are interviewed as above; insulin daily dose is recorded; vital signs are measured; a full physical examination is performed including height and weight, and a 12-lead ECG is also be performed; insulin daily dose is recorded, and MMTT test is performed: C-peptide and glucose levels are measured prior to and after a standardized liquid meal (Ensure® or equivalent). Blood samples (7-point profile) are collected 10 minutes prior to the meal (-10) at meal start (0), and at 15, 30, 60, 90, 120 minutes after meal start. If the MMTT is postponed within 2 weeks, patients receive additional amount of study products; data is downloaded from the patient’s MDII or pump and the glucometer or CGM/Flash technology; fasting plasma glucose is obtained; laboratory tests, including urinalysis, CBC, blood chemistry, HbAlc and samples for cytokine, T cell population and TCR repertoire analyses are performed. C-SSRS is administered. Follow-up visits ( week 52)

[0117] During the follow-up visit patients/ patients’ parents/legal guardians are interviewed for concomitant illnesses and concomitant medications; insulin daily dose is recorded; vital signs, weight and height are measured; a full physical examination is carried out; data is downloaded from the patient’s MDII or pump and the glucometer or CGM/Flash technology; blood test for HbAlc is performed.

[0118] Patients also continue to be treated with a standard of care drug, such as insulin.

[0119] Patients are not allowed to take any other cannabinoid product in any form.

[0120] In addition, special caution is taken in the concomitant administration of cannabinoids with the following classes of drugs, due to potential pharmacodynamic effects: 1. Hypoglycemic drugs: there may be drops in blood glucose at the initiation of cannabis use which may require dose adjustments. 2. Hypertension drugs: there may be drops in blood pressure with cannabis use which may require dose adjustments. 3. Sympathomimetic drugs (including local eye or nasal drugs that have the potential of systemic effects): there may be an increased potential for tachycardia or hypertensions with cannabis use. 4. CNS suppressor drugs (e.g. sleep medicines, sedatives, alcohol, opiates): there may be an increased effect of sedation, dizziness, ataxia, loss of balance and risk of falling, increased risk with driving and operating dangerous machinery. With opiates there is an increased risk of breathing suppression. 5. Muscle relaxants (e.g. benzodiazepines): there may be an increased risk of muscle weakness and risk of falling. 6. Anticholinergic agents (e.g. tricyclic anti-depressants, antihistamines): there may be an increased potential for tachycardia and dizziness.

[0121] The outcomes measured are: preservation of beta-cell mass as indicated by AUCo-2_h for a mixed meal tolerance test (MMTT) stimulated C-peptide concentration-time curve relative to baseline; change in peak MMTT stimulated C-peptide concentration (Cmax, C-peptide) relative to baseline; change in fasting C-peptide from baseline; change in fasting plasma glucose from baseline; change in total daily insulin dose in IU/kg body weight (three-day average) from baseline; change in basal insulin dose in IU/kg body weight (three-day average) from Baseline; change in insulin bolus dose in IU/kg body weight (three-day average) from Baseline; percentage of patients that maintain stimulated peak C-peptide > 0.2nmol/L; percentage of patients that achieve glycemic target of HbAlc < 7.5%; percent of subjects who require a daily insulin dose < 0.5 IU/kg body weight after 12 months from diagnosis; change over time in patients' 4-point glucose levels from pre-treatment; change in mean glucose from the week prior to Baseline, based on reading from CGM or Flash technology; change over time in patients’ % time in 70-180 mg/dL glucose range from pre-treatment; change over time in patients’ % time above 70-180 mg/dL glucose range from pre-treatment; change over time in patients’ % time below 70-180 mg/dL glucose range from pre-treatment.

[0122] It is expected that that the treatment with CBD will results in reduction of the autoimmune- driven destruction of b-cells in the newly diagnosed T1DM patients.

REFERENCES

Hao et al, 2016, Fall in C-Peptide during First 4 Years From Diagnosis of Type 1 Diabetes: Variable Relation to Age, HbAlc, and Insulin Dose, Diabetes Care 39:1664-1670.

Naftali et al. Cannabis induces a clinical response in patients with Crohn’s disease: a prospective placebo-controlled study. Clin Gastroenterol Hepatol. 2013; 11(10): 1276-1280.

Pacifici et al. Modulation of the Immune System in Cannabis Users. JAMA. 2003 ;289(15): 1929-1931.

Yeshurun et al. Cannabidiol for the Prevention of Graft-versus-Host-Disease after Allogeneic Hematopoietic Cell Transplantation: Results of a Phase II Study. Biol Blood Marrow Transplant. 2015; 21(10): 1770-1775.

Claims

1. A composition comprising cannabidiol (CBD) or an enantiomer, diastereomer, or racemate thereof as a sole cannabinoid, for use together with a standard of care (SoC) medication in the treatment of type 1 diabetes mellitus (T1DM) in a subject in need thereof.

2. The composition for use of claim 1, consisting essentially of CBD.

3. The composition for use of claim 1 or 2, suitable for administration sublingually, orally, or by inhalation.

4. The composition for use of any one of claims 1-3, wherein the daily dose of the CBD is from about 30 mg to about 600 mg CBD per day, preferably from about 100 mg to about 300 mg CBD per day.

5. The composition for use of any one of claims 1-4, suitable for administration once, twice, or three times a day.

6. The composition for use of any one of claims 1-5, wherein the subject is newly diagnosed with T1DM, such as within about 20 weeks prior to the start of the treatment.

7. The composition for use of any one of claims 1-6, wherein the subject is between 5 and 30 years old at the start of the treatment.

8. The composition for use of any one of claims 1-7, wherein the subject is a child at the start of the treatment.

9. The composition for use of any one of claims 1-7, wherein the subject is an adult.

10. The composition for use of any one of claims 1-9, wherein the subject is a male subject.

11. The composition for use of any one of claims 1 -9, wherein the subject is a female subject.

12. The composition for use of any one of claims 1-11, wherein the subject has one or more islet-specific auto antibodies before the treatment.

13. The composition for use of any one of claims 1-12, wherein the subject has a non-fasting peak C-peptide > 0.2 nmol/1 during mixed-meal tolerance test (MMTT) before the treatment.

14. The composition for use of any one of claims 1-13, wherein the daily insulin usage of said subject is < 1 U/kg per day before the treatment.

15. The composition for use of any one of claims 1-14, wherein the subject does not suffer from pancreatitis before the treatment.

16. The composition for use of any one of claims 1-15, wherein the treatment is manifested in preventing a decrease in endogenous insulin level relative to insulin level before the treatment.

17. The composition for use of any one of claims 1-16, wherein the treatment results in at least one outcome selected from the group consisting of: a reduction or no increase in HbAlc levels; an increase or no reduction in C-peptide levels following a mixed meal tolerance test (MMTT); a reduction or no increase in the number of diabetic ketoacidosis episodes; a reduction or no increase in the number of hypoglycemic episodes; a reduction or no increase in fasting glucose levels; and a reduction or no increase in daily insulin usage.

18. The composition for use of any one of claims 1-17, wherein the SoC medication is insulin.

19. The composition for use of any one of claims 1-18, wherein the SoC medication is administered at a sub-therapeutic dose.

20. A composition comprising cannabidiol (CBD) or an enantiomer, diastereomer, or racemate thereof as a sole cannabinoid, for use in improving the efficacy of a standard of care (SoC) treatment in a subject suffering from type 1 diabetes mellitus (T1DM) and treated with an SoC medication.

21. A method for treating type 1 diabetes mellitus (T1DM), comprising administering to a subject in need thereof a therapeutically effective amount of a composition comprising cannabidiol (CBD) or an enantiomer, diastereomer, or racemate thereof as a sole cannabinoid, together with a standard of care (SoC) medication.

22. A method for improving the efficacy of a standard of care (SoC) treatment in a subject suffering from type 1 diabetes mellitus (T1DM) and administered with an SoC medication, said method comprising further administering to said subject a therapeutically effective amount of a composition comprising cannabidiol (CBD) or an enantiomer, diastereomer, or racemate thereof as a sole cannabinoid.