FIELD OF THE INVENTION

[0001] The present invention relates to the use of cannabidiol (CBD) for the treatment of seizures associated with rare epilepsy syndromes. In particular the seizures associated with rare epilepsy syndromes that are treated are those which are experienced in patients diagnosed with Lissencephaly.

[0002] In a further embodiment the CBD used is in the form of a highly purified extract of cannabis such that the CBD is present at greater than 95% of the total extract (w/w) and the cannabinoid tetrahydrocannabinol (THC) has been substantially removed, to a level of not more than 0.15% (w/w).

[0003] Preferably the CBD used is in the form of a botanically derived purified CBD which comprises greater than or equal to 98% (w/w) CBD and less than or equal to 2% (w/w) of other cannabinoids. More preferably the other cannabinoids present are THC at a concentration of less than or equal to 0.1% (w/w); CBD-C1 at a concentration of less than or equal to 0.15% (w/w); CBDV at a concentration of less than or equal to 0.8% (w/w); and CBD-C4 at a concentration of less than or equal to 0.4% (w/w). The botanically derived purified CBD preferably also comprises a mixture of both trans-THC and cis-THC. Alternatively, a synthetically produced CBD is used.

[0004] Most preferably the other cannabinoids present are THC at a concentration of about 0.01% to about 0.1% (w/w); CBD-C1 at a concentration of about 0.1% to about 0.15% (w/w); CBDV at a concentration of about 0.2% to about 0.8% (w/w); and CBD-C4 at a concentration of about 0.3% to about 0.4% (w/w). Most preferably still the THC is present at a concentration of about 0.02% to about 0.05% (w/w).

[0005] Where the CBD is given concomitantly with one or more other anti-epileptic drugs (AED), the CBD may be formulated for administration separately, sequentially or simultaneously with one or more AED or the combination may be provided in a single dosage form.

BACKGROUND TO THE INVENTION

[0006] Epilepsy occurs in approximately 1% of the population worldwide, (Thurman et al., 2011) of which 70% are able to adequately control their symptoms with the available existing anti-epileptic drugs (AED). However, 30% of this patient group, (Eadie etal., 2012), are unable to obtain seizure freedom from the AED that are available and as such are termed as suffering from intractable or “treatment-resistant epilepsy” (TRE). [0007] Intractable or treatment-resistant epilepsy was defined in 2009 by the International League Against Epilepsy (I LAE) as “failure of adequate trials of two tolerated and appropriately chosen and used AED schedules (whether as monotherapies or in combination) to achieve sustained seizure freedom ” (Kwan et al., 2009).

[0008] Individuals who develop epilepsy during the first few years of life are often difficult to treat and as such are often termed treatment resistant. Children who undergo frequent seizures in childhood are often left with neurological damage which can cause cognitive, behavioral and motor delays.

[0009] Childhood epilepsy is a relatively common neurological disorder in children and young adults with a prevalence of approximately 700 per 100,000. This is twice the number of epileptic adults per population.

[0010] When a child or young adult presents with a seizure, investigations are normally undertaken in order to investigate the cause. Childhood epilepsy can be caused by many different syndromes and genetic mutations and as such diagnosis for these children may take some time.

[0011] The main symptom of epilepsy is repeated seizures. In order to determine the type of epilepsy or the epileptic syndrome that a patient is suffering from an investigation into the type of seizures that the patient is experiencing is undertaken. Clinical observations and electroencephalography (EEG) tests are conducted and the type(s) of seizures are classified according to the ILEA classification.

[0012] Generalized seizures, where the seizure arises within and rapidly engages bilaterally distributed networks, can be split into six subtypes: tonic-clonic (grand mal) seizures; absence (petit mal) seizures; clonic seizures; tonic seizures; atonic seizures and myoclonic seizures.

[0013] Focal (partial) seizures where the seizure originates within networks limited to only one hemisphere, are also split into sub-categories. Here the seizure is characterized according to one or more features of the seizure, including aura, motor, autonomic and awareness / responsiveness. Where a seizure begins as a localized seizure and rapidly evolves to be distributed within bilateral networks this seizure is known as a bilateral convulsive seizure, which is the proposed terminology to replace secondary generalized seizures (generalized seizures that have evolved from focal seizures and are no longer remain localized).

[0014] Focal seizures where the subject’s awareness / responsiveness is altered are referred to as focal seizures with impairment and focal seizures where the awareness or responsiveness of the subject is not impaired are referred to as focal seizures without impairment.

[0015] Lissencephaly, which literally means "smooth brain," is a rare, gene-linked brain malformation characterized by the absence of normal convolutions in the cerebral cortex and an abnormally small head (microcephaly). ¹ It is caused by defective neuronal migration during embryonic development. Symptoms may include unusual facial appearance, difficulty swallowing, failure to thrive, muscle spasms, seizures, severe psychomotor retardation, and hands, fingers, or toes may be deformed.

[0016] The prognosis for children with Lissencephaly depends on the degree of brain malformation. Some may have near-normal development and intelligence whereas many others will die before ten years of age whereby the cause of death is commonly aspiration of food or fluids, respiratory disease, or severe seizures.

[0017] There is no cure for Lissencephaly, but children can show progress in their development over time. Supportive care may be needed to help with comfort, feeding, and nursing needs, and a gastrostomy tube may be needed if feeding becomes difficult. Seizures may be helped by anticonvulsant medications.

[0018] Cannabidiol (CBD), a non-psychoactive derivative from the cannabis plant, has demonstrated anti-convulsant properties in several anecdotal reports, pre-clinical and clinical studies both in animal models and humans. Three randomized control trials showed efficacy of the purified pharmaceutical formulation of CBD in patients with Dravet and Lennox-Gastaut syndrome.

[0019] Based on these three trials, a botanically derived purified CBD preparation was approved by FDA in June 2018 for the treatment of seizures associated with Dravet and Lennox-Gastaut syndromes.

[0020] In 2014 an LA newspaper reported the treatment of a child with Lissencephaly using CBD. ² There is no mention of the composition of CBD used nor the types of seizures that were reduced by treatment.

[0021] Another 2019 Texan newspaper article highlighted the use of cannabis oil to treat a child with Lissencephaly. ³ Again, there is no disclosure of the composition of the cannabis oil used nor the types of seizures treated.

[0022] An article in 2017 ⁴ describes the use of CBD hemp oil in the treatment of seizures associated with Lissencephaly in conjunction with various anti-epileptic drugs. The description of the product "Palmetto Harmony" states that the product is made with two ingredients, MCT oil and hemp flower extract, and that it contains a full-spectrum terpene profile.

[0023] A presentation by Salyer in 2019 ⁵ describes a single case whereby the off-label use of Epidolex was trialled in the treatment of seizures associated with Lissencephaly in combination with various antiepileptic drugs. There is no mention or suggestion of the types of seizures treated with the drug.

[0024] WO 2019/145700, WO 2015/193668 and WO 2016/203239 are the applicant’s previous patent applications which are directed to highly purified CBD for use in the treatment of seizures in treatment-resistant epilepsy in combination with anti-epileptic drugs. There is no disclosure of the specific disease indication, Lissencephaly, in any of the documents.

[0025] The applicant has found by way of an open label, expanded-access program that treatment with CBD resulted in a significant reduction in seizures in patients with Lissencephaly.

BRIEF SUMMARY OF THE DISCLOSURE

[0026] In accordance with a first aspect of the present invention there is provided a cannabidiol (CBD) preparation for use in the treatment of Lissencephaly.

[0027] In a further embodiment, the seizures associated with Lissencephaly are atonic, tonic, tonic-clonic, myoclonic and absence seizures.

[0028] In a further embodiment, the CBD preparation comprises greater than 95% (w/w) CBD and not more than 0.15% (w/w) tetrahydrocannabinol (THC).

[0029] Preferably the CBD preparation comprises greater than or equal to 98% (w/w) CBD and less than or equal to 2% (w/w) other cannabinoids, wherein the less than or equal to 2% (w/w) other cannabinoids comprise the cannabinoids tetrahydrocannabinol (THC); cannabidiol- C1 (CBD-C1); cannabidivarin (CBDV); and cannabidiol-C4 (CBD-C4), and wherein the THC is present as a mixture of trans-THC and cis-THC.

[0030] Preferably the CBD preparation is used in combination with one or more concomitant anti-epileptic drugs (AED).

[0031] Preferably the one or more AED is selected from the group consisting of: valproic acid, levetiracetam, clobazam, vigabatrin, zonisamide, lacosamide, zonisamide and phenobarbital.

[0032] In one embodiment the CBD is present is isolated from cannabis plant material. Preferably at least a portion of at least one of the cannabinoids present in the CBD preparation is isolated from cannabis plant material.

[0033] In a further embodiment the CBD is present as a synthetic preparation. Preferably at least a portion of at least one of the cannabinoids present in the CBD preparation is prepared synthetically.

[0034] Preferably the dose of CBD is greater than 5 mg/kg/day. More preferably the dose of CBD is 20 mg/kg/day. More preferably the dose of CBD is 25 mg/kg/day.

[0035] In accordance with a second aspect of the invention there is provided a method of treating seizures associated with Lissencephaly comprising administering a cannabidiol (CBD) preparation to the subject in need thereof. DEFINITIONS

[0036] Definitions of some of the terms used to describe the invention are detailed below:

[0037] Over 100 different cannabinoids have been identified, see for example, Handbook of Cannabis, Roger Pertwee, Chapter 1, pages 3 to 15. These cannabinoids can be split into different groups as follows: Phytocannabinoids; Endocannabinoids and Synthetic cannabinoids (which may be novel cannabinoids or synthetically produced phytocannabinoids or endocannabinoids).

[0038] “Phytocannabinoids” are cannabinoids that originate from nature and can be found in the cannabis plant. The phytocannabinoids can be isolated from plants to produce a highly purified extract or can be reproduced synthetically.

[0039] “Highly purified cannabinoids” are defined as cannabinoids that have been extracted from the cannabis plant and purified to the extent that other cannabinoids and non-cannabinoid components that are co-extracted with the cannabinoids have been removed, such that the highly purified cannabinoid is greater than or equal to 95% (w/w) pure.

[0040] “Synthetic cannabinoids” are compounds that have a cannabinoid or cannabinoid-like structure and are manufactured using chemical means rather than by the plant.

[0041] Phytocannabinoids can be obtained as either the neutral (decarboxylated form) or the carboxylic acid form depending on the method used to extract the cannabinoids. For example, it is known that heating the carboxylic acid form will cause most of the carboxylic acid form to decarboxylate into the neutral form.

[0042] “Treatment-resistant epilepsy” (TRE) or “intractable epilepsy” is defined as per the I LAE guidance of 2009 as epilepsy that is not adequately controlled by trials of one or more AED.

[0043] “Atonic seizures,” also known as drop attacks, occur when a person suddenly loses muscle tone resulting in their head or body possibly going limp. In some children, only their head drops suddenly. They can begin in one area or side of the brain (focal onset) or both sides of the brain (generalized onset).

[0044] “Tonic seizures” can be generalised onset, affecting both sides of the brain, or they can be focal onset, starting in just one side of the brain. If a tonic seizure starts in both sides of the brain, all muscles tighten and the subject’s body goes stiff. If standing, they may fall to the floor, their neck may extend, eyes open wide and roll upwards, whilst their arms may raise upwards and legs stretch or contract. If a tonic seizure starts in one side of the brain muscles tighten in just one area of the body. Tonic seizures usually last less than one minute.

[0045] “Tonic-clonic seizures” (also called convulsions) has replaced the term “grand mal.” When a subject experiences a tonic-clonic seizure, they lose consciousness, muscles stiffen, and jerking movements are seen. This type of seizure usually lasts 1 to 3 minutes and takes longer for the subject to recover. It usually begins on both sides of the brain but can start in one side and spread to the whole brain.

[0046] “Myoclonic seizures” are brief shock-like jerks of a muscle or group of muscles which can occur in a variety of epilepsy syndromes that have different characteristics. During a myoclonic seizure, the subject is usually awake and able to think clearly. Such seizures usually do not last more than a second or two and whilst there can be just one, sometimes many will occur within a short time.

[0047] “Absence seizures” has replaced the term “petit mal seizures.” Absence seizures cause lapses in awareness, sometimes with staring, and are more common in children. They begin and end abruptly, lasting only a few seconds. Such seizures can be so brief they sometimes are mistaken for daydreaming and may not be detected for months. They are a type of generalized onset seizures, meaning they begin in both sides of the brain at the same time.

[0048] “Focal seizures with impairment” usually start in a small area of the temporal lobe or frontal lobe of the brain and involve other areas of the brain within the same hemisphere that affect alertness and awareness. Most subjects experience automatisms during a focal seizure with impaired consciousness.

DETAILED DESCRIPTION

PREPARATION OF HIGHLY PURIFIED CBD EXTRACT

[0049] The following describes the production of the highly-purified (>95% w/w) cannabidiol extract which has a known and constant composition.

[0050] In summary the drug substance used is a liquid carbon dioxide extract of high-CBD containing chemotypes of Cannabis sativa L. which had been further purified by a solvent crystallization method to yield CBD. The crystallisation process specifically removes other cannabinoids and plant components to yield greater than or equal to 95% CBD. Although the CBD is highly purified because it is produced from a cannabis plant rather than synthetically there is a small number of other cannabinoids which are co-produced and co-extracted with the CBD. Details of these cannabinoids and the quantities in which they are present in the medication are as described in Table A below.

Table A: Composition of highly purified CBD extract

> - greater than NMT - not more than

PREPARATION OF BOTANICALLY DERIVED PURIFIED CBD [0051] The following describes the production of the botanically derived purified CBD which comprises greater than or equal to 98% w/w CBD and less than or equal to other cannabinoids was used in the open label, expanded-access program described in Example 1 below.

[0052] In summary the drug substance used in the trials is a liquid carbon dioxide extract of high-CBD containing chemotypes of Cannabis sativa L. which had been further purified by a solvent crystallization method to yield CBD. The crystallisation process specifically removes other cannabinoids and plant components to yield greater than 95% CBD w/w, typically greater than 98% w/w.

[0053] The Cannabis sativa L. plants are grown, harvested, and processed to produce a botanical extract (intermediate) and then purified by crystallization to yield the CBD (botanically derived purified CBD).

[0054] The plant starting material is referred to as Botanical Raw Material (BRM); the botanical extract is the intermediate; and the active pharmaceutical ingredient (API) is CBD, the drug substance.

[0055] All parts of the process are controlled by specifications. The botanical raw material specification is described in Table B and the CBD API is described in Table C.

Table B: CBD botanical raw material specification

Table C: Specification of an exemplary botanically derived purified CBD preparation

[0056] The purity of the botanically derived purified CBD preparation was greater than or equal to 98%. The botanically derived purified CBD includes THC and other cannabinoids, e.g., CBDA, CBDV, CBD-C1 , and CBD-C4.

[0057] In some embodiments, the CBD preparation comprises not more than 0.15% THC based on total amount of cannabinoid in the preparation. In some embodiments, the CBD preparation comprises about 0.01% to about 0.1% THC based on total amount of cannabinoid in the preparation. In some embodiments, the CBD preparation comprises about 0.02% to about 0.05% THC based on total amount of cannabinoid in the preparation.

[0058] In some embodiments, the CBD preparation comprises about 0.2% to about 1.0% CBDV based on total amount of cannabinoid in the preparation. In some embodiments, the CBD preparation comprises about 0.2% to about 0.8% CBDV based on total amount of cannabinoid in the preparation. [0059] In some embodiments, the CBD preparation comprises about 0.3% to about 0.5%

CBD-C4 based on total amount of cannabinoid in the preparation. In some embodiments, the CBD preparation comprises about 0.3% to about 0.4% CBD-C4 based on total amount of cannabinoid in the preparation.

[0060] In some embodiments, the CBD preparation comprises about 0.1% to about 0.15% CBD-C1 based on total amount of cannabinoid in the preparation.

[0061] Distinct chemotypes of the Cannabis sativa L. plant have been produced to maximize the output of the specific chemical constituents, the cannabinoids. Certain chemovars produce predominantly CBD. Only the (-)-trans isomer of CBD is believed to occur naturally. During purification, the stereochemistry of CBD is not affected.

Production of CBD botanical drug substance

[0062] An overview of the steps to produce a botanical extract, the intermediate, are as follows: a) Growing b) Direct drying c) Decarboxylation d) Extraction - using liquid CO2 e) Winterization using ethanol f) Filtration g) Evaporation

[0063] High CBD chemovars were grown, harvested, dried, baled and stored in a dry room until required. The botanical raw material (BRM) was finely chopped using an Apex mill fitted with a 1 mm screen. The milled BRM was stored in a freezer prior to extraction.

[0064] Decarboxylation of CBDA to CBD was carried out using heat. BRM was decarboxylated at 115°C for 60 minutes.

[0065] Extraction was performed using liquid CO2 to produce botanical drug substance (BDS), which was then crystalized to produce the test material. The crude CBD BDS was winterized to refine the extract under standard conditions (2 volumes of ethanol at -20°C for approximately 50 hours). The precipitated waxes were removed by filtration and the solvent was removed to yield the BDS.

Production of botanically derived purified CBD preparation

[0066] The manufacturing steps to produce the botanically derived purified CBD preparation from BDS were as follows: a) Crystallization using C ₅ -C ₁₂ straight chain or branched alkane b) Filtration c) Vacuum drying

[0067] The BDS produced using the methodology above was dispersed in C5-C12 straight chain or branched alkane. The mixture was manually agitated to break up any lumps and the sealed container then placed in a freezer for approximately 48 hours. The crystals were isolated via vacuum filtration, washed with aliquots of cold C5-C12 straight chain or branched alkane, and dried under a vacuum of <10mb at a temperature of 60°C until dry. The botanically derived purified CBD preparation was stored in a freezer at -20°C in a pharmaceutical grade stainless steel container, with FDA food grade approved silicone seal and clamps.

Physicochemical properties of the botanically derived purified CBD [0068] The botanically derived purified CBD used in the clinical trial described in the invention comprises greater than or equal to 98% (w/w) CBD and less than or equal to 2% (w/w) of other cannabinoids. The other cannabinoids present are THC at a concentration of less than or equal to 0.1% (w/w); CBD-C1 at a concentration of less than or equal to 0.15% (w/w); CBDV at a concentration of less than or equal to 0.8% (w/w); and CBD-C4 at a concentration of less than or equal to 0.4% (w/w).

[0069] The botanically derived purified CBD used additionally comprises a mixture of both trans-THC and cis-THC. It was found that the ratio of the trans-THC to cis-THC is altered and can be controlled by the processing and purification process, ranging from 3.3:1 (trans-THC:cis- THC) in its unrefined decarboxylated state to 0.8:1 (trans-THC:cis-THC) when highly purified. [0070] Furthermore, the cis-THC found in botanically derived purified CBD is present as a mixture of both the (+)-cis-THC and the (-)-cis-THC isoforms.

[0071] Clearly a CBD preparation could be produced synthetically by producing a composition with duplicate components.

[0072] Example 1 below describes the use of a botanically derived purified CBD in an open label, expanded-access program to investigate the clinical efficacy and safety of purified pharmaceutical cannabidiol formulation (CBD) in the treatment of Lissencephaly.

EXAMPLE 1: CLINICAL EFFICACY AND SAFETY OF PURIFIED PHARMACEUTICAL CANNABIDIOL (CBD) IN THE TREATMENT OF PATIENTS DIAGNOSED WITH LISSENCEPHALY

Study design [0073] Subjects were required to be on one or more AEDs at stable doses for a minimum of two weeks prior to baseline and to have stable vagus nerve stimulation (VNS) settings and ketogenic diet ratios for a minimum of four weeks prior to baseline.

[0074] Patients were administered botanically derived purified CBD in a 100 mg/ml_ sesame oil- based solution.

[0075] A maximum dose of 50 mg/kg/day could be utilised for patients who were tolerating the medication but had not achieved seizure control; these patients had further weekly titration by 5mg/kg/day.

[0076] There were 6 patients in this study, and each received CBD for at least 1 month. Modifications were made to concomitant AEDs as per clinical indication.

[0077] Seizure frequency, intensity, and duration were recorded by caregivers in a diary during a baseline period of at least 28 days. Changes in seizure frequency relative to baseline were calculated after at least 2 weeks and at defined timepoints of treatment.

Statistical Methods:

[0078] Patients may be defined as responders if they had more than 50% reduction in seizure frequency compared to baseline. The percent change in seizure frequency was calculated as follows:

% change= ((weekly seizure frequency time interval)-( weekly seizure frequency Baseline)) x100 seizure (weekly seizure frequency Baseline) frequency

[0079] The percent change of seizure frequency may be calculated for any time interval where seizure number has been recorded. For the purpose of this example the percent change of seizure frequency for the end of the treatment period was calculated as follows:

% reduction = ((weekly seizure frequency Baseline) - (weekly seizure frequency End)) x100 seizure frequency (weekly seizure frequency Baseline)

Results

Patient description [0080] The 6 patients enrolled in the open label, expanded-access program were diagnosed with Lissencephaly. These patients experienced several different seizure types including atonic, tonic, tonic-clonic, myoclonic, absence and focal seizures with impairment and were taking several concomitant AEDs. [0081] The age of patients ranged from 4-14 years, three were male and three were female as detailed in Table 1 below.

Table 1: Patient demographics and concomitant medication VPA = valproic acid, LEV = levetiracetam, CLB = clobazam, VGB = vigabatrin, ZNS = zonisamide, LCS = lacosamide, ZNS = zonisamide, PHB = phenobarbital, RFN = rufinamide

Study medication and concomitant medications

[0082] All five patients were given at least 5 mg/kg/day of CBD, four patients were titrated up to 25 mg/kg/day (#2, 3, 5, 6) and one patient was titrated up to 45 mg/kg/day (#6).

[0083] The average number of concomitant AEDs at the time of starting CBD was three per patient (range: 1-4, median: 3).

Clinical changes [0084] Tables 2A-F illustrate the seizure frequency for each patient as well as the dose of

CBD given.

Table 2A: Seizure frequency data for Patient 1

[0085] Patient 1 was treated for 4 weeks and experienced a 11.1% reduction in tonic-clonic seizures and a 75.0% reduction in myoclonic seizures over the treatment period. Table 2B: Seizure frequency data for Patient 2

[0086] Patient 2 was treated for 120 weeks and experienced a 91.7% reduction in tonic- clonic seizures and a 91.0% reduction in atonic seizures over the treatment period. Table 2C: Seizure frequency data for Patient 3

[0087] Patient 3 was treated for 144 weeks and experienced an 88.9% reduction in tonic- clonic seizures over the treatment period. Table 2D: Seizure frequency data for Patient 4

[0088] Patient 4 was treated for 24 weeks and experienced a 36.8% reduction in tonic seizures, a 61.5% reduction in tonic-clonic seizures, a 35.0% reduction in myoclonic seizures and a 5.2% reduction in absence seizures over the treatment period.

Table 2E: Seizure frequency data for Patient 5

[0089] Patient 5 was treated for 8 weeks and experienced a 71.4% reduction in tonic seizures and an 87.5% reduction in tonic-clonic seizures over the treatment period.

Table 2F: Seizure frequency data for Patient 6

[0090] Patient 6 was treated for 132 weeks and did not experience a reduction in seizures over the treatment period. [0091] Overall, patients reported an average reduction in seizure frequency of 60.0%. The median reduction in seizure frequency was 71.4% and one patient experienced a reduction of 91.7% in their seizure frequency (#2).

[0092] CBD was effective in reducing the frequency of the following seizure types: atonic, tonic, tonic-clonic, myoclonic and absence.

Conclusions

[0093] These data indicate that CBD was able to significantly reduce the number of seizures associated with Lissencephaly. Clearly the treatment is of significant benefit in this difficult to treat epilepsy syndrome given the high response rate experienced in all patients. [0094] In conclusion, this study signifies the use of CBD for treatment of seizures associated with Lissencephaly. Seizure types include atonic, tonic, tonic-clonic, myoclonic and absence. seizures for which seizure frequency rates decreased significantly, by up to 91.7%.

References

1. https://www.ninds.nih.gov/Disorders/All-Disorders/lissenceph alv-lnformation-Paqe

National Institute of Neurological Disorders and Stroke. Retrieved 2020-06-23

2. https://www.latimes.com/socal/glendale-news-press/news/tn-qn p-cannabis- compound-found-to-help-child-with-seizures-20141231-storv.ht ml “Cannabis compound found to help child with seizures.” (2014). LA Times

3. https://www.ksat.com/health/2019/05/16/local-familv-speaks-a bout-how-medical· cannabis-has-helped-their-son/ “Local family speaks about how medical cannabis has helped their son.” (2019).

4. Palmetto Harmony (2017) "Fighting Lissencephaly: Harmony's Story" https://palmettoharmony.com/blog/2017 /02/10/fighting-lissencephalyharmonys-story/

5. Salyer (2019) "Avery Lissencephaly Seizures & CBD ON" https://www.bexarcountypasociety.org/mwginternal/de5 fs23 hu 73 ds/progress?id=p4- kEe83 02bC8zo Y7QjRHy-7GcQviWdRAsXHRcYuUx4,&dl