Use of cannabinoids in the treatment of epilepsy

Abstract

The present disclosure relates to the use of cannabidiol (CBD) for the reduction of total convulsive seizure frequency in the treatment of “treatment-resistant epilepsy” (TRE). In particular, the disclosure relates to the use of CBD of treating TRE when the TRE is Dravet syndrome; myoclonic absence seizures or febrile infection related epilepsy syndrome (FIRES). The disclosure further relates to the use of CBD in combination with one or more anti-epileptic drugs (AEDs).

Claims

1. A method of treating seizures associated with a type of treatment-resistant epilepsy, which is Lennox-Gastaut syndrome or Dravet syndrome, in a patient in need thereof, comprising administering to the patient a pharmaceutical composition comprising a cannabidiol (CBD) drug substance and testing liver function, wherein the CBD drug substance comprises at least 98% w/w CBD, and wherein the CBD is administered at a starting dose of about 5 mg/kg/day, and then the dose is increased by increments of about 5 mg/kg.

2. The method of claim 1, wherein the dose of CBD is increased up to a maximum of about 25 mg/kg/day.

3. The method of claim 1, wherein the dose of CBD is increased to about 10 mg/kg/day.

4. The method of claim 1, wherein the dose of CBD is increased to about 20 mg/kg/day.

5. The method of claim 1, wherein the dose of CBD is increased to a dose ranging from about 10 mg/kg/day to about 20 mg/kg/day.

6. The method of claim 1, wherein the CBD is synthetic.

7. The method of claim 1, wherein the CBD drug substance comprises not more than 0.15% w/w Δ.sup.9THC.

8. The method of claim 1, wherein the CBD drug substance comprises not more than 0.15% w/w CBDA, not more than 1.0% w/w CBDV, not more than 0.15% w/w Δ9THC, and not more than 0.5% w/w CBD-C4.

9. The method of claim 1, wherein the administering treats convulsive seizures.

10. The method of claim 1, wherein the administering reduces seizure frequency.

11. The method of claim 1, wherein the administering reduces total convulsive seizure frequency by at least 50% compared to the number of convulsive seizures experienced during a baseline period before CBD was administered.

12. The method of claim 3, wherein the administering treats convulsive seizures.

13. The method of claim 3, wherein the administering reduces seizure frequency.

14. The method of claim 3, wherein the administering reduces convulsive seizure frequency by at least 50% compared to the number of convulsive seizures experienced during a baseline period before CBD was administered.

15. The method of claim 4, wherein the administering treats convulsive seizures.

16. The method of claim 4, wherein the administering reduces seizure frequency.

17. The method of claim 4, wherein the administering reduces convulsive seizure frequency by at least 50% compared to the number of convulsive seizures experienced during a baseline period before CBD was administered.

18. The method of claim 1, wherein the type of treatment-resistant epilepsy is Lennox-Gastaut syndrome, and the dose of the CBD is increased to about 10 mg/kg/day or about 20 mg/kg/day.

19. The method of claim 18, wherein the patient's convulsive seizure frequency is reduced by at least 50% compared to the number of convulsive seizures experienced during a baseline period before CBD was administered.

20. The method of claim 18, wherein the dose of the CBD is increased to about 10 mg/kg/day.

21. The method of claim 18, wherein the dose of the CBD is increased to about 20 mg/kg/day.

22. The method of claim 1, wherein the type of treatment-resistant epilepsy is Dravet syndrome, and the dose of the CBD is increased to about 10 mg/kg/day or about 20 mg/kg/day.

23. The method of claim 22, wherein the patient's convulsive seizure frequency is reduced by at least 50% compared to the number of convulsive seizures experienced during a baseline period before CBD was administered.

24. The method of claim 22, wherein the dose of the CBD is increased to about 10 mg/kg/day.

25. The method of claim 22, wherein the dose of the CBD is increased to about 20 mg/kg/day.

26. The method of claim 1, wherein the testing is performed at baseline.

27. The method of claim 1, wherein the testing is performed after administering the CBD drug substance.

28. The method of claim 27, wherein the testing is performed 4 weeks or 12 weeks after initiating treatment.

29. The method of claim 1, wherein the testing is performed at baseline and after administering the CBD drug substance.

30. The method of claim 29, wherein the testing is performed after 4 weeks or 12 weeks of treatment.

Description

DETAILED DESCRIPTION

(1) Preparation of Highly Purified CBD Extract

(2) The following describes the production of the highly-purified (>98% w/w) cannabidiol extract which has a known and constant composition which was used for the expanded access trials described in Examples below.

(3) 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 98% CBD.

(4) 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 (drug substance).

(5) 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.

(6) Both the botanical starting material and the botanical extract are controlled by specifications. The drug substance specification is described in Table 1 below.

(7) TABLE-US-00004 TABLE 1 CBD Specification Test Test Method Limits Appearance Visual Off-white/pale yellow crystals Identification A HPLC-UV Retention time of major peak corresponds to certified CBD Reference Standard Identification B GC-FID/MS Retention time and mass spectrum of major peak corresponds to certified CBD Reference Standard Identification C FT-IR Conforms to reference spectrum for certified CBD Reference Standard Identification D Melting Point 65-67° C. Identification E Specific Optical Conforms with certified CBD Rotation Reference Standard; −110° to −140° (in 95% ethanol) Total Purity Calculation ≥98.0% Chromatographic HPLC-UV ≥98.0% Purity 1 Chromatographic GC-FID/MS ≥98.0% Purity 2 Impurities (Other HPLC-UV NMT 0.15% w/w Cannabinoids): NMT 1.0% w/w CBDA NMT 0.15% w/w CBDV NMT 0.5% w/w Δ.sup.9 THC CBD-C4 Residual Solvents: GC NMT 0.5% w/w Alkane NMT 0.5% w/w Ethanol Residual Water Karl Fischer NMT 1.0% w/w NMT—Not more than

(8) The purity of the CBD drug substance achieved is greater than 98%. The possible impurities are related cannabinoids: CBDA, CBDV, CBD-C4 and THC.

(9) Distinct chemotypes of Cannabis sativa L. plant have been produced to maximize the output of the specific chemical constituents, the cannabinoids. One type of plant produces predominantly CBD. Only the (−)-trans isomer occurs naturally, furthermore during purification the stereochemistry of CBD is not affected.

(10) Production of the Intermediate

(11) An overview of the steps to produce a botanical extract, the intermediate, are as follows: 1. Growing 2. Decarboxylation 3. Extraction No. 1—using liquid CO.sub.2 4. Extraction No. 2—‘winterization’ using ethanol 5. Filtration 6. Evaporation

(12) High CBD chemovars were grown, harvested and dried 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 for up to 3 months prior to extraction.

(13) Decarboxylation of CBDA to CBD was carried out using a large Heraeus tray oven. The decarboxylation batch size in the Heraeus is approximately 15 Kg. Trays were placed in the oven and heated to 105° C.; the BRM took 96.25 minutes to reach 105° C. Held at 105° C. for 15 Minutes. Oven then set to 150° C.; the BRM took 75.7 minutes to reach 150° C.; BRM held at 150° C. for 130 Minutes. Total time in the oven was 380 Minutes, including 45 minutes cooling and 15 Minutes venting.

(14) Extraction No 1 was performed using liquid CO.sub.2 at 60 bar/10° C. to produce botanical drug substance (BDS) which was used for crystallisation to produce the test material.

(15) The crude CBD BDS was winterised in Extraction No 2 under standard conditions (2 volumes of ethanol at minus 20° C. for around 50 hours). The precipitated waxes were removed by filtration and the solvent evaporated using the rotary evaporator (water bath up to 60° C.) to yield the BDS.

(16) Production of the Drug Substance

(17) The manufacturing steps to produce the drug substance from the intermediate botanical extract are as follows: 1. Crystallization using C5-C12 straight chain or branched alkane 2. Filtration 3. Optional recrystallization from C5-C12 straight chain or branched alkane 4. Vacuum drying

(18) Intermediate botanical extract (12 kg) produced using the methodology above was dispersed in C5-C12 straight chain or branched alkane (9000 ml, 0.75 vols) in a 30 litre stainless steel vessel.

(19) The mixture was manually agitated to break up any lumps and the sealed container then placed in a freezer for approximately 48 hours.

(20) The crystals were isolated by vacuum filtration, washed with aliquots of cold C5-C12 straight chain or branched alkane (total 12000 ml), and dried under a vacuum of <10 mb at a temperature of 60° C. until dry before submitting the drug substance for analysis.

(21) The dried product was stored in a freezer at minus 20° C. in a pharmaceutical grade stainless steel container, with FDA food grade approved silicone seal and clamps.

(22) Examples 1 to 3 below describe the use of a highly purified Cannabis extract comprising cannabidiol (CBD). Cannabidiol is the most abundant non-psychoactive cannabinoid in the Cannabis plant. Previous studies in animals have demonstrated that CBD has anticonvulsant efficacy in multiple species and models.

(23) Example 1 describes data produced in an expanded access treatment program in children with TRE.

(24) Examples 2 to 4 demonstrates the efficacy of CBD in children with Dravet syndrome, myoclonic absence seizures and FIRES respectively.

Example 1: Efficacy of Cannabidiol in Children and Young Adults with Treatment-Resistant Epilepsy

(25) Materials and Methods

(26) Twenty-seven children and young adults with severe, childhood onset treatment-resistant epilepsy (TRE) were tested with a highly purified extract of cannabidiol (CBD) obtained from a Cannabis plant. The participants in the study were part of an expanded access compassionate use program for CBD.

(27) All patients entered a baseline period of 4 weeks when parents/caregivers kept prospective seizure diaries, noting all countable motor seizure types.

(28) The patients then received a highly purified CBD extract (greater than 98% CBD w/w) in sesame oil, of known and constant composition, at a dose of 5 mg/kg/day in addition to their baseline anti-epileptic drug (AED) regimen.

(29) The daily dose was gradually increased by 2 to 5 mg/kg increments until intolerance occurred or a maximum dose of 25 mg/kg/day was achieved.

(30) Patients were seen at regular intervals of 2-4 weeks. Laboratory testing for hematologic, liver, kidney function, and concomitant AED levels was performed at baseline, and after 4, 8 and 12 weeks of CBD therapy.

(31) Results

(32) There were 27 children and young adult patients who received at least 3 months of treatment all of whom suffered from treatment-resistant epilepsy.

(33) All patients were taking at least two concomitant anti-epileptic drugs. These included clobazam; levetiracetam; topiramate; stiripentol; phenobarbital; lacsamide; valproic acid; zonisamide. The average number of concomitant antiepileptic drugs being taken was 2.7. The majority took either clobazam and/or valproic acid.

(34) Co-treatment of CBD with clobazam was a significant predictor of a positive treatment response of greater than 50% responder rate. There was an odds ratio (OR) of 3.3 for total seizure reduction and of 1.9 for convulsive seizures. The OR evaluates whether the odds of a certain event or outcome is the same for two groups. Specifically, the OR measures the ratio of the odds that an event or result will occur to the odds of the event not happening. An OR greater than 1 signifies that patients treated with a combination of CBD with clobazam will have a better odds of having a positive reduction in seizures than if they were not taking this combination of medications.

(35) The median number of seizures that these patients suffered from before starting treatment was 30 seizures per month, with a range of 4 to 2,800 seizures per month being recorded.

(36) Efficacy results for the 27 patients are summarized in Table 2 below.

(37) TABLE-US-00005 TABLE 2 Changes in Seizure Frequency with CBD Therapy Month 3 All patients (n = 27) Responder rate (>50% reduction) [%] 13 [48%] Responder rate (>70% reduction) [%] 11 [41%] Responder rate (>90% reduction) [%]  6 [22%] Seizure free [%]  2 [7%]

(38) Table 2 shows that after 3 months of therapy, 48% of patients had an equal to or greater than >50% reduction in seizures.

(39) Remarkably, two of the patients, equating to 7%, were entirely free from seizures at the three month stage.

(40) None of the 27 subjects withdrew during the 3-month treatment period and adverse events were mild and well tolerated. Common adverse events included somnolence, fatigue, decreased appetite, increased appetite and diarrhoea.

(41) In five subjects their dose of clobazam was reduced due to its sedative effect.

Conclusions

(42) These preliminary results indicate that CBD significantly reduces the number of seizures in a high proportion of patients that do not respond well to existing AED. The cannabidiol was generally well-tolerated in doses up to 25 mg/kg/day.

(43) It was surprising that in this group of patients which are treatment-resistant such a high number were able to gain an effect. The fact that nearly half of the patients (48%) benefitted from at least a fifty percent reduction in the number of seizures that they suffered from was remarkable.

(44) Furthermore, nearly a quarter (22%) of patients whose seizures were not controlled with at least two anti-epileptic drugs, experienced a reduction of 90% of the number of seizures they were experiencing and 7% were completely seizure free at the end of the 3 month trial period.

(45) Even more remarkable were the results for some defined sub-sets of this generic group and these are set out on Examples 2 to 4 below.

Example 2: Efficacy of Cannabidiol in Children and Young Adults with Treatment Resistant Dravet Syndrome

(46) Materials and Methods

(47) Nine children and young adults with treatment-resistant Dravet syndrome were part of an expanded access compassionate use program for highly purified CBD extract as described in Example 1.

(48) Results

(49) All nine patients with Dravet syndrome were taking at least two concomitant anti-epileptic drugs. These were largely AED operating via GABA and included clobazam; levetiracetam; topiramate; stiripentol; phenobarbital; lacsamide; valproic acid; and zonisamide. The average number of concomitant antiepileptic drugs being taken was 2.7.

(50) The mean number of seizures that these patients suffered from before starting treatment was 35 seizures per month, with a range of 6 to 112 seizures per month recorded.

(51) Efficacy results for the 9 patients are summarized in Table 3 below.

(52) TABLE-US-00006 TABLE 3 Changes in Seizure Frequency with CBD Therapy in Dravet Syndrome patients All patients excluding Dravet All Dravet patients patients patients (n = 9) (n = 27) (n = 18) Responder rate (>50% reduction) 5 [56%] 13 [48%] 8 [44%] [%] Responder rate (>70% reduction) 4 [44%] 11 [41%] 7 [39%] [%] Responder rate (>90% reduction) 3 [33%]  6 [22%] 3 [17%] [%] Seizure free [%] 2 [22%]  2 [7%] 0

(53) Table 3 shows that after 3 months of therapy, 56% of patients had an equal to or greater than 50% reduction in seizures, a third had a 90% reduction and remarkably 22%, were entirely free from seizures at the three month stage.

(54) None of the 9 subjects withdrew during the 3-month treatment period and adverse events were mild and well tolerated. Common adverse events included somnolence, fatigue, decreased appetite, increased appetite and diarrhoea.

Conclusions

(55) These data demonstrate that in this sub-group of patients with treatment-resistant Dravet syndrome a surprisingly high number were able to gain a dramatic reduction in the number of seizures.

(56) Nearly a quarter (22%) of patients were entirely seizure free at the end of the 3 month trial period. This would not be expected in this group of patients who were taking a large number of different anti-epileptic medications and yet were still suffering from a large number of seizures per day.

Example 3: Efficacy of Cannabidiol in Children and Young Adults with Treatment Resistant Myoclonic Absence Seizures

(57) Materials and Methods

(58) Four children and young adults with treatment-resistant myoclonic absence seizures were part of an expanded access compassionate use program for highly purified CBD extract as described in Example 1.

(59) Results

(60) All four patients with myoclonic absence seizures were taking at least two concomitant anti-epileptic drugs. These were largely AED operating via GABA and included clobazam; levetiracetam; topiramate; stiripentol; phenobarbital; lacsamide; valproic acid; and zonisamide. The average number of concomitant antiepileptic drugs being taken was 27.

(61) Efficacy results for the four patients are summarized in Table 4 below.

(62) TABLE-US-00007 TABLE 4 Changes in Seizure Frequency with CBD Therapy in patients with myoclonic absence seizures (MAS) All patients MAS All excluding MAS patients patients patients (n = 4) (n = 27) (n = 23) Responder rate (>50% reduction) 2 [50%] 13 [48%] 11 [48%] [%] Responder rate (>70% reduction) 2 [50%] 11 [41%]  9 [39%] [%] Responder rate (>90% reduction) 1 [25%]  6 [22%]  5 [22%] [%] Seizure free [%] 0  2 [7%]  2 [9%]

(63) Table 4 shows that after 3 months of therapy, half of the patients had an equal to or greater than 50% reduction in seizures, one patient (25%) had a 90% reduction at the three month stage.

(64) None of the 4 subjects withdrew during the 3-month treatment period and adverse events were mild and well tolerated. Common adverse events included somnolence, fatigue, decreased appetite, increased appetite and diarrhoea.

Conclusions

(65) These data demonstrate that in this sub-group of patients with treatment-resistant MAS a surprisingly high number were able to gain a reduction in the number of seizures.

Example 4: Efficacy of Cannabidiol in Children with Treatment Resistant Febrile Infection Related Epilepy Syndrome (FIRES)

(66) Febrile Infection Related Epilepsy Syndrome (FIRES) is a catastrophic epileptic encephalopathy with an unidentified aetiology that comprises a small minority of all patients with refractory status epilepticus.

(67) This syndrome occurs in previously healthy children with 66-100% of survivors becoming developmentally disabled. The mortality rate is up to 30%. There is a critical need for new therapies to treat this condition.

(68) Materials and Methods

(69) Three patients with FIRES, with an age range of from 4 to 15 years, were treated with CBD under an expanded access program as described previously in Example 1.

(70) Safety laboratory studies, physical/neurological exams, 24 hour video/EEG and seizure types and frequencies were assessed at baseline and one month after starting CBD.

(71) A highly purified extract of CBD as an oral solution in sesame oil was used at a concentration of 25 mg/mL.

(72) Treatment was initiated at a dose of 10 mg/kg/day given in two divided doses, increasing by 5 mg/kg/day every 3 days.

(73) Following seizure improvement an average of 2 AEDs were weaned.

(74) Results

(75) Prior to initiation of treatment with highly purified CBD, the patients all suffered from refractory seizures or status epilepticus. These had been treated with anaesthetics including midazolam infusion, pentobarbital infusion, propofol infusion, and isofluorane infusion, additionally patients also were given steroids including lidocaine infusion, and methylprednisolone and other treatments including ketamine, fosphenytoin, thiamine, rituximab, cyclophosphamide, intravenous immunoglobulin, and a hypothermia protocol.

(76) At the time of initiation of CBD, the patients were taking between three and five anti-epileptic drugs including: levetiracetam, clobazam, perampanel, phenobarbital, phenytoin, carbamezapine, felbamate, ketogenic diet, lamotrigine, valproic acid and vagus nerve stimulation therapy.

(77) Baseline 24 hour EEG of seizures were recorded. The total seizures at baseline and during the treatment period are shown in Table 5. Patient 1 was shown to be seizure free after starting treatment for almost all of the treatment period, with the number of seizures being reduced from 7 to 0.3 over a 24 week period. Patient 2 had a 50% reduction in seizures after 4 weeks however the seizure frequency increased after a further 4 weeks then started to decrease again after 16 weeks of treatment. The most remarkable response was seen in Patient 3, who suffered from 5600 seizures at baseline. The number of seizures were dramatically reduced after 4 weeks and at week 24 this patient was still demonstrating a greater than 90% reduction in the number of seizures.

(78) The type of seizures that occurred in the three FIRES patients were all complex partial seizures (focal seizures with impairment). None of the FIRES patients suffered from focal seizures with secondary generalisation or convulsive seizures.

(79) TABLE-US-00008 TABLE 5 Total Seizure Data Change % Responder Responder Responder Frequency from Change from (> = 50% (> = 70% (> = 90% Seizure Visit (per month) Baseline Baseline Reduction) Reduction) Reduction) Free Patient 1 BL 4.0 n/a n/a n/a n/a n/a n/a Wk 4 0.0 −4.0 −100.0 Yes Yes Yes Yes Wk 8 1.0 −3.0 −75.0 Yes Yes No No Wk 12 0.0 −4.0 −100.0 Yes Yes Yes Yes Wk 16 0.0 −4.0 −100.0 Yes Yes Yes Yes Wk 24 0.3 −3.7 −92.0 Yes Yes Yes No Patient 2 BL 7.0 n/a n/a n/a n/a n/a n/a Wk 2 0.8 −6.2 −88.6 Yes Yes No No Wk 4 3.0 −4.0 −57.1 Yes No No No Wk 8 10.0 3.0 42.9 No No No No Wk 12 8.0 1.0 14.3 No No No No Wk 16 4.0 −3.0 −42.9 No No No No Patient 3 BL 5600.0 n/a n/a n/a n/a n/a n/a Wk 4 47.2 −5552.8 −99.2 Yes Yes Yes No Wk 8 9.2 −5590.8 −99.8 Yes Yes Yes No Wk 12 141.6 −5458.4 −97.5 Yes Yes Yes No Wk 24 542.0 −5058.0 −90.3 Yes Yes Yes No

(80) Follow up laboratory tests showed no changes in safety studies or concomitant AED levels. No treatment related adverse effects were observed.

Conclusions

(81) CBD treatment was very well tolerated and associated with a dramatic and nearly immediate greater than 90% improvement in clinical and electrographic seizure burden in two of the three children with refractory seizures or status epilepticus due to FIRES.

(82) After a reduction in seizures the patients were able to walk and verbalise once more.

Summary Table and Conclusions

(83) Table 6 below summarises the data obtained in the three sub-sets: Dravet syndrome; myoclonic absence seizures (MAS) and febrile infection related epilepsy syndrome (FIRES) after 12 weeks of treatment which have been described in the Examples 2 to 4 above. In addition the data for the remainder of the patients with other epilepsy syndromes are detailed. These data which exclude the patients with Dravet, MAS and FIRES show a far lower responder rate than for the specified sub-sets of the above specified sub-sets of epilepsy.

(84) In particular, the responder rate for patients obtaining a greater than 90% reduction in their seizures is reduced from 33% in Dravet patients to only 8% in the unspecified group. This suggests that patients suffering from a TRE of sub-type Dravet syndrome, myoclonic absence seizures or FIRES will respond better to treatment with highly purified CBD than patients with other epilepsy sub-types.

(85) TABLE-US-00009 TABLE 6 Changes in Seizure Frequency with CBD Therapy in patients with sub- type TRE and all patients excluding the sub-types. All patients (excluding Dravet, MAS Dravet MAS FIRES and FIRES) patients patients patients (n = 13) (n = 9) (n = 4) (n = 3) Responder rate (>50% 5 [38%] 5 [56%] 2 [50%] 2 [67%] reduction) [%] Responder rate (>70% 4 [31%] 4 [44%] 2 [50%] 2 [67%] reduction) [%] Responder rate (>90% 1 [8%] 3 [33%] 1 [25%] 2 [67%] reduction) [%] Seizure free [%] 0 2 [22%] 0 1 [33%]

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