CANNABINOIDS IN THE TREATMENT OF EPILEPSY

Abstract

The present disclosure relates to the use of cannabidiol (CBD) in the treatment of absence seizures. In particular, the disclosure relates to the use of CBD for reducing absence seizures in patients suffering with etiologies that include: Lennox-Gastaut Syndrome; Tuberous Sclerosis Complex; Dravet Syndrome; Doose Syndrome; CDKL5; Dup15q;, Jeavons syndrome; Myoclonic Absence Epilepsy; Neuronal ceroid lipofuscinoses (NCL) and brain abnormalities. 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 absence seizures in a subject diagnosed with Lennox-Gastaut Syndrome, Myoclonic Absence Epilepsy, or Dravet Syndrome, comprising administering to the subject a drug product comprising a cannabidiol (CBD) drug substance, wherein the CBD is administered at a starting dose of about 5 mg/kg/day, and the starting dose is gradually increased by 2-5 mg/kg increments up to a maximum dose of 25 mg/kg/day, wherein the CBD drug substance has a purity of at least 98% (w/w) CBD and comprises no more than 0.15% (w/w) 9-tetrahydrocannabidiol.

2. The method according to claim 1, wherein the absence seizures are myoclonic absence seizures.

3. The method according to claim 1, wherein the epilepsy is treatment-resistant epilepsy (TRE).

4. The method according to claim 1, wherein the CBD is administered in combination with one or more concomitant anti-epileptic drugs (AED).

5. The method according to claim 1, wherein the subject is diagnosed with Lennox-Gastaut Syndrome.

6. The method according to claim 1, wherein the subject is diagnosed with Dravet Syndrome.

7. The method according to claim 1, wherein the subject is diagnosed with Myoclonic Absence Epilepsy.

8. The method according to claim 1, wherein the CBD is a highly purified extract of Cannabis.

9. The method according to claim 8, wherein the extract further comprises up to 1% CBDV.

10. The method according to claim 1, wherein the CBD is present as a synthetic compound.

11. The method according to claim 4, wherein the one or more concomitant AED is selected from the group consisting of: sodium valproate; lamotrigine; clobazam; and clonazepam.

12. The method according to claim 4, wherein the number of different concomitant anti-epileptic drugs that are used in combination with the CBD is reduced compared to the number of concomitant anti-epileptic drugs that are used prior to administering CBD.

13. The method according to claim 4, wherein the dose of the concomitant AED that are used in combination with the CBD is reduced.

14. The method according to claim 5, wherein the dose of CBD is increased to 10 mg/kg/day.

15. The method according to claim 5, wherein the dose of CBD is increased to 20 mg/kg/day.

16. The method according to claim 6, wherein the dose of CBD is increased to 10 mg/kg/day.

17. The method according to claim 6, wherein the dose of CBD is increased to 20 mg/kg/day.

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

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

20. The method according to claim 1, wherein the dose of CBD is increased by 5 mg/kg increments.

21. The method according to claim 5, wherein the dose of CBD is increased by 5 mg/kg increments.

22. The method according to claim 6, wherein the dose of CBD is increased by 5 mg/kg increments.

23. The method according to claim 1, wherein the drug product is an oral solution.

24. The method according to claim 23, wherein the oral solution comprises ethanol, a sweetener, fruit flavoring, and sesame oil.

25. The method according to claim 23, wherein the CBD is present in the oral solution at about 100 mg/mL.

Description

EXAMPLE 1

Efficacy of Cannabidiol Reducing Absence Seizures in Children and Young Adults With Intractable Epilepsy

Materials and Methods

[0107] Of 137 children and young adults with severe, childhood onset treatment-resistant epilepsy (TRE), forty-two suffered from epilepsy that was characterised by absence seizures. These subjects were tested with a highly purified extract of cannabidiol (CBD) obtained from a Cannabis plant. All subjects presented with absence type seizures, often in addition to other generalised and/or focal seizures. The participants in the study were part of an expanded access compassionate use program for CBD.

[0108] The epileptic syndromes that these patients suffered from were as follows: Lennox-Gastaut Syndrome; Myoclonic Absence Epilepsy; Tuberous Sclerosis Complex; Dravet Syndrome; Doose Syndrome; Jeavons Syndrome; CDKL5; Dup15q; Neuronal ceroid lipofuscinoses (NCL) and brain abnormalities.

[0109] Seizure types experienced by these patients included: tonic, clonic, tonic-clonic, myoclonic, atonic, absence, myoclonic-absence, focal seizures without impairment, focal seizures with impairment and focal seizures evolving to bilateral convulsive seizures.

[0110] All patients entered a baseline period of 4 weeks when parents/caregivers kept prospective seizure diaries, noting all countable seizure types.

[0111] 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.

[0112] 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.

[0113] 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 every 4 weeks of CBD therapy.

[0114] The patients on the study were all taking at least one concomitant AED. These included clobazam, clonazepam, clorazepate, desmethylclobazam, diazepam, ethosuximide, felbamate, gabapentin, ketogenic diet, lacosamide, lamotrigine, levetiracetam, lorazepam, midazolam, N-desmethylclobazam, nordiazepam, phenytoin, stiripentol, topiramate, trazodone, vagus nerve stimulation, valproic acid, vigabatrin, and zonisamide.

Results

[0115] Of the 42 children and young adult patients who received treatment with CBD, there were 28 patients who received treatment for at least 12 weeks of treatment all of whom suffered from absence type seizures.

[0116] A summary of the 50% responders, based on 12 weeks of treatment are summarized in Table 7 below.

TABLE-US-00007 TABLE 7 Summary of 50% responders after 12 weeks of treatment Absence seizures Total seizures (n = 28) (n = 137) >50% reduction in 64% (n = 18) 46% (n = 63) seizures <50% reduction in 36% (n = 10) 54% (n = 74) seizures

[0117] Table 7 shows that after 3 months of therapy, a remarkable 64% of patients had an equal to or greater than >50% reduction in absence seizures, these data infer that the CBD is very effective at reducing this type of seizure.

Conclusions

[0118] These data indicate that CBD significantly reduces the number of absence type seizures in a high proportion of patients that do not respond well to existing AED.

[0119] 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 two thirds of the patients (64%) benefitted from at least a fifty percent reduction in the number of absence seizures that they suffered from was remarkable.

EXAMPLE 2

Efficacy of Cannabidiol Reducing Myoclonic Absence Seizures in Children and Young Adults With Intractable Epilepsy

Materials and Methods

[0120] Of 137 children and young adults with severe, childhood onset treatment-resistant epilepsy (TRE), ten suffered from epilepsy that was characterised by myoclonic absence seizures. These subjects were tested with a highly purified extract of cannabidiol (CBD) obtained from a Cannabis plant. All subjects presented with myoclonic absence type seizures, often in addition to other generalised and/or focal seizures. The participants in the study were part of an expanded access compassionate use program for CBD.

[0121] The epileptic syndromes that these patients suffered from were as follows: Myoclonic Absence Epilepsy; Doose Syndrome; and epilepsy of unknown cause.

[0122] All patients entered a baseline period of 4 weeks when parents/caregivers kept prospective seizure diaries, noting all countable seizure types.

[0123] 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.

[0124] 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.

[0125] 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 every 4 weeks of CBD therapy.

[0126] The patients on the study were all taking at least one concomitant AED. These included clobazam, clonazepam, clorazepate, diazepam, ethosuximide, ketogenic diet, lacosamide, lamotrigine, levetiracetam, lorazepam, midazolam, and valproic acid.

Results

[0127] Of the 10 children and young adult patients who received treatment with CBD, there were 8 patients who received treatment for at least 12 weeks of treatment all of whom suffered from myoclonic absence type seizures.

[0128] A summary of the 50% responders, based on 12 weeks of treatment are summarized in Table 8 below.

TABLE-US-00008 TABLE 8 Summary of 50% responders after 12 weeks of treatment Myoclonic absence seizures Total seizures (n = 10) (n = 137) >50% reduction in 75% (n = 6) 46% (n = 63) seizures <50% reduction in 25% (n = 2) 54% (n = 74) seizures

[0129] Table 8 shows that after 3 months of therapy, a remarkable 75% of patients had an equal to or greater than >50% reduction in absence seizures, these data infer that the CBD is very effective at reducing this type of seizure.

Conclusions

[0130] These data indicate that CBD significantly reduces the number of myoclonic absence seizures in a high proportion of patients that do not respond well to existing AED.

[0131] 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 three quarters of the patients (75%) benefitted from at least a fifty percent reduction in the number of myoclonic absence seizures that they suffered from was remarkable.

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