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Nabilone in C.I.N.V.

Nabilone in C.I.N.V. August 2007. Introduction. Present a scientific validation for cannabinoids (CBs) asserting their therapeutic effects through Omnineuromodulation CBs activate CB1 endocannabinoid receptors, which are omnipresent throughout the Central Nervous System (CNS)

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Nabilone in C.I.N.V.

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  1. NabiloneinC.I.N.V. August 2007

  2. Introduction • Present a scientific validation for cannabinoids (CBs) asserting their therapeutic effects through Omnineuromodulation • CBs activate CB1 endocannabinoid receptors, which are omnipresent throughout the Central Nervous System (CNS) • Action on these receptors modulates neuronal signaling • Review evidence showing how omnineuromodulation underlies the therapeutic role of CBs in the management of Chemotherapy-Induced Nausea and Vomiting (CINV)

  3. The Ubiquitous CB1 • Endogenous CBs are a major class of neuromodulators, acting through receptors, CB1 and CB2 • CB1 receptors are primarily located on CNS neurons • Levels exceed those of nearly all neurotransmitter receptors • Exogenous CBs exert their effects by driving this innate system, often mimicking and enhancing its natural functions

  4. The Ubiquitous CB1 • The omnipresent central distribution of CB1, has led to the term, Omnineuromodulator,to describe CB action • Therapeutic effects are primarily due to agonist action in brain regions that mediate nausea/vomiting, appetite, and neuropathic pain

  5. Omnineuromodulation • Nabilone acts on presynaptic CB1 receptors, similar to endocannabinoids • Inhibits the release of excitatory (e.g., glutamate) and inhibitory (e.g., GABA) neurotransmitters • The primary effect on neuronal signaling appears to be inhibitory, but network effects may be complex and hence modulatory in nature • Endogenous CB1 ligands act “backwards” from classical neurotransmitters by serving as retrograde synaptic messengers

  6. A Sequential Overview of Omnineuromodulation

  7. Neurotransmitter (NT) released from vesicles within the presynaptic neuron activates the postsynaptic neuron

  8. Activation of the postsynaptic neuron leads to the biosynthesis and nonvesicular release of an endocannabinoid, likely via a calcium mediated process

  9. The endocannabinoid diffuses back to and binds to the presynaptic CB1 receptor

  10. The CB1 receptor activates a G protein which can lead to a number of presynaptic downstream events (e.g., effects on ion currents) that result in the inhibition of neurotransmitter release

  11. CB agents, acting as Omnineuromodulators, circumvent this multi-step process by directly activating CB1 receptors to stimulate the endogenous CB system, enhancing its function

  12. Summary of Actions of the Cannabinoids 5 Cannabinoid Therapy(nabilone) Neurotransmitter (NT) from presynaptic neuron activates the postsynaptic neuron. 1 Inhibition ofNeurotransmitterRelease Activated postsynaptic neuron releases endocannabinoids. 2 CB1 Receptor 4 PresynapticNeuron Endogenous CB1 ligand diffuses back to and binds to the presynaptic CB1 receptor. 3 1 Endogenous CannabinoidRetrograde Signaling 3 2 CB1 receptor activates a G-protein, leading to inhibition of NT release. 4 NeurotransmitterReceptor PostsynapticNeuron Nabilone is thought to activate CB1 receptors directly, mimicking the effects of endocannabinoids. 5 Endogenous and ExogenousCannabinoids Reduce Neuronal Signaling *see notes for references

  13. Anti-emetic, Anti-nausea Effects of Cannabinoids

  14. Causes of nausea and vomiting/emesis: Viral illness Cancer Chemotherapy Radiotherapy

  15. The Nucleus of the Solitary Tract (NTS) in the DVC receives information about: • Blood-borne emetics via the brainstem (BS) “Chemo-receptor Trigger Zone” • Abdominal irritants via vagal afferents • NTS neurons, in turn, project to a BS central pattern generator, which coordinates vomiting behavior Dorsal Vagal Complex (DVC) - NTS

  16. Cortex Limbic System Brainstem Emetic Circuitry Higher cortical and limbic regions(governing taste, smell, sight, pain, memory and emotion) can suppress or stimulate nausea/vomiting through descending connections to the BS emetic circuitry

  17. Cannabinoids are thought to exert their antiemetic effects primarily via action on CB1 receptors in the NTS and higher cortical and limbic regions • Indirect, partial actions on 5-HT and DA signaling via 5-HT3 and D2 receptors are implicated Cortex Limbic System Brainstem Emetic Circuitry Dorsal Vagal Complex - NTS

  18. Summary • CB agonists act as Omnineuromodulators—a term that describes their role in activating CB1 endocannabinoid receptors, which are omnipresent throughout the CNS and modulate neuronal signaling • Evidence shows that Omnineuromodulation underlies the therapeutic role of CB agents in the treatment of CINV, Cachexia, and Neuropathic Pain

  19. Approved License for the treatment of nausea and vomiting associated with cancer chemotherapy in patients who have failed to respond adequately to conventional anti-emetic treatments

  20. Nabilone delivers:1 • Convenient BID dosing: The usual adult dosage is 1 or 2 mg BID • Predictable pharmacokinetics: Peak plasma concentrations occur within 2 hours following oral administration • Long acting: 8 to 12 hour duration of action • Not detected by the EMIT test2 • In anti-emetic phase III studies, involving 316 cancer patients receiving a variety of chemotherapeutics (including cisplatin), nabilone was shown to be superior in efficacy to placebo, as well as to prochlorperazine, in:1 • Reduction of vomiting episodes • Reduction of nausea severity • Improvement in appetite • Investigators’ global impression of efficacy3 *see notes for references

  21. Nabilone Pivotal Studies

  22. Primary Endpoint: Patient-Rated Efficacy Criteria Placebo-Controlled, Fixed-Dose Trials Number of vomits Nausea severity: 0=none, 1=mild, 2=moderate, 3=severe Food intake: 0=none, 1=less than usual, 2=usual amount or average, 3=more than usual Data on File: Protocols 9, 20 and 28. Valeant Pharmaceuticals International.

  23. Active-Controlled, Fixed-Dose Trials Primary Endpoint: Patient-Rated Efficacy Criteria Number of vomits Nausea severity: 0=none, 1=mild, 2=moderate, 3=severe Food intake: 0=none, 1=less than usual, 2=usual amount or average, 3=more than usual Data on File: Protocols 9, 20 and 28. Valeant Pharmaceuticals International.

  24. Active-Controlled, Fixed-Dose Trials Primary Endpoint: Investigator-Rated Efficacy and Safety Efficacy: 1=very good, 2=good, 3=fair, 4=poor, 5=very poor Safety: Based on the frequency of adverse events Data on File: Protocols 9, 20 and 28. Valeant Pharmaceuticals International.

  25. Active-Controlled, Flexible-Dose Trial Primary Endpoint: Patient-Rated Efficacy Criteria Number of vomits Nausea severity: 0=none, 1=mild, 2=moderate, 3=severe Food intake: 0=none, 1=less than usual, 2=usual amount or average, 3=more than usual Data on File: Protocols 9, 20 and 28. Valeant Pharmaceuticals International.

  26. Patients Prefer Nabilone Active-Controlled, Fixed-Dose Trials Placebo-Controlled, Fixed-Dose Trials 73% 77% 20% 12% 12% 7% Preferred Nabilone Preferred Nabilone Preferred Prochlorperazine Preferred Placebo No Preference No Preference

  27. Summary: Nabilone and Reduction of Vomiting Frequency C I N V - Chemotherapy Induced Nausea and Vomiting

  28. Nabilone Reduces the Frequency of Vomiting Reduction in Frequency of Vomiting N=129 *P < 0.01 N=75 **P < 0.007 Prochlorperazine Placebo Nabilone Nabilone Data on File: Protocol #9, #20, and #28. Valeant Pharmaceuticals North America.

  29. Nabilone Significantly Reduces Vomiting Frequency Einhorn LH, et al. J Clin Pharmacol. 1981;21:64S-69S.

  30. Nabilone: Superior to Prochlorperazine in Patients with Severe CINV CR=complete response; PR=partial response Herman TS, et al. N Engl J Med. 1979;300:1295-1297.

  31. Summary: Nabilone and Reduction of Vomiting Frequency CINV is an established indication for Nabilone Clinical trials have confirmed the efficacy of Nabilone in reducing frequency of vomiting in cancer patients receiving chemotherapy Nabilone is an important addition to the physician’s armamentarium against the nausea and vomiting associated with chemotherapy in patients who have failed to respond adequately to conventional antiemetic therapy

  32. Nabilone: In reduction of Nausea C I N V - Chemotherapy Induced Nausea

  33. Control of Nausea Cannabinoids: A Systematic Review 30 randomized, comparative studies of cannabinoids with placebo or other antiemetics (oral Nabilone [nabilone]= 16 studies; oral dronabinol=11 studies; intramuscular levonatrodol=1 study) Active control= prochlorperazine, metoclopramide, chlorpromazine, haloperidol, domperidone, and alizapride Tramèr MR, et al. BMJ. 2001;323:1-8.

  34. Comparative Efficacy of Nabilone vs. Prochlorperazine N=129 *P < 0.001 N=75 **P < 0.007 *Based on patients’ report (daily average): 0=none; 1=mild; 2=moderate; 3=severe Data on File: Protocol #9, #20, and #28. Valeant Pharmaceuticals North America.

  35. Nabilone Significantly Reduces Nausea Severity Score: 0=none; 1=mild; 2=moderate; 3=severe Einhorn LH, et al. J Clin Pharmacol. 1981;21:64S-69S.

  36. Severity of Nausea Significantly Reduced with Nabilone Ahmedzai S, et al. Br J Cancer. 1983;48:657-663.

  37. Summary: Nausea Nausea is more difficult to control than is vomiting Control of nausea remains a significant unmet need in cancer patients receiving chemotherapy Nabilone has demonstrated efficacy in reducing the severity of nausea Patients prefer Nabilone over placebo and active controls (prochlorperazine, metoclopramide, chlorpromazine, thiethylperazine, haloperidol, domperidone, alzapride)

  38. Other benefits:Impact of Nabilone on Pain A Retrospective Chart Review Several reductions in acute pain exacerbations and nighttime pain Relief within 1 week of beginning Nabilone (n=1) Patients’ testimonial Taking Nabilone at night made pain more localized, and relief lasted until the following afternoon Nabilone made pain “livable” Nabilone “takes the edge off” Berlach DM, et al. Am Acad Pain Med. 2006;7:25-29.

  39. Other Benefits of Nabilone 3 patients continued to take Nabilone for benefits other than pain relief Improvement in quality or duration of sleep Decreased nausea or vomiting • Sleep improvements (n=1) • Decreased nausea & increased appetite (n=1) • Decreased nausea and vomiting and increased sleep (n=1) • 25% of patients • 50% of patients Berlach DM, et al. Am Acad Pain Med. 2006;7:25-29.

  40. Benefits of Cannabinoids in Cancer Patients: A Retrospective Case Study Methodology *Data on file

  41. Edmonton Symptom Assessment System (ESAS)

  42. Reasons for Cannabinoid Discontinuation • 12/17 (71%) due to side effects • Drowsiness • Dizziness • Delirium • 5/17 (29%) advised by other MDs • Discontinuation Rate: • Overall = 20.7% • Adjusted = 14.6%

  43. Differentiating Between the Cannabinoids: Pharmacokinetics NabiloneTM (nabilone) Package Insert. Valeant Pharmaceuticals North America; 2006. Marinol® (dronabinol) Package Insert. Solvay Pharmaceuticals, Inc.

  44. Cannabinoid Metabolism *Main metabolizing isoenzyme • Metabolized principally through the CYP450 2C9 isoenzyme • No inhibitory or inducing effect on any of the isoenzymes • Competes with very few medications at the metabolic level, including opioids • Examples of medications metabolized by CYP3A4: anti-fungals, methadone, many anti-depressants, HIV protease inhibitors Nabilone Nahas GG, Surim KM, Harvet DJ, Agurell S, eds. Marihuana and Medicine. Totowa, NJ: Human Press; 1999: 74-116. .

  45. Safety Overview of Cannabinoids Cannabinoids should not be taken with alcohol, sedatives, hypnotics, or other psychoticomimetic substances Ataxia Confusion Depersonalization Dizziness Euphoria Paranoid reaction Somnolence Thinking abnormal Nabilone (NabiloneTM) Package Insert; San Diego, Valeant Pharmaceuticals North America; 2006; Dronabinol (Marinol® ) Package Insert. Marietta, Ga: Solvay Pharmaceuticals, Inc.; 2003.

  46. Summary Treatment Challenges Clinical Trial Results Unique MOA of Cannabinoids • CINV—a highly prevalent side effect of cancer treatment • Persistent CINV is associated with several adverse sequelae • Pain is often under-diagnosed and under-treated • Target ubiquitous CB receptors in the CNS and periphery • CINV: agonism of CB1 receptors inhibits neurotransmitters • Pain: neuromodulatory effects involving both CB1 and CB2 receptors • Support the use of cannabinoids to treat refractory CINV • Suggest that cannabinoids may be useful adjunctive therapy for pain

  47. END SLIDE QUESTIONS?

  48. Adverse Events can be reported to the drug safety department at Valeant Pharmaceuticals at UKsafety@valeant.com

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