CogniCann for dementia: A second pharmaceutical candidate
MGC has announced plans to conduct a Phase II clinical trial of CogniCann in patients with mild dementia and Alzheimer’s disease (AD). CogniCann is MGC’s GMP-certified medical cannabis pharmaceutical product, which has been specifically formulated for the treatment of key dementia symptoms and improving specific cognitive functions. Each 10m bottle of CogniCann contains 250mg THC and 170mg CBD. The trial leverages IP secured through the company’s Medical Advisory Board, led by Professor Uri Kramer, which is based on experience gained through the use of medicinal cannabis products in Israel.
Ethics approval has been received to conduct the study in partnership with the Institute for Health Research at the University of Notre Dame in Western Australia. The trial, which will recruit a total of 50 subjects aged 65 years and older, is expected to commence in early 2019, subject to TGA approval. The 16-week trial will use a randomised, double blind, crossover, placebo-control design to evaluate behavioural changes, quality of life, level of discomfort and pain in dementia patients living in residential aged care facilities (Exhibit 3).
CogniCann’s impact on dementia symptoms will be assessed by validated questionnaires such as the Mini-Mental State Examination (MMSE), Neuropsychiatric Inventory (NPI), Cohen-Mansfield Agitation Inventory, Quality of Life – Alzheimer’s Disease (QoL-AD) and the Abbey Pain Scale.
Exhibit 3: Trial design for the CogniCann Phase II in dementia patients
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Source: MGC Pharmaceuticals announcement. Note: *Adverse events (AE) will be recorded with each dose in the titration phase and on the last dose of the intervention phase.
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Medicinal cannabis and dementia
Cannabis targets a system in the brain known as the endocannabinoid system, which comprises receptors called CB1 and CB2. The endocannabinoid system is involved in memory, appetite regulation and response to stress. Memory loss is a key feature of AD, and agitation and aggression are commonly observed symptoms in AD and other forms of dementia. This has prompted a number of investigators to explore the potential for cannabis and cannabinoids to ameliorate dementia symptoms.
Preclinical studies show potential efficacy of cannabinoids in AD
Several studies in cell culture and animal models have shown that cannabinoids can reduce oxidative stress, neural inflammation, and the formation of amyloid plaques and neurofibrillary tangles, the key hallmarks of AD. Some studies have shown that cannabinoids appear to remove the amyloid plaques that are a hallmark of AD from nerve cells grown in the lab. A study in an animal model of AD found that a combination of THC and CBD preserved memory, reduced learning impairment and decreased levels of soluble beta amyloid1-42, a key component of amyloid plaques found in the brains of patients with AD. Some researchers believe that targeting the CB2 receptor (eg with CBD) could control the activity of microglia cells, preventing the potentially harmful overactivation of the immune system in the brain seen in AD.
Clinical studies in dementia have focused on THC monotherapy, with mixed results
Most clinical studies of cannabinoids in dementia have focused on THC monotherapy, rather than THC/CBD combinations like CogniCann. A scientific review published in 2015 identified four small studies, all using THC monotherapy, in a total of 60 dementia patients suffering from behavioural disturbances. While the studies were either not randomised or included a limited number of participants, they observed reduced levels of disturbed behaviour and agitation in THC-treated patients (Ahmed et al 2015). However, a subsequent 60-patient randomised study (van den Elsen et al 2015, clinicaltrials.gov identifier NCT01608217) found that there was no benefit of low-dose oral THC in dementia-related neuropsychiatric symptoms such as agitation and aggression, or in quality of life.
In contrast to the negative findings from the van den Elsen study, in July 2018 the synthetic cannabinoid nabilone (Cesamet, Mylan/Meda Pharmaceuticals) successfully met its primary endpoint of reducing agitation and aggression in a randomised 39-patient Phase II/III study in AD patients (NCT02351882). Nabilone is a synthetic cannabinoid analogue of THC that causes minimal euphoria. In addition to meeting the primary endpoint of improving agitation as measured by the Cohen-Mansfield Agitation Inventory, nabilone also improved quality of life, cognition and overall neuropsychiatric symptoms. Although the treatment was well tolerated, there was an increase in sedation (drowsiness/sleepiness, 45% on nabilone vs 16% on placebo).
Despite the fact that the results of the investigator-sponsored Phase II/III study of nabilone are positive, larger trials and replication would be needed to make recommendations that would change clinical practice. Nabilone is currently approved in the US and certain European countries for the treatment of chemotherapy-related nausea and vomiting. The study was sponsored by the Sunnybrook Research Institute in Canada, and we could not find any evidence that Mylan plans to conduct a confirmatory study of nabilone in dementia.
In addition to the completed trials above, our search of clinicaltrials.gov identified two ongoing studies of cannabis or cannabinoids in dementia. The first was a 60-patient randomised Phase II study in dementia-related agitation and aggression (NCT03328676). This study, which is being conducted by TO Pharmaceuticals, a subsidiary of Tikun Olam, is investigating the effect of Avidekel, a low THC cannabis oil (THC:CBD 1:20). The study commenced in December 2017 and is expected to complete in November 2019.
The second study is an investigator-sponsored, 160-patient Phase II pilot study of dronabinol for the treatment of agitation in AD (NCT02792257). The trial, which commenced in March 2017, is expected to report top-line results in August 2020. Dronabinol (Marinol, AbbVie), a synthetic oral formulation of THC, is FDA-approved for anorexia/weight loss in AIDS and for nausea/vomiting associated with chemotherapy.
The successful nabilone study and the ongoing studies of dronabinol and Avidekel raise the possibility that CogniCann could face competition from an established cannabinoid-based therapy for dementia-related AD symptoms by the time MGC generates efficacy data for CogniCann for this indication.
The Alzheimer’s disease and dementia market
A recent meta-analysis found that the prevalence of dementia worldwide for people aged 60 years or older ranged from 5-7%; the prevalence in the US was 6.5% while in Western Europe it was 7.3%. Dementia is estimated to affect 50 million people worldwide currently, with the number expected to triple to 152 million by 2050. About two-thirds of dementia patients have AD; other common dementia syndromes include vascular dementia, mixed dementia, Lewy body dementia or frontotemporal degeneration.
Over 90% of people with dementia experience at least one neuropsychiatric symptom over the course of their disease. Agitation, psychosis and mood disorders are the three main neuropsychiatric syndromes of dementia. Agitation (including aggression and non-aggressive agitation) occur in 20% of people with AD living in the community and in 40-60% of individuals with dementia living in care facilities.
As we do not have data on the proportion of dementia patients living in care facilities, we conservatively assume that the addressable market of patients with agitation or other neuropsychiatric symptoms that are not adequately controlled by non-pharmacological interventions represents 10% of dementia patients. This represents 550,000 patients in North America, 950,000 patients in Central and Western Europe and 40,000 patients in Australia.
The market research group EvaluatePharma estimated that the market for AD drugs was valued at ~US$2.4bn in 2018 and forecasts it to grow to US$5.7bn by 2024. The approved AD drugs fall into two drug classes. Cholinesterase inhibitors, such as donepezil, galantamine and rivastigmine, slow down the breakdown of the neurotransmitter acetyl choline, which is involved in memory and judgement. Memantine helps control a different brain chemical needed for learning and memory. Namzaric is a combination of memantine and donezepil. These drugs have been shown to improve cognition and behaviour in people with AD, but do not slow down disease progression.