Development of anti-epileptic cannabinoids: from discovery to the clinic
Submitting Institution
University of ReadingUnit of Assessment
Allied Health Professions, Dentistry, Nursing and PharmacySummary Impact Type
HealthResearch Subject Area(s)
Medical and Health Sciences: Neurosciences, Pharmacology and Pharmaceutical Sciences
Summary of the impact
Epilepsy, a condition that affects ca. 1% of the world's population, has
severe clinical consequences; people with epilepsy (PWE) and poorly
controlled seizures exhibit nearly an order of magnitude increase in
premature death relative to the general population. About one-third of PWE
do not benefit from treatment with currently approved medicines. Although
historical evidence has suggested that cannabis might be useful in the
control of epilepsy, work initiated by Drs Ben Whalley and Gary Stephens
at University of Reading revealed that non-psychoactive components of
cannabis can control epileptic seizures in animal models. This finding has
led to a funded collaboration of ca £1.4M with GW Pharmaceuticals (UK) and
Otsuka Pharmaceuticals (Japan) to establish a case for translation of two
such components, cannabidiol (CBD) and cannabidavarin (CBDV), to human
clinical drug trials. In particular, Reading research has resulted in GW
trialling CBD (Phase 2, 50 participants, design stage) for a new
indication of epilepsy treatment. A Phase 1 trial for CBDV (20
participants) began in July 2013, with a Phase 2 trial to begin
immediately after successful completion of Phase 1. Results from the use
of CBD on an open-label basis have shown major quality-of-life
improvements for the patients concerned.
Underpinning research
Evidence of the effects of cannabis in PWE remains contradictory, with
both anticonvulsant and pro-convulsant effects being reported. The
psychoactive component of cannabis, Δ9-THC, causes cognitive
decline and can induce seizures in vivo in healthy animals. These
adverse effects mean that the use of Δ9-THC itself as an epilepsy treatment
remains undesirable.
In 2000, Whalley independently initiated experiments investigating the
anti-epileptiform (`anti-epilepsy-like') effects of non-psychoactive
(i.e. non-Δ9-THC) constituents of cannabis[1,2]. In
2005, he continued to investigate the effects of isolated components of
cannabis in hyperexcitability model systems under an agreement with GW
Pharmaceuticals[3], the only company to have successfully
developed non-synthetic cannabis-based medicines (e.g. Sativex in 1999)
for clinical use. From 2007 onwards, Whalley and Stephens received funding
from GW Pharmaceuticals (UK) and their central nervous system
drug-discovery partner, Otsuka Pharmaceuticals, to conduct the necessary
preclinical research to establish if any plant cannabinoids represented a
legitimate candidate for clinical anti-epileptic drug development. This
funding, (ca £1.4M to date), has been both continuous and increasing to
the present day.
During this time, Whalley and Stephens studied several pure cannabinoids
and identified five that exert notable anti-epileptiform effects in
isolated acute sections of live rodent brain in which epilepsy-like
activity had been induced[4,5,6,7]. Of these five, they showed
that two (CBD and CBDV) have significant anticonvulsant effects in several
whole-animal models of acute generalised (pentylenetetrazole, maximal
electroshock and DBA/2 audiogenic), temporal lobe (pilocarpine), partial
(penicillin) and status epilepticus-induced spontaneous recurrent
seizures[4,5,6,8]. The magnitude of the effects and the doses
used were comparable to those of the positive controls used (i.e.
clinically-used effective anticonvulsants such as sodium valproate,
ethosuximide and phenobarbital) [4,5,6,8]. Moreover,
neurotoxicity testing of both CBD and CBDV established that the observed
anticonvulsant effects did not arise from sedation or toxicity induced by
CBD or CBDV[4,5,6,8] . Furthermore, neither CBD nor CBDV
induce any serious adverse effects in these tests in animal models, even
at the highest anticonvulsant doses; a finding in direct contrast to all
three positive controls (see above) tested at anticonvulsant doses in
animal models, which caused notable, diverse and undesirable adverse
effects[4,5,6,8]. Whalley and Stephens have also shown that
long-term (3 months) CBDV treatment continues to exert anti-epileptic
effects without adverse effects upon cognition or motor function in rats.
The use of CBD and CBDV for the treatment of epilepsy is covered by
several patents owned by GW and Otsuka upon which Whalley and Stephens
both appear as named inventors.
Whalley and Stephens have established their expertise in this area during
the past ~10 years and their publication track record demonstrates that
their expertise was initiated and established independently of the
programme's commercial sponsors (Whalley 37 peer-reviewed publications and
h-index=9, Stephens 51 peer-reviewed publications and h-index=20). Whalley
has also authored the American Herbal Pharmacopeia's monograph on cannabis
and epilepsy, demonstrating his established expertise and reputation. The
researchers were approached to collaborate in this work on the basis of
this established track record in cannabinoid and/or epilepsy research and
have dominated this research area during the past 10 years; they are the
only group actively and persistently investigating the anti-epileptic
potential of individual plant cannabinoids with a clear clinical strategy
in place. This research is a fundamental prerequisite for successful
translation to the clinic. Dr Whalley joined the University of Reading in
2005 as a Lecturer in Pharmacy Practice and is currently a Senior Lecturer
in Pharmacology. Dr Stephens joined the University of Reading in 2005 as
Lecturer in Pharmacology and is currently a Reader in Pharmacology.
References to the research
All outputs have been published in high quality peer reviewed journals
and have been internally assessed as of at least 2* quality.
1. Whalley BJ et al. A novel component of cannabis extract
potentiates excitatory synaptic transmission in rat olfactory cortex in
vitro. Neurosci. Lett. 365, 58-63 (2004). [IF=2.1]
2. Wilkinson, JD et al. Medicinal Cannabis: is Δ9-tetrahydrocannabinol
necessary for all its effects? J. Pharm. Pharmacol. 55: 1687-1694
(2003)
3. Ma Y-L et al.The phytocannabinoid Δ9-tetrahydrocannabivarin
modulates inhibitory neurotransmission in the cerebellum. Brit. J.
Pharmacol. 154, 204-215 (2008). doi: 10.1038/bjp.2008.57.
[IF = 5.1, REF submission]
4. Hill AJ et al. Cannabidivarin is anticonvulsant in mouse and
rat in vitro and in seizure models Br. J. Pharmacol. 167,
1629-1642 (2012). doi: 10.1111/j.1476-5381.2012.02207.x. [IF = 5.1, REF
submission]
5. Jones NA et al. Cannabidiol displays anti-epileptiform and
anti-seizure properties in vitro and in vivo. J. Pharmacol.
Exp. Ther. 332, 569-577 (2012). doi:
10.1124/jpet.109.159145. [IF=3.9, REF submission]
6. Hill TD et al. Cannabidivarin-rich cannabis extracts are
anticonvulsant in mouse and rat via a CB1 receptor-independent mechanism.
Br. J. Pharmacol. (2013) doi: 10.1111/bph.12321. [IF = 5.1, REF
submission]
7. Hill, AJ et al. Δ9-tetrahydrocannabivarin
suppresses in vitro epileptiform and in vivo seizure activity in adult
rat. Epilepsia 51(8) 1522-1532 (2010)
8. Jones, NA et al. Cannabidiol exerts anti-convulsant effects in
animal models of temporal lobe and partial seizures Seizure
21(5):344-52.(2012)
Details of the impact
Premature mortality is 2-3 times higher in PWE than the general
population, rising to 9 times higher in people with uncontrolled or poorly
controlled epilepsy. Up to 50% of PWE who gain control of their seizures
using current medication (and ~35% do not) will lose this control during
the course of their lives as a result of changes in the brain caused by
the seizures. All existing anti-epileptic medicines cause notable
cognitive, motor and teratogenic adverse effects at therapeutically
effective doses. As such, there is a substantial unmet clinical need
within the ~50 million PWE worldwide for new, effective and well-tolerated
drug treatments. Our extensive preclinical research findings that show CBD
and CBDV are well-tolerated and exert significant anti-epileptiform,
anti-seizure and anti-epileptic effects in animal models has directly
triggered the translation of this research into human clinical trials.
Translation to clinical trials: changes to industrial activities
With only ~1 in 1,000 new drug entities reaching the Phase 1 clinical
trial stage, our development of two novel anti-epileptic drugs to
this point is highly significant. Phase 1 trials alone, which help
determine a drug's safe dosage range, pharmacokinetics and safety profile
in healthy human volunteers take ~1 year to complete and cost on average
>£1 million, and so represent a notable investment by the
pharmaceutical industry on the basis of research conducted by University
of Reading academics [a]. In addition to this investment,
GW Pharmaceuticals now own patents on which Whalley and Stephens are
named as inventors [b].
Phase 1 trials on CBD were originally carried out by GW Pharmaceuticals
in the context of treating multiple sclerosis. On the basis of the Reading
research with CBD in the context of treating epilepsy, GW Pharmaceuticals
has now invested in a Phase 2 clinical trial of CBD for this new
indication [c,d] This Phase 2 study, which is currently in its
design stage, will include 50 participants and will evaluate the efficacy
of the drug in the treatment of epilepsy.
This change in activity for GW Pharmaceuticals represents a
significant impact which, having been made, commits GW to a substantial
financial and organisational commitment.
Similarly, it is on the basis of original research carried out with CBDV
at Reading that GW Pharmaceuticals began a Phase 1 trial for CBDV in July
2013 (20 participants) [c,e].
Again, this change in activity for GW Pharmaceuticals represents
a significant impact; an indication of the commitment of the company to
this compound is that a Phase 2 trial will immediately follow upon
successful completion of Phase 1.
New drugs with good efficacy in drug-resistant epilepsy will markedly
reduce the number of treatment-resistant patients and offer improved
tolerability with fewer adverse effects. Taking into account the number of
PWE worldwide, a conservative estimate suggests that millions of lives
will be affected positively if these new treatments progress onwards to
market.
Use in the community: reduction in seizures, benefits to the health of
individuals
In addition to our research findings having the necessary significance to
justify two separate clinical trials, CBD is also already being used now
in the treatment of drug-resistant paediatric epilepsy, where an immediate
and highly significant clinical impact has been demonstrated [f].
The prognosis for children with epilepsies of this type is extremely poor;
they experience dozens of seizures each day, have cognitive disability
before school age, are generally confined to a wheelchair before secondary
school age and around 30% die before reaching adulthood. Two children in
the US with drug-resistant epilepsy are now receiving CBD on an
open-label, named patient basis and this programme has recently been
further expanded [d]. Initial results of a survey of a 19
paediatric patients with epilepsy taking CBD have now been published: 13
of 19 children had marked improvements in seizure control with the
majority showing an 80% reduction in seizure frequency[f]. The
individual impact upon one of the children receiving CBD from GW
Pharmaceuticals is powerfully illustrated by a message from received from
his mother [g] stating:
"He had had sixty eight seizures the day before he started CBD. The
day he rode the zip line he had just five, each about 10 seconds long.
Days later he was down to three and then to one. The day we flew home he
had none. So thank you -- for giving my 11 year old the chance to ride
the zip line just like any other kid; for making it possible for us to
have fun....and for giving our family some badly-needed hope after
battling epilepsy for the last seven and a half years"
Changes in public awareness of, and perceptions of, cannabinoid usage[h]
Our work has now been featured in The Sunday Telegraph, on BBC
local and national television and radio, in Epilepsy Review Magazine
(a public magazine of the Epilepsy Society), as a featured
interview with Whalley on Epilepsy Action Radio during National
Epilepsy Week 2011, The Washington Post, NBC News and Sky News.
The work also attracted >400 attendees to Dr Whalley's public lecture
entitled "Cannabis: drug of abuse or medicinal use?" at the
University of Reading, UK, in October 2008. The work has also generated
numerous invited presentations for Drs Whalley and Stephens, including the
Comprehensive Epilepsy Centre, Langone School of Medicine and New York
University (2013, USA), and the Joint Spanish-Italian Meeting on
Cannabinoid Research (SEIC/IRES), Madrid (2012).
In an area where there is a vast amount of purely anecdotal and
pseudoscientific information in circulation, particularly on individual
web sites and weblogs, this extensive media coverage has made a
significant contribution towards bringing rigorous, peer-reviewed
cannabinoid science to the attention of the public.
Sources to corroborate the impact
a) Contracts held by the university funding underpinning research
(>£1.4M since 2007) 01/2012-01/2013 GW Pharmaceuticals (£100,000)
Anticonvulsant potential of phytocannabinoids (project expansion) ;
08/2010-07/2013 GW Pharmaceuticals (~£976,722) Anticonvulsant potential of
phytocannabinoids (programme extension); 08/2009-08/2010 GW
Pharmaceuticals (£140,000) Anticonvulsant potential of phytocannabinoids
(project expansion); 09/2007-2010 GW Pharmaceuticals (£353,000) (†)
b) Patents owned by GW Pharmaceuticals and on which Whalley and
Stephens are named as inventors: PCT/GB2010/051066 "Use of one or
combination of phytocannabinoids in the treatment of epilepsy"
(http://bit.ly/1g6wOB1) ; PCT/GB2011/050649 "Use of cannabidivarin in the
treatment of epilepsy" (http://bit.ly/1eZb07q) ; PCT/GB2012/050002 "Use of
the phytocannabinoid CBD with standard anti-epileptic drugs (SAEDs) in the
treatment of epilepsy" (http://bit.ly/1cmhLT7) ; PCT/GB2012/052284 "A
pharmaceutical composition comprising the phytocannabinoids cannabidivarin
(CBDV) and cannabidiol (CBD)" (http://bit.ly/17rG8uJ
)
c) Confirmation from GW Pharmaceuticals of the origins of the
research are available from the Chairman of GW Pharmaceuticals (*)
d) Availability of CBD (`Epidiolex') on a named patient basis http://bit.ly/1a9KCT2
e) Confirmation of Phase 1 clinical trial http://www.gwpharm.com/Phase1Epilepsy.aspx
f) Porter, BE and Jacobson, C. Report of a parent survey of
cannabidiol-enriched cannabis use in pediatric treatment-resistant
epilepsy. Epilepsy & Behavior. (2013). Advance online article
doi:10.1016/j.yebeh.2013.08.037
g) Internal GW email, containing an account from the mother of the
child receiving CBD (†)
h) Sample of popular news articles regarding research Compound in
cannabis may help treat epilepsy, researchers say, Los Angeles Times
(14th Sept 2012, http://tinyurl.com/nezebum);
Cannabis anti-convulsant shakes up epilepsy treatment, New Scientist
(12th Sept 2012, http://tinyurl.com/pcdthnd);
Ben Whalley speaks to Canada's biggest talk radio station (Newstalk
1010, 06:15 15th Sept 2012); Cannabis could be used to treat
epilepsy, Daily Telegraph (10th April 2011, http://tinyurl.com/3ltdb8d)
(†) Available upon request
(*) Contact details provided separately as per guidance