- Achieved primary efficacy measure with both
EPIDIOLEX doses as compared to placebo -
GW Pharmaceuticals plc and its U.S. subsidiary Greenwich
Biosciences Inc. (NASDAQ: GWPH, GW, the Company or the Group), the
world leader in the science, development, and commercialization of
cannabinoid prescription medicines, today announced positive
top-line results of a randomized, double-blind, placebo-controlled
Phase 3 clinical trial of EPIDIOLEX® (cannabidiol or CBD) CV in the
treatment of seizures associated with Tuberous Sclerosis Complex
(TSC), a rare and severe form of childhood-onset epilepsy. In this
trial, EPIDIOLEX met its primary endpoint, which was the reduction
in seizure frequency compared to baseline of the Epidiolex 25
mg/kg/day dose group vs placebo (p=0.0009). Results for both
the 25 and 50 mg/kg/day dose groups were similar, with seizure
reductions of 48.6% and 47.5% from baseline respectively, vs 26.5%
for placebo (50 mg/kg/day vs placebo, p=0.0018). All key secondary
endpoints were supportive of the effects on the primary endpoint.
The safety profile observed is consistent with findings from
previous studies, with no new safety risks identified.
“The positive outcome in this trial of EPIDIOLEX
in patients with Tuberous Sclerosis Complex expands both our
knowledge of this newly available medicine and its potential
utility beyond the current indications,” stated Elizabeth Thiele,
M.D., Ph.D., Director of the Herscot Center for Tuberous Sclerosis
Complex at Massachusetts General Hospital, Professor of Neurology
at Harvard Medical School and the lead investigator of the trial.
“Data from previous controlled clinical trials of EPIDIOLEX have
shown clinically meaningful seizure reductions and consistent
safety and tolerability in children and adults with Lennox-Gastaut
syndrome and Dravet syndrome. Based on the positive results of this
trial in TSC patients, EPIDIOLEX, if approved for this additional
indication, may become an important treatment option also in this
disease state with significant unmet medical need.”
“The positive results from this trial represent
the fifth positive Phase 3 trial for EPIDIOLEX and follows the
recent U.S. launch of EPIDIOLEX for the treatment of seizures
associated with Lennox-Gastaut syndrome and Dravet syndrome. These
new data show EPIDIOLEX reduced TSC-associated seizures, which
include both focal and generalized seizures types, expanding the
body of reliable science supporting the use of EPIDIOLEX,” stated
Justin Gover, GW’s CEO. “With these data, we look forward to
submitting an sNDA to the FDA in the fourth quarter with the goal
of expanding the product label in 2020 to help the lives of
patients suffering with TSC.”
“Some of the most challenging and frustrating
aspects of tuberous sclerosis complex (TSC) are seizures that
cannot be effectively controlled by existing medications,”
explained Kari Luther Rosbeck, President and CEO of the Tuberous
Sclerosis Alliance, “A new safe and effective treatment option such
as Epidiolex is desperately needed. Further, we are grateful
to GW, the researchers and the members of the TSC community who
participated in this clinical trial. We are truly excited
about the potential approval of Epidiolex to treat seizures in TSC
as it brings much needed hope to those with TSC and their families
who live daily with this difficult disorder.”
Trial Overview and Results
Patients aged 1-65 years with a confirmed
diagnosis of treatment-resistant TSC were eligible to participate
in this Phase 3, randomized double-blind placebo-controlled trial.
The trial randomized 224 patients into three arms, where EPIDIOLEX
25 mg/kg/day (n=75), EPIDIOLEX 50 mg/kg/day (n=73) or placebo
(n=76) was added to current anti-epileptic drug (AED) treatment.
The average age of trial participants was 14 years (range
1-57). On average, patients were taking 3 AEDs, having previously
tried and discontinued 4 other AEDs. The most common concomitant
AEDs in this trial were valproic acid (45 percent), vigabatrin (33
percent), levetiracetam (29 percent), and clobazam (27
percent).
TSC associated seizures, as measured in the
primary endpoint of this trial, differ from previous Epidiolex
clinical trials in LGS and Dravet syndrome. These seizure types
comprise focal motor seizures without impairment of consciousness
or awareness; focal seizures with impairment of consciousness or
awareness; focal seizures evolving to bilateral generalized
convulsive seizures; and generalized seizures (tonic–clonic, tonic,
clonic, or atonic) that are countable. The median baseline seizure
frequency of the TSC associated seizure types was 57 per month.
The primary endpoint of the study was the change
in seizure frequency over the 16-week treatment period (4-week
titration followed by 12-week maintenance at the target dose)
compared to baseline for the 25 mg/kg/day EPIDIOLEX arm vs placebo.
The results for both the 25 and 50 mg/kg/day arms were similar,
with seizure reductions of 48.6% and 47.5% from baseline,
respectively, vs 26.5% for placebo (25mg/kg/day vs placebo,
p=0.0009 and 50 mg/kg/day vs placebo, p=0.0018). All key
secondary endpoints were supportive of the effects on the primary
endpoint.
Previous clinical trials have evaluated the
safety and efficacy of EPIDIOLEX at 10 mg/kg/day and 20 mg/kg/day,
and U.S. prescribing information recommends a maintenance dose of
10 mg/kg/day. The TSC trial data represent the first pivotal safety
data at the 25 mg/kg/day and 50 mg/kg/day dose levels.
The most common adverse events in patients
receiving EPIDIOLEX in this study (≥10% and greater than placebo)
include somnolence; decreased appetite; diarrhea; constipation;
vomiting; transaminase elevations; pyrexia; seizure; cough; and
infections. The incidence of diarrhea, vomiting, transaminase
elevations, somnolence, and rash were higher in the 50 mg/kg/day
group as compared to the 25 mg/kg/day group.
Regarding laboratory investigations, 12 percent
of patients in the 25 mg/kg/day group experienced ALT elevations
>3 ULN compared to 25 percent of patients in the 50 mg/kg/day
group and none in patients on placebo. Consistent with the U.S.
prescribing information, patients on concomitant valproic acid and
on the higher dose experienced a higher rate of ALT elevations.
There were no cases of Hy’s law observed and there were no deaths
in this trial.
Dr. Volker Knappertz, GW’s Chief Medical
Officer, said, “We are delighted to report this positive trial in
patients with TSC. Both doses studied in this trial have been shown
to be equally effective. There is a lower incidence of known
adverse events and laboratory changes in the 25 mg/kg/day group
compared with 50 mg/kg/day. As a result, we expect to focus our
label expansion discussions with the FDA on the lower dose, which
is close to the dose range already included in the U.S. prescribing
information.”
This trial was conducted at more than 40
clinical sites in more than 6 countries. Detailed findings
from this clinical trial will be reported at a future medical
conference and subsequently published in a medical journal.
The EPIDIOLEX clinical development program now
includes five randomized, controlled Phase 3 clinical trials
(N=1,454) in LGS, Dravet syndrome and TSC. The previously completed
Phase 3 studies have been published in The New England Journal of
Medicine1,2, and the Lancet3. EPIDIOLEX represents the only
development program of a plant-derived cannabinoid medication
approved by the FDA.
1,2: Devinsky O, Patel AD, Cross HJ, et al.
Effect of Cannabidiol on Drop Seizures in the Lennox–Gastaut
Syndrome. N Engl J Med. 2018 May; 378:1888-1897. doi:
10.1056/NEJMoa1714631; Devinsky et al. Trial of cannabidiol for
drug resistant seizures in the Dravet syndrome. N Engl J Med.
2017 May 25;376(21):2011-2020. doi: 10.1056/NEJMoa1611618.3: Thiele
EA, Marsh ED, French JA, et al. Cannabidiol in patients with
seizures associated with Lennox-Gastaut syndrome (GWPCARE4): a
randomised, double-blind, placebo-controlled phase 3 trial. The
Lancet. 2018 March; 391(10125):1085-1096. doi:
10.1016/S0140-6736
About Tuberous Sclerosis Complex
(TSC)
Tuberous sclerosis complex (TSC) is a rare
genetic condition that causes tumors to grow in many different
organs of the body. Almost all of these tumors are benign and grow
most often in the brain, skin, heart, eyes, kidneys and lungs and
can cause a variety of health problems. The symptoms of TSC usually
appear before a child is 6 months old. The severity of the
condition can vary widely — in some children the disease is very
mild, while other children may have
life-threatening complications. At least two children born
each day will have tuberous sclerosis complex. The disorder affects
as many as 40,000 to 80,000 individuals in the United States and
about 1 to 2 million individuals worldwide, with an estimated
prevalence of one in 6,000 newborns. Epilepsy is present in
greater than 90 percent of patients with TSC and may progress to
become intractable to medication. More than 60 percent of
individuals with TSC and epilepsy do not achieve seizure control
with standard treatments such as antiepileptic drugs, epilepsy
surgery, ketogenic diet, or vagus nerve stimulation, compared to
30-40 percent of individuals with epilepsy who do not have TSC who
remain drug resistant. TSC is a leading cause of genetic epilepsy,
often occurring in the first year of life as either focal seizures
or infantile spasms. Untreated early-onset seizures are
associated with an increased risk of autism and intellectual
disability.
About EPIDIOLEX® (cannabidiol) oral
solution
EPIDIOLEX, the first prescription, plant-derived
cannabinoid medicine in the United States and the first in a new
class of anti-epileptic medications, is a pharmaceutical
formulation of highly purified cannabidiol (CBD) now FDA approved
for the treatment of seizures associated with Lennox-Gastaut
syndrome (LGS) or Dravet syndrome in patients two years of age or
older. GW has submitted a Marketing Authorization Application (MAA)
to the European Medicines Agency (EMA) for Epidyolex (European
brand name) with an expected opinion date in the second quarter of
2019. GW has received Orphan Drug Designation from the FDA, for
EPIDIOLEX for the treatment of Dravet syndrome, LGS and TSC, each
of which are severe childhood-onset, drug-resistant syndromes. GW
has also received Orphan Designation from the European Medicines
Agency, or EMA, for Epidyolex for the treatment of seizures
associated with LGS, Dravet syndrome and TSC.
Important Safety Information
CONTRAINDICATION: HYPERSENSITIVITY
EPIDIOLEX (cannabidiol) oral solution is contraindicated in
patients with a history of hypersensitivity to cannabidiol or any
ingredients in the product.
WARNINGS & PRECAUTIONS
Hepatocellular Injury:
EPIDIOLEX can cause dose-related transaminase elevations.
Concomitant use of valproate and elevated transaminase levels at
baseline increase this risk. Transaminase and bilirubin levels
should be obtained prior to starting treatment, at one, three, and
six months after initiation of treatment, and periodically
thereafter, or as clinically indicated. Resolution of transaminase
elevations occurred with discontinuation of EPIDIOLEX, reduction of
EPIDIOLEX and/or concomitant valproate, or without dose reduction.
For patients with elevated transaminase levels, consider dose
reduction or discontinuation of EPIDIOLEX or concomitant
medications known to affect the liver (e.g., valproate or
clobazam). Dose adjustment and slower dose titration is recommended
in patients with moderate or severe hepatic impairment. Consider
not initiating EPIDIOLEX in patients with evidence of
significant liver injury.
Somnolence and Sedation:
EPIDIOLEX can cause somnolence and sedation that generally
occurs early in treatment and may diminish over time; these effects
occur more commonly in patients using clobazam and may be
potentiated by other CNS depressants.
Suicidal Behavior and Ideation:
Antiepileptic drugs (AEDs), including EPIDIOLEX, increase the
risk of suicidal thoughts or behavior. Inform patients, caregivers,
and families of the risk and advise to monitor and report any
signs of depression, suicidal thoughts or behavior, or unusual
changes in mood or behavior. If these symptoms occur, consider if
they are related to the AED or the underlying illness.
Withdrawal of Antiepileptic Drugs:
As with most AEDs, EPIDIOLEX should generally be withdrawn
gradually because of the risk of increased seizure frequency and
status epilepticus.
Adverse Reactions:
The most common adverse reactions in patients receiving
EPIDIOLEX (≥10% and greater than placebo) include somnolence;
decreased appetite; diarrhea; transaminase elevations; fatigue,
malaise, and asthenia; rash; insomnia, sleep disorder and
poor-quality sleep; and infections. Hematologic abnormalities were
also observed.
Pregnancy:
EPIDIOLEX should be used during pregnancy only if the potential
benefit justifies the potential risk to the fetus. Encourage women
who are taking EPIDIOLEX during pregnancy to enroll in the North
American Antiepileptic Drug (NAAED) Pregnancy Registry.
Drug Interactions:
Moderate or strong inhibitors or inducers of CYP3A4 and CYP2C19
may affect EPIDIOLEX exposure. EPIDIOLEX may affect exposure to
CYP2C19 substrates (e.g., clobazam, diazepam) or others.
Concomitant use of EPIDIOLEX and valproate increases the incidence
of liver enzyme elevations. Dosage adjustment of EPIDIOLEX or other
concomitant medications may be necessary.
Drug Abuse:
EPIDIOLEX is a Schedule V controlled substance and has a
low potential for abuse.
Indications:
EPIDIOLEX (cannabidiol) oral solution is indicated for
the treatment of seizures associated with Lennox-Gastaut syndrome
(LGS) or Dravet syndrome (DS) in patients 2 years of age and
older.
Please refer to the EPIDIOLEX full Prescribing Information for
additional important information.
About GW Pharmaceuticals plc and
Greenwich Biosciences, Inc.Founded in 1998, GW is a
biopharmaceutical company focused on discovering, developing and
commercializing novel therapeutics from its proprietary cannabinoid
product platform in a broad range of disease areas. GW, along with
its U.S. subsidiary Greenwich Biosciences, has received U.S. FDA
approval for EPIDIOLEX (cannabidiol) oral solution for the
treatment of seizures associated with Lennox-Gastaut syndrome (LGS)
or Dravet syndrome in patients two years of age or older and which
is now available by prescription in the U.S. The Company has
submitted a regulatory application in Europe for the adjunctive
treatment of seizures associated with LGS and Dravet syndrome. The
company continues to evaluate EPIDIOLEX in additional rare epilepsy
conditions including Tuberous Sclerosis Complex (TSC) andRett
syndrome. GW commercialized the world’s first plant-derived
cannabinoid prescription drug, Sativex® (nabiximols), which is
approved for the treatment of spasticity due to multiple sclerosis
in numerous countries outside the United States and for which the
company is now planning a U.S. Phase 3 trial. The Company has a
deep pipeline of additional cannabinoid product candidates which
includes compounds in Phase 1 and 2 trials for epilepsy,
glioblastoma, and schizophrenia. For further information, please
visit www.gwpharm.com.
Forward-looking statementsThis
news release contains forward-looking statements that reflect GW's
current expectations regarding future events, including statements
regarding financial performance, the timing of clinical trials, the
timing and outcomes of regulatory or intellectual property
decisions, the relevance of GW products commercially
available and in development, the clinical benefits of EPIDIOLEX
(cannabidiol) oral solution and the safety profile and commercial
potential of EPIDIOLEX. Forward-looking statements involve risks
and uncertainties. Actual events could differ materially from those
projected herein and depend on a number of factors, including
(inter alia), the success of GW’s research strategies, the
applicability of the discoveries made therein, the successful and
timely completion and uncertainties related to the regulatory
process, and the acceptance of Sativex, EPIDIOLEX and other
products by consumer and medical professionals. A further list and
description of risks and uncertainties associated with an
investment in GW can be found in GW’s filings with the U.S.
Securities and Exchange Commission, including the most recent Form
10-KT filed on February 26, 2018. Existing and prospective
investors are cautioned not to place undue reliance on
forward-looking statements, which speak only as of the date hereof.
GW undertakes no obligation to update or revise the information
contained in this press release, whether as a result of new
information, future events or circumstances or otherwise.
Enquiries:
GW
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