MOUNTAIN VIEW, Calif.,
Dec. 21, 2015 /PRNewswire/
-- Alexza Pharmaceuticals, Inc. (Nasdaq: ALXA) today announced
interim results of its Phase 2a study of AZ-002
(Staccato® alprazolam) in epilepsy patients.
AZ-002 produced a dose-related decrease in mean Standardized
Photosensivity Range (SPR), the primary endpoint in the
study. AZ-002 is being developed for the management of
epilepsy in patients with acute repetitive seizures (ARS).
ARS occurs in a subset of patients with epilepsy who regularly
experience breakthrough seizures, despite treatment with a regular
regimen of anti-epileptic drugs.
This study employs the intermittent photic sensitivity (IPS)
model in patients with epilepsy who previously exhibited
photoparoxysmal responses on their electroencephalogram (EEG).
The IPS model provides a means for assessing the effects of
potential therapeutics in epilepsy patients in a controlled
laboratory setting by measuring epileptiform changes on the EEG to
varying frequencies of flashes of light. In addition to
producing a dose-related decrease in mean SPR, there have been no
serious adverse events reported to date and AZ-002 was generally
safe and well tolerated in the study patients.
"Our team has been working with some of the key thought leaders
in the field of epilepsy to assess the clinical viability of AZ-002
for ARS. We are encouraged with the preliminary data from the
interim analysis of our AZ-002 Phase 2a study," said Thomas B. King, President and CEO of
Alexza. "We believe that AZ-002, if developed and approved,
could offer great benefit to epilepsy patients who experience
seizure emergencies like ARS."
AZ-002 Study Interim Analysis Results and Clinical Trial Design
Summary
The interim analysis from this study shows that AZ-002 had
dose-related effects on the SPR, no serious adverse effects
and was well tolerated in the patients studied. There were
also dose-related changes in two visual-analogue scales for
sedation and for alertness, which are established pharmacodynamic
markers of benzodiazepine drug activity. Importantly, in both
measures the pharmacodynamic effect was demonstrated at the
two-minute time point, which was the first assessment in the study,
demonstrating the rapid onset of effect of alprazolam as delivered
by the Staccato technology.
The AZ-002 Phase 2a study is an in-clinic, randomized,
placebo-controlled, double-blind design, 5-way crossover evaluating
patients with epilepsy using the IPS model, with the primary
endpoint being reduction in mean SPR. This exploratory study
has enrolled 3 patients to date (of the 6 planned) at three U.S.
clinical centers. The interim analysis was conducted at the
midpoint in this study. The primary aim of this study is to
assess the safety and the pharmacodynamic EEG effects of a single
dose of AZ-002 at three dose strengths (0.5mg, 1.0mg and 2.0mg) vs.
placebo (administered twice during the 6-week protocol for each
patient).
Interim IPS Results for AZ-002
- For the placebo dose (administered twice during the study
period), the mean SPR was approximately 7 at all time points, from
pre-dose baseline to 6 hours post dosing.
- For the 0.5 mg dose, the mean SPR at baseline was 6.3 and the
maximal effect occurring at the 1 hour time point) was 3.3,
reflecting approximately a 48% decrease in the mean SPR.
- For the 1.0 mg dose, the mean SPR at baseline was 7 and the
maximal effect, occurring at the 2 minute time point, was 3,
reflecting approximately a 42% decrease in the mean SPR.
- For the 2.0 mg dose, the mean SPR at baseline was 6.7 and the
maximal effect, occurring at the 2 min time point, was 2,
reflecting approximately a 70% decrease in the mean SPR.
- Duration of effect also appeared to be dose-related. The
observed reduction in SPR was approximately 4 hours and 6
hours for the 0.5mg and 1.0mg doses. At the six-hour time point
(the last time point measured), the 2.0 mg dose still exhibited IPS
activity, with the mean SPR remaining below baseline.
The most frequently reported adverse events in subjects
receiving AZ-002 were sedation and/or somnolence. At the 1.0
mg and 2.0 mg doses, there was a rapid onset of effect observed at
2 minutes post inhalation, which can be attributed to the IV-like
pharmacokinetics resulting from Staccato drug delivery.
In previous clinical studies, where more than 100 subjects and
patients have been dosed, AZ-002 demonstrated dose-proportionality,
exhibited a median Tmax (time to peak plasma
concentration) of two minutes, and was generally safe and
well-tolerated.
The Intermittent Photic Stimulation Model
The Intermittent Photic Stimulation (IPS) model has been used
successfully to evaluate potential anti-seizure effects of new
agents in early stage development in small groups of patients with
photically-induced generalized epileptiform responses on their
electroencephalogram (EEG), called photoparoxysmal responses (PPR).
The number of flash frequencies at which PPR can be elicited
(delineated by upper and lower thresholds elicited during IPS) can
be used as a quantitative measure of photosensitivity and therefore
epileptogenic threshold. When patients with PPR receive
single test doses of possible anti-seizure medication, changes in
the number of frequencies at which a PPR response is identified on
the EEG can be used to screen for antiepileptic effects without
triggering actual seizures. In photosensitivity studies, the
patient is exposed to IPS at 14 predetermined unequally separated
frequencies in order to detect changes in response around typical
upper and lower frequency thresholds. Each flash frequency that
elicits a photosensitive response is considered one
"step." The ranges in Hz between the upper bound and the
lower bound for each patient are transformed into a metric, called
the standardized photosensitive range (SPR). The maximum SPR is 14,
based on the total number of flash frequencies tested.
Acute Repetitive Seizures (ARS)
Epilepsy, a disorder of recurrent seizures, affects approximately
2.5 million Americans, making it the third most common
neurological disorder in the United States. ARS refers to
seizures that are serial, clustered or crescendo, and ones that are
distinct from the patient's usual seizure pattern. Typically
there is recovery between the seizures in the
cluster1.
Among the implications of ARS are concerns for patient
safety. Seizure effects generally correlate directly with
seizure duration. Prolonged or recurrent seizure activity
persisting for 30 minutes or more may result in serious injury,
health impacts or death. If left untreated, ARS has been
reported to evolve into status epilepticus, a life-threatening
condition in which the brain is in a state of persistent seizure
which has a mortality rate of 3% in children and 26% in
adults.2
Benzodiazepines are considered to be medications of first choice
for the treatment of ARS. The most immediate treatment for
out-of-hospital care and the only U.S. Food and Drug
Administration-approved product for acute repetitive seizures is
rectal diazepam gel. Treatment may produce central nervous
system depression. Oral, buccal, and sublingual
benzodiazepines (lorazepam, diazepam), which are not approved for
patients with ARS, are sometimes used for treatment, but only if
the risk of aspiration is not a concern and it is recognized that
the absorption time will be increased. Nasal benzodiazepine
products, available in some countries, are not yet available in the
United States. Intravenous benzodiazepines are rapidly
acting, but must be administered by a healthcare professional in a
medical facility.
The ability to treat a patient quickly is clinically imperative
to avoid the epilepsy becoming status epilepticus or causing other
serious complications3. Alexza believes that a
product that can be administered easily in the home setting to
effectively treat ARS may result in avoiding a trip to the hospital
for treatment or diminish the use of the rectal formulation of
diazepam. AZ-002 could be administered after the first
seizure in a cluster, with the aim of preventing further
seizures. The caregiver could provide dosing assistance
between seizures. The product could also be used in a
healthcare facility, thus avoiding the use of an IV or a rectal
formulation of a benzodiazepine.
While there are not firm incidence and prevalence numbers in the
literature, there are estimated to be less than 200,000 people with
ARS in the United States, which
could make AZ-002 eligible for orphan product status.
More information on this Phase 2a study can be found at
www.clinicaltrials.gov. Alexza owns full development and
commercial rights to AZ-002.
About Alexza Pharmaceuticals, Inc.
Alexza Pharmaceuticals is focused on the research, development, and
commercialization of novel, proprietary products for the acute
treatment of central nervous system conditions. Alexza's
products and development pipeline are based on the
Staccato® system, a hand-held inhaler designed to
deliver a pure drug aerosol to the deep lung, providing rapid
systemic delivery and therapeutic onset, in a simple, non-invasive
manner. Active pipeline product candidates include AZ-002
(Staccato alprazolam) for the management of epilepsy in
patients with acute repetitive seizures and AZ-007 (Staccato
zaleplon) for the treatment of patients with middle of the night
insomnia.
ADASUVE® is Alexza's first commercial product and is
currently available in 20 countries, approved for sale by the U.S.
Food and Drug Administration, the European Commission and in
several Latin American countries. Teva Pharmaceuticals
USA, Inc., a subsidiary of Teva
Pharmaceutical Industries Ltd., is Alexza's current commercial
partner for ADASUVE in the United
States, though Alexza has announced its intention to
reacquire the United States
commercial rights from Teva with an estimated target completion
date of January 2016. Grupo Ferrer Internacional SA is
Alexza's commercial partner for ADASUVE in Europe, Latin
America, the Commonwealth of Independent States countries,
the Middle East and North Africa countries, Korea, Philippines and Thailand.
ADASUVE® and Staccato® are registered
trademarks of Alexza Pharmaceuticals, Inc. For more
information about Alexza, the Staccato system technology or
the Company's development programs, please visit
www.alexza.com.
This news release contains forward-looking statements that
involve significant risks and uncertainties. Any statement
describing the Company's expectations or beliefs is a
forward-looking statement, as defined in the Private Securities
Litigation Reform Act of 1995, and should be considered an at-risk
statement. Such statements are subject to certain risks and
uncertainties, particularly those inherent in the process of
developing and commercializing drugs, including the ability of
Alexza and Ferrer to effectively and profitably commercialize
ADASUVE, Alexza's ability to secure a new U.S. commercial partner
for ADASUVE and the terms of any such partnership, estimated
product revenues and royalties associated with the sale of ADASUVE,
the adequacy of the Company's capital to support the Company's
operations, and the Company's ability to raise additional funds and
the potential terms of such potential financings.
Additionally, there are risks and uncertainties inherent in the
process of negotiating the acquisition of the U.S. rights for
ADASUVE from Teva and restructuring the obligations under the
outstanding note from Teva. Alexza does not have a defined timeline
for this process and is not confirming that the process will result
in any specific action or transaction. The Company's
forward-looking statements also involve assumptions that, if they
prove incorrect, would cause its results to differ materially from
those expressed or implied by such forward-looking statements.
These and other risks concerning Alexza's business are described in
additional detail in the Company's Annual Report on Form 10-K for
the year ended December 31, 2014 and
the Company's other Periodic and Current Reports filed with the
Securities and Exchange Commission. Forward-looking statements
contained in this announcement are made as of this date, and the
Company undertakes no obligation to publicly update any
forward-looking statement, whether as a result of new information,
future events or otherwise.
Reference:
1. Cereghino, JJ., 2007. Identification and treatment
of acute repetitive seizures in children and adults
2. Boggs, J., 2004. Mortality Associated with Status
Epilepticus
3. Dreifuss, Fritz E., 1998. Comparison of Rectal
Diazepam Gel and Placebo for Acute Repetitive Seizures
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