--Preliminary Analysis: RYANODEX Provides
Benefit for Patients--
--Eagle Plans to Meet with FDA to Discuss
Next Steps--
Eagle Pharmaceuticals, Inc. (“Eagle” or “the Company”)
(Nasdaq:EGRX) today announced completion of enrollment of the
Company’s second clinical study to further evaluate the safety and
efficacy of RYANODEX® (dantrolene sodium for injectable suspension)
for the treatment of exertional heat stroke (“EHS”), an
investigational new indication for the product.
The randomized and double-blinded study was conducted at four
Emergency Departments in the Makkah region of Saudi Arabia during
the 2018 Hajj Season, which took place August 19-24, 2018. The
study enrolled seven severely ill EHS patients. Based on a
preliminary analysis of the data, EHS patients who received
RYANODEX plus Standard of Care (“SOC”), which consists of body
cooling by physical methods and supportive measures, showed an
additive benefit compared to patients receiving cooling only.
The two treatment groups had comparable baseline
characteristics, including severe hyperthermia and severe
neurological dysfunction. Patients randomized to Group A (RYANODEX
plus SOC) had a mean baseline core body temperature of 107.8 °F and
mean Glasgow Coma Scale (GCS) score of 5. Similarly, patients in
Group B (SOC only) had a mean core body temperature of 107.2 °F and
mean GCS score of 5 at baseline. A GCS score of 5 represents severe
brain injury.
Preliminary evaluation of the data show that of the four
patients dosed with RYANODEX, two had restoration of neurological
functioning, and another patient showed substantial improvement
over the course of the study. The fourth patient, who had an
initial core body temperature of 112.1 °F, remained unchanged. In
contrast, the SOC group had three patients. One patient had
restoration of neurological functioning, one remained with severe
impairment and one subject showed further deterioration of
neurological functioning.
This preliminary assessment is consistent with the data from the
study conducted in 2015, in which patients dosed with RYANODEX plus
SOC showed an additive benefit compared to patients receiving SOC
only.
During the 2018 Hajj, overall emergency room visits were
dramatically decreased from previous years due to well-implemented
crowd management, lower temperatures, lower humidity and other
external factors. As a result, the number of EHS patients available
for study enrollment was also significantly less than in previous
years, and therefore much lower than anticipated. The Company
intends to complete the analysis of the data and meet with the U.S.
Food and Drug Administration (“FDA”) to discuss next steps.
“Our preliminary evaluation of the data indicates that the
patients receiving RYANODEX showed an improved outcome compared to
patients treated with cooling only. We have now conducted two
randomized, controlled studies and have obtained comparable results
in both studies. We have 41 subjects for a rare disease with FDA
fast-track and Orphan Drug designations, and no other approved
drugs to treat EHS,” stated Scott Tarriff, Chief Executive
Officer.
“Based upon the collective results of our two clinical trials as
well as other work performed by the Company and researchers around
the world, we believe there is sufficient data to provide evidence
of safety and efficacy for the use of RYANODEX for the treatment of
EHS. We plan to meet with the FDA to discuss the next steps in
making this very important product available to those afflicted
with exertional heat stroke,” concluded Tarriff.
This study was conducted in compliance with all current FDA
regulations and is the second trial conducted by Eagle. The study
intended to provide confirmatory evidence of the Company’s initial
safety and efficacy study of RYANODEX for EHS conducted in
September 2015 and to satisfy the FDA’s requirements to amend
Eagle’s original NDA.
Additional details about the study can be found at
www.ClinicalTrials.gov (ClinicalTrials.gov Identifier:
NCT03600376).
Results of 2015 Study
Eagle’s initial study was conducted from September 22-27, 2015,
at the Emergency Departments of four hospitals during the Hajj
pilgrimage in the Makkah region, Saudi Arabia.
The open-label, randomized, 2-arm study was primarily designed
to assess the change in the level of neurological impairment in
subjects suffering from the symptoms of EHS, from baseline to 90
minutes post-randomization, using the Glasgow Coma Scale
(“GCS”).
The use of a validated and well-known instrument to evaluate
neurological functioning, such as the Glasgow Coma Scale, provides
a reliable assessment of CNS impairment and its progression over
time.
The study enrolled 34 EHS patients between 18-45 years of
age.
Subjects were randomized 1:1 into two groups to receive either
RYANODEX plus SOC, (Group A, n=17), or SOC alone (Group B,
n=17).
Per study protocol, all subjects experienced exertional physical
activity within the previous 24 hours, and demonstrated hallmark
clinical features of EHS, including:
- Presence of neurological impairment,
evaluated using the Glasgow Coma Scale (“GCS”);
- Baseline core body temperature of 104°
F (40° C) or greater; and,
- Tachycardia (at least 100 heart beats
per minute)
Baseline disease characteristics were comparable between the two
groups, including a mean GCS score (Group A: 6.1 vs. Group B: 5.9)
representing severe neurological impairment, and severe
hyperthermia (Group A: 106.5° F (41.4° C) vs. Group B: 106.7° F
(41.5° C).
Efficacy
Patients were evaluated at baseline and at regular time
intervals post-randomization for changes in level of consciousness
using GCS, and core body temperature.
Study results showed that a greater proportion of patients
treated with Ryanodex plus SOC exhibited a clinically meaningful
improvement in their neurological functioning (GCS ≥ 13) within 90
minutes (29.4%) and within 24 hours post-randomization (47.1%),
compared with SOC only-treated subjects (11.8% and 23.5%,
respectively).
In addition, pre-specified odds ratio analysis showed that odds
of achieving a GCS score ≥ 13 within 90 minutes postrandomization
was about 3 times greater for subjects in the Ryanodex plus SOC
group than for subjects who received SOC-only and remained almost
unchanged at or prior to 24 hours postrandomization. Also, the
median time to reach first rectal temperature ≤ 38°C was shorter in
the Ryanodex plus SOC group (90.0 minutes) than in the SOC only
group (103.0 minutes).
Safety
Overall, safety findings were comparable between the two study
groups, and there were no serious drug-related adverse events.
Fewer patients experienced treatment-emergent adverse events in
Group A (64.7%), as compared to Group B (76.5%), and the incidence
of serious adverse events in each of the two treatment arms was
comparable. In summary, the safety results of the study are
consistent with the known, and well characterized, safety profile
of RYANODEX.
About the Glasgow Coma Scale
The Glasgow Coma Scale (“GCS”) is a validated tool that
functions as a common scoring system among medical practitioners
for measuring and describing the varying degrees of level of
consciousness in a person following an acute brain injury.1
Widely accepted as reliable and objective, this scoring system
is used by trained staff at the site of a potential brain injury,
as well as in emergency departments and intensive care units. The
GCS was selected for this study as an objective and accurate method
to measure the state of mental impairment and the subsequent
improvement of test subjects.
The GCS measures three key functions: Eye Opening, Motor
Response and Verbal Response.
Eye Opening
(E)
4 = spontaneous
3 = to voice
2 = to pain
1 = none
Motor Response
(M)
6 = normal
5 = localized to pain
4 = withdraws to pain
3 = decorticate posture (an abnormal
posture that can include rigidity, clenched fists, legs held
straight out, and arms bent inward toward the body with the wrists
and fingers bend and held on the chest)
2 = decerebrate (an abnormal posture that
can include rigidity, arms and legs held straight out, toes pointed
downward, head and neck arched backwards)
1 = none
Verbal Response
(V)
5 = normal conversation
4 = disoriented conversation
3 = words, but not coherent
2 = no words, only sounds
1 = none
____________________________
1Teasdale G, Jennett B. (1974). "Assessment of coma and impaired
consciousness. A practical scale." Lancet 13 (2): 81–4.
Clinicians use the GCS to assess the eye opening response, the
verbal response, and the motor response in patients with an
impaired level of consciousness. The total GCS score is the sum of
the scores for each of these functions, classified as follows2:
Classification
Total Glasgow Coma Scale Score Severe
3 – 8 Moderate 9 – 12 Mild
13 – 15
About Exertional Heat Stroke
The two types of heat stroke – classical and exertional - are
the most severe forms of heat illness. Classical heat stroke often
results from passive exposure to heat, as observed during heat
waves, and mostly affects very young and elderly people. In
contrast, EHS is a rare disease, mostly impacting young - otherwise
healthy - people, performing intense physical activity in hot
weather environments. EHS is a life-threatening and unpredictable
condition, characterized by an acute hyperthermic-hypermetabolic
status, which may result in severe neurological, renal and liver
damage, or even death, if not treated promptly. Currently, the
treatment of EHS is limited to body surface cooling and supportive
measures; despite the use of cooling, up to 30% of EHS victims
suffer long-term neurological sequelae.
About RYANODEX
RYANODEX® (dantrolene sodium) for injectable suspension is
indicated for the treatment of malignant hyperthermia in
conjunction with appropriate supportive measures, and for the
prevention of malignant hyperthermia in patients at high risk.
Important Safety Information
RYANODEX® is not a substitute for appropriate supportive
measures in the treatment of malignant hyperthermia, including:
Discontinuing triggering anesthetic agents
Increasing oxygen
Managing the metabolic acidosis
Instituting cooling when necessary
____________________________
2 "What Is the Glasgow Coma Scale?"
www.brainline.org, n.d. Web.
<http://www.brainline.org/content/2010/10/what-is-the-glasgow-coma-scale.html>.
Administering diuretics to prevent late kidney injury due to
myoglobinuria (the amount of mannitol in RYANODEX® is insufficient
to maintain diuresis).
Precautions should be taken when administering RYANODEX®
preoperatively for the prevention of malignant hyperthermia,
including monitoring vital signs, avoiding known triggering agents,
and monitoring for early clinical and metabolic signs of malignant
hyperthermia that may indicate additional treatment is needed.
The administration of dantrolene sodium is associated with loss
of grip strength and weakness in the legs, as well as drowsiness,
dizziness, dysphagia, dyspnea, and decreased inspiratory capacity.
Patients should not be permitted to ambulate without assistance
until they have normal strength and balance. Care must be taken to
prevent extravasation of RYANODEX® into the surrounding tissue due
to the high pH of the reconstituted RYANODEX® suspension and
potential for tissue necrosis.
RYANODEX® full Prescribing Information can be found at
www.RYANODEX.com
About Eagle Pharmaceuticals, Inc.
Eagle is a specialty pharmaceutical company focused on
developing and commercializing injectable products that address the
shortcomings, as identified by physicians, pharmacists and other
stakeholders, of existing commercially successful injectable
products. Eagle’s strategy is to utilize the FDA's 505(b)(2)
regulatory pathway. Additional information is available on the
company’s website at www.eagleus.com.
Forward-Looking Statements
This press release contains forward-looking information within
the meaning of the Private Securities Litigation Reform Act of
1995, as amended and other securities laws. Forward-looking
statements are statements that are not historical facts. Words such
as “will,” “continue,” “may,” “believe,” “intends,”
“anticipate(s),” “plan,” “enables,” “potentially,” “entitles,” and
similar expressions are intended to identify forward-looking
statements. These statements include statements regarding future
events including, but not limited to: the safety and efficacy of
RYANODEX for the treatment of EHS; FDA approval of the use of
RYANODEX for the treatment of EHS; the timing and level of success
of a future launch of RYANODEX; successful compliance with FDA and
other governmental regulations applicable to manufacturing
facilities, products and/or businesses; the commercial success of
Eagle’s commercial portfolio, including RYANODEX, if and when
launched; and other factors that are discussed in Eagle’s Annual
Report on Form 10-K for the year ended December 31, 2017, and its
other filings with the U.S. Securities and Exchange Commission. All
of such statements are subject to certain risks and uncertainties,
many of which are difficult to predict and generally beyond Eagle’s
control, that could cause actual results to differ materially from
those expressed in, or implied or projected by, the forward-looking
information and statements. Such risks include, but are not limited
to: whether the FDA will ultimately approve RYANODEX for the
treatment of EHS; whether Eagle’s studies will support the safety
and efficacy of RYANODEX for the treatment of EHS; whether Eagle’s
management and/or board of directors will be effective in managing
Eagle’s business, future growth and market protection, including
with respect to RYANODEX; whether Eagle will maintain successful
compliance with the FDA and other governmental regulations; and
other risks described in Eagle’s filings with the U.S. Securities
and Exchange Commission. Readers are cautioned not to place undue
reliance on these forward-looking statements that speak only as of
the date hereof, and we do not undertake any obligation to revise
and disseminate forward-looking statements to reflect events or
circumstances after the date hereof, or to reflect the occurrence
of or non-occurrence of any events.
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version on businesswire.com: https://www.businesswire.com/news/home/20180830005157/en/
Investor Relations for Eagle Pharmaceuticals,
Inc.:In-Site Communications, Inc.Lisa M. Wilson,
212-452-2793lwilson@insitecony.com
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