CAMBRIDGE, Mass., Dec. 2, 2018 /PRNewswire/ -- Blueprint Medicines
Corporation (NASDAQ: BPMC), a leader in discovering and developing
targeted kinase medicines for patients with genomically defined
diseases, today announced updated results for the Phase 1 EXPLORER
clinical trial of avapritinib, a potent and highly selective
inhibitor of D816V mutant KIT, the common disease driver in nearly
all patients with systemic mastocytosis (SM). The updated EXPLORER
trial data in patients with advanced SM showed durable clinical
responses that deepened over time, regardless of disease subtype,
prior therapy or starting dose. Avapritinib was generally
well-tolerated, and most adverse events (AEs) reported by
investigators were Grade 1 or 2. These results will be presented
today in an oral presentation at the 60th American
Society of Hematology Annual Meeting and Exposition in San Diego, California.
As of the data cutoff date of September
30, 2018, the updated results from the ongoing EXPLORER
trial showed an overall response rate (ORR) of 83 percent.
Twenty-four percent of patients had a complete response with a full
or partial recovery of peripheral blood counts (CR/CRh). Responses
deepened over time, with a median time to initial response of two
months and a median time to CR/CRh of nine months. The median
duration of response (DoR) was not reached, and the 12-month DoR
rate was 76 percent.
In addition, statistically significant improvements in
patient-reported disease symptoms were observed. A 41 percent mean
reduction (p=0.043) in patient-reported disease symptoms was
demonstrated on the Advanced SM Symptom Assessment Form
(AdvSM-SAF), the first patient-reported outcomes tool designed
specifically to assess advanced SM.
"Systemic mastocytosis is a complex rare disorder that causes
debilitating symptoms across all forms of the disease and reduced
survival in advanced patients," said Jason
Gotlib, M.D., professor of
Medicine, Hematology, at the Stanford
University Medical Center and an investigator on the
EXPLORER trial. "The updated EXPLORER study results show that
selectively targeting D816V mutant KIT with avapritinib led to
profound and durable clinical activity in patients with advanced
systemic mastocytosis, including significant improvements in
patient-reported disease symptoms and quality of life. Combined
with encouraging preliminary data from an initial cohort of
indolent systemic mastocytosis patients from the EXPLORER study,
these results highlight the potential of avapritinib to improve
objective and subjective measures of disease burden across the
spectrum of mastocytosis subtypes."
"The data further validate Blueprint Medicines' precision
therapy approach, where we target genetic drivers of disease with
potent and highly selective inhibitors," said Andy Boral, M.D., Ph.D., Chief Medical Officer
of Blueprint Medicines. "With robust clinical data from the
EXPLORER trial, favorable FDA feedback on potential registration
pathways and Breakthrough Therapy Designation for advanced systemic
mastocytosis, we believe avapritinib has a strong foundation for
expedited development across all forms of the disease. In
particular, the new data showing a significant decrease in symptom
burden in patients enrolled in the EXPLORER trial increase our
confidence in avapritinib's potential in indolent systemic
mastocytosis."
Data Highlights from the Ongoing Phase 1 EXPLORER Clinical
Trial
As of the data cutoff date of September
30, 2018, 67 patients were treated with avapritinib in the
dose escalation and expansion portions of the Phase 1 EXPLORER
clinical trial, including 23 patients with aggressive SM (ASM), 30
patients with advanced SM with an associated hematological neoplasm
(SM-AHN), seven patients with mast cell leukemia (MCL) and seven
patients with indolent or smoldering SM. Forty patients (60
percent) had a prior treatment, including 14 patients (23 percent)
who had previously received Rydapt® (midostaurin).
Safety Data
As of the data cutoff date, avapritinib was generally
well-tolerated. Most AEs were reported by investigators as Grade 1
or 2. Across all enrolled patients, 52 patients (78 percent)
remained on treatment as of the data cutoff date. Three patients (4
percent) discontinued treatment with avapritinib due to
treatment-related AEs.
Across all grades, the most common non-hematological
treatment-emergent AEs (regardless of relationship to avapritinib)
reported by investigators (>15 percent) were periorbital edema,
fatigue, nausea, diarrhea, peripheral edema, vomiting, cognitive
effects, hair color changes, arthralgia, dizziness and abdominal
pain. The most common hematological treatment-emergent AEs reported
by investigators (>10 percent) were anemia, thrombocytopenia and
neutropenia. Grade 3 and 4 treatment-related AEs occurred in 44
patients (66 percent), and these events were most commonly
hematological AEs, typically in patients with low blood counts
(cytopenias) at study entry.
Clinical Activity Data
IWG-MRT-ECNM Assessments and Objective Measures of Mast Cell
Burden
As of the data cutoff date, 29 patients were evaluable for
response by the modified IWG-MRT-ECNM criteria, a rigorous method
for assessing clinical response in advanced SM patients with
regulatory precedent in the U.S. and Europe. Responses were centrally reviewed by a
committee of SM experts.
Avapritinib demonstrated durable clinical responses across all
doses studied and in each subtype of advanced SM – ASM, SM-AHN and
MCL. The duration of treatment was up to 31 months as of the data
cutoff date, with a median follow-up time of 14 months in evaluable
patients.
Across all evaluable patients at all doses, the ORR was 83
percent. Seven patients had a CR/CRh (24 percent, two pending
confirmation), 14 patients had a partial response (48 percent,
three pending confirmation) and three patients had clinical
improvement (10 percent, one pending confirmation). Three of the
pending responses were previously confirmed responses (two partial
responses, one clinical improvement) that are transitioning to a
deeper response. No patients had
documented disease progression per modified IWG-MRT-ECNM
criteria.
In addition, strong clinical activity was demonstrated in
evaluable patients treated with a starting dose of less than or
equal to 200 mg once daily (QD), the dose under evaluation in the
ongoing registration-enabling Phase 2 PATHFINDER clinical trial in
patients with advanced SM. These 10 patients had an ORR of 90
percent and a CR/CRh rate of 50 percent (one complete response
pending confirmation).
All patients evaluable on objective measures of mast cell burden
showed reductions from baseline. These results were shown
regardless of disease subtype, prior therapy (including midostaurin
or the investigational agent DCC-2618), or co-mutation status.
These measures consisted of declines in bone marrow mast cells,
serum tryptase, spleen volume and KIT D816V mutant allele
burden.
At baseline, 22 SM patients received steroids for mastocytosis
symptoms. As of the data cutoff date, 18 patients (80 percent)
decreased their steroid dose, including nine patients (41 percent)
who were able to entirely discontinue their steroids.
Patient-Reported Outcomes
As of the data cutoff date, 32 patients in the dose expansion
portion of the Phase 1 EXPLORER trial were evaluated using the
AdvSM-SAF, the first patient-reported outcomes tool developed
specifically for advanced SM patients. It was designed to evaluate
symptoms across the gastrointestinal domain (abdominal pain,
diarrhea, nausea and vomiting) and skin domain (spots, itching and
flushing), as well as fatigue. Patients reported their symptoms
daily using an electronic diary.
In advanced SM patients, benefits were shown across each
individual symptom studied. There was a 41 percent improvement from
baseline in the AdvSM-SAF Total Symptom Score (p=0.043). The most
symptomatic patients (n=16, top 50th percentile) had the
largest mean improvement in the AdvSM-SAF Total Symptom Score (46
percent, p=0.038).
In addition, an improvement in patient-reported quality of life
was observed. As of the data cutoff date, 30 patients were
evaluated using the European Organization for Research and
Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-30), a
validated and commonly used patient-reported outcomes tool in
oncology clinical trials. Results showed a statistically
significant improvement in quality of life score, approaching
levels observed in healthy aged-matched controls, with a pronounced
improvement observed in the most symptomatic patients.
Proof-of-Concept in Indolent and Smoldering SM
All evaluable patients with indolent and smoldering SM showed
profound reductions in bone marrow mast cells, serum tryptase,
spleen volume and KIT D816V mutant allele burden. The data also
showed avapritinib led to improvements in patient-reported
symptoms. These encouraging data support Blueprint Medicines'
planned Phase 2 PIONEER clinical trial in patients with indolent
and smoldering SM.
About the Clinical Development Program for Avapritinib in
SM
Blueprint Medicines is pursuing a broad clinical development
program for avapritinib across advanced, indolent and smoldering
forms of SM. Avapritinib is currently being evaluated in two
ongoing clinical trials for advanced SM: the Phase 1 EXPLORER
clinical trial and the registration-enabling Phase 2 PATHFINDER
clinical trial.
The Phase 1 EXPLORER clinical trial of avapritinib was designed
to identify the recommended Phase 2 dose for further study and
demonstrate proof-of-concept in advanced SM. The dose escalation
portion is complete, and the expansion portion of the trial is
enrolling patients with ASM, SM-AHN and MCL at multiple sites in
the United States and United Kingdom. Trial objectives include
assessing safety and tolerability, response per modified
IWG-MRT-ECNM criteria and patient-reported outcomes.
The Phase 2 PATHFINDER clinical trial is an open-label,
single-arm, registration-enabling clinical trial in patients with
advanced SM. Patient dosing is now ongoing in the clinical trial,
which is designed to enroll up to 60 advanced SM patients at sites
in the United States, Canada and Europe. The primary efficacy endpoints are ORR
and DoR based on modified IWG-MRT-ECNM criteria.
Blueprint Medicines expects to initiate the Phase 2 PIONEER
clinical trial, a randomized, placebo-controlled,
registration-enabling trial in patients with indolent and
smoldering SM, by the end of 2018. The trial's primary endpoint
will be symptom reductions for avapritinib versus placebo based on
the Indolent and Smoldering SM Assessment Form Total Symptom Score.
All patients who complete the dose-finding (part 1) and
placebo-controlled efficacy (part 2) portions of this trial will
have an opportunity to receive avapritinib in an open-label
extension (part 3).
SM patients and clinicians interested in ongoing or planned
clinical trials can contact the Blueprint Medicines study director
at SM@blueprintmedicines.com or 1-617-714-6707. Additional details
are available at www.pathfindertrial.com, www.pioneertrial.com or
www.clinicaltrials.gov.
About SM
SM results from the abnormal proliferation and survival of mast
cells, which mediate allergic responses. There are several forms of
the disease, including indolent SM, smoldering SM and three
advanced subtypes – ASM, SM-AHN and MCL. The KIT D816V mutation
drives approximately 90 to 95 percent of all SM cases, causing
debilitating and difficult-to-manage symptoms such as pruritus,
flushing, headaches, bone pain, nausea, vomiting, diarrhea,
anaphylaxis, abdominal pain and fatigue. While these effects occur
across SM patients, symptom burden and poor quality of life are the
predominant disease manifestations of indolent and smoldering SM.
Advanced SM patients experience organ damage and a median overall
survival of about 3.5 years in ASM, two years in SM-AHN and less
than six months in MCL.
Currently, there are no approved therapies that selectively
inhibit KIT D816V in advanced SM, and no approved therapies for
indolent and smoldering SM. New treatments are needed that are more
effective and better tolerated than existing advanced SM therapy,
as well as for indolent and smoldering SM patients whose symptoms
are often not well controlled with symptom-directed therapies.
About Avapritinib
Avapritinib is a potent and selective oral inhibitor of KIT and
PDGFRA mutant kinases. It is a type 1 inhibitor designed to target
the active kinase conformation; all oncogenic kinases signal via
this conformation. Avapritinib has demonstrated broad inhibition of
KIT and PDGFRA mutations associated with gastrointestinal stromal
tumors (GIST), and the most potent activity against activation loop
mutations, which currently approved therapies for GIST do not
inhibit. In contrast with existing multi-kinase inhibitors,
avapritinib has shown marked selectivity for KIT and PDGFRA over
other kinases. In addition, avapritinib is uniquely designed to
selectively bind and inhibit D816V mutant KIT, the primary driver
of disease in approximately 90 to 95 percent of all SM patients.
Preclinical studies have shown avapritinib potently inhibited KIT
D816V at sub-nanomolar potencies with minimal off-target
activity.
Blueprint Medicines is initially developing avapritinib, an
investigational medicine, for the treatment of advanced GIST,
advanced SM, and indolent and smoldering SM. The U.S. Food and Drug
Administration has granted avapritinib two Breakthrough Therapy
Designations, one for the treatment of PDGFRα D842V-driven GIST and
one for advanced SM.
Blueprint Medicines has an exclusive collaboration and license
agreement with CStone Pharmaceuticals for the development and
commercialization of avapritinib and certain other drug candidates
in Mainland China, Hong Kong,
Macau and Taiwan. Blueprint Medicines retains
development and commercial rights for avapritinib in the rest of
the world.
About Blueprint Medicines
Blueprint Medicines is developing a new generation of targeted
and potent kinase medicines to improve the lives of patients with
genomically defined diseases. Its approach is rooted in a deep
understanding of the genetic blueprint of cancer and other diseases
driven by the abnormal activation of kinases. Blueprint Medicines
is advancing multiple programs in clinical development for subsets
of patients with gastrointestinal stromal tumors, hepatocellular
carcinoma, systemic mastocytosis, non-small cell lung cancer,
medullary thyroid cancer and other advanced solid tumors, as well
as multiple programs in research and preclinical development. For
more information, please visit www.blueprintmedicines.com.
Cautionary Notes Regarding Forward-Looking Statements
This press release contains forward-looking statements within
the meaning of the Private Securities Litigation Reform Act of
1995, as amended, including, without limitation, statements
regarding plans and timelines for the clinical development of
avapritinib, including plans and timelines for the ongoing Phase 1
EXPLORER clinical trial, ongoing Phase 2 PATHFINDER clinical trial
and planned Phase 2 PIONEER clinical trial; expectations regarding
the potential for the Phase 1 EXPLORER clinical trial, Phase 2
PATHFINDER clinical trial or Phase 2 PIONEER clinical trial to be
registration-enabling for avapritinib in SM; Blueprint Medicines'
ability to implement its clinical development plans for avapritinib
in SM; expectations regarding the potential benefits of avapritinib
in treating patients with SM, including advanced, indolent and
smoldering SM; expectations regarding the development of
avapritinib as a treatment for patients with SM, including
advanced, indolent and smoldering SM; expectations regarding the
potential for expedited development of avapritinib; and Blueprint
Medicines' strategy, business plans and focus. The words "may,"
"will," "could," "would," "should," "expect," "plan," "anticipate,"
"intend," "believe," "estimate," "predict," "project," "potential,"
"continue," "target" and similar expressions are intended to
identify forward-looking statements, although not all
forward-looking statements contain these identifying words. Any
forward-looking statements in this press release are based on
management's current expectations and beliefs and are subject to a
number of risks, uncertainties and important factors that may cause
actual events or results to differ materially from those expressed
or implied by any forward-looking statements contained in this
press release, including, without limitation, risks and
uncertainties related to the delay of any current or planned
clinical trials or the development of Blueprint Medicines' drug
candidates, including avapritinib, BLU-554, BLU-667 and BLU-782;
Blueprint Medicines' advancement of multiple early-stage efforts;
Blueprint Medicines' ability to successfully demonstrate the safety
and efficacy of its drug candidates; the preclinical and clinical
results for Blueprint Medicines' drug candidates, which may not
support further development of such drug candidates; actions of
regulatory agencies, which may affect the initiation, timing and
progress of clinical trials; Blueprint Medicines' ability to
develop and commercialize companion diagnostic tests for its
current and future drug candidates, including companion diagnostic
tests for avapritinib for PDGFRα D842V-driven GIST, BLU-554 for
FGFR4-driven hepatocellular carcinoma and BLU-667 for RET-driven
non-small cell lung cancer; the success of Blueprint Medicines'
current and future collaborations, including its cancer
immunotherapy collaboration with F. Hoffmann-La Roche Ltd and
Hoffmann-La Roche Inc. and its collaboration with CStone
Pharmaceuticals. These and other risks and uncertainties are
described in greater detail in the section entitled "Risk Factors"
in Blueprint Medicines' Quarterly Report on Form 10-Q for the
quarter ended September 30, 2018, as
filed with the Securities and Exchange Commission (SEC) on
October 30, 2018, and any other
filings that Blueprint Medicines has made or may make with the SEC
in the future. Any forward-looking statements contained in this
press release represent Blueprint Medicines' views only as of the
date hereof and should not be relied upon as representing its views
as of any subsequent date. Except as required by law, Blueprint
Medicines explicitly disclaims any obligation to update any
forward-looking statements.
Trademarks
Rydapt® is a registered trademark of Novartis AG. All other
trademarks and trade names in this press release are the property
of Blueprint Medicines Corporation or used with permission.
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