Lead investigators from US and French Phase Ib/II clinical trials
of APR-246 and Azacitidine (AZA) in patients with TP53 mutant MDS
and AML, presented positive data on Monday at the 2019 ASH Annual
Meeting. Both trials are evaluating the safety and efficacy of
Aprea Therapeutics, Inc. (Nasdaq: APRE) lead product candidate,
APR-246, in combination with azacitidine for the treatment of TP53
mutant MDS and AML.
Dr. David Sallman of the Moffitt Cancer Center, the lead
investigator on the US Trial, presented on 33 evaluable MDS
patients as of the data cutoff, with an overall response rate (ORR)
of 88%, and a 61% complete remission (CR) rate, by International
Working Group (IWG) criteria. With a median duration of follow-up
of 10.8 months, the median duration of response was 8.4 months and
the median duration of CR was 7.3 months. Seventeen (52%) evaluable
MDS patients discontinued therapy to pursue stem cell transplant.
Median overall survival (OS) for all enrolled patients (n=55) was
10.8 months. Median OS in responding patients versus non-responders
was 13.7 vs. 3.9 months. Adverse events, regardless of causality,
were mostly grade 1/2. Grade 3+ adverse events occurring in ≥20% of
patients were limited to cytopenias and infection, consistent with
underlying hematopoietic malignancies, and no exacerbation of the
expected AZA-related safety profile has been observed.
Prof. Thomas Cluzeau reported preliminary data for 24 evaluable
MDS patients enrolled before June 2019 in the French trial being
conducted by the Groupe Francophone des Myélodysplasies, which is
led by Prof. Pierre Fenaux and who is also the lead investigator of
the French trial. Following the oral presentation, the GFM informed
Aprea that the analysis presented and previously reported included
three MDS patients who achieved a complete remission (CR) but were
enrolled after May 2019 and therefore should not have been included
among the 24 evaluable patients under the specified enrollment
cutoff. In addition, there were two additional MDS patients
enrolled before June 2019 who had responded. The updated data for
24 evaluable MDS patients enrolled before June 2019 are overall
response rate (ORR) of 71% and complete remission (CR) rate of 54%
by IWG criteria. Inclusive of the CRs in 3 MDS patients enrolled
after May 2019, the updated data for 27 evaluable MDS patients are
ORR of 74% and CR rate of 59%. With a median duration of follow-up
of 6.4 months, the median overall survival (OS) for all enrolled
patients (n=53) had not been reached. In addition, all
responding patients were alive at data cutoff. Relative to
baseline, mutant TP53 variant allele frequency (VAF) was
significantly decreased in responding patients and undetectable in
all patients who achieved a CR.
Updated summary information on both trials can be found on the
Company’s investor relations website at https://ir.aprea.com.
About the US Clinical Trial
Eligible patients in the Phase Ib/II clinical trial include
HMA-naïve, TP53 mutated MDS, oligoblastic acute myeloid leukemia
(AML, ≤ 30% blasts), MDS-myeloproliferative neoplasm (MDS-MPN)
overlap and chronic myelomonocytic leukemia (CMML). In the Phase Ib
part of the clinical trial, patients received APR-246 in a 3+3 dose
escalation design (50, 75, 100 mg/kg lean body weight) IV daily
over 4 days in a lead-in phase (days -14 to -10), followed by the
same dose of APR-246 (days 1-4) and AZA 75 mg/m2 SC/IV daily for 7
days (days 4-10 or 4-5 and 8-12) in 28-day cycles. In the Phase II
part of the clinical trial, patients receive APR-246 as a 4,500 mg
fixed dose IV daily (days 1-4) and AZA daily for 7 days (days 4-10
or 4-5 and 8-12) in 28-day cycles. Primary objective in Phase Ib
part of the clinical trial was safety, with AEs graded by CTCAE
v4.03 and DLT assessment over 6 weeks. Secondary endpoints included
response rate by IWG 2006 criteria, PFS, OS, as well as serial next
generation sequencing and p53 immunohistochemistry for evaluation
of clonal suppression and depth of remission. In the Phase II part
of the clinical trial the primary endpoint is CR rate.
About the French Clinical Trial
Eligible patients in the Phase Ib/II clinical trial include HMA
naïve, TP53 mutated MDS and acute myeloid leukemia (AML). All
enrolled patients were to receive APR-246 as a 4,500 mg fixed dose
IV daily (days 1-4) and AZA over 7 days (days 4-10 or 4-5 and 8-12)
in 28-day cycles. The primary endpoint of the trial is CR rate.
About Myelodysplastic Syndrome
Myelodysplastic syndromes (MDS) represents a spectrum of
hematopoietic stem cell malignancies in which bone marrow fails to
produce sufficient numbers of healthy blood cells. Approximately
30-40% of MDS patients progress to acute myeloid leukemia (AML) and
mutation of the p53 tumor suppressor protein is thought to
contribute to disease progression. Mutations in p53 are found in up
to 20% of MDS and AML patients and are associated with poor overall
prognosis.
About p53 and APR-246
The p53 tumor suppressor gene is the most frequently mutated
gene in human cancer, occurring in approximately 50% of all human
tumors. These mutations are often associated with resistance
to anti-cancer drugs and poor overall survival, representing a
major unmet medical need in the treatment of cancer.
APR-246 is a small molecule that has demonstrated reactivation
of mutant and inactivated p53 protein – by restoring wild-type p53
conformation and function – and thereby induce programmed cell
death in human cancer cells. Pre-clinical anti-tumor activity
has been observed with APR-246 in a wide variety of solid and
hematological cancers, including MDS, AML, and ovarian cancer,
among others. Additionally, strong synergy has been seen with
both traditional anti-cancer agents, such as chemotherapy, as well
as newer mechanism-based anti-cancer drugs and immuno-oncology
checkpoint inhibitors. In addition to pre-clinical testing, a Phase
I/II clinical program with APR-246 has been completed,
demonstrating a favorable safety profile and both biological and
confirmed clinical responses in hematological malignancies and
solid tumors with mutations in the TP53 gene.
A pivotal Phase 3 clinical trial of APR-246 and azacitidine for
frontline treatment of TP53 mutant MDS is ongoing. APR-246 has
received Orphan Drug and Fast Track designations from the FDA for
MDS, and Orphan Drug designation from the EMA for MDS, AML and
ovarian cancer.
About Aprea Therapeutics
Aprea Therapeutics Inc., (NASDAQ: APRE) is a biopharmaceutical
company headquartered in Boston, Massachusetts with research
facilities in Stockholm, Sweden, focused on developing and
commercializing novel cancer therapeutics that reactivate the
mutant tumor suppressor protein p53. The Company’s lead product
candidate is APR-246, a small molecule in clinical development for
hematologic malignancies, including myelodysplastic syndromes (MDS)
and acute myeloid leukemia (AML). For more information, please
visit the company website at www.aprea.com.
The Company may use, and intends to use, its investor relations
website at https://ir.aprea.com as a means of disclosing
material nonpublic information and for complying with its
disclosure obligations under Regulation FD.
Forward-Looking Statements
Certain information contained in this press release includes
“forward-looking statements”, within the meaning of Section 27A of
the Securities Act of 1933, as amended, and Section 21E of the
Securities Exchange Act of 1934, as amended, related to our
clinical trials and regulatory submissions. We may, in some cases
use terms such as “predicts,” “believes,” “potential,” “continue,”
“anticipates,” “estimates,” “expects,” “plans,” “intends,” “may,”
“could,” “might,” “likely,” “will,” “should” or other words that
convey uncertainty of the future events or outcomes to identify
these forward-looking statements. Our forward-looking statements
are based on current beliefs and expectations of our management
team that involve risks, potential changes in circumstances,
assumptions, and uncertainties. Any or all of the
forward-looking statements may turn out to be wrong or be affected
by inaccurate assumptions we might make or by known or unknown
risks and uncertainties. These forward-looking statements are
subject to risks and uncertainties including risks related to the
success and timing of our clinical trials or other studies and the
other risks set forth in our filings with the U.S. Securities and
Exchange Commission, including our Quarterly Report on Form
10-Q. For all these reasons, actual results and developments
could be materially different from those expressed in or implied by
our forward-looking statements. You are cautioned not to place
undue reliance on these forward-looking statements, which are made
only as of the date of this press release. We undertake no
obligation to publicly update such forward-looking statements to
reflect subsequent events or circumstances.
Source: Aprea Therapeutics, Inc.
Corporate Contacts:
Christian S. Schade
President and Chief Executive Officer
chris.schade@aprea.com
Gregory A. Korbel
Vice President of Business Development
greg.korbel@aprea.com
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