LEXINGTON, Mass., June 11, 2021 /PRNewswire/ -- Curis, Inc.
(NASDAQ: CRIS), a biotechnology company focused on the development
of innovative therapeutics for the treatment of cancer, today
announced updated data from its ongoing Phase 1/2 open-label,
single arm, dose escalation and expansion trial of CA-4948, a
novel, small molecule IRAK4 kinase inhibitor, in patients with
acute myeloid leukemia (AML) or high-risk myelodysplastic syndromes
(MDS) at the European Hematology Association 2021 Virtual Congress
(EHA).
"As we have observed increasingly mature sets of data, we
continue to be pleased by the steady progression of clinical
activity demonstrated by CA-4948 monotherapy in this historically
difficult-to-treat late-line population," said James Dentzer, President and Chief Executive
Officer of Curis. "We believe these updated data further support
the growing body of evidence that CA-4948's anti-cancer activity
continues to deepen the longer patients remain on drug, which is
enabled by its safety and durability profile to date. Further,
after backfilling patient cohorts and evaluating additional data
after the April 30, 2021 cut-off date
for today's presentation, we have concluded 300mg BID is the
optimal dose to take into Phase 2 studies."
Mr. Dentzer added, "We are especially pleased with the outcomes
seen to date for patients with spliceosome or FLT3 mutations. All
three patients with a spliceosome mutation achieved an objective
response. The FLT3 patient also achieved an objective response and,
after two cycles of CA-4948, the patient's FLT3 mutation was found
to be completely eradicated. While these are early days, and we
have a limited set of patient data, we are very encouraged about
the potential CA-4948 may have to become a disease-modifying
alternative for these late-line patients, where no approved
therapies currently exist."
Mr. Dentzer continued, "In addition to the updated clinical data
presented today, we are also excited by the preclinical combination
synergy data announced, demonstrating that CA-4948 increases
anti-cancer activity in AML cell lines resistant to clinically
relevant concentrations of azacitidine and venetoclax, as well as
synergistic antileukemic activity in combination with venetoclax
and azacitidine. We look forward to initiating dosing in the Phase
1/2 combination study of CA-4948 plus azacitidine and CA-4948 plus
venetoclax in patients with R/R AML and MDS later this year."
"As a clinician for patients with high-risk MDS or AML, I am
acutely aware of the challenges of these diseases and the
limitations of existing treatments. I continue to be very
encouraged by the data coming out of this study," said Dr.
Guillermo Garcia-Manero, Chief of
the Section of Myelodysplastic Syndromes within the Department of
Leukemia at The University of Texas MD
Anderson Cancer Center and a lead investigator in the study. "This
is a late-line population, in which patients have few options
following repeated treatment failures and as a result, have deeply
damaged and dysfunctional marrow, which severely limits their odds
of hematologic recovery. Having an effective, non-myelosuppressive
drug that does not further damage their already fragile marrow is
of critical importance. The fact that some hematologic recovery has
been observed and appears to continue while patients remain on
therapy is an indication that CA-4948 may have the potential to
provide, for the first time, a well-tolerated and clinically active
treatment for this subset of heavily diseased patients."
The reported data are from Curis's ongoing open-label, single
arm Phase 1/2 dose escalation 3+3 study of orally administered
CA-4948 monotherapy in adult patients with AML or high-risk MDS. A
total of 22 patients (11 with high-risk MDS, 11 with AML) were
enrolled across dose cohorts of 200 mg BID, 300 mg BID, 400 mg BID,
and 500 mg BID. The primary objective of the study is to determine
the maximum tolerated dose (MTD) and recommended Phase 2 dose
(RP2D) for CA-4948 based on safety and tolerability, dose-limiting
toxicities (DLT), and any biologic activity, pharmacokinetic (PK),
and pharmacodynamic (PD) findings from the trial population.
Additional objectives include characterization of CA-4948's
pharmacokinetic parameters and biomarker correlations.
Key findings from an oral presentation today at EHA presented by
Dr. Garcia-Manero from an April 30,
2021 cutoff in 17 evaluable patients (9 MDS and 8 AML),
include:
- Bone marrow blast reductions observed at all tested doses in 10
of 12 patients who were evaluable for bone marrow response
(elevated blast count at baseline and at least one malignancy
assessment following first cycle).
- 5 objective responses observed included:
-
- 1 patient experiencing a full hematologic recovery CR
- 1 patient with CRi with negative minimal residual disease
- 1 patient with partial response
- 2 patients with marrow CRs
- 3 patients had SF3B1 or U2AF1 spliceosome mutation and all 3
achieved marrow CR or better.
- All patients with objective responses also saw signs of
hematologic recovery.
- Genomic analyses from multiple patients show disease
modification by CA-4948:
-
- DNA sequencing demonstrates disease modification with the
reduction of cancer-associated variant allele frequency after
CA-4948 treatment
- RNA sequencing demonstrates disease modification with the
reduction of long/short ratio of IRAK4 after CA-4948 treatment
- No significant myeloid suppressive adverse events were
observed.
Key findings from additional information included in today's
management's KOL presentation:
- An AML patient with spliceosome mutation SF3B1 who has
experienced a durable objective response has been on study for over
8 months. In December 2020, this
patient was reported as having a Marrow CR and has since improved
to a CRi with negative minimal residual disease.
- An AML patient with a FLT3 mutation, whose disease had relapsed
after prior treatment with decitabine and venetoclax and was
refractory to subsequent treatment with gilteritinib, experienced a
partial response (90% decrease in marrow blast count, from 60% to
6%) as well as elimination of detectable FLT3 mutation based on
genomic analysis post-treatment with CA-4948.
- An AML patient with 4 prior lines of chemotherapy treatment
showed reduction of IRAK4-L expression following CA-4948 treatment
as well as a full recovery of hematologic parameters and has been
on study for over 7 months.
Key findings in determining 300mg BID to be the Recommended
Phase 2 Dose include:
- Safety: No DLTs
observed
- PK/PD: PK exposure
correlates with 98% target inhibition
- Efficacy: 12 evaluable patients in the
study had elevated blasts at baseline;
4
of these patients were dosed at 300mg BID;
All 4 patients achieved blast reductions, including CRi and
negative MRD
- Including additional patients enrolled after the April 30, 2021 cut-off at doses higher than the
Recommended Phase 2 Dose, a total of 4 DLTs were observed:
-
- 400mg: 13% of patients experienced DLT (2 Grade 3
rhabdomyolysis)
- 500mg: 66% of patients experienced DLT (1 Grade 3
rhabdomyolysis and 1 Grade 3 syncope)
- All three rhabdomyolysis cases were quickly detected by
elevated CPK and resolved after dosing interruption; no cases
involved renal dysfunction.
Key findings from a poster presentation today at EHA of
preclinical data in AML cell lines:
- Combination with CA-4948 increased the antitumor effect of
azacitidine
- Combination with CA-4948 increased the antitumor effect of
venetoclax
- Combination with CA-4948 increased the antitumor effect of
venetoclax + azacitidine
- We believe synergistic activity observed in leukemia cells
provides a rationale for clinical testing of CA-4948 + azacitidine,
CA-4948 + venetoclax, and the triplet combination of all three
agents together in patients with AML.
Webcast Event Information
Curis management will host a virtual KOL event today,
June 11, 2021 at 8:00 am ET to discuss these results with Dr.
Guillermo Garcia-Manero. To access
the webcast, please visit the Events & Presentations section of
the Curis website at www.curis.com.
About CA-4948
CA-4948 is an IRAK4 kinase inhibitor and IRAK4 plays an
essential role in the toll-like receptor (TLR) and interleukin-1
receptor (IL-1R) signaling pathways, which are frequently
dysregulated in patients with AML and MDS. Third parties have
recently discovered that the long form of IRAK4 (IRAK4-L) is
oncogenic and preferentially expressed in over half of patients
with AML and MDS. The overexpression of IRAK4-L is believed to be
driven by a variety of factors, including specific spliceosome
mutations such as SF3B1 and U2AF1.
About Curis, Inc.
Curis is a biotechnology company focused on the development of
innovative therapeutics for the treatment of cancer. In 2015, Curis
entered into a collaboration with Aurigene in the areas of
immuno-oncology and precision oncology. As part of this
collaboration, Curis has exclusive licenses to oral small molecule
antagonists of immune checkpoints including the VISTA/PDL1
antagonist CA-170, and the TIM3/PDL1 antagonist CA-327, as well as
the IRAK4 kinase inhibitor, CA-4948. CA-4948 is currently
undergoing testing in a Phase 1/2 trial in patients with
non-Hodgkin's lymphoma both as a monotherapy and in combination the
with BTK inhibitor ibrutinib. Curis is also evaluating CA-4948 in a
Phase 1/2 trial in patients with acute myeloid leukemia and
myelodysplastic syndromes, for which it has received Orphan Drug
Designation from the U.S. Food and Drug Administration. In
addition, Curis is engaged in a collaboration with ImmuNext for
development of CI-8993, a monoclonal anti-VISTA antibody,
which is currently undergoing testing in a Phase 1 trial in
patients with solid tumors. Curis is also party to a collaboration
with Genentech, a member of the Roche Group, under which Genentech
and Roche are commercializing Erivedge® for the
treatment of advanced basal cell carcinoma. For more information,
visit Curis' website at www.curis.com.
Cautionary Note Regarding Forward-Looking Statements:
This press release contains forward-looking statements within
the meaning of the U.S. Private Securities Litigation Reform Act of
1995, including, without limitation, statements regarding any
expectations of the potential for the Company's proprietary drug
candidate CA-4948, including with respect to the potency,
anti-cancer activity, durability and tolerability of CA-4948,
future studies with respect to CA-4948, the potential advantages
and benefits of CA-4948 and small molecule checkpoint antagonists,
and the Company's plans to advance its development programs.
Forward-looking statements may contain the words "believes,"
"expects," "anticipates," "plans," "intends," "seeks," "estimates,"
"assumes," "will," "may," "could" or similar expressions. These
forward-looking statements are not guarantees of future performance
and involve risks, uncertainties, assumptions and other important
factors that may cause actual results to be materially different
from those indicated by such forward-looking statements. For
example, Curis may experience adverse results, delays and/or
failures in its drug development programs and may not be able to
successfully advance the development of its drug candidates in the
time frames it projects, if at all. Curis's drug candidates may
cause unexpected toxicities, fail to demonstrate sufficient safety
and efficacy in clinical studies and/or may never achieve the
requisite regulatory approvals needed for commercialization.
Favorable results seen in preclinical studies and early clinical
trials of Curis's drug candidates may not be replicated in later
trials. There can be no guarantee that the collaboration agreements
with Aurigene and ImmuNext, or the CRADA with NCI, will continue
for their full terms, that Curis or its collaborators will each
maintain the financial and other resources necessary to continue
financing their respective portions of the research, development
and commercialization costs, or that the parties will successfully
discover, develop or commercialize drug candidates under the
collaborations. Regulatory authorities may determine to delay or
restrict Genentech's and/or Roche's ability to continue to develop
or commercialize Erivedge in BCC. Erivedge may not demonstrate
sufficient or any activity to merit its further development in
disease indications other than BCC. Competing drugs may be
developed that are superior to Erivedge. In connection with its
agreement with Oberland Capital, Curis faces risks relating to the
transfer and encumbrance of certain royalty and royalty-related
payments on commercial sales of Erivedge, including the risk that,
in the event of a default by Curis or its wholly-owned subsidiary,
Curis could lose all retained rights to future royalty and
royalty-related payments, Curis could be required to repurchase
such future royalty and royalty-related payments at a price that is
a multiple of the payments it has received, and its ability to
enter into future arrangements may be inhibited, all of which could
have a material adverse effect on its business, financial condition
and stock price. Curis will require substantial additional capital
to fund its business. If it is not able to obtain sufficient
funding, it will be forced to delay, reduce in scope or eliminate
some of its research and development programs, including related
clinical trials and operating expenses, potentially delaying the
time to market for, or preventing the marketing of, any of its
product candidates, which could adversely affect its business
prospects and its ability to continue operations, and would have a
negative impact on its financial condition and its ability to
pursue its business strategies. Curis faces substantial
competition. Curis and its collaborators face the risk of potential
adverse decisions made by the FDA and other regulatory authorities,
investigational review boards, and publication review bodies. Curis
may not obtain or maintain necessary patent protection and could
become involved in expensive and time-consuming patent litigation
and interference proceedings. Unstable market and economic
conditions, natural disasters, public health crises, political
crises and other events outside of Curis's control could
significantly disrupt its operations or the operations of third
parties on which Curis depends, and could adversely impact Curis's
operating results and its ability to raise capital. For example,
the COVID-19 pandemic may result in closures of third-party
facilities, impact enrollment in clinical trials or impact sales of
Erivedge by Genentech and/or Roche. The extent to which the
COVID-19 pandemic may impact Curis's business or operating results
is uncertain. Other important factors that may cause or contribute
to actual results being materially different from those indicated
by forward-looking statements include the factors set forth under
the caption "Risk Factors" in Curis's most recent Form 10-K and
Form 10-Q and the factors that are discussed in other filings that
Curis periodically makes with the Securities and Exchange
Commission. In addition, any forward-looking statements represent
the views of Curis only as of today and should not be relied upon
as representing Curis's views as of any subsequent date. Curis
disclaims any intention or obligation to update any of the
forward-looking statements after the date of this press release
whether as a result of new information, future events or otherwise,
except as may be required by law.
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