-- THE-630 demonstrates encouraging safety
profile through Cohort 6 (18 mg), supportive of continued dose
escalation --
-- Dose-dependent reductions observed in ctDNA
KIT-mutant allele fractions for both major classes of KIT
resistance mutations at exposures consistent with preclinical
predictions observed in Predictive Resistance Assay™ --
-- Evidence of clinical activity observed in
heavily pre-treated patient population at exposures below target,
with 8 out of 9 evaluable patients treated in Cohorts 4-6 (9 to 18
mg) achieving stable disease --
-- Dose escalation ongoing to achieve target
exposure of 100 nM predicted for pan-variant KIT activity,
projected in Cohort 8 (40 mg) --
-- Company to host virtual investor event
today at 5:30pm ET --
CAMBRIDGE, Mass., May 25, 2023
/PRNewswire/ -- Theseus Pharmaceuticals, Inc. (NASDAQ: THRX)
(Theseus or the Company), a clinical-stage biopharmaceutical
company focused on improving the lives of cancer patients through
the discovery, development, and commercialization of transformative
targeted therapies, today announced initial dose escalation data
from the ongoing phase 1/2 trial of THE-630 in patients with
advanced gastrointestinal stromal tumors (GIST).
Theseus will host a virtual investor webcast today at
5:30pm ET to discuss this update.
"THE-630 has shown strong clinical proof of mechanism through
Cohort 6 with a safety and pharmacokinetic profile supportive of
continued dose escalation," said Tim
Clackson, Ph.D., President
and Chief Executive Officer of Theseus. "Importantly, with
dose-dependent activity observed against both major classes of KIT
resistance mutations, coupled with the increased frequency of
stable disease at the higher doses tested thus far, we believe
THE-630 could have a best-in-class profile and provide a
much-needed alternative to combat the complex resistance that
drives rapid progression of GIST. We are also encouraged by the
further validation of our PRA, with reductions in ctDNA observed
for specific mutations consistent with our preclinical predictions.
These data support our ability to reach target exposures in Cohort
8, and we look forward to reporting data through Cohort 8 later
this year."
"The emerging potential activity in both classes of resistance
mutations in the activation loop and ATP binding pocket is
promising, as it is critically important to be active against both
to provide a meaningful clinical benefit for patients," said
Suzanne George, M.D., Associate
Division Chief, Sarcoma Center, Dana-Farber Cancer Institute, and a
principal investigator on the phase 1/2 trial.
Reporting data on THE-630 through Cohort 6 (n=23);
currently dosing Cohort 7
- As of April 21, 2023, 25 patients
have been treated in the dose escalation portion of the trial: 23
patients enrolled in Cohorts 1-6 (3, 4, 6, 9, 12, 18 mg); 2
patients enrolled in Cohort 7 (27 mg).
-
- Following the data cutoff, both Cohort 7 patients subsequently
cleared the dose-limiting toxicity (DLT) observation period without
experiencing a DLT.
- All patients had metastatic KIT-mutant GIST.
- Patients in the trial had a median of 4 prior therapies (range
2 to 8); 70% of patients with ≥4 prior tyrosine kinase inhibitors
(TKIs).
-
- All patients received prior treatment with imatinib and
sunitinib.
- 65% of patients received prior treatment with ripretinib
and regorafenib.
Safety profile supportive of continued dose escalation;
pharmacokinetics (PK) consistent with once-daily oral
dosing
- The observed safety profile is consistent with the class and
with preclinical data.
- Treatment-related adverse events (TRAEs) were observed in 65%
of patients.
-
- Of 89 TRAEs reported, 84 (94%) were grades 1-2 and 5 (6%) were
grade ≥3 (3 of which occurred in Cohorts 1 and 2).
- The most common TRAEs (occurring in ≥10% of patients)
included fatigue, increased AST, diarrhea, nausea, dry mouth,
and dyspnea.
- In Cohort 2 (4 mg), a 9th-line, 64-year-old patient
with hyperlipidemia experienced a myocardial infarction (MI) on
study day 6 after being hospitalized for adverse events unrelated
to study drug, and subsequently died. The event was considered a
DLT as the relationship between THE-630 and the MI could not be
incontrovertibly ruled out.
-
- No cardiac ischemic AEs of any grade have been reported in the
other 22 patients in the study, including at significantly higher
exposure levels.
- No additional DLTs or treatment-related serious adverse events
have been observed, and the maximum tolerated dose (MTD) has not
been reached.
- PK profile approximately linear and consistent with once-daily
oral dosing.
Reductions in ctDNA of both classes of KIT
resistance mutations, consistent with preclinical PRA
predictions
- THE-630 reduced the allele frequency across all major classes
of KIT activating and resistance mutations in a manner consistent
with preclinical predictions seen in the Predictive Resistance
Assay (PRA), including dose-dependent and potent reduction of exon
13 mutation V654A, the most common resistance mutation seen in
GIST.
-
- Pre- and post-baseline samples were available for 19 patients,
including 2 in Cohort 6 (18 mg).
- KIT mutations were detected in 84% of patients (16 out of 19);
5 patients had more than one resistance mutation at baseline (range
2 to 6).
- ctDNA reductions were observed more frequently at higher doses,
with 6 out of 6 patients treated in Cohorts 4-6 (9 to 18 mg)
showing reductions in all KIT mutant variants present at baseline,
including activating mutations detected in exons 9 and 11, and
resistance mutations detected in exons 13, 14, and 17.
- Based on clinical PK through Cohort 6, and consistent with
ctDNA observations to date, THE-630 is projected to achieve
exposures consistent with pan-variant inhibition across all major
classes of KIT mutations, as predicted by the PRA, in Cohort
8.
Evidence of prolonged stable disease observed
- Disease stabilization was observed more frequently at higher
doses, with 8 out of 9 evaluable patients treated in Cohorts 4-6 (9
to 18 mg) achieving stable disease as best response, a disease
control rate of 89%.
- A patient with 5 prior lines of therapy and KIT exon 11 and
exon 17 (N822K) mutations detected in ctDNA at baseline had
prolonged stable disease, receiving THE-630 for 36 weeks (enrolled
in Cohort 2 [4 mg] with subsequent escalation to 6 mg and then 9
mg), with strong ctDNA reductions of both mutations observed.
- A patient with KIT exon 11 and exon 13 (V654A) mutations
detected in pre-treatment tumor biopsy remains on therapy with
stable disease maintained through at least 24 weeks (enrolled in
Cohort 5 [12 mg] and subsequently escalated to 18 mg).
"Today's data provide early clinical evidence that THE-630 could
potentially meet a critical need in patients with refractory GIST,"
said David Kerstein, M.D., Chief
Medical Officer of Theseus. "We are particularly excited by the
observed dose-dependent reductions in KIT mutations, along with
disease stabilization. With the encouraging early safety profile,
we look forward to continuing dose escalation to a recommended
phase 2 dose for THE-630."
Virtual Investor Event
Theseus will host a virtual investor event to review these
initial clinical results today, beginning at 5:30pm ET. The event will be webcast live and can
be accessed in the Events section of the Company's investor
relations website at https://ir.theseusrx.com/events. A replay of
the webcast will be archived and available for 90 days following
the event.
Date: Thursday, May 25, 5:30pm ET
Webcast link:
https://edge.media-server.com/mmc/p/izmfuvof/
Register for dial-in:
https://register.vevent.com/register/BI54a9015fcbd64a6a996a40c017a76abf
About THE-630
THE-630 is a pan-variant tyrosine kinase inhibitor (TKI) of the
receptor tyrosine kinase KIT, designed for patients with GIST that
have developed resistance to earlier lines of therapy.
THE-630 Clinical Trial Background and Clinical Development
Plan
Trial THE630-21-101 is a phase 1/2 open label, multicenter,
first-in-human dose escalation and expansion trial designed to
evaluate the safety, pharmacokinetics, and anti-tumor activity of
oral THE-630 (NCT Number: NCT05160168). The trial is expected to be
conducted in two parts: a dose escalation phase, followed by an
expansion phase. The patient population of the initial dose
escalation phase (phase 1) of the trial will include patients with
unresectable or metastatic GIST who had disease progression on or
are intolerant to imatinib therapy and have also received at least
one of the following: sunitinib, regorafenib, ripretinib, or
avapritinib. The primary objective of the dose escalation phase is
to determine the safety profile of THE-630, including the
dose-limiting toxicities, maximum tolerated dose, and the
recommended phase 2 dose.
Once a recommended dose has been determined in the dose
escalation phase, the dose expansion phase (phase 2) will enroll
patients with unresectable or metastatic GIST into three cohorts
defined by prior therapy, including a second-line cohort and a
fifth-line cohort. The primary objective of the expansion phase is
to evaluate the anti-tumor activity of THE-630 in these GIST
patient populations.
Data from the phase 1/2 clinical trial is expected to inform
further clinical development of THE-630 including the design of the
planned registrational trials for THE-630. Theseus is prioritizing
the development of THE-630 in second-line GIST, where a pan-variant
KIT inhibitor with activity against all major classes of
activating, or cancer-causing, and resistance mutations has the
potential to deliver meaningful clinical benefit over the current
standard of care. Theseus also plans to evaluate THE-630 in
fifth-line GIST, where there is currently no available therapy and
therefore a significant unmet need.
About Theseus Pharmaceuticals, Inc.
Theseus is a clinical-stage biopharmaceutical company focused on
improving the lives of cancer patients through the discovery,
development, and commercialization of transformative targeted
therapies. Theseus is working to outsmart cancer resistance by
developing pan-variant tyrosine kinase inhibitors (TKIs) to target
all classes of cancer-causing and resistance mutations that lead to
clinically relevant variants in a particular protein in a given
type of cancer. Theseus' lead product candidate, THE-630, is a
pan-variant KIT inhibitor for the treatment of patients with
advanced gastrointestinal stromal tumors (GIST), whose cancer has
developed resistance to earlier lines of kinase inhibitor therapy.
Theseus is also developing THE-349, a fourth-generation, selective
epidermal growth factor receptor (EGFR) inhibitor for
C797X-mediated resistance to first- or later-line osimertinib
treatment in patients with non-small cell lung cancer (NSCLC), and
a pan-variant BCR-ABL inhibitor for the treatment of
relapsed/refractory chronic myeloid leukemia (CML) and newly
diagnosed Philadelphia
chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). For
more information, visit www.theseusrx.com.
Cautionary Statement Regarding Forward Looking
Statements
Certain statements included in this press release are not
historical facts but are forward-looking statements for purposes of
the safe harbor provisions under the United States Private
Securities Litigation Reform Act of 1995. Forward-looking
statements generally are accompanied by words such as "believe,"
"may," "will," "estimate," "project," "anticipate," "expect,"
"plan," "predict," "potential," "on track," "seem," "outlook,"
"continue," "intend," and similar expressions that predict or
indicate future events or trends or that are not statements of
historical matters, but the absence of these words does not mean
that a statement is not forward-looking. These forward-looking
statements include, but are not limited to, statements regarding:
Theseus' strategy, future operations, prospects and plans; the
structure and timing of its preclinical studies and clinical
trials, expected milestones, and objectives of management; the
significance of initial dose escalation data from the ongoing phase
1/2 trial of THE-630 in patients with advanced GIST; the timing for
the presentation of further data for THE-630 and significance of
such results; Theseus' plans regarding the phase 1/2 dose
escalation and expansion clinical trial for THE-630; and the
ability of THE-630 to achieve desired drug exposure levels and
inhibit KIT variants.
Actual results may differ materially from those indicated by
such forward-looking statements as a result of various important
risks, uncertainties and other factors, including, but not limited
to: uncertainties inherent in preclinical studies and clinical
trials; risks and uncertainties regarding whether results from
preclinical studies and clinical trials will be predictive of the
results of future trials; risks related to the expected timing of
submissions to regulatory authorities and timing for review by such
regulatory authorities; risks related to market volatility and
global economic conditions; and other risks, uncertainties and
other factors such as those described from time to time in the
reports Theseus files with the Securities and Exchange Commission
(SEC), including Theseus' Form 10-K for the year ended December 31, 2022 and subsequent Quarterly
Reports on Form 10-Q which will be on file with the SEC and
available on the SEC's website at https://www.sec.gov/. However,
new risk factors and uncertainties may emerge from time to time
which may cause actual results to differ materially from those
anticipated or implied by the forward-looking statements in this
press release, and it is not possible to predict all risk factors
and uncertainties. Accordingly, readers are cautioned not to place
undue reliance on these forward-looking statements. Any
forward-looking statements contained in this press release are
based on the current expectations of Theseus' management team and
speak only as of the date hereof, and Theseus specifically
disclaims any obligation to update any forward-looking statement,
whether as a result of new information, future events or otherwise,
except as required by law.
Theseus Contact
Christen Baglaneas
Director, Corporate Communications & Investor Relations
Theseus Pharmaceuticals
857-706-4993
christen.baglaneas@theseusrx.com
Investor Contact
Josh
Rappaport
Stern Investor Relations
212-362-1200
josh.rappaport@sternir.com
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SOURCE Theseus Pharmaceuticals