Monte Rosa Therapeutics, a clinical-stage biotechnology company
developing novel molecular glue degrader (MGD)-based medicines,
today announced interim data from the Phase 1 dose escalation part
of its ongoing Phase 1/2 open-label, multicenter study of MRT-2359
in patients with MYC-driven solid tumors, including lung cancers
and high-grade neuroendocrine cancer. MRT-2359 is an
investigational, orally bioavailable, GSPT1-directed MGD discovered
by Monte Rosa Therapeutics. Cancers driven by MYC overexpression
have been demonstrated to be dependent on GSPT1, creating a
therapeutic opportunity.
Interim clinical data from the MRT-2359 study
have demonstrated favorable tolerability, pharmacokinetic (PK), and
pharmacodynamic (PD) profiles in heavily pre-treated patients with
lung cancers and high-grade neuroendocrine cancer. In addition,
MRT-2359 has been observed to significantly reduce GSPT1 protein
levels in patient tumors and has shown evidence of tumor size
reductions, including partial responses, in heavily pretreated
patients with biomarker-positive tumors. Monte Rosa is continuing
with dose level and schedule optimization in this ongoing
study.
“We’re highly encouraged by the safety profile,
the depth of pharmacodynamic modulation of GSPT1 in tumors, and
even more so by the early evidence of anti-tumor activity of
MRT-2359 in patients with biomarker-positive cancers,” said Markus
Warmuth, M.D., Chief Executive Officer of Monte Rosa Therapeutics.
“We believe these results, the first ever to show clinical activity
of a rationally designed molecular glue degrader in solid tumors,
represent an important advance for the field and underscore the
potential for MRT-2359 to benefit patients living with a variety of
difficult-to-treat cancers. We are excited to learn more about the
clinical profile of MRT-2359 in our ongoing Phase 1/2 clinical
study, and early next year we plan to provide further clarity on
the expected timing for the full Phase 1 data disclosure in
2024.”
Summary of available study results:
- As of the analysis cutoff date of
September 7, 2023, 21 patients had been dosed, with 15 of the 21
patients evaluable for efficacy.
- Optimal PD modulation of GSPT1 by
MRT-2359 was observed at all dose levels, consistent with its
designed activity based on preclinical studies. Following MRT-2359
dosing, approximately 60% reduction in GSPT1 protein expression was
observed in peripheral blood mononuclear cells and tumor tissue
biopsies. Similar levels of degradation were observed across all
dose levels, suggesting saturated PD responses from 0.5 mg to 2 mg
and supporting that pharmacodynamically, 0.5 mg is a fully active
dose. The level of GSPT1 degradation observed was in line with the
levels seen in preclinical studies that were associated with
anti-tumor activity.
- Of the 15 evaluable patients that
have been administered MRT-2359 across three dose cohorts (0.5 mg,
1 mg, and 2 mg in a 5 days on-drug, 9 days off-drug dosing
schedule), six were identified as biomarker-positive in indicated
tumor types, specifically N-MYC high non-small cell lung cancer
(NSCLC) adenocarcinoma, L-/N-MYC high small cell lung cancer
(SCLC), L-/N-MYC high-grade neuroendocrine tumors (prostate,
bladder, and others) and neuroendocrine tumors of the lung.
- Clinical activity was seen across
all dose levels. Of the six biomarker-positive patients, two
achieved a partial response (PR), one confirmed and one
unconfirmed, and one patient experienced durable stable disease
(SD). Additionally, one patient who had an unevaluable biomarker
status also experienced durable SD.
- The MRT-2359 safety profile
supports further clinical development, with no signs of
hypotension, cytokine release syndrome (CRS) or clinically
significant hypocalcemia observed at any dose level, all of which
have been reported as safety limitations of other GSPT1 degraders.
The 0.5 mg and 1 mg dose levels resulted in Grade 1 or 2
treatment-related adverse events (AEs) only. At the 2 mg dose
level, Grade 4 thrombocytopenia (dose-limiting toxicity (DLT), n=2)
and Grade 4 neutropenia (non-DLT, n=1) were observed, findings
consistent with preclinical toxicology studies. No patients
discontinued treatment due to AEs at any dose level, and the Grade
4 AEs observed at the 2 mg dose were transient and resolved with
dose reductions.
"Observing clinical activity in multiple
patients who have exhausted all other treatment options strengthens
our optimism about the potential of MRT-2359 for patients with
MYC-driven solid tumors. This represents a sizable patient group,
encompassing many cancer types, that currently experience
significant unmet need. We continue to explore optimal doses and
dosing schedules as we collect clinical data from this ongoing
Phase 1/2 study," said Filip Janku, M.D., Ph.D., Chief Medical
Officer of Monte Rosa Therapeutics.
Jordi Rodon Ahnert, M.D., Ph.D., Associate
Professor, The University of Texas MD Anderson Cancer Center and
Principal Investigator on the study, commented: “While the
molecular role of MYC as a common driver of numerous cancers has
been well appreciated for decades, the development of an effective
therapeutic targeting this pathway has remained elusive. An
effective drug for MYC-driven cancers could represent an important
new therapeutic approach with applicability against many cancers.
These early MRT-2359 data suggest that this highly specific MGD is
clinically active in a treatment-refractory population and strongly
support continued development.”
Monte Rosa Therapeutics is continuing with dose
and schedule optimization as well as enrollment of
biomarker-positive patients into various backfill cohorts of the
Phase I part of the study. The company is currently dosing MRT-2359
at 1.5 mg in a 5 days on-drug, 9 days off-drug dosing schedule and,
based on the observed safety profile, is considering a 21 days
on-drug, 7 days off-drug dosing regimen.
Conference CallMonte Rosa
Therapeutics will host a conference call and webcast today at 8:00
a.m. ET to discuss the interim PK/PD and clinical data for
MRT-2359. To participate via telephone and join the call live,
please register in advance here. Upon registration, telephone
participants will receive a confirmation email detailing how to
join the conference call, including the dial-in number and a unique
passcode. A live webcast of the call will also be available on the
Investors section of the Monte Rosa website at ir.monterosatx.com,
and a replay of the call will be available at the same link
approximately two hours after its completion. The replay will be
available for at least 30 days following the conclusion of the
call.
About MRT-2359
MRT-2359 is a potent, selective, and orally
bioavailable investigational molecular glue degrader (MGD) that
induces the interaction between the E3 ubiquitin ligase component
cereblon and the translation termination factor GSPT1, leading to
the targeted degradation of GSPT1 protein. The MYC transcription
factors (c-MYC, L-MYC, and N-MYC) are well-established drivers of
human cancers that maintain high levels of protein translation,
which is critical for uncontrolled cell proliferation and tumor
growth. Preclinical studies have shown that this addiction to
MYC-induced protein translation creates a dependency on GSPT1. By
inducing degradation of GSPT1, MRT-2359 is designed to exploit this
vulnerability, disrupting the protein synthesis machinery and
leading to anti-tumor activity in MYC-driven tumors.
About the Phase1/2 Study of MRT-2359
The Phase 1/2, open-label, multicenter study is
designed to assess the safety, tolerability, PK, PD and preliminary
clinical activity of MRT-2359 in patients with previously treated
selected solid tumors, including non-small cell lung cancer
(NSCLC), small cell lung cancer (SCLC), high-grade neuroendocrine
cancer of any primary site, diffuse large B-cell lymphoma (DLBCL)
and solid tumors with L-MYC or N-MYC amplification. In the Phase 1
portion of the study, patients receive escalating doses of MRT-2359
to determine the maximum tolerated dose (MTD) and recommended Phase
2 dose (RP2D). Once the RP2D is determined, the anti-tumor activity
of MRT-2359 will be assessed as part of the Phase 2 portion of the
study, which includes molecular biomarkers for stratification and
selection.
For more information visit clinicaltrials.gov (Study Identifier:
NCT05546268).
About Monte Rosa
Monte Rosa Therapeutics is a clinical-stage
biotechnology company developing highly selective molecular glue
degrader (MGD) medicines for patients living with serious diseases
in the areas of oncology, autoimmune and inflammatory diseases, and
more. MGDs are small molecule protein degraders that have the
potential to treat many diseases that other modalities, including
other degraders, cannot. Monta Rosa’s QuEEN™ (Quantitative and
Engineered Elimination of Neosubstrates) discovery engine combines
AI-guided chemistry, diverse chemical libraries, structural biology
and proteomics to identify degradable protein targets and
rationally design MGDs with unprecedented selectivity. The QuEEN
discovery engine enables access to a wide-ranging and
differentiated target space of well-validated biology across
multiple therapeutic areas. Monte Rosa has developed the industry’s
leading pipeline of MGDs, which spans oncology, autoimmune and
inflammatory disease and beyond. For more information, visit
www.monterosatx.com
Forward-Looking Statements
This communication includes express and implied
“forward-looking statements,” including forward-looking statements
within the meaning of the Private Securities Litigation Reform Act
of 1995. Forward-looking statements include all statements that are
not historical facts and in some cases, can be identified by terms
such as “may,” “might,” “will,” “could,” “would,” “should,”
“expect,” “intend,” “plan,” “objective,” “anticipate,” “believe,”
“estimate,” “predict,” “potential,” “continue,” “ongoing,” or the
negative of these terms, or other comparable terminology intended
to identify statements about the future. Forward-looking statements
contained herein include, but are not limited to, statements about
our ongoing pre-clinical and clinical development of our GSPT1
degrader referred to as MRT-2359, including our expectations
regarding the potential relevance of certain interim clinical data,
and our expectations for the nature and timing of our clinical
development of MRT-2359, the potential for MRT-2359 to benefit
patients living with a variety of difficult-to-treat cancers and
MYC-driven solid tumors, our plans to continue the Phase 1/2 Study
of MRT-2359, including its anticipated progress, clinical trial
design and our ability to enroll the requisite number of patients
and dose each dosing cohort in the intended manner, our QuEEN™
discovery engine and our view of its potential to identify
degradable protein targets and rationally design MGDs with
unprecedented selectivity, our pipeline of MGDs being the industry
leader, spanning oncology, autoimmune and inflammatory diseases and
beyond, as well as our expectations of success for our programs and
the strength of our financial position, among others. By their
nature, these statements are subject to numerous risks and
uncertainties, including those risks and uncertainties set forth in
our most recent Annual Report on Form 10-K for the year ended
December 31, 2022, filed with the U.S. Securities and Exchange
Commission on March 16, 2023, and any subsequent filings, that
could cause actual results, performance or achievement to differ
materially and adversely from those anticipated or implied in the
statements. You should not rely upon forward-looking statements as
predictions of future events. Although our management believes that
the expectations reflected in our statements are reasonable, we
cannot guarantee that the future results, performance, or events
and circumstances described in the forward-looking statements will
be achieved or occur. Recipients are cautioned not to place undue
reliance on these forward-looking statements, which speak only as
of the date such statements are made and should not be construed as
statements of fact. We undertake no obligation to publicly update
any forward-looking statements, whether as a result of new
information, any future presentations, or otherwise, except as
required by applicable law. Certain information contained in these
materials and any statements made orally during any presentation of
these materials that relate to the materials or are based on
studies, publications, surveys and other data obtained from
third-party sources and our own internal estimates and research.
While we believe these third-party studies, publications, surveys
and other data to be reliable as of the date of these materials, we
have not independently verified, and make no representations as to
the adequacy, fairness, accuracy or completeness of, any
information obtained from third-party sources. In addition, no
independent source has evaluated the reasonableness or accuracy of
our internal estimates or research and no reliance should be made
on any information or statements made in these materials relating
to or based on such internal estimates and research.
InvestorsAndrew Funderburk, Kendall
IRir@monterosatx.com
MediaCory Tromblee, Scient
PRmedia@monterosatx.com
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