Interim late-breaking clinical data validate not-alpha profile of THOR-707 (SAR444245), Sanofi’s novel investigational IL-2...
08 Abril 2021 - 11:01PM
Interim late-breaking clinical data validate not-alpha
profile of THOR-707 (SAR444245), Sanofi’s novel investigational
IL-2
- Early clinical results are consistent with preclinical studies
and suggest THOR-707 (SAR444245) may promote an anti-tumor immune
response without alpha-mediated side effects, both alone and in
combination with anti-PD-1
- THOR-707, a precisely PEGylated, engineered version of IL-2
built on Sanofi’s Synthorin™ technology platform, is being studied
in a trial of adults with advanced or metastatic solid tumors
PARIS – April 9, 2021 – Interim
data from a first-in-human trial evaluating the safety, therapeutic
activity and maximum tolerable dose of THOR-707 (SAR444245), a
highly differentiated not-alpha interleukin-2 (IL-2) candidate, as
a monotherapy and in combination with anti-PD-1, will be presented
Saturday, April 10 as a late-breaking poster presentation at the
American Association for Cancer Research (AACR) Annual Meeting. The
Saturday late-breaking poster session will include additional
updated data.
Interim safety, anti-tumor activity and
biomarker data further validate the not-alpha IL-2 profile seen
preclinically. In both the combination and monotherapy settings,
initial activity was observed, with three confirmed partial
responses, which includes patients who have received prior
anti-PD-1 therapeutics.
"THOR-707 has a potentially best-in-class
profile and reinforces the promise of our Synthorin technology
platform to overcome difficult targets with precision biology,”
said John Reed, M.D. Ph.D., Global Head of Research &
Development, Sanofi. “The activity observed both as single agent
and with an anti-PD-1 further strengthens our belief that as a
unique not-alpha IL-2, THOR-707 could become a backbone of future
immuno-oncology therapies. We will continue to explore the
molecule’s potential for best-in-disease combinations.”
THOR-707 is a precisely PEGylated version of
IL-2, where the PEG chain is attached to a novel amino acid
inserted at a location on IL-2 that prevents it from engaging the
alpha-receptor and binding to immune receptors that cause drug
toxicities (IL-2R-alpha, CD25). The engineered IL-2 retains
near-native binding to the beta-gamma receptors that selectively
expand tumor-killing T effector cells and Natural Killer (NK) cells
without the alpha-mediated immunosuppressive effects of regulatory
T cells or eosinophil-mediated vascular leak syndrome.
Interim results indicate a similar pattern where
CD8+ T cells and NK cells increased after the first dose of
THOR-707 and sustained throughout the entire cycle , with a dose
escalating effect; this effect was enhanced when combined with
KEYTRUDA® (pembrolizumab). No significant increases in CD4+
regulatory
T
cells or eosinophils were observed, indicative of not-alpha IL-2
receptor selectivity.
No dose-limiting toxicities were observed for
THOR-707 at reported doses, up to 24 μg/kg as monotherapy and 16
μg/kg in combination. The most common treatment emergent adverse
events (TEAEs) following the first dose included flu-like symptoms,
fever, vomiting/nausea and chills. Symptoms were transient and
resolved with standard supportive care. Among G3-4 related
toxicities was a transient decrease in lymphocyte count, which
preceded T cell expansion.
No eosinophilia or vascular leak syndrome was
reported at any doses tested. IL-5 levels remained at or below the
lowest level of detection, suggesting a rationale for the lack of
IL-5 associated toxicity observed during treatment.
“Novel approaches, such as not-alpha IL-2, seek
to activate this powerful immune pathway while mitigating current
challenges with dosing and safety to potentially expand the patient
population who could benefit from treatment,” said Filip Janku,
M.D. Ph.D., Associate Professor, Department of Investigational
Cancer Therapeutics, Division of Cancer Medicine, The University of
Texas MD Anderson Cancer Center, Houston, TX. “Preclinically,
THOR-707 appeared to activate an anti-tumor immune response without
an increased risk of alpha-mediated toxicities, such as
eosinophilia or vascular leak syndrome. While early, the interim
clinical data at AACR align very closely to what we saw in
preclinical research and suggest further study of this not-alpha
IL-2 molecule is warranted, both alone and in combination with a
synergistic treatment such as anti-PD-1.”
THOR-707 dose escalation has progressed beyond
projected monotherapy RP2D of 24 μg/kg Q3W to 32 μg/kg Q3W to
further characterize the upper bounds of the dose range.
In addition to testing THOR-707 in combination
with KEYTRUDA, Sanofi is planning to evaluate the activity of this
novel biologic in combination with other anti-PD-1 antibodies,
including Libtayo®1, (cemiplimab) anti-CD38 antibody Sarclisa®
(isatuximab) and anti-EGFR.
Editor’s Note: Sanofi
previously entered into an agreement with Merck & Co. Inc.,
Kenilworth, NJ, USA (known as MSD outside the U.S. and Canada) to
conduct a Phase 2 trial evaluating THOR-707 combined with or in
sequenced administration with KEYTRUDA.
About THOR-707 (SAR444245)
THOR-707 is a precisely PEGylated engineered
version of IL-2 with an increased half-life being investigated for
the treatment of many types of malignancies. Additionally,
pharmacology is being assessed to determine if THOR-707 may allow
for less frequent dosing. In pre-clinical experiments, THOR-707
exhibited the ability to induce the expansion of CD8+T-cells
suggesting potential for anti-tumor effects both as single agent as
well as in combination with an anti-PD-1 monoclonal antibody.
THOR-707 is not approved by any regulatory authority.
THOR-707 is the first molecule from the
Synthorin™ technology platform. Synthorins are novel proteins built
on Sanofi’s unique Expanded Genetic Alphabet platform, which allows
scientists to fill important gaps in protein therapeutics by
vastly expanding the variety of building blocks available to
bioengineers. Used on its own or in combination with other Sanofi
technologies, the Expanded Genetic Alphabet platform is enabling
the company’s scientists and bioengineers to develop novel
biologics for cancer and other diseases.
About Sanofi Sanofi is dedicated to
supporting people through their health challenges. We are a global
biopharmaceutical company focused on human health. We prevent
illness with vaccines, provide innovative treatments to fight pain
and ease suffering. We stand by the few who suffer from rare
diseases and the millions with long-term chronic
conditions. With more than 100,000 people in 100 countries,
Sanofi is transforming scientific innovation into healthcare
solutions around the globe. Sanofi, Empowering
Life |
Sanofi Media Relations Contact Sally Bain
Tel: +1 781-264-1091 Sally.Bain@sanofi.com
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