SHANGHAI, June 19,
2024 /PRNewswire/ -- GenFleet Therapeutics, a
clinical-stage biotechnology company focusing on cutting-edge
therapies in oncology and immunology, announced China's National Medical Products
Administration (NMPA) has approved the clinical trial application
for GFH375 (VS-7375) in an open-label, multi-center phase I/II
study targeting advanced solid tumor patients with KRAS G12D
mutation. G12D mutation is the most prevalent KRAS mutation
detected in human cancers, and no G12D-targeted therapies have been
approved yet.
GFH375 is a highly potent and selective KRAS G12D inhibitor
targeting both "ON" (GTP-bound) and "OFF" (GDP-bound) states of the
protein. According to the latest preclinical findings posted at
2024 AACR annual meeting, GFH375 demonstrated preliminary safety
data, favorable oral bioavailability and potent efficacy across
preclinical models; moreover, GFH375 holds the potential for
treating G12D-mutant cancers with brain metastases.
GenFleet entered into a discovery and development collaboration
with Verastem Oncology (Nasdaq: VSTM) in 2023 to advance three
oncology programs. The first program selected is GFH375, which
represents a significant milestone as the GenFleet's first product
to achieve overseas out-licensing at preclinical stage and the IND
approval in China, underscoring
the company's expertise in the development of RAS-targeted
therapies.
The study (GFH375X1101) will be conducted at ~40 hospitals,
including the prominent Shanghai Chest Hospital. In phase I, the
study aims to evaluate the safety/tolerability and preliminary
efficacy of GFH375 in advanced G12D-mutant solid tumor patients.
Additionally, the phase I trial will determine the recommended
phase II dose (RP2D). Progressing into Phase II, the study will
further assess the efficacy of GFH375 for patients of advanced
solid tumors including pancreatic ductal adenocarcinoma (PDAC),
colorectal cancer (CRC), and non-small cell lung cancer (NSCLC) –
three cancer types with highest prevalence of G12D mutation; the
study will also investigate the underlying mechanisms of patients'
response and resistance to the treatment.
"I am excited that the clinical trial application for GFH375 has
been approved. The therapeutic landscape for G12D-mutant cancers
remains challenging with limited treatment options, highlighting
the significant unmet medical needs in this population. The G12D
mutation is one of the most prevalent KRAS mutations and the
development of G12D-targeted therapies has garnered significant
attention recently. We eagerly await favorable safety and efficacy
outcome for GFH375 in the upcoming trial, with the hope of
introducing a novel life-saving treatment for patients." stated Dr.
Shun Lu, professor of Dept. of
Medical Oncology, Shanghai Chest Hospital.
"We are delighted to enter in a clinical trial to assess the
clinical benefits of our G12D targeted program in monotherapy
setting and explore the possibilities of synergistic effects that
may arise from potential combination regimen in future. GenFleet's
expertise in developing RAS-targeted therapies has been exemplified
by the successful development of fulzerasib (GFH925, a KRAS G12C
inhibitor) and the NDA acceptance of its monotherapy for NSCLC in
China. This allows GenFleet to be
well positioned to advance our second RAS pathway inhibitor GFH375
into the clinical trial, as well as other RAS-inhibiting therapies
in our pipeline." stated Yu
Wang, Ph.D/M.D., Chief Medical Official of GenFleet.
References:
1. Impact of KRAS mutations and co-mutations on clinical
outcomes in pancreatic ductal adenocarcinoma, NPJ Precision
Oncology, Feb. 2024
2. Next batter up! Targeting cancers with KRAS G12D
mutations, Trends in Cancer (Cell Press), Nov. 2023
3. Pan-KRAS inhibitor disables oncogenic signaling and
tumor growth, Nature, May 2023
About KRAS G12D mutation and GFH375
RAS proteins, in active GTP-bound or inactive GDP-bound form,
are binary molecular switches controlling cellular responses in
signaling pathways including RAS-RAF-MEK-ERK and PI3K/AKT/mTOR.
Three RAS genes encode for protein isoforms, namely Kirsten Ras (KRAS), Harvey Ras (HRAS) and Neuroblastoma Ras (NRAS),
and KRAS is the most frequently mutated oncogene in humans. Among
KRAS mutations, G12D, G12V, and G12C represent the top three most
frequently mutated alleles. KRAS G12D mutation is commonly found in
pancreatic ductal adenocarcinoma, colorectal cancer, and lung
adenocarcinoma. A large percentage of patients harboring KRAS G12D
mutation are found without smoking history and with poor response
to PD-1 inhibitors. Mutant-selective G12D inhibitors hold promise
to benefit large segments of KRAS-driven PDAC patients since KRAS
G12D alterations are the most frequently occurring somatic change
in PDAC patients (about 40%) who are reported to have an overall
5-year survival rate lower than 10%.
GFH375 is an orally active, potent, highly selective
small-molecule KRAS G12D (ON/OFF) inhibitor designed to target the
GTP/GDP exchange, thereby disrupting the activation of downstream
pathways and effectively inhibiting tumor cell proliferation.
Preclinical studies demonstrated that the inhibition of GFH375 on
tumor growth is enhanced along with the increase in dosage and
duration of treatment; GFH375 also demonstrated low off-target risk
in kinase selectivity and safety target assays.
GenFleet entered into a discovery and development collaboration
with Verastem Oncology (Nasdaq: VSTM) to advance three novel
oncology discovery programs related to RAS pathway-driven cancers.
The risk-sharing structure of the collaboration provides Verastem
Oncology a milestone-based option to license up to three compounds.
The licenses would give Verastem Oncology development and
commercialization rights outside of China while GenFleet would retain rights
inside of the Chinese mainland, Hong
Kong, Macau, and
Taiwan.
About GenFleet Therapeutics
GenFleet Therapeutics, a clinical-stage biotechnology company
focusing on cutting-edge therapies, is dedicated to serving
significant global unmet medical needs in oncology and immunology.
Based on the deep understanding of disease biology and
translational medicine, GenFleet's proprietary and fully integrated
R&D platform highlights multiple cutting-edge products with
novel mechanisms and global IP.
Since its inception in 2017, GenFleet has built up
industry-leading capabilities and expertise in developing novel
drug candidates - both small molecules and biologics. Its pipeline
includes over 10 programs, many of which have entered
multi-regional clinical trials across China (including Taiwan), the United
States, Europe and
Australia. To date, GenFleet has
over 5 clinical studies encompassing IND stage to phase II studies
and completed co-development partnerships with numerous publicly
listed companies worldwide.
GenFleet is expected to progress additional programs into the
clinic, as well as transition from a clinical stage biotech company
into a commercial stage biopharmaceutical company in the next 3-5
years.
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