Dong-A ST Co. Ltd. has spent the last four
years building an R&D organization and using its chemistry chops to begin
developing first-in-class drug candidates against genetically validated
targets. A December cancer immunotherapy deal with AbbVie Inc. is the first
payoff from the work.
AbbVie agreed to pay Dong-A $40 million up
front and up to $485 million in milestones for exclusive worldwide rights
outside of South Korea to preclinical inhibitors of c-Mer proto-oncogene
tyrosine kinase (MERTK), a class of molecules AbbVie also was working on.
The program came out of a strategic shift
intended to expand Dong-A beyond its established business, which has included
selling imported drugs, generics, botanicals, biosimilars and branded small
molecules that are not first in class.
SVP and Head of Global Business Chae Lee said
the decision to expand to R&D on novel targets was made about five years
ago as the company considered how to globalize. One of the first steps was
hiring SVP and Head of Research Taeyoung Yoon. Yoon was previously a senior
research investigator at Novartis AG’s Novartis Institutes for BioMedical
Research (NIBR) for eight years.
He began with a drug discovery team of about
20 scientists.
Yoon chose not to start with de novo target
discovery, but with genetically validated targets that hadn’t been well studied
due to lack of tool compounds. Going forward, he plans to focus on discoveries
in South Korea.
“We would like to take an active role in
helping to translate such good science into something that’s druggable, then
introducing it to the Western and global markets,” said Lee.
Once it chooses a target, Dong-A makes tool
compounds to test therapeutic hypotheses successively at the level of proteins,
cells and animals.
According to Yoon, validating MERTK’s role in
cancer has been tricky because it is difficult to create an inhibitor that is
sufficiently selective.
MERTK is a member of the TAM (TYRO3-AXL-MERTK)
receptor family of transmembrane proteins. It sits upstream of BRAF and is
primarily expressed in subtypes of myeloid cells including some macrophages and
dendritic cells.
Yoon said MERTK induces immunosuppression when
nearby cells undergo apoptosis — a natural form of cell death that in normal
circumstances should not trigger the immune system. But when tumor cells die
via apoptosis, MERTK may contribute to the immunosuppressive tumor
microenvironment.
MERTK is overexpressed or hyperactivated in
multiple cancer types including prostate cancer, brain cancer and leukemia.
To improve selectivity of its inhibitors, Yoon
said Dong-A added bulky groups to its molecules outside of a flat portion
needed to fit within the MERTK active site. Yoon said the group created a
selective inhibitor in three years with a 10-person project team.
In a poster presented in November 2015 at the
AACR-NCIEORTC International Conference on Molecular Targets and Cancer
Therapeutics, Yoon and colleagues reported the design of a lead compound,
XL1547, with an IC50 of 1 nM that was over 300 times more selective for MERTK
than AXL. A follow-on compound, SA3686, was over 10 times more potent than
XL1547 in inhibiting MERTK and was suitable for oral dosing.
SA3686 was efficacious in a tumor allograft
model of subcutaneously implanted Ba/F3(CD8:MERTK) cells. Yoon declined to say
which animal was tested or how efficacy was measured.
Yoon said AbbVie reached out to Dong-A to
discuss the poster, which led to partnering discussions.
“Dong-A has identified potent and selective
MERTK inhibitors and brings medicinal and structural chemistry expertise to the
collaboration,” said AbbVie VP of Oncology Discovery Steve Davidsen in an email
to BioCentury.
Yoon added that selectivity is particularly
important because unlike many other tyrosine kinase inhibitors used in
oncology, MERTK inhibitors act mainly in healthy cells — which raises the bar
for safety.
“When you want to inhibit a host target, you
want to be very selective,” he said.
ENGINE FOR
GROWTH
Yoon is now expanding Dong-A’s drug discovery
group to more than 100 scientists and is drawing on his experience at NIBR to
create a culture of science and lower barriers to knowledge sharing.
Previously, Dong-A’s chemists, biologists and
ADME specialists were siloed across project-based teams that had little reason
to communicate with each other, which gave the specialists few chances to share
on-the-job learning.
Yoon said tackling novel targets requires a
deeper understanding of the science that uses “all of the connected wisdom
available,” so he is grouping the discovery researchers according to function —
putting all the chemists, biologists and ADME specialists into their own teams.
The new researchers will come from internal
teams that had previously been working on follow-on products in metabolic and
infectious diseases. He also hopes to build Dong-A’s clinical experience with
first-in-class programs through partnerships that will eventually let it keep
programs in-house longer.
As with the AbbVie deal, Yoon said Dong-A
hopes to find partners that have studied the same target so that both parties
can contribute knowledge, which could increase the odds a project will succeed.
Lee said in addition to offering a competitive
bid and a compatible culture, AbbVie’s in-house experience with MERTK gave the
pharma realistic expectations about how much information would be available
about the compounds’ biological activity at their early development stage. The
partners will collaborate to select a clinical candidate and perform GLP
toxicity studies. They intend to test combinations of MERTK inhibitors with
AbbVie’s immuno-oncology programs to treat solid tumors. AbbVie is responsible
for clinical development.
Lee declined to give a timeline for the
project.
Dong-A did say it expects the first compounds
from its target validation projects to reach the market in the mid-2020s. Yoon
said he hopes that in two or three years, two-thirds of the company’s pipeline
will be first-in-class molecules.