Turning Point Therapeutics’ Kinase Inhibitors Show High Potency against Targeted Oncogene Drivers and Their Mutations

Company Presents Four Studies at American Association for Cancer
Research (AACR) Annual Conference

Preclinical Data for Lead Asset Repotrectinib Continue to
Reinforce Preliminary Findings in Ongoing Phase 1/2 TRIDENT-1 Clinical

SAN DIEGO–(BUSINESS WIRE)–Turning Point Therapeutics, Inc., a clinical-stage precision oncology
company designing and developing novel drugs to address treatment
resistance, presented data from four studies at AACR 2019, highlighting
potent activity of its kinase inhibitors, including repotrectinib
against targeted oncogene drivers and many of their resistance
mutations, and TPX-0022, a novel MET/CSF1R/SRC inhibitor.

Two studies highlighted the higher potency of repotrectinib as compared
to other proxy investigational and the currently approved ROS1 and TRK
tyrosine kinase inhibitors (TKIs), Xalkori and Vitrakvi, against fusion
ROS1s, wildtype TRK, and many resistance mutations, including solvent
front, gatekeeper, and compound mutations.

Alexander Drilon, M.D., Clinical Director of the Early Drug Development
Service at Memorial Sloan Kettering Cancer Center and an investigator in
the Phase 1 portion of the ongoing TRIDENT-1 study of repotrectinib,
said, “As physicians adopt next-generation sequencing to identify
genomic alterations in different cancers, there is an increased need for
precision therapies that target specific oncogenes, such as TRK and
ROS1. Repotrectinib was found to have 10-fold or higher increased
potency when compared to proxy investigational and the currently
approved TRK inhibitors against wildtype (WT) TRK fusions and
solvent-front mutations. The findings — while early — are significant
and warrant continued clinical study.”

Data for TPX-0022, a novel, internally developed MET/CSF1R/SRC inhibitor
approaching IND submission in 1H 2019, were presented for the first time
at the conference. TPX-0022 was designed to target MET-driven
tumor cells, but also modulate the tumor microenvironment by inhibition
of CSF1R. This dual modulation has demonstrated significant tumor growth
inhibition in preclinical models.

The data shown in two posters highlighted the ability of TPX-0022 to
potently inhibit MET-driven cancer cells and the associated
signaling of known cancer pathways, inhibiting tumor growth and reducing
tumor associated macrophages. This dual mechanism of action showed tumor
regression and growth inhibition in multiple xenograft tumor models
harboring MET amplification or MET exon 14 skipping

“We are excited to share why we believe our lead asset, repotrectinib,
is a potential best-in-class ROS1 and TRK targeted TKI,” said Athena
Countouriotis, M.D., chief executive officer. “This is based on multiple
factors, including our ongoing Phase 1 TRIDENT-1 data and what we have
shown at AACR in terms of preclinical potency against fusion ROS1s and
resistance mutations, as well as WT and resistance mutations within
TRKA-C. We remain encouraged by the potential for repotrectinib to make
a difference in the lives of patients with a range of oncogene drivers,
both patients who have yet to be treated with a kinase inhibitor, as
well as those who have been treated with a prior kinase inhibitor and
developed treatment resistance through a specific mutation.”

Turning Point Therapeutics plans to initiate a registrational Phase 2
portion of the TRIDENT-1 Study in the second half of 2019.

Dr. Countouriotis added: “While in late stage preclinical development,
our MET/CSF1R/SRC kinase inhibitor, TPX-0022, has demonstrated promising
preclinical activity in an important pathway for the regulation of tumor
growth. We look forward to submitting our IND in the first half of 2019
and beginning our Phase 1 study in the second half of 2019.”

Additional highlights from the four studies include:

Title: Repotrectinib, a next generation TRK inhibitor, overcomes
TRK resistance mutations including solvent front, gatekeeper and
compound mutations
Session: Sunday Mar 31, 2019, 1:00 PM –
5:00 PM
Abstract Number: 4000

Repotrectinib was shown to be more than 10-fold as potent as a LOXO-195
proxy against wildtype TRK fusions and solvent-front mutations, and more
than 100-fold more potent against certain gatekeeper mutations.
Repotrectinib was the only TRK inhibitor active against the compound
mutation TRKA G595R/F589L (double mutation of solvent front and
gatekeeper) in preclinical Ba/F3 cells. In xenograft tumor models,
repotrectinib demonstrated significant tumor regression against wildtype
or mutated TRK fusions. In the ongoing TRIDENT-1 clinical trial
repotrectinib was active against the solvent front mutation ETV6-TRKC
G623E in an entrectinib-resistant patient with a salivary gland tumor
(-82%, confirmed partial response, RECIST v1.1). Tumor regression (-33%)
was achieved in a larotrectinib-resistant cholangiocarcinoma patient
with LMNA-TRKA G595R and F589L mutations.

Title: Repotrectinib, a new generation ROS1 inhibitor, is highly
potent against fusion ROS1s and emerging resistance mutations
Session: Monday
April 1, 2019, 8:00 AM – 12:00 PM
Abstract Number: 4832

Repotrectinib demonstrated higher potency as compared to other ROS1
inhibitors against multiple ROS1 fusions and mutations, especially the
solvent front and gatekeeper mutations. In xenograft tumor models,
repotrectinib treatment resulted in tumor regression against wildtype or
solvent-front ROS1 fusion genes. Repotrectinib demonstrated a strong
inhibition profile against wildtype and various mutated ROS1s across
different fusion partners when compared to many other ROS1 TKIs.

Title: TPX-0022, a polypharmacology inhibitor of MET/CSF1R/SRC
for treatment of cancers with abnormal HGF/MET signaling
Session: Monday
April 1, 2019, 8:00 AM – 12:00 PM
Abstract Number: 3719

TPX-0022 potently inhibited cell proliferation of the MET-amplified
MKN-45 (IC50 < 0.2 nM) and SNU-5 (IC50 < 0.2
nM) gastric cancer cells. TPX-0022 caused suppression of MET
auto-phosphorylation at an IC50 of approximately 0.3 nM in
MKN-45 cell line. TPX-0022 also potently inhibited the phosphorylation
of MET downstream signaling effectors, including AKT, ERK, STAT3 and
PLCγ2 in a dose-dependent manner. In the cancer cell line and
patient-derived xenograft tumor models from gastric, lung and liver
cancers harboring MET amplification or MET exon14 skipping
mutations, TPX-0022 caused dramatic tumor regression and tumor growth
inhibition. The tumor inhibitory effect was associated with drastic
inhibition of MET activity.

Title: TPX-0022, a polypharmacology inhibitor of MET/CSF1R/SRC
inhibits tumor growth by promoting anti-tumor immune responses
Session: Monday
April 1, 2019, 8:00 AM – 12:00 PM
Abstract Number: 3749

TPX-0022 demonstrated potent CSF1R inhibitory activity and the ability
to inhibit tumor growth and promote a pro-inflammatory anti-tumor
microenvironment. In contrast, the potency of a proxy compound of the
type II CSF1R inhibitor PLX-3397 demonstrated a strong dependency on the
concentration of mouse CSF1, as the anti-proliferation IC50
shifted from <0.1 nM to 146.4 nM when CSF1 concentration changed from
baseline to 1 ng/mL. Finally, in the MC38 syngeneic mouse model,
TPX-0022 effectively reduced tumor associated macrophages (TAM), altered
the polarity of TAMs toward a more M1 phenotype, increased cytotoxic T
cells and inhibited the growth of MC38 tumors.

About Repotrectinib

Repotrectinib (TPX-0005) is a potent and orally bioavailable
investigational small molecule kinase inhibitor of ROS1, TRKs and ALK.
The clinical benefits of targeting ROS1, TRK, or ALK fusion kinases have
been demonstrated with multiple kinase inhibitors already approved or in
clinical studies. The successes of these therapies are often
overshadowed by the development of acquired resistance. The acquired
solvent front mutations including ROS1 G2032R, TRKA G595R and TRKC
G623R, and ALK G1202R render common clinical resistance to the current
ROS1, TRK, and ALK inhibitors.

Repotrectinib has demonstrated potency against wildtype and mutated
ROS1, TRK and ALK kinases, especially the clinically significant solvent
front mutations, gatekeeper mutations, and emerging compound mutations
after multiple lines of treatment. Repotrectinib may provide a new
opportunity to inhibit the abnormal signaling of ROS1, TRK or ALK in
solid malignancies, and overcome multiple resistance mechanisms seen in
resistant patients. Repotrectinib is currently being evaluated in a
Phase 1/2, open-label, multi-center, first-in-human study of the safety,
tolerability, pharmacokinetics and anti-tumor activity in patients with
advanced solid tumors harboring ALKROS1, or NTRK1-3 rearrangements
called TRIDENT-1 (www.clinicaltrial.gov number
NCT03093116). Interested patients and physicians can also contact the TP
Therapeutics Oncology Clinical Trial Hotline at 1-858-276-0005 or email [email protected].

About Turning Point Therapeutics Inc.

Turning Point Therapeutics is a clinical-stage precision oncology
company with a pipeline of internally discovered investigational drugs
designed to address key limitations of existing cancer therapies. The
company’s lead program, repotrectinib, is a next-generation kinase
inhibitor targeting genetic drivers of non-small cell lung cancer and
advanced solid tumors. Repotrectinib has shown antitumor activity and
durable responses among kinase inhibitor treatment-naïve and pre-treated
patients, and is planned to enter a registrational Phase 2 study in the
second half of 2019. Turning Point’s kinase inhibitors are designed to
bind to their targets with greater precision and affinity than existing
therapies, with a novel, compact structure that has demonstrated an
ability to potentially overcome treatment resistance common with other
kinase inhibitors. The company is driven to develop therapies that mark
a turning point for patients in their cancer treatment. For more
information, visit www.tptherapeutics.com.


Jim Mazzola
[email protected]

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