"PharmAbcine's Hopes Rise As Tanibirumab Set For Keytruda Combo Trials"
03 Sep 2018 ANALYSIS
PharmAbcine CEO Jin-San Yoo talks
to Scrip about the company’s overseas clinical trial strategy,
pipeline assets, and ambitions for lead candidate TTAC-0001, which the company
sees as superior to Avastin. The Korean biotech, which is engaged in various
global collaborations on its investigative antibody drugs, hopes that tie-ups
can lead to bigger outcomes going forward.
Following the successful completion of a
Phase IIa study in Australia for its lead asset TTAC-0001 (tanibirumab) for
recurrent glioblastoma, South Korea's PharmAbcine Inc. is set to launch diverse
clinical trials for the fully humanized therapeutic antibody as well as for
other pipeline assets, for some of which research and collaboration deals
with Merck & Co. Inc. have already
The Korean firm's main emphasis at
present is on TTAC-0001, and a relative lack of side-effects and adverse
reactions in comparison with other similar acting drugs is one of the main
potential advantages for the drug being stressed by PharmAbcine.
"All marketed anticancer drugs have
side effects ranging from Grade 1 to 5, but TTAC-0001 only showed minor
side-effects with Grade 1-2. It is super safe," declared PharmAbcine CEO
Jin-San Yoo in an interview with Scrip on the sidelines of the
AFOB (Asian Federation of Biotechnology) Summer Forum held recently in Incheon,
"Merck is already progressing
many Keytruda [pembrolizumab]/Avastin [bevacizumab]
and Keytruda/Cyramza [ramucirumab] trials, so it doesn't really
have to do Keytruda and TTAC-0001 [in combination] trials. But we reached an
agreement [on these studies] thanks to our drug's superior efficacy and
TTAC-0001 blocks the vascular
endothelial growth factor/vascular endothelial growth factor receptor-2
(VEGF/VEGFR-2) signal pathway in a manner similar to Avastin, but also acts to
block VEGF-C and -D, and binds to VEGFR-2 in addition to VEGF-A.
Although the antibody is a KDR
(hVEGFR-2) antagonist, it hasn't shown any serious side-effects similar to Avastin
or Cyramza during Phase I and II studies. Avastin's potential side-effects
include gastrointestinal perforation, wounds that don't heal, serious bleeding,
and severe high blood pressure, while for Cyramza these can include bleeding,
arterial thromboembolic events, and high blood pressure.
"People wonder why TTAC-0001
doesn't show the side-effects that all the other VEGF pathway antagonists have.
Although it is a KDR/VEGF antagonist, TTAC-0001 is a unique antibody drug that
doesn't show side effects such as hypertension and bleeding gastric lung
perforation," the CEO touted.
Its main adverse reaction was reversible
(Grade 1-2) capillary hemangioma on the skin with a 50% incidence; it has also
shown minor levels (Grade 1-2) of headache, nausea and dizziness.
Other than these potential advantages
and lower toxicity than competitors, TTAC-0001 - which has received development
funding from the state-run Korea Drug Development Fund (KDDF) - is expected to
show efficacy in several indications such as HER2-negative breast cancer. It
has already shown efficacy in an Avastin-resistant tumor model and is
anticipated as a possible option for disease resistant to that drug.
It is also the only therapeutic antibody
with cross-species reactivity for VEGFR-2 in rodents that is available for
translational research opportunities and selection of optimal indications; as a
result, this is expected to increase the success rate in clinical trials,
according to the KDDF.
Although PharmAbcine had to withdraw an
IND submission in South Korea for a Phase II trial with TTAC-0001, and opted
instead to proceed with the trial in Australia, this has ironically worked out
favorably as the firm could instead gain clinical trial data in Caucasians,
which is seen as a key requirement for global pharmas, Dr. Yoo said.
At that time, South Korea’s Ministry of
Food and Drug Safety had expressed concerns over the incidence of capillary
hemangioma and asked PharmAbcine to investigate the mode of action on animal
models to better elucidate this. However, the company couldn't find any
suitable models that demonstrated the problem, so had to voluntarily withdraw
"While global key opinion leaders
including neuro-oncologists, the Australian regulatory body [TGA], US FDA, and
Merck's clinical trial team have all said such a side effect isn't even
considered as such, only the South Korean drug authority has made an issue of
this," he said.
However, "If capillary hemangioma
is a problem, why did Korean KOLs say tanibirumab should move on to a Phase II
study, why did Australia approve a Phase II, why did Merck agree a combination
therapy deal with us, and why did the US FDA recommend to add a new arm of
higher dose tanibirumab in the new Phase II trial and granted ODD [orphan drug
designation] for the treatment of GBM [glioblastoma multiforme]?"
Some capillary hemangioma cases were
observed during clinical trials of other VEGFR-2 inhibitors, but the developers
are progressing trials without major issues, he noted.
Dr. Yoo, who previously worked at the
Howard Hughes Medical Institute at Stanford Medical Center, The Scripps
Research Institute, LG Life Sciences and KRIBB (Korea Research Institute of
Bioscience & Biotechnology), founded PharmAbcine in 2008. The company
received its Series A financing from investors led by Novartis and OrbiMed in
2009 in the middle of the global economic recession.
Gearing Up For
PharmAbcine expects the combo therapy
trials of TTAC-0001 and Keytruda with Merck to start in the fourth quarter,
beginning in Australia and expanding into the US and Europe as well as South
Korea. In the Phase Ib/II trials for the combo therapy, the company aims to
investigate the treatment of recurrent GBM as well as triple-negative,
metastatic breast cancer, which are seen as having the greatest unmet needs.
The company also filed an IND with the
US FDA in late July to launch a new Phase II study in the US for TTAC-0001 for
cerebral edema in Avastin-refractory recurrent GBM patients.
"All brain cancer patients suffer
from cerebral edema. Of Avastin's annual [global] sales, about KRW700bn [$630m]
is used for cerebral edema to improve quality of life of brain cancer patients.
However, if the patients develop resistance to Avastin, they have no other
option but to suffer," Dr. Yoo observed.
In its Australian study, PharmAbcine
observed that TTAC-0001 alleviates cerebral edema in a different pattern versus
Avastin. While Avastin targets VEGF-A-mediated edema, tanibirumab targets the
VEGF A, C and D-mediated form of the condition.
On gaining an IND approval from the US
FDA, the company will begin the trial program looking at recurrent GBM patients
resistant to Avastin, to manage cerebral edema and potentially extend life
Once the US Phase II combo study begins,
the company also plans to conduct a new Phase II in Australia with the same
After completion of a Phase IIa study in
Australia on 12 recurrent GBM patients last year, PharmAbcine plans to move on
to Phase IIb using the proceeds from a planned initial public offering on South
Korea's Kosdaq market this year. Based on this trial data, the company aims to
get regulatory approval in Australia on condition it conducts a Phase III trial
after the drug's launch, and plans to select a sales partner in Australia with
strong oncology marketing capability.
PharmAbcine has also put forward seven
non-clinical stage pipeline assets for research collaborations with an
undisclosed global pharma partner, including three mono- or bispecific
"The undisclosed global pharma was
also interested in the remaining four, but it wanted to evaluate them after
their data further matured as it has already put a lot of resources in our
assets," Dr. Yoo said.
"Once we have positive safety and
efficacy data on the Keytruda/TTAC-0001 combo therapy trials, Merck could be a
perfect partner for further business development with PharmAbcine.”
As for other assets within its pipeline,
PMC-122 is a PD-L1 and CD47 dual targeting molecule that is said to be superior
to existing PD-1 combinations. The bispecific antibody enhances immunity and
has anti-tumor efficacy.
CD47, which has been found to be
over-expressed in many different tumor cells, interacts with signal-regulatory
protein alpha (SIRP-a), an inhibitory transmembrane receptor present on myeloid
cells. The CD47/SIRPa interaction leads to cell-to cell responses including
inhibition of phagocytosis, so blocking CD47 turns off the "don’t
eat me" signal and favors phagocytosis.
PMC-309 is an anti-VISTA antagonistic
fully human lgG antibody for cancer therapy, which is also funded by the KDDF.
Inhibiting VISTA activity by PMC-309 may induce anti-tumor immunity in a
different manner to T-cell-activating immune checkpoint inhibitors.
VISTA (V-domain Ig Suppressor of T cell
activation) is known as a negative immune regulator which is mainly expressed
on myeloid-derived suppressor cells and also on T-cells. Because anti-tumor
immune response enhanced by VISTA inhibition has a different mechanism compared
to T-cell-mediated immune activation, combination therapy with other immune
checkpoint inhibitors may be considered as an alternative treatment for
non-applicable patients to anti-PD1/PD-L1 therapeutics.
Other pipeline assets include PMC-001,
(a DIG-KT, bispecific antibody neutralizing both VEGF-VEGFR2 and
angiopoietin1/2-TIE2 pathways simultaneously), PMC-002 (a bispecific antibody
neutralizing both the same pathways simultaneously), PMC-002R (another
bispecific antibody acting on these same pathways simultaneously), and
PMC-005BL (an anti-EGFRvIII Ab for ADC, CAR-T/NK/macrophage).
The company is in addition developing
several biosimilars including PMC-901 (bevacizumab), PMC-902 (aflibercept), and
From the editors of PharmAsia News.