Antibody Therapeutics Patients First!

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Interview of Dr. Jin-San Yoo, CEO of PharmAbcine with informa
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  • 작성일 2018-09-03 17:07:13
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"PharmAbcine's Hopes Rise As Tanibirumab Set For Keytruda Combo Trials"

03 Sep 2018 ANALYSIS

Executive Summary

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 been agreed. 

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, South Korea.

"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 safety." 

 

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.


Side-Effect Benefits?


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.


Development Plans


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 the IND.

"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 Trial Programs


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 span. 


Planned IPO 


Once the US Phase II combo study begins, the company also plans to conduct a new Phase II in Australia with the same protocol.

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 antibodies.

"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.”


Other Pipeline Assets


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 PMC-904 (omalizumab).


From the editors of PharmAsia News.

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