Aiming For Key Tech Catch-Up
BY JUNG WON SHIN
South Korea is stepping on the gas to develop its own mRNA COVID-19 vaccine and eventually next generation mRNA platform technology for use in other diseases, to meet its goal of becoming a global vaccine hub.
South Korea is moving quickly to reduce what is sees as a gap in mRNA vaccine technology with major countries by forming a strategic consortium of pharma firms to speed up the development of its own COVID-19 vaccine using the platform by next year. In the coming years, the aim is to develop next generation platform technology that can be applied to other diseases.
In a recent joint ministry statement, the national government also highlighted an urgent need to develop and commercialize its own mRNA vaccine technology, given that this is expected to change the paradigm of vaccines going forward. As shown over the past 18 months, the advantages include rapid development and manufacture compared to traditional vaccines, along with now proven superior efficacy and relative safety, the government noted.
While developers in the US and Europe have succeeded through accumulated research and technologies, relevant South Korean technologies are still in the early stages, prompting the government vow to provide aggressive support.
A consortium to develop next generation mRNA vaccine platform technology has now been formed, led by three major domestic pharma firms –Hanmi Pharmaceutical Co., Ltd., ST Pharm and GC Pharma - and supported by KIMCo, the Korea Innovative Medicines Consortium. KIMCo is a non-profit organization established by the Korea Pharmaceutical and Bio-Pharma Manufacturers Association (KPBMA) and 56 individual pharma firms last year to support anti-infective and innovative medicines and global commercialization.
The so-called K-mRNA consortium will build on the strengths of the three firms in active pharmaceutical ingredients, vaccines and new drug development to obtain relevant technology and establish mass production systems to achieve not only COVID-19 mRNA vaccine self-sufficiency but also build up a basis for global exports. The goal is to materialize independent technology development by 2022 and manufacture 100 million doses of the vaccine within two years, enough for two doses for every South Korean citizen.
By 2023, the consortium aims to establish a mass production system using the platform to produce more than one billion doses for supply both at home and abroad. More broadly, the aim is to use the mRNA platform to step up global competitiveness for novel cancer vaccines and other innovative drugs.
The three participating pharmas plan to invest a combined total of at least KRW700bn ($618m) in progressing clinical trials, obtaining core APIs and establishing mass production facilities.
Going forward, the K-mRNA consortium plans to add more participants, including other Korean pharmas, biotechs and research institutes relevant to the development and production of mRNA technology and raw materials.
During the consortium launch ceremony organized by the KPBMA, Kyungjin Kim, president and CEO of ST Pharm, a subsidiary of Dong-A Socio Holdings, said that the API-focused contract development and manufacturing organization had actually been developing mRNA platform technology for four years, beginning with oncolytic vaccines. With the pandemic, the company then jumped into COVID-19 vaccines.
ST Pharm, whose major global clients include Roche Holding AG, Novartis AG and Gilead Sciences, Inc., currently has an mRNA COVID-19 vaccine candidate, STP2104, at the preclinical stage, which it plans to take into Phase I this year and file for an emergency use authorization (EUA) in the first half of next year.
The firm estimates it can produce about 500 million doses of mRNA vaccine bulk materials and claimed it is the only company globally to have its own capping technology and lipid nanoparticle drug delivery technology in addition to capabilities for raw materials.
While concerns are rising that a new chapter of the pandemic may be beginning with new virus variants, Kim said “mRNA vaccines will enable us to rapidly deal with such virus variants. I think the consortium will make a mark in the South Korean pharma industry. We have confidence we can develop the vaccine by the end of 2022.”
As a leading South Korean vaccine specialist, GC Pharma meanwhile has know-how in influenza vaccines and plans to use this expertise within the consortium, president E C Huh noting COVID-19 vaccines may become seasonal going forward. “Many pharmas believe mRNA is the future of biologics. With the pandemic, mRNA vaccines were rapidly commercialized and GC Pharma was anxious to catch up."
Se-Chang Kwon, president and CEO of Korean pharma major Hanmi Pharm, said his company has experience across all cycles of new drug development and is currently developing COVID-19 diagnostic kits, a preventive vaccine and a therapeutic. It has capacity for more than 100 million doses worth of three key raw materials for mRNA vaccines.
Hanmi’s Pyeongtaek Bio plant has bulk substance capability for mRNA and DNA vaccines and the site is also capable of manufacturing enzymes for RNA synthesis and processing, via processes involving Escherichia coli-based fermentation and purification. In addition, subsidiary Hanmi Fine Chemical has capabilities to produce synthetic raw materials including nucleotides, bulk drug substances, intermediates and peptides, as well as lipids, which may prove useful in mRNA vaccine formulations.
“The vaccine paradigm has changed because of the pandemic. The prediction that the most promising vaccine may be mRNA has become reality," Kwon said. "We are also targeting a prevention level that is the same or higher than the Pfizer and Moderna vaccines."
The consortium sees these western vaccines as unlikely to satisfy all demand and noted multiple considerations such as how effective they are against variants and how long their protection will last, as well as distribution costs if they have be administered seasonally.
Kyung-Hwa Huh, CEO of KIMCo, noted that it had become increasingly urgent for South Korea to develop its own vaccine capabilities given there are no signs of an end to the pandemic and the emergence of new virus variants. Other South Korean firms progressing mRNA COVID-19 vaccines include GeneOne Life Science, Inc. and EyeGene, Inc.
As part of the initiative, and based on survey results, the government has identified seven technology areas for support. These are: antigen design and optimization; raw material production; in vitro transcription vector and mRNA manufacture; manufacture of vaccine receptors such as lipid nanoparticles; refining; mass production; and efficacy evaluation.
South Korean mRNA vaccine technologies are seen about three years behind those of leading countries and the support aims to rapidly close this technology gap.
In the short term, relevant ministries will help enable candidates to enter clinical trials, while longer term official objectives are to encourage basic and proprietary technologies in prediction, diagnosis, treatment and prevention of new infectious diseases.
Aside from the mRNA COVID-19 vaccines, five South Korean firms are progressing clinical trials with other types of COVID-19 vaccines, with the leaders aiming to enter Phase III trials in the second half of this year.
EuBiologics Co., Ltd. and SK Bioscience are each progressing Phase I/II trials for synthetic antigen candidates, Genexine, Inc. and GeneOne Life Science, Inc. are moving forward with Phase I/IIa and Phase I work, respectively, for their DNA vaccine candidates, while Cellid, Inc. is progressing a Phase I/IIa trial for its viral vector-based candidate.
The government will focus on supporting Phase III trials in the second half and companies’ investment in production facilities, by selecting candidates with high potential for success and global credibility once these enter Phase III or have interim Phase II results.
Meanwhile, SK Bioscience, an affiliate of major Korean conglomerate SK Group, has become the first domestic firm to submit an IND to begin a Korean Phase III trial with its COVID-19 vaccine candidate GBP510, jointly developed with the University of Washington Antigen Design Research Institute in the US with support from the Bill & Melinda Gates Foundation and CEPI (the Coalition for Epidemic Preparedness Innovations).
The antigen has a structure to maximize immune effect and SK’s gene recombination technology and the university’s Self-Assembly Nanoparticle design technology have been applied to the receptor-binding protein.
SK Bioscience will discuss with regulatory authorities the final exact candidate to take into Phase III, taking into account trial results for its other contender NBP2001. The company and the Seoul-based International Vaccine Institute also plan to file Phase III INDs in stages in Europe and Southeast Asia, with a goal to commercialize the vaccine in the first half of next year. The total Phase III program will include 4,000 healthy adults.
If GBP510 is commercialized, it will be supplied globally through the COVAX facility.
Role For Internal/External Collaborations
South Korea’s Ildong Pharmaceutical has begun a major transformation from an OTC-focused firm to an innovative R&D-based operation that aims to compete with global big pharma rivals, helped by both internal and external alliances, its R&D head says in an interview with Scrip.
With a recently acquired clinical pharmacology firm and new drug development affiliate under its wing, Ildong Pharmaceutical Co., Ltd. is aiming to transform into an innovative R&D-based operation that can truly compete shoulder-to-shoulder with global big pharma companies.
“As Gilead Sciences, Inc. has grown into a high-ranking global big pharma from a small biotech within a short period of time, this is the direction Ildong wants to go,” said Alan Choi, vice-president and R&D department head at the South Korean company said in an interview with Scrip. “Our new drug development projects are increasing sharply and the number can’t even be compared to a few years ago.”
Last year, Ildong invested 14% of annual revenues in R&D, up from 11% in 2019, indicating its intent to boost innovative R&D. Such a change was possible because of a consensus in the company to shift the business focus away from its traditional focus on over-the-counter products and toward original drug development.
Alan Choi, Vice President and Head of R&D, Ildong Pharmaceutical
The Korean pharma is pursuing a “quick win, fast fail” strategy that aims to maximize the efficiency of the new drug development process. This means it will not limit work to specific therapeutic areas but will explore all possible projects from the discovery stage and determine the potential success of these as soon as possible. The focus will be on investing in those candidates with the highest potential, said Choi, who has previously worked for Johnson & Johnson as well as South Korea’s Ministry of Health and Welfare.
“Speed is a crucial factor in new drug development. This is particularly important as competition is getting fiercer with the rapidly increasing Chinese firms focusing on new drug development. As a result, it is becoming difficult to gain first-in-class status,” explained Choi.
Reflecting the trend for many multinational pharmas to reduce development times through process efficiency, Ildong’s R&D team is aiming to file for patents after the discovery of drug substances and then enter the IND stage within two years.
From the project discovery stage, evaluation will be based on three factors – market attractiveness, differentiation, and internal capabilities to progress the asset. To help rapidly decide on the success potential of any given project, Ildong says it intends to capitalize on new clinical pharmacology affiliate AIMS BioScience, acquired by parent Ildong Holdings in 2020.
Ildong is also collaborating with Germany’s Evotec SE, which runs the fully-integrated clinical-enabling package INDiGO, which can reduce development times by maximizing the efficiency of the preclinical stage development process, Choi explained.
In July 2019, Ildong Holdings set up a new no-research, development-only company Idience as an affiliate to focus primarily on oncology. This will help to more rapidly and efficiently progress pipeline projects in cancer and attract investment funds. Indeed, Idience already raised KRW40bn ($34.7m) from financial investors early this year.
While Ildong Pharmaceutical and Idience are separate entities, they are collaborating closely, Choi noted. The internal model is that Idience licenses in Ildong’s promising oncology pipeline assets and progresses development, but Idience is also bringing in new external candidates from biotechs and academia to take these forward and either seek commercialization or license out to third parties.
As one example, late last year Idience completed a South Korean Phase I study with the PARP inhibitor IDX-1197 (venadaparib), licensed in from Ildong, and took it into a Phase Ib/IIa trial. It also received a US IND approval for the molecule and began recruiting for the international Phase I study. The affiliate recently set up a US office to help speed up global clinical trials.
In another strategic move, Ildong Holdings last year acquired a controlling stake in AIMS BioScience in a bid to set itself apart from other South Korean pharmas. AIMS is a bioventure that offers consultations on the clinical pharmacology essential for new drug development and determining project value. However, advancement in this field in South Korea has been comparatively slow because of a lack of both experienced clinical pharmacologists and awareness.
“Until now, the importance of clinical pharmacology has been underestimated in South Korea," Choi said. "We are trying to overcome such limitations by bringing in clinical pharmacology consulting firm and including this in our new drug development process. This is clearly a differentiated approach versus other pharmas.”
While oncology is the main therapeutic focus at Idience, Ildong Pharmaceutical is progressing its pipelines in other fields as well.
“The most important area in new drug projects is whether the pipeline has the potential to clearly resolve unmet needs of the disease,” Choi explained. Using this benchmark, the company is focusing on liver disease (non-alcoholic steatohepatitis), metabolic disease (type 2 diabetes) and ophthalmology (dry eye, wet age-related macular degeneration and glaucoma). In particular, eye disease is an area with high market demand along with the general rise in average life expectancy.
The company is also developing an ARDS (acute respiratory distress syndrome) contender that might also be applied to the rare disease indication of pulmonary hypertension.
Its leading novel asset at present is IDG16177, an oral GPR40 agonist for type 2 diabetes, which has begun a Phase I study in Germany that is expected to be completed by 2022. The country was selected based on considerations including speed, convenience of recruitment and trial cost.
IDG16177 acts to induce insulin secretion and control blood glucose levels by activating GPR40 (G-protein-coupled receptor 40) in pancreatic beta cells. Ildong sees its advantages as minimization of hypoglycemia following administration and higher safety margins versus Takeda’s same class drug fasiglifam (TAK-875); this was discontinued at the Phase III stage in 2013 following concerns around liver safety.
Through assays, Ildong has worked to minimize the occurrence of drug-induced liver injury, and recently presented non-clinical data to the American Diabetes Association conference.
Choi observed that, in the modern pharma industry, barriers between companies are collapsing and individual firms with closed structures can’t keep up with the speed of drug development advancements along. “I think the ability to combine each company’s characteristics, advantages, technologies and R&D experiences through open innovation will become the core competitiveness of the pharma industry,” he predicted.
The strength of Ildong’s R&D team is its ability to discover outstanding new candidates, he added - at the development stage the aim is to maximize pipeline value through aggressive external collaborations. While a major goal is to recoup increased R&D expenses through such license deals, the main hope is to find partners that can successfully progress Ildong's projects through to regulatory approval and market launch.
Aside from licensing deals, the executive stressed the company is also open to other business models such as co-research deals and joint ventures.
In terms of licensing-in, Ildong is considering bringing in mainly late-stage assets with a primary goal to receive market authorizations in South Korea. It will evaluate these after considering synergies with its existing products, non-competition terms of existing contracts and its own marketing and sales capabilities.