Carmine Therapeutics Files for IPO Following $900M Collaboration and $5M Investment from Takeda to Advance Novel RBCEV-Based Nucleic Acid Delivery Platform

On July 1, Carmine Therapeutics (Bomi Biologics) announced a research collaboration agreement with Takeda to discover, develop, and commercialize transformative non-viral gene therapies for two rare diseases, leveraging Carmine Therapeutics’ REGENT™ technology (based on red blood cell-derived extracellular vesicles).

Under the terms of the agreement, Carmine Therapeutics will receive an upfront payment as research funding and is eligible for milestone payments totaling over $900 million, along with tiered royalties. Upon completion of preclinical validation studies, Takeda will have the option to secure a license for the project and will be responsible for clinical development and commercialization. Additionally, Takeda has provided a $5 million convertible loan to support the development of Carmine Therapeutics’ new REGENT™ platform.

Carmine Therapeutics, founded only in 2019, is a startup following the U.S. model. Despite its short history, its founding team has been exploring core technologies for many years.

The core technology founders of Carmine are primarily a married couple, Dr. Shi Jiahai and Dr. Li Yueming.

As early as 2010, while studying in Harvey Lodish’s laboratory, Shijia Hai had already begun conducting research related to red blood cells. He developed synthetic red blood cells as in vivo carriers for protein therapeutics. This achievement marked a breakthrough from zero to one in synthetic red blood cell therapy and became one of the foundational pillars for Harvey Lodish’s subsequent establishment of Rubius Therapeutics.

Rubius is a biopharmaceutical company focused on synthetic red blood cell therapies. Founded in 2013, it completed three rounds of financing totaling $245 million prior to its initial public offering (IPO), with Flagship Pioneering providing substantial support in its development and operations. In July 2018, Rubius successfully listed on the NASDAQ, achieving a market capitalization of nearly $2 billion.

“From financing to its eventual IPO, Flagship Pioneering played a pivotal role by providing comprehensive support to Rubius in both capital raising and corporate management. Therefore, after successfully developing synthetic red blood cell-derived extracellular vesicles as in vivo nucleic acid drug carriers and achieving another breakthrough from zero to one, we began seeking similar capital partnerships worldwide. We look forward to replicating Rubius’s successful model,” said Shi Jiahai.

While Shi Jiahai was seeking investors, XQ Lin, Founding Managing Partner of Esco Ventures, was also on the lookout for projects. Modeled after mature business models in the U.S. market, Esco Ventures aims to promote the translation of scientific research into commercial applications in the Asia-Pacific region.

“Among the hundreds of projects we have analyzed in recent years, we identified that the red blood cell extracellular vesicle technology developed by Professor Shi Jiahai’s research team at City University of Hong Kong has the potential to become a world-leading drug delivery platform. This is one of the key reasons why we chose to commercialize it in Cambridge, Boston, near MIT,” said Lin Xiangqian.

Lin Xiangqian graduated from the Wharton School of the University of Pennsylvania in 2009. In February 2011, he assumed the roles of President and Chief Executive Officer of Esco Group in Singapore. In 2014, he spearheaded the establishment of Esco Ventures and served as its Managing Partner, beginning to apply his accumulated investment and operational expertise to the development of Esco Group. In 2018, Esco Ventures further refined its investment focus by launching Esco Ventures X, which concentrates on high-incidence diseases in Asia and rare diseases in the United States. Emulating the overseas integrated model of research, education, industry, and investment in the innovative drug sector, Esco Ventures X identifies the most promising technological inventors through assessments of the return on investment for high-tech innovations, and subsequently facilitates the commercial translation of these technologies through capital operations.

Thus, Shi Jiahai and Lin Xiangqian quickly reached an agreement, making Carmine one of the key projects deeply incubated by Esco Ventures. Lin Xiangqian assumed the role of Founding CEO of Carmine, steering the company’s early-stage development.

Shortly after its establishment, Carmine Therapeutics secured a $3.4 million seed financing round led by Esco Ventures, with participation from Legend Star. The company has now entered into a collaboration agreement with Takeda Pharmaceutical Company valued at up to $900 million and received an additional $5 million investment. Indeed, Carmine’s rapid development over the past year and a half has lived up to Esco Ventures’ expectations.

Carmine’s core technology focuses on delivery systems using RBCEVs (red blood cell extracellular vesicles) as carriers.

Currently, the most commonly used delivery vectors in the field of nucleic acid therapeutics are AAV (adeno-associated virus) and LNPs (lipid nanoparticles), with a small number of companies also employing LV (lentiviral vectors), exosomes, and other platforms as delivery vehicles.

AAV was initially considered a promising drug delivery vector due to its low immunogenicity and the fact that the DNA fragments delivered into target cells do not integrate into the host chromosome. However, as research has advanced, more application-level challenges have emerged. For instance, the packaging capacity of single-stranded AAV is limited to no more than 5 kb, with even smaller capacity for double-stranded AAV. Moreover, after a single administration of a given AAV serotype, the body mounts a strong immune response, leading to rapid clearance by the immune system upon subsequent administration of the same vector, thereby rendering it ineffective. These issues currently constrain the development of AAV-based gene therapies.

Lipid nanoparticles (LNPs) are currently the most widely used delivery vector type for nucleic acid therapeutics. The first RNAi drug approved by the U.S. FDA in 2018, Onpattro, utilized an LNP-based delivery system. LNPs exhibit a favorable safety profile, with both carrier capacity and delivery efficiency meeting the current requirements for drug delivery vehicles. However, the organ selectivity of LNPs remains limited. Their primary delivery target is the liver, while delivery efficiency to other tissues and organs is relatively lower.

Carmine’s choice of RBCEV has effectively addressed nearly all the challenges currently faced by carriers used in drug delivery.

In terms of capacity, RBCEVs can load DNA fragments of up to 11 kb, which is sufficient for most application scenarios. Furthermore, in relevant experiments conducted by Carmine Therapeutics, delivery of fragments as long as 34.2 kb has been achieved, albeit with slightly lower efficiency. In addition to DNA fragments, other types of nucleic acids, such as mRNA, antisense oligonucleotides, and siRNA, can be successfully loaded into RBCEVs. The absence of nuclei and mitochondria in red blood cells ensures that the RBCEVs they secrete contain minimal endogenous nucleic acids, thereby serving as a natural blank nucleic acid delivery vehicle.

Compared with the limited organ selectivity of LNPs, RBCEVs can be delivered to a variety of different organ tissues. In mouse experiments, significant delivery effects were observed in the lungs, liver, kidneys, bone tissue, and immune cells.

Moreover, the primary raw material Carmine uses to produce RBCEVs is blood from type O donors. This ensures a large, readily available supply and controllable costs.

Carmine has established its proprietary REGENT™ technology platform using RBCEVs as drug delivery vehicles. Leveraging the unique characteristics of RBCEVs, the REGENT platform offers four key advantages: safety and efficacy, cost controllability, off-the-shelf availability, and multi-organ targeting.

In practical applications, Carmine isolates red blood cells from the blood of type O donors, induces them to secrete RBCEVs in vitro, and then purifies them to obtain high-purity RBCEVs. DNA, miRNA, and other cargo are loaded into the RBCEVs using Carmine’s proprietary transfection method, and the final product is administered to patients via injection to achieve therapeutic effects.

Preliminary mouse experiments have confirmed that the use of RBCEVs for the delivery of DNA, miRNA, mRNA, and even CRISPR-Cas9 systems can achieve high delivery efficiency. Furthermore, the components delivered into cells remain functionally active, exerting their effects on downstream target genes or target sequences.

Carmine has currently established its corporate headquarters in Boston, USA. The team consists of more than a dozen members and is projected to grow to over twenty by 2020. Although the project is still in its early stages, Carmine has already begun allocating resources in Boston and initiating its CMC (Chemistry, Manufacturing, and Controls) strategy.

In terms of its future pipeline strategy, Carmine will primarily focus on the development of drugs for rare diseases. This strategic choice is mainly driven by Carmine’s current priority to advance its product candidates in the United States, where the regulatory approval pathway for orphan drugs can expedite their entry into clinical trials.

“Some have also suggested that we consider conducting investigator-initiated clinical trials in China to provide a basis for early-stage R&D. However, given our current strategic direction, we are likely to focus more on our own development and prioritize creating high-quality products first. We will then formulate specific clinical development plans based on the progress of our product R&D,” said Lin Xiangqian.

Regarding the exorbitant prices of several currently marketed rare disease drugs, Lin Xiangqian also shared his views: “Compared with gene therapies based on viral vector technology, Carmine’s technology platform enables better cost control.”

As one of the top 20 pharmaceutical companies worldwide, Takeda Pharmaceutical has long focused on the field of rare diseases, with a portfolio that includes blockbuster drugs such as vedolizumab for Crohn’s disease and Velcade for multiple myeloma. Following its acquisition of Shire, another major player in the rare disease sector, Takeda has become a highly accomplished international pharmaceutical giant in rare disease treatment. Its willingness to invest heavily in a collaboration with Carmine Therapeutics, based in Cambridge, Boston, underscores its strong recognition of Carmine’s technological capabilities. Moreover, this partnership with Takeda marks only the beginning of Carmine’s growth trajectory, as several other pharmaceutical companies are currently in discussions with Carmine, seeking to establish collaborative agreements.

Madhu Natarajan, Head of Rare Disease Drug Discovery at Takeda, stated: “Takeda is expanding its gene therapy portfolio by building a network of innovative partners, such as Carmine Therapeutics, who are pursuing non-viral vector approaches that can surpass current technologies. Developing alternative gene therapy delivery vectors, such as the REGENT™ platform—which addresses the challenges associated with adeno-associated virus (AAV) gene therapies—is critical to enabling next-generation treatments for rare diseases in the future.”

Lin Xiangqian and the Esco Ventures team have been instrumental in Carmine’s operations and business design, enabling the successful initiation of commercial collaborations with pharmaceutical giants.

Esco Ventures draws on proven business models to build comprehensive technical judgment, commercial value assessment capabilities, and an operational talent team. By establishing the Esco Ventures Founding, Lab Centers, and Morphosis programs, it conducts early-stage validation and discovery of innovative projects and scientific concepts. Meanwhile, it assembles teams with strong scientific backgrounds. Through comprehensive analysis of investment elements—including technical solutions, market prospects, team credentials, IP protection, and platform value enhancement—and following a systematic investment process (platform technology assessment guided by unmet market needs, 100% angel investment in new startups, and recruitment of external professional managers to build international commercial operation teams for new companies), Esco Ventures enables the rapid implementation and development of innovative platform technologies with the support of industry capital.

Lin Xiangqian stated, “The Carmine Therapeutics project has achieved phased validation of the success of Esco Ventures’ venture incubation model, which is leading in Asia. Going forward, more cutting-edge innovative technologies will be developed through commercial incubation, further demonstrating our team’s capability to drive Asian biopharmaceutical venture incubation to new heights.”

“Achieving our current results within 18 months is an excellent start for us. We also hope to achieve more rapid development in the coming years, thereby demonstrating that we are not only capable of independently achieving breakthroughs from zero to one in scientific research in Asia, but also of translating high-end scientific discoveries into applications and bringing them to market,” said Shi Jiahai.