Threebrooks Therapeutics’ antibody dementia drug breaks BBB barrier, drawing global spotlight

[by Yu, Suin] "To survive, one must pursue an untrodden path. For early-stage ventures to endure amid global competition, adopting a clear 'differentiation strategy' is indispensable."

Threebrooks Therapeutics (hereinafter referred to as Threebrooks), an early-stage biotechnology venture founded just three years ago, made its debut at the 2025 Bio International Convention (BIO USA) this year. Despite being a first-time participant, the company attracted meeting requests from multiple global pharmaceutical companies and presented its Alzheimer's disease treatment candidate, ‘3BT-1’ (development code).

3BT-1 is currently undergoing lead compound optimization and has not yet entered preclinical trials. Nevertheless, its high technological sophistication and promising therapeutic target, which faces limited competition, have already drawn strong interest from major global pharmaceutical firms.

Kim Seong-young, CEO of Threebrooks, discussed the distinctive characteristics of the company’s ion channel-based treatments for brain diseases and its competitive advantages in an interview with <THE BIO> held on October 27. The interview took place at the Institute of Membrane Proteins, located in the Pohang Convergence Technology Industrial Complex in North Gyeongsang Province, where the company’s headquarters are based.

'TRPML1' boosts autophagy and promotes waste clearance… Growing major pharmaceutical investments, including from Merck

Kim has devoted nearly two decades to research in electrophysiology and ion channel science, having previously served as head of the ion channel novel drug team at Daewoong Pharmaceutical and as founder and research director at iN Therapeutics, an in-house venture. Motivated by a strong entrepreneurial spirit, he relocated to Pohang in January 2023.

He chose Pohang for its well-established innovation ecosystem, which supports the growth of startups and their transition toward major mergers and acquisitions (M&A). Additionally, the region’s world-class structural biology infrastructure, including particle accelerators and cryo-electron microscopy (cryo-EM) facilities, offered what he regarded as an ideal environment for advancing electrophysiology and ion channel-based novel drug development research.

"Pohang has a well-established ecosystem for venture startups. Typically, when a startup is founded on technology originating from POSTECH, POSTECH Holdings participates as an initial investor. This is then followed by TIPS, POSCO Technology Investment, and other venture capital firms providing subsequent funding," Kim noted. "Companies that successfully scale through this process are often integrated into the POSCO Group as future growth drivers or proceed to public listing, thereby creating a virtuous cycle."

Over the past three years, Kim has actively leveraged various support programs and regional infrastructure to concentrate on business incubation. At present, his primary research focus is on developing a small-molecule therapeutic targeting TRPML1, a lysosomal ion channel activator. TRPML1 is an ion channel protein located on the lysosomal membrane, responsible for facilitating the transport of calcium ions from within the lysosome into the cells. Simply put, ion channels are membrane proteins that enable the passage of ions such as sodium, calcium, and potassium, which are essential for maintaining cellular and systemic homeostasis in the human body.

TRPML1 functions by activating the autophagy-lysosomal pathway (ALP), which facilitates the clearance of intracellular waste and helps reduce neuroinflammation. From a mechanistic standpoint, this process can be compared to immunotherapy in oncology, which enhances immune function to eliminate cancer cells. In contrast to existing antibody-based treatments such as LEQEMBI and Kisunla, which directly target and remove accumulated brain proteins like amyloid beta, this approach is differentiated in that it stimulates autophagy, the cells’ intrinsic self-cleaning mechanism, thereby promoting the natural removal of pathological waste.

Owing to these unique properties, TRPML1 has recently emerged as a next-generation protein target, garnering significant global attention. In fact, the multinational pharmaceutical company MSD (Merck, U.S.) acquired Calporta Therapeutics and Caraway Therapeutics for about KRW 800 billion (approximately USD 558.9 million) each to secure TRPML1 target assets. Moreover, the Michael J. Fox Foundation, the world's largest Parkinson's disease research organization, also recognized TRPML1 as one of its five most innovative therapeutic targets.

Another key advantage of Threebrook Therapeutics' compound lies in its small-molecule design. Kim explained that, unlike existing antibody-based therapies, which exhibit a blood-brain barrier (BBB) ​​penetration rate of only about 0.1%, this novel small-molecule drug demonstrates a significantly higher brain penetration rate, apart from offering a competitive edge with its oral formulation.

"As the body ages, autophagy function declines, resulting in the gradual accumulation of amyloid beta and tau proteins, key factors contributing to neurodegenerative diseases such as Alzheimer's and Parkinson's," Kim explained. "In particular, when calcium ion channels malfunction, lysosomal waste clearance becomes impaired, leading to intracellular accumulation disorders. Our compound, 3BT-1, restores and promotes autophagy function by regulating calcium ion channel activity."

"Unlike antibody-based treatments that only target amyloid beta, 3BT-1 not only eliminates pathogenic protein aggregates such as amyloid beta and tau but also repairs damaged mitochondria. In addition, it mitigates neuroinflammation, thereby preventing the occurrence of amyloid-related imaging abnormalities (ARIA), a major adverse effect associated with conventional antibody treatments," Kim further emphasized.

Kim described protein aggregates and neuroinflammation as being ‘interconnected like a ring of fire.’ "As protein aggregates accumulate, they induce neuroinflammation, which in turn damages the ALP, thereby hindering the clearance of these aggregates," he explained. "Conversely, neuroinflammation may also precede aggregation, which is why it is essential to eliminate both the protein aggregates and the neuroinflammation simultaneously. However, antibody-based therapies are incapable of controlling neuroinflammation."

"The core concept of 3BT-1 is 'clearing.' The drug eliminates the key markers of Alzheimer's disease, protein aggregates, damaged mitochondria, and neuroinflammation. It is being developed both as a monotherapy and in combination with antibody-based drugs, with the expectation of achieving complementary therapeutic effects," he further commented.

The key to successful global technology transfer lies in 'differentiation'... Joint efforts between Korean and international research teams aim to enhance efficacy and strengthen translational research

However, 3BT-1 extends beyond the mere activation of TRPML1. Although the competitive landscape in this field remains relatively small, the company recognized the need for distinct differentiation, particularly amid the presence of global players like Libra Therapeutics and Casma Therapeutics.

Kim pointed out that most competitors have concentrated exclusively on activating the TRPML1 homotetramer (a complex composed of four identical proteins). In contrast, his team initiated the development of a novel drug capable of activating the TRPML1/TRPML3 heterotetramer (a complex consisting of four different proteins).

"Many of the global pharmaceutical companies we met expressed interest in adopting our technology even at the candidate discovery stage, prior to entering clinical trials. However, they all posed the same critical question: 'What sets you apart from your competitors?'" he explained. "Korean venture capitalists (VC) also raised this question repeatedly, leading us to the clear conclusion that differentiation is the only path to survival."

"TRPML1 is a six-transmembrane protein that assembles into four-part homotetramers, forming channels through which calcium ions can pass. Upon further investigation, we discovered that in the human body, TRPML1 does not exist only in this form, it can also form mixed complexes, creating TRPML1/TRPML3 heterotetramers," Kim remarked. "To maximize the drug's therapeutic efficacy, it is essential to activate both configurations simultaneously. For this reason, we are conducting ongoing research in collaboration with structural biology experts Professor Lee Jie-oh of POSTECH and Professor Kim Hyun-jin of Sungkyunkwan University."

Furthermore, the company is conducting translational research in collaboration with the Alzheimer's Disease Research Center at Boston University Medical Campus (BUMC), utilizing actual patient brain tissue to increase the clinical relevance and potential of its new drug development efforts. In degenerative brain diseases such as Alzheimer's and Parkinson's, efficacy observed in animal models often fails to translate successfully into clinical trials. This discrepancy arises because rodent brains can appear to improve cognitive function, whereas in humans, the disease mechanisms are far more intricate.

"We are conducting joint research with Professor Lee Jung-hee of Boston University Chobanian & Avedisian School of Medicine and Dr. Ryu Hoon of KIST to analyze the expression and functional role of TRPML1 in the brain tissue of Alzheimer's disease patients," Kim said. "In recognition of our research innovation, we were selected for the ‘Global Collaborative Project’ by the 'Ministry of SMEs and Startups,' securing KRW 1.5 billion (approximately USD 1 million) in funding over three years. Building on this foundation, we aim to understand the precise mechanism of action of our drug candidate and enhance the potential for novel drug development," he added.

"Our goal is to initiate non-clinical toxicity testing (GLP-Tox) in the second half of 2026, and we also plan to secure KRW 4 to 5 billion in pre-Series A funding to support the preparation of an Investigational New Drug (IND) package for Phase 1 clinical trial," Kim further noted.

Generating revenue through non-clinical CRO and food business operations… Advancing technology transfer and IPO plans

Kim plans to prioritize technology transfer of 3BT-1 and the establishment of internal revenue streams, with the ultimate goal of pursuing an initial public offering (IPO) by 2030. The company’s internal revenue model includes operations in the non-clinical contract research organization (CRO) sector and the food business. Currently, Threebrooks offers electrophysiology experimental services based on its proprietary lysosomal patch-clamp technology, while simultaneously preparing to enter the food sector to diversify cash flow sources.

He reflected on the early days of founding the company, which coincided with the onset of the so-called ‘bio-investment ice age,’ stating, "Our original plan was to sustain the company through national R&D projects during the ice age and then take off when the next boom cycle arrived. However, early-stage ventures continue to face extremely challenging conditions." He added with concern, "In the past, startups could first secure investment and then use that funding to generate clinical data. Now, however, we are expected to demonstrate technology transfer performance before receiving investment. The system has been reversed."

"We are currently developing internal revenue-generating businesses capable of ensuring sustainable cash flow. Among these, our CRO business, which leverages advanced electrophysiology technology, has gained strong traction, as many companies developing brain disease treatments are entrusting us with their CRO responsibilities. In fact, we expect to exceed our sales target this year, achieving around KRW 500 million in annual revenue," Kim further commented.

Kim stated that the company’s upcoming food business will center on ‘aging prevention,’ leveraging the mechanisms of action used in its current drug development programs. "The market for functional ingredients that activate autophagy is expected to be substantial. We are preparing to expand into functional foods and nutritional supplements, which can generate revenue more quickly than pharmaceuticals, and we anticipate full-scale commercialization to begin around the year after next," he further added.

Regarding technology transfer, Kim explained that the company is considering a collaborative development model similar to that of Yuhan Corporation's lung cancer drug, ‘Leclaza.’ Under this approach, Threebrooks plans to co-develop its drug candidates with major Korean biopharmaceutical companies, and subsequently license them out to global pharmaceutical firms once clinical data are established.

Leclaza was originally developed by the Korean biotechnology company Oscotec and subsequently licensed to Yuhan Corporation in 2015. Later, Yuhan Corporation granted global licensing rights for Leclaza to the multinational pharmaceutical company Johnson & Johnson (J&J). It became the first anticancer drug developed in Korea to receive approval from the U.S. Food and Drug Administration (FDA) and is currently marketed worldwide.

"I believe the ideal structure for a venture company is to first collaborate with a domestic pharmaceutical firm to conduct clinical trials, and then, once the results are promising, transfer the technology to a larger global partner,” Kim further explained. “To this end, we are currently engaged in an open innovation project with Daewoong Pharmaceutical and are also exploring joint research and technology transfer opportunities with other companies." He outlined the company’s roadmap, aiming to finalize a technology transfer agreement with a Korean pharmaceutical company next year, followed by a global technology transfer deal between 2029 and 2030.

In the long term, Kim expressed that his ultimate goal is to develop treatments for pediatric brain diseases. "I have a family member who has suffered from a pediatric brain disease, which has given me a deep sense of interest and urgency in this field. In particular, pediatric epilepsy has very limited treatment options, and once neuronal damage occurs, it is extremely difficult to recover, often leaving patients with lifelong aftereffects," Kim remarked.

“However, pediatric diseases are a field that major pharmaceutical companies rarely pursue, as clinical trial design is complex and market potential is limited,” Kim further emphasized. “My goal is to secure funding through technology transfer in areas with high commercial value and strong marketability, such as Alzheimer’s disease treatments, and then reinvest those profits to directly conduct research on pediatric brain diseases.”