Braegen Pharmaceuticals Advances Global First-in-Class Alzheimer's Drug BrAD-R13 with Dual-Mechanism Strategy and Files for IPO

Shanghai Braegen Pharmaceutical Co., Ltd. (established in April 2015 and located in Shanghai Zhangjiang Science City) is an innovative pharmaceutical company focused on the research and development of First-in-Class drugs in the field of central nervous system disorders.

The Company has licensed patented inventions from Emory University in the United States in accordance with international practices. It boasts a highly efficient R&D team led by Dr. Ye Keqiang, Tenured Professor at Emory University, as Chief Scientific Advisor, along with a full-process technical management team covering medicinal chemistry, pharmacology, and clinical research. The Company currently possesses multiple world-leading core technologies and patented inventions. Its product pipeline is primarily focused on the central nervous system (CNS) field, featuring an innovative Alzheimer’s disease (AD) drug approved by the FDA and poised to enter clinical trials, as well as two pre-IND investigational drugs under development for various CNS indications.

In May 2019, the BrAD-R13 project, as the world’s first small-molecule TrkB receptor agonist, garnered significant attention in the field of Alzheimer’s disease (AD) drug development upon receiving implicit approval for clinical trials from the U.S. Food and Drug Administration (FDA). According to the FDA’s clinical trial authorization, BrAD-R13 is intended for the treatment of mild-to-moderate Alzheimer’s disease, offering new hope for AD—a “R&D black hole” that has plagued patients and pharmaceutical companies for decades.

In August this year, VCBeat met with Dr. Zhang Zhihong, Deputy General Manager of Braegen, at its office in the Shanghai Pilot Free Trade Zone. He told VCBeat that the company had originally planned to initiate the overseas Phase I clinical trial for the BrAD-R13 project in early 2020, but it was postponed due to the impact of the COVID-19 pandemic. “We quickly adjusted our plans and are preparing to submit the clinical trial application to China’s NMPA by the end of 2020, expecting to obtain clinical approval in 2021 to launch the domestic Phase I clinical trial.”

Dr. Zhang Zhihong, Deputy General Manager of Braegen Pharmaceutical

A few days before this meeting, Biogen, an innovative pharmaceutical company in the field of neuroscience in the United States, announced that its New Drug Application (NDA) for the investigational Alzheimer’s disease (AD) drug Aducanumab had been accepted by the FDA and granted Priority Review status. Dr. Zhang Zhihong stated that, for the AD drug development sector, which has long struggled to achieve major breakthroughs, the acceptance of Aducanumab’s NDA undoubtedly sends a positive signal. He expressed his hope that more teams will join efforts in the research, development, and commercial translation of new drugs aimed at conquering AD.

Dr. Zhang Zhihong stated that Braegen plans to complete the Phase Ia and Phase Ib studies of the BrAD-R13 project within the next two years, and rapidly advance to the pivotal Phase IIa trial for proof-of-concept. Meanwhile, the drug will be expanded to cover multiple CNS indications, including rare diseases, with the aim of accelerating the market approval process.

According to the 2018 World Alzheimer Report, there are currently over 50 million people living with Alzheimer’s disease (AD) worldwide. With the accelerating trend of population aging, this number is projected to reach 150 million by 2050. At present, global annual healthcare expenditures on AD exceed $1 trillion and are expected to double to $2 trillion by 2030. However, despite the vast market potential for AD therapies, pharmaceutical companies both in China and abroad face a difficult decision in determining whether to initiate or terminate their AD drug development pipelines.

In January 2019, Roche announced the termination of two Phase III clinical trials of crenezumab for the treatment of early Alzheimer’s disease (patients with prodromal or mild AD). Prior to this, Eli Lilly’s solanezumab had failed in Phase III clinical trials twice; Merck & Co. announced the termination of its Phase III project verubecestat; Johnson & Johnson announced the termination of the Phase II/III project atabecestat; and Eli Lilly and AstraZeneca jointly announced the termination of the global Phase III clinical trial program for lanabecestat. The repeated failures of numerous multinational pharmaceutical companies have given rise to the characterization of Alzheimer’s disease drug development as a “R&D black hole.”

Dr. Zhang Zhihong told VCBeat that there are currently two mainstream approaches to Alzheimer’s disease (AD) drug development internationally: one focuses on “symptomatic treatment” from a pathophysiological perspective, aiming to alleviate symptoms and improve patient benefits; most currently marketed drugs fall into this category, such as donepezil and memantine. The other approach targets the “root cause” from a pathological perspective, seeking to slow disease progression by eliminating the underlying causes. The investigational drugs shelved by multinational pharmaceutical companies such as Roche, Merck & Co., and Eli Lilly all adopted this “root-cause” strategy.

When discussing the reasons why new Alzheimer’s disease (AD) drug development projects are difficult to sustain, Dr. Zhang Zhihong believes there are two main factors: First, the pathogenesis of AD is not thoroughly understood. “Disease-modifying” drugs developed against a single target often succeed in Phase II trials but fail in Phase III due to inconsistent clinical endpoints. Second, given the long disease course and diverse symptoms of AD, purely symptomatic treatments struggle to demonstrate clinically meaningful patient benefits at the endpoints of lengthy clinical trials, which typically last 18–24 months.

Currently, the academic understanding of the pathogenesis of Alzheimer’s disease (AD) remains in a “gray box” state. Since German physician Alois Alzheimer first identified and defined the disease in 1901, its pathological diagnostic hallmarks have been amyloid plaques and neurofibrillary tangles. The molecular biological basis underlying these hallmarks is the aggregation and deposition caused by abnormal spatial conformations of Aβ and Tau proteins, which subsequently exert neurotoxic effects and lead to disease. However, single-target drugs developed as “curative” strategies based on this pathological foundation have ultimately failed to pass Phase III clinical trials for FDA approval. This suggests that these two targets may not be the root cause of AD pathogenesis, and that single-target therapies cannot achieve a “curative” effect.

In contrast, the currently marketed Alzheimer’s disease (AD) drugs, while alleviating patients’ clinical symptoms to some extent from a “symptomatic treatment” perspective, fail to halt or delay disease progression. Consequently, long-term pharmacological therapy offers very limited benefits. The management of AD is akin to “sailing against the current: if you do not advance, you retreat.” As the disease progresses, declines in learning and memory, along with cognitive impairment, inevitably worsen gradually. Therefore, symptomatic pharmacotherapy targeting only pathophysiological manifestations is merely a drop in the bucket.

The innovation of the BrAD-R13 project lies in its simultaneous targeting of both pathophysiological and pathological levels, employing a “dual-core drive” strategy that addresses both the root causes and symptoms to treat Alzheimer’s disease (AD).

Symptomatic Treatment:The core symptoms of Alzheimer’s disease (AD) are the decline in learning and memory capabilities. From a physiological perspective, this function is closely related to synaptic plasticity of neuronal cells in the brain. The BDNF-TrkB signaling pathway in the central nervous system is currently one of the most thoroughly studied mechanisms associated with this physiological function. Clinical medicine also indicates that the regulatory role of this pathway is inhibited in AD patients. BrAD-R13 can activate this signaling pathway, exerting neuroprotective effects and modulating synaptic plasticity, thereby improving patient symptoms.

Addressing the Root Cause:In Alzheimer’s disease (AD) patients, the aggregation and deposition of Aβ and Tau are typical pathological hallmarks that progress with the course of the disease. Amelioration of disease progression is inevitably accompanied by changes in these two biomarkers. Our study demonstrates that BrAD-R13 delays disease progression by activating the BDNF-TrkB signaling pathway, which inhibits δ-secretase—a key upstream protease responsible for the cleavage of both Aβ and Tau—thereby simultaneously suppressing the production of Aβ and Tau.

Dr. Zhang Zhihong told VCBeat that although clinical data from human studies for the BrAD-R13 project have not yet been obtained, the preclinical data accumulated to date have given us great confidence in the clinical potential of this drug. On one hand, earlier trials in multiple CNS animal models have fully validated its safety and efficacy. Pharmacodynamic studies showed that long-term oral administration of BrAD-R13 in 5xFAD transgenic mice activated TrkB and its downstream signaling pathways in the brain, producing neuroprotective effects including reduced synaptic loss and improved electrophysiology. Meanwhile, AD-related biomarkers (such as Aβ and Tau) were also reduced, ultimately leading to improved learning and memory capabilities in behavioral tests. On the other hand, because BrAD-R13 not only reduces the aggregation and deposition of Aβ and Tau but also improves clinical symptoms such as learning and memory decline by regulating synaptic plasticity through the BDNF-TrkB pathway, it provides more predictable achievability of clinical endpoints for future clinical studies.

In addition to Alzheimer’s disease, Braegen is also advancing the BrAD-R13 project toward clinical trials for multiple indications in the central nervous system (CNS) field, including Parkinson’s disease, brain injury repair, schizophrenia, and amyotrophic lateral sclerosis (ALS). The company has already accumulated substantial preclinical data and will gradually initiate clinical development for these indications.

Prior to joining Braegen, Dr. Zhang Zhihong, who holds a background in biomedical sciences, was dedicated to research on neurodegenerative diseases. He participated in multiple studies investigating the pathogenesis of Alzheimer’s disease, Parkinson’s disease, depression, and prion diseases. Later, he transitioned from technical R&D to project management in drug development, focusing on the early-stage development of First-in-Class drugs and the formulation and execution of dual filing strategies for both China and the United States.

Dr. Zhang Zhihong joined Shanghai Braegen Pharmaceutical Co., Ltd. during its preparatory phase and has been overseeing the development of the BrAD-R13 project ever since. In his view, drug development for Alzheimer’s disease (AD) is akin to a relay race. Viewed through the lens of a 4x100-meter relay, the target identification and drug screening phase corresponds to the first 100 meters, typically conducted by scientists at universities or research institutes. The final 100-meter sprint, representing large-scale Phase III clinical trials, is critical and usually undertaken by multinational pharmaceutical companies. “The two middle 100-meter segments represent the process by which innovative pharmaceutical companies rapidly advance projects from preclinical studies to early-stage clinical validation,” Dr. Zhang pointed out. “This stage requires both professional management teams to steer the direction and continuous capital infusion to provide momentum.”

Currently, the trend in Alzheimer’s disease (AD) drug development is increasingly shifting toward innovative targets and multi-pathway mechanisms. Scientists and clinical resources capable of integrating new target screening with translational medicine to validate target combinations hold a distinct advantage. Meanwhile, large pharmaceutical companies are systematically dismantling their internal central nervous system (CNS) R&D departments or pipelines, sending a clear signal that innovation is migrating toward small and mid-sized biotech firms. The VIC (VC + IP + CRO) model adopted by Braegen Pharmaceutical effectively supports AD drug development and represents a highly efficient and popular asset-light approach to advancing new drug discovery.

Dr. Zhang Zhihong believes that to ensure a successful handover in Alzheimer’s disease (AD) drug development, thorough preparation is essential across every stage involving venture capital (VC), intellectual property (IP), and contract research organizations (CROs). First, regarding VC, leveraging capital to accelerate projects and mobilizing the industrial resources behind such capital are key to speeding up project advancement. Second, in terms of IP, attention must be paid at all times, from initial intellectual property assessments during project initiation to the construction of patent pools during the project development phase. Third, R&D teams should select appropriate CRO partners based on project characteristics, effectively manage timelines and budgets during outsourced R&D activities, and conduct scientifically rigorous experimental designs and data analyses tailored to innovative drugs. “This requires close collaboration between both the client and service provider teams.”

It is understood that Braegen has multiple drug candidates in its pipeline that are being actively advanced. In the future, Braegen will continue to explore new targets and novel mechanisms, leveraging collaborative teamwork and concentrated resources to excel in new drug development.