Over $3.4 Billion in One Day: Two Blockbuster Alzheimer’s Deals Spark AD Therapeutics Surge

On the same day, two giants triggered two BD deals exceeding $1 billion each, igniting the Alzheimer's disease (hereinafter referred to as AD) track.

On August 6, 2024, local time, Eisai announced that it had signed a cooperation agreement with Seed Therapeutic, a subsidiary of Beyond Spring (万春医药), to discover, develop, and commercialize novel molecular glue degraders for multiple undisclosed neurodegenerative and oncology targets. Seed Therapeutics will lead the preclinical research related to neurodegenerative diseases and oncology.

According to the terms of the agreement, Seed Therapeutics is entitled to receive up to $1.5 billion in upfront payments as well as preclinical, clinical, regulatory, and sales milestone payments, along with tiered royalties upon Eisai's exercise of its exclusive rights under the strategic research collaboration. Seed Therapeutics will lead preclinical discovery activities for selected targets, including the selection of E3 ligases and the identification of molecular glue degraders; Eisai will have exclusive rights to develop and commercialize compounds generated from this collaboration.

On the other hand, Sangamo Therapeutics, Inc. (NASDAQ: SGMO, hereinafter referred to as Sangamo), a leader in gene therapy drugs and gene editing, announced that it has reached a licensing agreement with Genentech, a subsidiary of Roche Group, to develop intravenously administered genomic medicines for treating neurodegenerative diseases, including Alzheimer's disease. Molecular glue degraders have been a key focus area for major multinational corporations (MNCs) in recent years, and Eisai's collaboration marks its entry into the molecular glue degrader field.

Under the terms of the agreement, Sangamo is responsible for completing the technology transfer and certain preclinical activities, while Genentech will handle all clinical development, regulatory interactions, manufacturing, and global commercialization. Genentech is expected to pay Sangamo an upfront licensing fee and milestone payments totaling $50 million. Additionally, Sangamo is eligible to receive up to $1.9 billion in development and commercial milestones.

According to the agreement, Genentech has obtained the development rights for epigenetic inhibitors based on zinc finger proteins, targeting the MAPT gene that encodes the Tau protein. The Tau protein plays a crucial role in Alzheimer's disease and other tauopathies. Additionally, Genentech has secured the rights to use Sangamo's proprietary adeno-associated virus (AAV) capsid, STAC-BBB. This AAV capsid has demonstrated a strong ability to cross the blood-brain barrier (BBB) in non-human primate models.

Affected by this news, Sangamo's stock price increased by 29%.

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The R&D team of Seed Therapeutics is led by Avram Hershko, the discoverer of the ubiquitination-targeted protein degradation system and the 2004 Nobel Prize winner in Chemistry, as well as Dr. Lan Huang, CEO of BeyondSpring Pharmaceuticals. Notably, the R&D team of BeyondSpring Pharmaceuticals has deep technical accumulation in this field over many years: On November 12, 1999, Dr. Lan Huang solved the first E3 ligase structure of a protein degradation system in the world and published it in a scientific journal. Exactly 21 years later on the same day, Seed Therapeutics signed a collaboration with Eli Lilly.

The core technical experts of Seed Therapeutics also include Professor Ning Zheng and Professor Michele Pagano. Professor Ning Zheng, a researcher at the Howard Hughes Medical Institute, a TPD structural biologist, and a professor of pharmacology at the University of Washington, was the first to solve the novel CRL E3 structure in 2014, which was published in Nature Reviews Drug Discovery. Professor Michele Pagano is a researcher at the Howard Hughes Medical Institute, an expert in TPD biology and cancer, and the chair of the Department of Biochemistry and Molecular Pharmacology at New York University.

On this basis, the Seed Therapeutics research and development team has spent more than a decade continuously developing and accumulating, seeking to construct more unique compounds as potential treatments for various diseases.

Seed Therapeutics Independently Pioneers "Molecular Glue" Technology to Induce Protein Degradation Mechanisms Present in All Cells, Aiming to Identify and Degrade Disease-Causing Proteins That Are Not Typically Drug Targets. More Importantly, Seed Therapeutics’ Molecular Glue Program Focuses on NCEs with Chemical Properties Closer to Drug-Likeness, Which Differs from the Development Strategy of Proteolysis-Targeting Chimeras (PROTACs), a Strategy Characterized by Maximizing the Likelihood of Successful Drug Development in Subsequent Research Phases.

Molecular Glue: Small Molecules that Work Like Glue. They function by binding to an enzyme known as E3 ubiquitin ligase, altering its surface shape so that it can bind to the target protein. Once the three-way binding is formed, the E3 ligase adds a chain of ubiquitin molecules to the protein, thereby triggering the cell's protein degradation system to break down the target protein.

It should be noted that most drugs approved for the treatment of human diseases exert their therapeutic effects by binding to molecular targets inside or outside cells, thereby influencing signaling pathways or functions associated with those targets. The main targets of drugs and drug candidates discovered through this traditional approach are proteins within cells, which are crucial components of cellular structure. When these proteins malfunction, they can lead to the onset or progression of diseases. Notably, when using the aforementioned drug development strategy, less than 30% of disease-related proteins possess "druggable" potential. Therefore, during the development of treatments for various severe conditions, the limiting factor is the lack of druggable protein targets rather than insufficient understanding of the biological characteristics of the diseases themselves.

In other words, in traditional small-molecule drugs, the drug occupies the binding site by binding to the disease-causing target, preventing the target from functioning properly. However, for undruggable targets, the absence of a binding site means that traditional small molecules cannot bind to them. Inside cells, many physiological processes rely on the interactions of over 300,000 proteins with other proteins to be completed, such as rapid modifications and adjustments, or swift synthesis and degradation.

For molecular glue innovation, finding new E3 is an important route. The new therapy developed by Seed Therapeutics will use novel E3 to induce specific protein degradation, thereby functionally inhibiting pathogenic proteins or proteins associated with resistance to other therapies, ultimately breaking through this bottleneck. This breakthrough development strategy is expected to significantly benefit thousands of patients with severe diseases, including various cancer patients and Alzheimer's patients.

Eisai Leads $24 Million Series A3 Financing in Seed Therapeutics, Advancing Oral Degrader RBM39 to Phase I Clinical Trials

The other protagonist of the day, Sangamo, was founded in 1995 and went public in 2000. Formerly known as Sangamo BioSciences, the company is headquartered in Richmond, California, USA. It focuses on platform technologies for genome editing, gene regulation, and cell therapy. Its patented technology—zinc-finger DNA-binding protein (ZFP) technology—is used for specific genome modifications and gene regulation, enabling the precise knockout of genes or the insertion of therapeutic genes into exact locations. It is also one of the three major gene-editing technologies available today (the other two being transcription activator-like effector—TALEN, and clustered regularly interspaced short palindromic repeats—CRISPR).

Sangamo has been researching ZFN gene editing technology for over 20 years and is the primary patent holder of this technology. Thanks to Sangamo's research and development efforts, ZFN has achieved several firsts in the field of gene editing: the first to edit human cell genes, the first to edit genes in vitro, and the first to edit genes in vivo.

Compared with CRISPR, the main disadvantage of ZFN as a gene-editing tool is that it is time-consuming and cumbersome to develop high-quality gene-editing products. Although this obvious gap still exists, Sangamo has improved the development process, thereby shortening the development time of ZFN and reducing its cost. In the past, the development cycle of ZFN could last up to three months, and determining the final therapeutic ZFN usually took a year. After Sangamo's improvements, the development cycle has been shortened to 10 days, during which the constructs in cells are designed, assembled, and tested. The total time required for producing therapeutic ZFNs has been reduced to three months.

In 2016, Sangamo published a paper in Nature Communications, in which they developed a system that can select ZFNs capable of cutting genes at the correct location with a high ratio. Even at very high targeting activity, the off-target rate is still guaranteed to be reduced to the limit of detection or lower.

Sangamo is conducting early clinical trials by utilizing ZFN gene editing technology and collaborating with pharmaceutical companies such as Pfizer, Sanofi, and Takeda for late-stage clinical trials and commercial development to advance product applications in various technological directions.

However, even the most popular figures in business cooperation encounter setbacks at times. In 2023, Novartis announced it would terminate a 2020 agreement with Sangamo focused on researching gene regulation therapies to treat three neurodevelopmental disorders. At the same time, Biogen also stated it would end its agreement with Sangamo regarding gene therapy for neurological diseases. Both companies indicated that the decision to terminate the collaborations was based on an evaluation of their corporate development strategies, halting projects worth over a cumulative $400 million.

Fortunately, the termination strategies of Novartis and Biogen did not trigger a domino effect. After going through the layoff turmoil, Sangamo was eventually acquired by Roche. Boris Zaïtra, Head of Roche’s Business Development, stated: "With its experience, expertise, and resources in neuroscience research, Roche is already in a unique position to explore transformative approaches to treating neurodegenerative diseases, including gene therapy."

Compared to CRISPR, which is more favored in research and development but still poses safety risks, ZFN requires more protein engineering knowledge than CRISPR. However, Sangamo firmly believes that for therapeutic purposes, "the simplest may not be the best." This might explain why major MNCs are eager to collaborate with Sangamo to explore new possibilities for treatment.

Molecular glue degraders have been the focus of attention for MNCs in the past five years, with热度 no less than that of ADC. In this field, Pfizer, Eli Lilly, Sanofi, Novartis, Merck, Bayer, and others have already entered the赛道. Since 2023, MNCs such as BMS, Roche, and Merck have successively reached molecular glue technology platform/project collaborations with overseas biotech companies, with a potential total transaction value exceeding tens of billions of dollars.

Among them, Novartis has been actively pursuing mergers and acquisitions in molecular glue degraders. The most recent acquisition was in April 2024, when Novartis reached an exclusive strategic collaboration with Arvinas worth a total of $1.01 billion to co-develop ARV-766, an oral Proteolysis Targeting Chimera (PROTAC) for the treatment of metastatic castration-resistant prostate cancer (mCRPC), as well as a preclinical candidate protein degradation therapy targeting AR-V7 for mCRPC. Additionally, in May 2024, Takeda signed a $1.2 billion agreement with Shanghai Degron Biomedical to develop novel molecular glue degraders for the treatment of oncology, neuroscience, and inflammatory diseases.

Eisai, with over 40 years of research history in the field of neurodegenerative diseases, has concentrated its business resources on the dementia field since entering the Alzheimer's domain for the first time in 1983. This time, recognizing the potential of molecular glue in the Alzheimer's field, it can be said that Eisai has "followed the trend" to join.

However, the fundamental reason these MNCs have collectively bet on platforms is that, although molecular glues are highly ideal, the number of discovered molecular glue degraders remains very limited to date. Their discovery process is largely accidental, lacking systematic discovery and design strategies. Therefore, large pharmaceutical companies hope to bet on new technology platforms, even leveraging AI technology, to accelerate the discovery of molecular glues.

On the other hand, Roche's clinical-stage neurology R&D pipeline includes 12 new molecular entities (NMEs), among which the antibody trontinemab fuses an anti-β-amyloid (Aβ) antibody with a protein domain targeting transferrin receptor 1 (TfR1). This fusion facilitates trontinemab’s crossing of the blood-brain barrier through TfR1-mediated endocytosis.

In the first half of 2024, the research team led by Víctor Montal from the Hospital de Sant Pau in Barcelona, Spain, published a research paper titled "APOE4 homozygosity represents a distinct genetic form of Alzheimer’s disease" in the journal Nature Medicine. The research team proposed that APOE4 should be regarded as a pathogenic gene for AD, further laying a solid theoretical foundation for gene therapy.

Against the backdrop of Eli Lilly's Lacanemab (Lecanemab), the world's first breakthrough targeted drug addressing the root cause of Alzheimer's disease (AD), being approved and poised to usher AD treatment into a new era of "causal treatment," Roche's increased investment in gene therapy not only further solidifies its own AD portfolio but also explores more possibilities.