Cassava Therapeutics' Strategic Move: Dr. Angélique Bordey and the TSC Breakthrough

Cassava Sciences, Inc. (NASDAQ: CASA) has taken a bold step in its quest to address rare neurodevelopmental disorders by appointing Dr. Angélique Bordey, a leading neurobiologist specializing in tuberous sclerosis complex (TSC), as its Chief Scientific Officer. This move positions Cassava to accelerate its preclinical program targeting TSC, a genetic disorder affecting roughly 1 million people globally. With a 2025 milestone to advance its lead candidate into clinical trials, the company is betting on Bordey’s expertise to unlock therapies for a condition where existing treatments fall short.

The TSC Opportunity: A Rare Disease with High Unmet Need

TSC is a multisystem disorder caused by mutations in the TSC1 or TSC2 genes, which regulate the mTOR signaling pathway. The disease manifests as benign tumors in organs like the brain, kidneys, and heart, as well as neurological complications such as epilepsy, autism spectrum disorder (ASD), and cognitive deficits. Approximately 80–90% of TSC patients experience seizures, often resistant to current therapies like antiepileptics and mTOR inhibitors (e.g., everolimus). Despite these treatments, a significant portion of patients remain undertreated, creating a clear market gap for novel approaches.

Dr. Bordey’s Expertise: Bridging Science and Clinical Impact

Dr. Bordey’s research has been pivotal in linking mTOR pathway dysregulation to TSC’s neurological manifestations. Her 2024 studies in eLife and Journal of Neuroscience revealed how mutations in TSC1 and other mTOR pathway genes disrupt cortical development, synaptic connectivity, and neuronal excitability—key drivers of epilepsy and ASD. For example, her team demonstrated that reducing Filamin A (FLNA), a protein involved in cytoskeletal structure, restored synaptic function in mouse models of TSC-associated ASD. This discovery underpins Cassava’s strategy to repurpose simufilam, a small molecule that targets FLNA, as a potential therapy for TSC-related seizures.

Bordey’s work also emphasizes the need for personalized therapies. In a 2024 review chapter, she highlighted that different mTOR pathway mutations (e.g., TSC1 vs. Rheb) produce distinct seizure mechanisms, suggesting that “one-size-fits-all” mTOR inhibitors may not suffice. This aligns with Cassava’s focus on simufilam, which could address pathway-specific dysfunctions.

Cassava’s Strategic Play: Simufilam and the Yale Collaboration

In February 2025, Cassava entered an exclusive license agreement with Yale University to develop simufilam for TSC-related seizures. The deal grants rights to a U.S. patent based on Bordey’s 2020 research, which showed simufilam reduced seizures in TSC mouse models. Cassava has since prioritized preclinical studies to validate simufilam’s efficacy, collaborating with the TSC Alliance to ensure alignment with patient needs. While no clinical trials have yet been announced, the company aims to leverage this preclinical data to advance toward human testing in the near term.

Financial Position: Navigating Post-Alzheimer’s Setbacks

Cassava’s pivot to TSC comes after the discontinuation of its Phase 3 Alzheimer’s trials (RETHINK-ALZ and REFOCUS-ALZ) in late 2024. Despite the setbacks, the company remains financially stable. As of December 2024, Cassava held $128.6 million in cash, with projected Q1 2025 cash usage of $16–$20 million—primarily for winding down Alzheimer’s operations. Management has emphasized cost discipline, including a 33% workforce reduction, to prioritize the TSC program. This focus could position Cassava to capitalize on the rare disease market, which is projected to exceed $40 billion by 2028.

Risks and Considerations

While Cassava’s strategy is promising, risks abound. Preclinical success does not guarantee clinical efficacy, and simufilam’s safety profile in humans remains unproven. Additionally, competition exists: companies like Novartis (NVS) and Bristol-Myers Squibb (BMY) are advancing mTOR inhibitors for TSC. Cassava’s differentiation hinges on simufilam’s novel mechanism targeting FLNA—a protein whose role in TSC is only recently understood.

Conclusion: A High-Reward, High-Risk Play in Rare Diseases

Cassava’s TSC program represents a strategic pivot with significant potential. By leveraging Bordey’s deep expertise in mTOR biology and simufilam’s novel mechanism, the company aims to address a critical unmet need in a rare disease with a growing patient population. With $128.6 million in cash and a streamlined focus, Cassava is positioned to advance simufilam through preclinical and early-stage clinical testing. However, investors must weigh the risks of preclinical failure and regulatory hurdles against the upside of a first-in-class therapy for a $1 billion+ market opportunity. For those willing to take on the risk, Cassava’s TSC play could be a breakthrough—and a rare gem in the biotech space.