TMF Educational Update | ALS Session

This video provides an in-depth educational update on Amyotrophic Lateral Sclerosis (ALS), focusing heavily on accelerating clinical trials, novel therapeutic targets, and advancements in biomarker development. The session, featuring leading physicians and researchers from Mass General Hospital, emphasizes the shift in ALS research toward efficiency, partnership, and inclusivity, driven by philanthropic support and technological innovation. Key themes include the revolutionary design of platform trials, the molecular mechanisms driving ALS pathology, and the critical need to shorten the diagnostic timeline for patients.

The core of the presentation details the Healy ALS Platform Trial, a paradigm shift in clinical research methodology. Dr. James Berry explains that traditional trials are inefficient, requiring a complete redesign and rebuild for every new drug tested. The platform trial model, in contrast, builds a robust "stadium" (master protocol, centralized IRB, common infrastructure) once, allowing multiple therapies (regimens) to be tested simultaneously and sequentially, cutting costs by one-third and time in half. This design also maximizes participant benefit by increasing the ratio of active drug to placebo (3:1) and sharing a common placebo pool across regimens. The trial leverages advanced tools like DNA sequencing, well-heeled biomarkers (neurofilaments), and digital monitoring (speech) to find less invasive and more objective outcome measures, enhancing data collection efficiency.

Dr. Gazales Sadri Bakili then delves into the latest pre-clinical updates, focusing on molecular mechanisms such as protein aggregation, disrupted trafficking, and mitochondrial dysfunction. She highlights the importance of autophagy (cellular trash removal) as a therapeutic target and discusses how the mislocalization of the TDP-43 protein—a hallmark found in 90% of ALS cases—disrupts the expression of Stathmin 2, a protein critical for axonal regeneration. Furthermore, her lab’s work on Tau protein and its link to mitochondrial fragmentation (via increased Drp1 levels) suggests that targeting Tau could mitigate oxidative stress. This translational research is exemplified by the successful progression of Chromoline Sodium, an anti-inflammatory compound studied in her lab, into a Phase 2 clinical trial.

Finally, Dr. Suma Babu discusses the new era of clinical trials and novel approaches to clinical care. She highlights two recent successful trials: Tofersen (an antisense oligonucleotide, ASO) for SOD1 ALS, which showed a 33% reduction in toxic SOD1 protein and early signals of slowing disease progression; and AMX0035, which slowed functional decline and demonstrated a 6.5-month longer median survival benefit. Dr. Babu also emphasizes the role of biomarker development, specifically using PBR28 PET imaging to characterize neuroinflammation in the motor cortex. This imaging biomarker is being validated across multi-site studies to increase power and feasibility for use as a clinical trial readout, moving research beyond relying solely on functional scales. The presentation concludes with a focus on the "Think ALS" tool, a national initiative aimed at educating general neurologists to expedite diagnosis, reducing the current 12-month average delay from symptom onset to confirmed diagnosis.

Key Takeaways: • Platform Trials Revolutionize Efficiency: The Healy ALS Platform Trial model drastically cuts the time and cost of testing new therapies by using a single master protocol, centralized ethics review (IRB), and shared placebo groups, allowing for continuous drug evaluation. • Increased Access via Expanded Access Programs (EAPs): EAPs, which are FDA-regulated and often philanthropically supported, provide experimental therapies to ALS patients who are ineligible for main clinical trials due to advanced disease state or other characteristics, bridging the gap between research and clinical care. • New Genetic Therapies Show Promise: Antisense Oligonucleotide (ASO) programs, such as Tofersen for SOD1 ALS, demonstrate the ability to significantly reduce toxic protein levels (33% reduction in SOD1 protein) and offer early signals of clinical benefit, paving the way for ASO trials targeting other genes like C9orf72 and Ataxin 2. • Molecular Targets for Sporadic ALS: Pre-clinical research identifies key mechanisms, including the role of TDP-43 mislocalization in disrupting axonal regeneration (via Stathmin 2) and the link between hyperphosphorylated Tau and mitochondrial fragmentation (via Drp1), offering novel targets for drug development applicable to both familial and sporadic ALS. • Neuroinflammation as a Measurable Target: PBR28 PET imaging is a validated biomarker for measuring neuroinflammation in the motor cortex, showing increased signal robustness in faster-progressing patients. This imaging tool is now being used as a clinical trial readout to confirm if anti-inflammatory drugs (like Vertiperstat) are reaching their target and having a biological effect. • Expediting Diagnosis is Critical: The average time from symptom onset to ALS diagnosis is 12 months, a significant delay impacting early treatment access. The "Think ALS" tool is being developed to improve awareness and education among general clinicians to facilitate faster referral to multidisciplinary ALS clinics. • Importance of Biofluids and Data: The development of sensitive and specific biomarkers requires large-scale collection of biofluids (plasma, CSF, urine) and robust genetic sequencing (Project Mine, ALS Knowledge Portal) to uncover subtle genetic links and disease signatures, especially in sporadic cases. • Multidisciplinary Care is the Standard: The multidisciplinary ALS clinic remains the single most important resource, integrating specialized care from physical therapists, respiratory therapists, social workers, and physicians to optimize quality of life and longevity. • Diet and Weight Management: Maintaining weight and good nutrition is considered a crucial, non-pharmacological intervention for ALS patients, with some evidence suggesting its importance in slowing progression. • Advocacy for Telemedicine and Genetic Testing: Regulatory changes are needed to maintain the availability of cross-state telemedicine for specialized care and to improve insurance coverage for genetic testing, which is essential for identifying patients eligible for gene-specific therapies.

Tools/Resources Mentioned:

• Healy ALS Platform Trial: A clinical trial design methodology and ongoing trial.
• Healy ALS Platform Trial Expanded Access Program (EAP): Program providing access to experimental drugs (e.g., Verdipperstat) outside the main trial.
• Tofersen (ASO): Antisense oligonucleotide drug targeting SOD1.
• AMX0035 (Phenylbutrid and TUDCA): Combination drug targeting mitochondria and endoplasmic reticulum.
• PBR28 PET Imaging: Neuroimaging biomarker used to measure neuroinflammation.
• Think ALS Tool: Educational resource targeting general clinicians to expedite ALS diagnosis.
• ALS FRSR (Functional Rating Scale): Standard outcome measure for disease progression.
• MGH ALS Link: Email list/newsletter for updates on ALS research and opportunities.
• ClinicalTrials.gov: Online resource for finding clinical trials.
• Protacs (Proteolysis Targeting Chimeras): Novel technology for degrading specific proteins (e.g., Tau).

Key Concepts:

• Platform Trial: A clinical trial design that tests multiple interventions simultaneously under a single master protocol, maximizing efficiency and participant options.
• Antisense Oligonucleotide (ASO): A type of drug that binds to specific RNA molecules, blocking the production of toxic proteins (e.g., faulty SOD1 protein).
• Autophagy: A cellular process of self-degradation and recycling, often referred to as the "cellular trash removal system," which is disrupted in ALS.
• TDP-43 Mislocalization: A pathological hallmark in 90% of ALS cases where the TDP-43 protein moves from the nucleus to the cytoplasm, leading to axonal degeneration.
• Neuroinflammation: Immune response within the central nervous system, involving reactive glial cells (microglia and astrocytes), which contributes to disease progression in ALS.
• Expanded Access Protocol (EAP): A regulatory pathway allowing patients with serious illnesses to access experimental therapies outside of a formal clinical trial setting.

Examples/Case Studies:

• Tofersen Phase 1 Trial: Showed a 33% reduction in toxic SOD1 protein in cerebrospinal fluid (CSF) at the highest dose, correlating with early signals of slowed disease progression.
• AMX0035 Phase 2 Trial: Demonstrated a statistically significant slower functional decline over 24 weeks and a 6.5-month longer median survival benefit in the open-label extension phase.
• Chromoline Sodium: An anti-inflammatory compound whose pre-clinical success in the SOD1 mouse model (delaying onset, sparing motor neurons) led directly to its progression into a Phase 2 human clinical trial.
• PBR28 PET in Parkinson’s Disease: Used to show that the anti-inflammatory drug Vertiperstat reduced the inflammatory PET signal by 60% as early as eight weeks, confirming target engagement.