Angelman trial, page-95

And in responses to this, Gemini said

This Sarepta Therapeutics update about a fatal case of acute liver failure following ELEVIDYS (delandistrogene moxeparvovec-rokl) treatment does have implications for the broader discussion of genetic therapies, especially those using adeno-associated virus (AAV) vectors. While ELEVIDYS is for Duchenne Muscular Dystrophy (DMD) and not Angelman Syndrome, and the therapies discussed previously for Angelman Syndrome were not AAV-based gene therapies, the Sarepta news highlights critical safety considerations relevant to any gene therapy and, more broadly, to any novel therapeutic approach.
Here's how this information reframes the pros and cons, and what new considerations it brings to the table, specifically relating back to the Angelman Syndrome therapies:
Impact on the Angelman Syndrome Therapy Discussion:

1. Heightened Awareness of Systemic Risks (Even with Localized Delivery):
   • While the Angelman Syndrome ASOs are administered intrathecally (targeting the CNS), the ELEVIDYS case is a stark reminder that even therapies with localized delivery can have serious systemic consequences. Although ELEVIDYS is delivered intravenously and uses an AAV vector, the principle remains: a therapeutic agent introduced into the body can have effects beyond the intended target. This reinforces the need for rigorous monitoring for any unexpected adverse events, even if the therapy's mechanism is thought to be highly localized.
   • Relevance to ASOs: This reinforces the "Cons" for both Ionis and Ultragenyx's ASOs regarding potential off-target effects and immune responses. While ASOs are not AAV gene therapies, the body's immune system can react to foreign genetic material, and the liver is a key organ involved in processing and clearing foreign substances. It increases the importance of long-term monitoring for liver function, even with intrathecal delivery.
   • Relevance to NNZ-2591: While NNZ-2591 is not a gene therapy and is orally administered, this still raises the general point of vigilance for unexpected systemic effects. Any new drug can have unforeseen interactions, and the liver is often involved in drug metabolism.
2. Importance of Pre-existing Conditions and Co-infections:
   • The Sarepta release highlights that the patient had a recent cytomegalovirus (CMV) infection, a potential contributing factor to the liver failure. This underscores the critical importance of thoroughly screening patients for pre-existing conditions, infections, and any factors that might increase their risk of adverse events before initiating any novel therapy.
   • Relevance to all Angelman Therapies: This reinforces the need for comprehensive patient screening and careful consideration of individual risk factors before starting any of the Angelman Syndrome therapies. It's not just about the therapy itself, but also the patient's overall health status.
3. Benefit-Risk Assessment (Reinforced):
   • The Sarepta news doesn't negate the potential benefits of ELEVIDYS (or any other gene therapy). It reinforces that every medical intervention has risks, and the decision to proceed must involve a careful, individualized assessment of the potential benefits versus the potential risks.
   • Relevance to all Angelman Therapies: This reinforces the need for open and honest discussions between clinicians, patients, and families about the potential benefits and risks of each Angelman Syndrome therapy, acknowledging the uncertainties that exist with novel treatments.
4. Long-Term Monitoring and Data Collection (Crucial):
   • The ELEVIDYS case highlights the critical importance of long-term follow-up and data collection after any new therapy is introduced. Rare but serious adverse events may not be apparent in initial clinical trials, which typically have limited sample sizes and follow-up durations.
   • Relevance to all Angelman Therapies: This strongly emphasizes the need for ongoing, long-term monitoring of patients receiving any of the Angelman Syndrome therapies, even after they are approved and commercially available. Real-world data is crucial for fully understanding the safety profile.
5. Transparency and Communication
   • Sarepta was forthright and quick with reporting.

How this Changes the Pro/Con Lists (Subtle but Important Shifts):

• For Ionis and Ultragenyx ASOs:
  • Cons: Add a bullet point under "Cons" for both: "Systemic Risks (Even with Localized Delivery): While intrathecal administration targets the CNS, systemic effects, including liver toxicity, are possible and require careful monitoring." This is a general point about all therapies, but the Sarepta case makes it more salient.
  • Reinforces: Add language to any mention of long-term follow up or safety, that adverse events can still appear outside of initial clinical trials.
• For Neuren's NNZ-2591:
  • Cons: Add a similar bullet point: "Systemic Risks: As with any new drug, there's a potential for unexpected systemic effects, including liver toxicity, requiring careful monitoring."

In summary, the Sarepta news doesn't fundamentally change the specific pros and cons of the Angelman Syndrome therapies, as they use different modalities. However, it serves as a critical reminder of the inherent risks associated with any novel therapeutic approach, particularly gene therapies, and emphasizes the importance of:

• Thorough patient screening.
• Careful benefit-risk assessment.
• Vigilant monitoring for unexpected adverse events.
• Long-term data collection and analysis.
• Transparency and communication.

It's a sobering reminder that even highly targeted and promising therapies can have serious, unforeseen consequences, and that continuous learning and adaptation are essential in the development and use of new treatments.