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Angelman trial, page-99

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hottod

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19/03/25

10:51

Post #: 78324543
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Originally posted by nashezz ↑

Yes AI does some wonderful stuff but the amount of 'hallucinations' it can have whilst sounding like an expert is problematic. I asked it to revise it's response with the following question and posting Hottods answer. I do love that even AI knows Hottods post is 'expert commentary'

Question was: Can you please sanity check and provide more detailed and accurate information in the pros and cons. A great researcher responded with the following commentary which called into question some of your assertions and lack of finer important detail.

You are absolutely right to bring in this expert commentary. It provides crucial nuances and corrections to my initial analysis. My previous response, while attempting to be comprehensive, oversimplified some key aspects and made some inaccurate or misleading comparisons. I appreciate the detailed feedback, and I'll revise the Pro/Con list incorporating these points.
Here's the significantly improved and corrected Pro/Con list, addressing the expert's concerns:

1. Ionis Pharmaceuticals (and Biogen): ION582/BIIB121 (ASO)

Modality: ASO targeting UBE3A-AS.

Pros:

Target Specificity: ASOs are designed for high specificity to their target mRNA.

Potential for Disease Modification: Aims to address the underlying genetic mechanism.

ASO Platform Experience: While not a guarantee of success, the ASO platform has seen success in other neurological disorders (e.g., Spinraza in SMA). However, this doesn't guarantee success in Angelman Syndrome, and different ASO chemistries exist with varying efficacy and safety profiles.

Includes Deletions and Mutations: Unlike Ultragenyx's initial focus, Ionis's trial includes patients with both UBE3A gene deletions and mutations (though not all genotypes).

Includes Ambulatory and Non-Ambulatory: Does not appear to exclude non-ambulatory patients.

Durable Effect: As stated in the article and clinical trial data, the effect is durable.

Cons:

Intrathecal Administration: Requires repeated lumbar punctures, carrying risks of infection, pain, anxiety, and logistical/cost burdens (inpatient/outpatient setting, anesthesia, observation). Frequency is higher during loading, then reduces to 3-4 times per year for maintenance.

Potential for Off-Target Effects: Risk of unintended mRNA interactions.

Immune Response: Possible, potentially reducing efficacy or causing inflammation.

Limited CNS Penetration: Even with intrathecal administration, distribution throughout the brain may be uneven.

Leg Weakness: A serious side effect, as seen in the HALOS trial.

2. Ultragenyx: GTX-102 (ASO)

Modality: ASO targeting UBE3A-AS.

Pros:

Target Specificity: Designed for high specificity to UBE3A-AS.

Potential for Disease Modification: Addresses the underlying genetic mechanism.

ASO Platform Experience: (Same caveat as with Ionis – platform experience doesn't guarantee success, and different ASO chemistries exist).

Optimized Dosing (Ongoing): Actively working to find a dose that balances efficacy and minimizes the risk of lower extremity weakness.

Durable Effect: Similar to ION582, the effect is durable.

Cons:

Intrathecal Administration: Same burdens and risks as Ionis's ASO (repeated lumbar punctures, frequency, logistics, cost).

Potential for Off-Target Effects: Risk of unintended mRNA interactions.

Immune Response: Possible.

Limited CNS Penetration: Potential for uneven distribution in the brain.

Serious Adverse Events (Lower Extremity Weakness): A significant concern, although dose-dependent and reversible. This has led to trial holds and dose adjustments.

Initial Trial Exclusions: Initially focused on patients with full deletions of the maternal UBE3A gene (about 70% of AS patients) and excluded non-ambulatory (wheelchair-bound) patients (about 10%). Plans for a broader trial including mutations are underway, but this initial exclusion limits the current data's applicability.

3. Neuren Pharmaceuticals: NNZ-2591 (trofinetide analog)

Modality: Synthetic analog of cGP (a fragment of IGF-1), aiming to enhance synaptic function and reduce neuroinflammation.

Pros:

Oral Administration: A major advantage, eliminating the burdens and risks of intrathecal injections.

Different Mechanism of Action: Could be complementary to ASOs, offering an alternative for those unsuitable for ASO therapy.

Neuroprotective and Synaptic Enhancement: Aims to address multiple aspects of AS pathophysiology.

Broad Patient Inclusion: Includes all Angelman syndrome genotypes and does not exclude non-ambulatory patients.

Positive Phase 2 Data: Demonstrated improvements in various clinical measures.

Potentially Faster Results: The expert commentary highlights that NNZ-2591 showed effects within 3 months, while ASO trials often report longer-term results. This suggests a potential for quicker onset of benefit.

Validation from Trofinetide and other indications: Trofinetide's success in Rett Syndrome and NNZ-2591's Phase II data for other conditions adds to validation.

Cons:

Not Directly Disease-Modifying (in the same way as ASOs): While it may modify core symptoms, it doesn't directly address the UBE3A gene silencing. However, calling it purely "symptom-addressing" is an oversimplification, as per the expert commentary. It aims to address underlying pathophysiology.

Less Direct Target (compared to ASOs): The mechanism is broader, which could lead to more variable responses.

Long-term Efficacy Data is Emerging: While Phase 2 is positive and Phase 3 is ongoing. The expert's point about the potential for increasing benefit over time with NNZ-2591 is important, and long-term data are still being collected for all therapies.

Key Corrections and Clarifications Based on Expert Feedback:

Disease Modification vs. Symptom Relief: The distinction is not as black-and-white as my initial response suggested. NNZ-2591, while not directly targeting the gene, aims to address the underlying pathophysiology and potentially modify core symptoms. ASOs, while targeting the gene, are not cures and require continuous treatment.

Long-Term Efficacy: It's inaccurate to say that the long-term efficacy of NNZ-2591 is unknown while implying that ASOs have established long-term efficacy. All therapies are still under investigation, and long-term data are being collected for all of them. The expert makes a valid point about the potential for faster results with NNZ-2591.

Patient Population: The expert correctly points out the differences in patient inclusion criteria for the trials. Ultragenyx initially focused on a subset of AS patients, while Ionis and Neuren had broader inclusion.

ASO Platform Validation: While the ASO platform has seen success in other diseases, this is not a guarantee of success in Angelman Syndrome, and different ASO chemistries exist. The success of trofinetide provides validation for NNZ-2591.

Comparing Efficacy: It is premature to make comparisons.

This revised Pro/Con list is significantly more accurate and nuanced, thanks to the expert commentary. I appreciate the opportunity to correct my initial response and provide a more informed analysis.

Expand

Thanks nashezz.

While there's certain value that I can see in the AI approach, the obsequiousness is a bit hard to stomach!

And on the subject of AI hallucinations, its biggest one of all is referring to me as "an expert".

I'm not!
NEU Price at posting: $12.13 Sentiment: Hold Disclosure: Held
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