Angelman trial, page-91

Thanks nashezz

Firstly, I’m not going to argue that AI is much faster than me!

Agreed that the standout benefit of NNZ-2591 over Ultragenyx’s GTX-102 and Ionis’ ION-582 is its oral dosage format.

Both of the competitor offerings are antisense therapies that require intrathecal (lumbar puncture) administration. In the first year of treatment during the loading stage that can be as often as once a month but after that, during the maintenance phase, administration would typically be 3 to 4 times a year.

As well as the risk, pain and anxiety that can be associated with the procedure there is the time and cost involved, as the procedure requires use of a health professional in an inpatient or outpatient setting and use of anaesthesia. While the actual injection only takes a few minutes, there is likely also an observation period of a couple of hours following each procedure.

A further difference is the patient population to be treated. Neuren has included all Angelman syndrome genotypes in its testing of NNZ-2591 and has not excluded non-ambulatory patients.

Ultragenyx’s Phase 2 study and its current Phase 3 study include only patients with full deletion of the maternal UBE3A gene, which is roughly 70% of the AS patient population. Ultragenyx says it is planning a second trial that will also include patients with gene mutation. Also, Ultragenyx’s trials exclude patients in wheelchairs (roughly 10% of the patient population).

Ionis has included patients with both UBE3A gene deletions and mutations but not two other less common genotypes that Neuren is including. Unlike Ultragenyx, Ionis doesn’t appear to be excluding non-ambulatory patients.

I disagree with the AI summary’s sharp distinction between NNZ-2591as “symptom addressing only” vs. the two antisense therapies as “disease-modifying” and the suggestion that the antisense therapies are “cures” whereas NNZ-2591 is not. The authors of the published Phase 3 trofinetide trial in Rett syndrome comment that the results suggest that “trofinetide is potentially capable of modifying core symptoms consistent with the underlying pathophysiology of the syndrome.” This could also be said of NNZ-2591. Further, even though antisense therapies specifically target the gene that causes the condition and are potentially disease-modifying, they will not cure the condition. Like NNZ-2591, these treatments must be continued for life to maintain effect.

I also disagree with the AI angle that the long-term efficacy of NNZ-2591 in AS is unknown, suggesting that the antisense therapies are superior on this point. This is probably an assumption based on the longer Phase 2 trials held for the antisense therapies. Ultragenyx measured efficacy over roughly 12 months and 18 months, Ionis measured efficacy after 6 months of treatment and Neuren measured efficacy after 3 months, with titration still occurring during the first 6 weeks of that period. One might argue that the results reported by Ultragenyx took a year or more of treatment to achieve, whereas NNZ-2591 has demonstrated effect within just 3 months. From the experience of trofinetide, it can be reasonably assumed that longer treatment with NNZ-2591 will only improve results. It’s still to be fully proven, but one of the potential advantages of NNZ-2591 over antisense therapies is faster results.

I further question the AI suggestion that the ASO technology has an advantage as it “has been successfully used in other neurological disorders like Spinal Muscular Atrophy (SMA) with Spinraza (nusinersen), providing a degree of validation for the approach.” While this is true to some degree, it ignores the differing types of ASO technology, with some more successful than others. Further, it fails to acknowledge that trofinetide’s success provides a degree of validation for the approach used in NNZ-2591 and that NNZ-2591 has had further validation provided by Phase 2 success in two other indications.

As for comparisons of degree of efficacy between the three therapies, I think it’s too difficult to judge at this stage. All three therapies demonstrated broad benefits in Phase 2 but given different trial designs, sizes, exclusions, outcome measures, trial durations, ways of reporting etc. I don’t think anything meaningful can be concluded at this stage about effectiveness.

Now, can I just cut and paste the disclaimer at the end of the AI summary...