Biotech: Angelman KOL Somewhat Cautious On Upcoming Phase III, But Also Notes Plenty Of Regulatory Flexibility Should Data Be Mixed

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Biotech: Angelman KOL Somewhat Cautious On Upcoming Phase III, But Also Notes Plenty Of Regulatory Flexibility Should Data Be Mixed

Biotech: Angelman KOL Somewhat Cautious On Upcoming Phase III,

But Also Notes Plenty Of Regulatory Flexibility Should Data Be Mixed

That said, our KOL is careful to distinguish between his conviction in the biology and his

confidence in the specific statistical outcome of the pivotal trials. Notably, our KOL thinks "not

a huge majority, but certainly a sizable majority" have responded to ASOs, but he notes that

responses vary enormously in magnitude, that the natural history of Angelman syndrome is

step-wise and non-linear (making placebo separation genuinely difficult), caregiver input in

assessment can be biased, and predicting which patients will respond most robustly is not

possible at this point.

KOL Is Cautiously Optimistic On RARE, And Watchful on MDRI - On sham vs placebo control,

our KOL suggests that the former is a logistic nightmare and FDA was receptive of IONS's placebo

design after investigators who participated in the RARE trial wrote a strong advocacy letter. On

safety, he is not concerned about radiculopathy at the current lower dose, acknowledging a small

residual but manageable risk and unlikely to affect the benefit-risk conversation with families. On

the primary endpoint, he regards the Bayley-4 cognition domain as the most objective available

scale in this population given that it is assessed directly by a trained examiner rather than

being caregiver-reported. However, our KOL notes mid-trial introduction of the MDRI (recall,

RARE now splits the alpha between Bayley-4 cognition and its compiled rating scale MDRI at

p=0.04 and p=0.01, respectively), and not inconceivable to think RARE might have had some