Ionis looks average in amyloidosis

In June Ionis said that its hereditary transthyretin-mediated amyloid polyneuropathy project eplontersen had hit in phase 3; today it gave the magnitude of transthyretin knockdown, and though it is statistically significant the effect is similar to that seen with the three approved drugs. More interestingly, it does not look as good as that seen with Intellia’s much earlier-stage rival project, NTLA-2001. Eplontersen’s safety looks clean, putting it ahead of Ionis’s approved product Tegsedi, but so does NTLA-2001’s, so Intellia could still be a threat. Ionis and its partner Astrazeneca intend to file an NDA by the end of 2022; Stifel believes eplontersen could seize a 30% share within the silencer market in the long term. This is currently split roughly 90%-10% between Alnylam’s Onpattro and Tegsedi.

Cross-trial comparison of therapies for hereditary transthyretin amyloid polyneuropathy  
Drug Description Trial Time point Pbo-adj chg on mNIS+7 Pbo-adj chg on Norfolk QoL-DN Mean chg in serum TTR
Onpattro (Alnylam) IV TTR RNAi therapeutic, given every 3wk Ph3 Apollo 18mth -34 -21 84%
Amvuttra (Alnylam) SC TTR RNAi therapeutic, given every 3mth Ph3 Helios-A 9mth -17 -16 83%
Tegsedi (Ionis) SC TTR antisense, given once weekly Ph2/3 (NCT01737398) 15mth -20 -12 74%
Eplontersen (Ionis/AZ) SC TTR antisense, given once monthly Ph3 Neuro-
8mth* Hit  (p<0.0001) Hit  (p<0.0001) 82% (p<0.0001)
NTLA-2001 (Intellia) IV in vivo Crispr-edited project Ph1 (NCT04601051) 6mth Not given  Not given  93%**
TTR=transthyretin. mNIS+7=modified neuropathy impairment score +7. Norfolk QoL-DN=Norfolk quality of life questionnaire-diabetic neuropathy. *Interim data; final readout at 66wk. All eplontersen p values are comparisons with historical control. **With 1mg/kg dose. Source: drug labels, company releases.

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