Eplontersen hits – but how hard?
Astrazeneca and Ionis are to file eplontersen for hereditary transthyretin-mediated amyloid polyneuropathy after a planned interim analysis in the phase 3 Neuro-TTRansform trial came out positive. The antisense oligonucleotide achieved a statistically significant and clinically meaningful change from baseline in serum transthyretin concentration versus what Astra called “an external placebo group” – historical control. It also hit the trial’s other co-primary endpoint, change from baseline on mNIS+7 score, a measure of neuropathic disease progression, versus external placebo. The partners have not disclosed the extent of eplontersen’s success, but a look at the three approved therapies for this subtype of transthyretin amyloidosis shows the sort of thing doctors will be looking for. It should be noted that unlike Neuro-TTRansform, the pivotal trials of these drugs did contain placebo arms. The control in Neuro-TTRansform was in fact Ionis’s own approved Tegsedi; so far no data on this arm have been released. Stifel analysts write that the extent of the improvement on mNIS+7 is crucial, and safety, described by Astra as “favourable”, with no specific concerns, will also be important given that Tegsedi’s label has a black box warning for thrombocytopenia and glomerulonephritis.
|Cross-trial comparison of therapies for hereditary transthyretin amyloid polyneuropathy|
|Company||Drug||Description||Trial||Time point||Pbo-adj chg on mNIS+7||Pbo-adj chg on Norfolk QoL-DN|
|Alnylam||Onpattro||IV TTR RNAi therapeutic, given every 3wk||Apollo||18mth||-34.0||-21.1|
|Alnylam||Amvuttra||SC TTR RNAi therapeutic, given every 3mth||Helios-A||9mth||-17.0||-16.2|
|Ionis||Tegsedi||SC TTR antisense, given once weekly||Unnamed||66wk (15.2mth)||-19.7||-11.7|
|Astrazeneca and Ionis||Eplontersen||SC TTR antisense, given once monthly||Neuro-TTRansform||35wk (8mth)*||Hit||Hit|
|mNIS+7 = modified neuropathy impairment score +7. Norfolk QoL-DN = Norfolk quality of life questionnaire-diabetic neuropathy. *Interim data; final readout at 66wk. Source: drug labels, company releases.|