Another Fabry flop, courtesy of 4D

Amid a narrowing pipeline of gene therapy candidates for Fabry disease, new doubts are creeping in about one of the contenders, 4D Molecular’s 4D-310. An update yesterday detailed three cases of atypical haemolytic uremic syndrome (aHUS) among six patients who have received the project so far – one of which was classified as grade four. This adverse event was seen in one patient in the initial data drop in 2021. 4D is now pausing enrolment into its current studies, although a pivotal trial is being planned. The group will also abandon the corticosteroid regimen it has been using for immunosuppression, in favour of a rituximab-sirolimus regimen that it hopes will prevent aHUS. In addition, 4D reported intriguing cardiac efficacy data from three patients in the phase 1/2 US Inglaxa study, but this was clearly not enough to reassure investors, who sent the group’s stock down 10% yesterday. More details on 4D-310’s efficacy and safety will be presented at the World Symposium in February. This meeting is also set to feature further results on Sangamo’s ST-920, which currently looks like the Fabry gene therapy project to beat – although the bar is low.

The Fabry gene therapy data so far
Project Company Trial Dose(s) AGA activity Note
4D-310 4D Molecular Inglaxa & Asia-Pacific trial 1x1013vg/kg (lowest dose) Feb 2022: 10 to 14-fold of mean normal in 2 pts;
Jan 2023: cardiac data in 3 US pts
Three cases of aHUS across 6 pts in US & Asia-Pacific trials; enrolment paused
ST-920 Sangamo Staar 0.5x1013, 1x1013, 3x1013 & 5x1013vg/kg Oct 2022: 2 to 30-fold of mean normal in 9 pts; 4 pts withdrawn from ERT Study now in dose-expansion phase
FLT190  Freeline Marvel-1 7.5x1011vg/kg (lowest dose) Nov 2021: subtherapeutic & near normal in 2 pts*;
Nov 2022: levels "sustained" for 1-3yrs
Dosing in 2nd cohort (1.5x1012vg/kg) began Sep 2022
Note: all studies ph1/2; *both pts experienced myocarditis; AGA=alpha-galactosidase A; ERT=enzyme-replacement therapy. Source: company releases.

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