Avidity Biosciences impressed investors with phase 1/2 data in Duchenne muscular dystrophy (DMD) Friday, extending its winning streak in the clinic. But closer examinations of the data revealed details that analysts said present a much more nuanced picture than implied by the headline result.
The top-line takeaway is Avidity linked delpacibart zotadirsen (del-zota), which uses an anti-TfR1 antibody to deliver an oligonucleotide to target cells, to a statistically significant 25% increase in dystrophin production. Avidity achieved the result in people amenable to exon 44 skipping. Sarepta Therapeutics, the leading force in DMD, made its name with drugs designed to skip exon 51.
Evercore ISI analysts identified the question of how to interpret Avidity’s data and extrapolate to exon 51 to cross-compare trials as one of two important points raised by the del-zota results. The analysts believe the result could translate into roughly 7% to 10% dystrophin expression if Avidity were looking at exon 51 instead of 44.
The other point raised by the analysts related to two patients who dropped out of the trial because of treatment-emergent adverse events. One adverse event was anaphylaxis, which fully resolved, and the other was a moderate infusion-related reaction.
Evercore analysts said the link between the drug candidate and anaphylaxis reaction is tricky to figure out mechanistically because it is unlikely to be related specifically to TfR1 or the payload. One theory, put forward by the analysts, is that the construct is more immunogenic than those Avidity uses in its other candidates, and non-neutralizing anti-drug antibodies trigger the reactions.
Steven Hughes, M.D., chief medical officer at Avidity, discussed the potential drivers of the reactions on a call with investors. The biotech lacks data on antidrug antibodies in the participants, he said. Such “reactions are completely expected with biologicals,” said Hughes, who believes the antibody is to blame.
“This is most likely to be due to the antibody component of the drug,” Hughes said. “RNAs are pretty inert, and particularly [phosphorodiamidate morpholino oligomers] are charge-neutral and have a very good track record with regard to hypersensitivity-type events. So, this being almost certainly attributable to the antibody allows us to look across all of our safety experience.”
Avidity uses the same targeting antibody in its myotonic dystrophy type 1 candidate, giving it a broader set of data to support its confidence in the safety of that component of del-zota. While raising the two questions about the data, the Evercore analysts called the results strong, outlined a path to accelerated approval and predicted $315 million in U.S. peak sales.