Entrada Therapeutics’ Duchenne muscular dystrophy (DMD) data have fallen well short of expectations, crashing the biotech’s stock as investors evaluated the fallout from a key readout expected to validate its platform.
Boston-based Entrada reported a 2.36% increase in dystrophin, the protein at the heart of DMD, over a baseline of 4% in the first cohort of patients to receive its exon 44 skipping drug candidate ENTR-601-44. The phase 1/2 result dramatically underperformed the expectations set by analysts, Avidity Biosciences’ rival exon 44 skipper delpacibart zotadirsen (del-zota) and Entrada executives.
Entrada CEO Dipal Doshi was unequivocal when discussing expectations at the J.P. Morgan Healthcare Conference in January. “We expect to see double-digit dystrophin production, which is really important,” Doshi said at the time. The drug candidate “goes straight up against del-zota,” Doshi said, adding that the plan was to “beat those data.”
Last year, Avidity, which Novartis acquired for $12 billion, linked del-zota to a 25% increase in dystrophin production. While Entrada’s data come from patients who received a low dose, Guggenheim Securities analysts predicted last month that the biotech needed to achieve double-digit dystrophin expression to stay on track to match or surpass its rival at higher doses.
The analysts’ base case was that Entrada would report 10% to 14% dystrophin restoration, an outcome they gave a 60% likelihood. If Entrada reported a single-digit result, an outcome the analysts predicted had a 20% probability, the Guggenheim team forecast the biotech’s stock could halve.
Their prediction was pretty accurate, with Entrada’s share price falling 59% to $6.57 when markets opened Thursday from a Wednesday closing price of $16.02.
Having called the ENTR-601-44 data “a platform-validating readout” last month, the analysts said Entrada must go “back to the drawing board” after seeing the results. A planned fourth-quarter readout from the higher-dose cohort will shed light on whether ENTR-601-44 can recover from Thursday's setback.
Entrada identified lower-than-expected plasma exposure in juvenile DMD patients as the cause of the lackluster data. Exposure was about 50% lower than in healthy adults and nonhuman primates (NHPs). While Entrada was initially surprised by the result, Doshi said in a statement that recent data on juvenile NHPs revealed a similar pattern.
Juvenile NHP data show “a steep, nonlinear exon skipping response” at higher plasma levels, Natarajan Sethuraman, Ph.D., president of R&D at Entrada, said on a conference call with analysts Thursday. The finding suggests that Entrada will see a jump in exon skipping that is disproportionate to the increase in dose in the second cohort, Sethuraman said. Entrada also plans to study a third dose cohort.