Entrada Therapeutics’ stock value has dropped by more than 57% after the efficacy of its Duchenne muscular dystrophy (DMD) therapy, ENTR-601-44, failed to impress investors in the first portion of an early-stage study.
In the two-part, Phase I/II ELEVATE-44 study (ISRCTN15088415), Entrada is investigating a 6 mg/kg dose of ENTR-601-44 in ambulatory DMD patients amenable to exon 44 skipping who are aged four to 20. During the trial, the oligonucleotide therapy prompted a 2.36% increase in dystrophin – a protein that is often lacking in patients with DMD.
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However, William Blair analysts note that this dystrophin boost, which was the key efficacy endpoint investors were focusing on, missed the company’s expectations of a 10% change from baseline.
While ENTR-601-44 prompted modest increases in dystrophin levels, the drug offered a significant 0.08-point improvement from baseline in mean change in time to rise (TTR) scores within the treatment group. A majority of participants experienced this positive effect, regardless of their age or disease severity.
ENTR-601-44 also demonstrated a favourable safety and tolerability profile, as there were no serious adverse events (AEs) or discontinuations in this portion of the study.
Despite these efficacy and safety-based silver linings, the overall readout appears to have tempered investor enthusiasm for the drug, as Entrada’s stock value dropped 57% after results debuted from $16.03 at market close on 6 May to $6.85 at the same time the following day.
ENTR-601-44 is a phosphorodiamidate morpholino oligonucleotide (PMO), which Entrada has designed to restore expression of the dystrophin protein, a crucial structural component of the muscle.
Novartis competition looms for Entrada
Entrada’s results come as Novartis-owned Avidity Biosciences prepares the biologics license application (BLA) for delpacibart zotadirsen (del-zota), for DMD patients amenable to exon 44 skipping. In a Phase I/II trial and an open-label extension study (NCT05670730; NCT06244082), the drug reversed disease progression and triggered a 25% increase in dystrophin production.
While Entrada’s preliminary results do not currently look as strong as del-zota, direct comparisons cannot be made without a head-to-head study.
However, the company did note that patients receiving the drug had a lower-than-expected maximum plasma concentration of ENTR-601-44 compared with the rate seen in healthy adult participants.
According to the biotech, this could have impacted the drug’s concentration in the muscle, and thus its ability to promote exon skipping and dystrophin production. In a statement, Entrada said that the second cohort in the study will likely experience better uptake.
Moving forward, William Blair analysts believe that data from the 12 mg/kg dose cohort will prove pivotal for the company, offering insights into the “relationships between dose, drug exposure, muscle tissue concentration and dystrophin expression.”
“An 18 mg/kg dosing cohort (or higher) will likely be needed to generate competitive data with del-zota. While ENTR-601-44’s clean safety profile to date is auspicious for increases in dosing required to hit such efficacy standards, the time required for trial progression will augment first-to-market advantages for del-zota,” analysts concluded.
