Forty patients enrolled, data expected by year-end, and Denali now owns the asset outright — that is the situation with DNL593 in GRN-related frontotemporal dementia after Takeda walked away from the collaboration in April. Takeda’s exit was framed as a strategic portfolio decision unrelated to efficacy or safety, but that framing matters less than the clinical reality: Denali is now the sole sponsor of a fully enrolled Phase 1/2 progranulin replacement study in a disease with no approved treatments and a genetically defined patient population that makes trial enrichment straightforward. The progranulin-replacement hypothesis in FTD-GRN is scientifically well-grounded, and the Protein TransportVehicle enabling DNL593 now has a commercially approved analogue in AVLAYAH to lend it mechanistic credibility.
AVLAYAH itself — tividenofusp alfa-eknm for MPS II — earned accelerated approval on March 25 and dosed its first commercial patient within a month, which is operationally fast for an ultra-rare pediatric enzyme replacement therapy requiring specialized infusion infrastructure. Accelerated approval means confirmatory evidence is still required; the global Phase 2/3 COMPASS study carries that obligation. The approval is meaningful beyond Hunter syndrome because it is the first drug to reach patients using transferrin receptor-mediated transcytosis, validating the core premise of Denali’s entire TransportVehicle platform across enzyme, protein, and now oligonucleotide modalities.
That oligonucleotide extension is where the longer-term clinical story lives. DNL628 dosed its first Phase 1b patient in March, targeting tau reduction via MAPT gene knockdown in Alzheimer’s disease. Tau-targeting antisense oligonucleotides have already shown CSF tau reduction in intrathecally delivered programs; the question DNL628 answers is whether intravenous delivery through an OTV can achieve comparable CNS penetration without lumbar puncture. That is not a small question — the answer determines whether oligonucleotide neurotherapeutics can scale beyond academic medical centers. Phase 1b data are expected in the first half of 2027.
The single marker to track before year-end is the DNL593 readout in FTD-GRN. A signal there — specifically, slowing of functional decline or measurable progranulin restoration in the CNS — would do more than validate one asset; it would confirm that IV-delivered protein replacement can reach the brain at therapeutically relevant concentrations, directly de-risking DNL952 in Pompe disease and the broader PTV pipeline in one data package.
Jon Napitupulu is Director of Media Relations at The Clinical Trial Vanguard. Jon, a computer data scientist, focuses on the latest clinical trial industry news and trends.
