Safety and pharmacokinetics of single ascending doses of TAK‐594/DNL593, a brain‐penetrant progranulin replacement therapy, in healthy volunteers: Interim results from Part A of a Phase 1/2 clinical trial

Abstract

AbstractBackgroundLoss of function mutations in the granulin (GRN) gene, which encodes the lysosomal protein progranulin (PGRN), account for 5‐10% of frontotemporal dementia (FTD‐GRN). Deficiency of PGRN in neurons and microglia results in lysosomal dysfunction, which in turn leads to neuroinflammation and neurodegeneration. TAK‐594/DNL593 is a novel PGRN replacement therapy that has been engineered to deliver PGRN across the blood brain barrier (BBB) and into lysosomes. In PGRN‐deficient mice, TAK‐594/DNL593 corrected age‐dependent elevations of disease biomarkers that are also observed in patients with FTD‐GRN (Logan et al. 2021).MethodsStudy DNLI‐H‐0001 (NCT05262023) is a Phase 1/2 randomized, placebo‐controlled study to evaluate the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of TAK‐594/DNL593 in 3‐parts. Part A evaluated single ascending doses of TAK‐594/DNL593 in healthy participants (randomized 6:2 drug to placebo). Part B, currently enrolling, will evaluate multiple doses of TAK‐594/DNL593 for 6 months in participants with FTD‐GRN (randomized 2:1 drug to placebo) and will be followed by Part C, an 18‐month open‐label extension.ResultsPart A enrolled 35 healthy participants. Single doses of intravenously administered TAK‐594/DNL593 were generally safe and well tolerated. There were no discontinuations related to drug. The majority of treatment emergent adverse events (TEAEs) were mild to moderate, and no infusion related reactions were observed. TAK‐594/DNL593 serum exposures increased in a greater than dose‐proportional manner with low to moderate variability in PK parameters. Cerebrospinal fluid (CSF) total PGRN concentration, sampled 24 hours post‐infusion, also increased dose dependently above baseline levels.ConclusionSingle dose safety and PK of TAK‐594/DNL593 in healthy participants support initiation of the multiple dose study in participants with FTD‐GRN. The dose‐dependent increase in CSF PGRN is consistent with delivery of TAK‐594/DNL593 across the BBB and supports the potential of TAK‐594/DNL593 to treat FTD‐GRN.