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Autosomal dominant polycystic kidney disease (ADPKD), caused by mutations in either PKD1 or PKD2 genes, is one of the most common human monogenetic disorders and the leading genetic cause of end-stage renal disease. Unfortunately, treatment options for ADPKD are limited. Here we report the discovery and characterization of RGLS4326, a first-in-class, short oligonucleotide inhibitor of microRNA-17 (miR-17), as a potential treatment for ADPKD. RGLS4326 is discovered by screening a chemically diverse and rationally designed library of anti-miR-17 oligonucleotides for optimal pharmaceutical properties. RGLS4326 preferentially distributes to kidney and collecting duct-derived cysts, displaces miR-17 from translationally active polysomes, and de-represses multiple miR-17 mRNA targets including Pkd1 and Pkd2. Importantly, RGLS4326 demonstrates a favorable preclinical safety profile and attenuates cyst growth in human in vitro ADPKD models and multiple PKD mouse models after subcutaneous administration. The preclinical characteristics of RGLS4326 support its clinical development as a disease-modifying treatment for ADPKD., Autosomal dominant polycystic kidney disease (ADPKD) is a leading genetic cause of end-stage renal disease with limited treatment options. Here the authors discover and characterize a microRNA inhibitor as a potential treatment for ADPKD.

The antibody-drug conjugate (ADC) brentuximab vedotin consists of the CD30-directed antibody attached to the microtubule-disrupting agent monomethyl auristatin E (MMAE). In pharmacokinetic models, including data from six studies (380 patients with classical Hodgkin's, systemic anaplastic large-cell, and cutaneous T-cell (CTCL) lymphomas), lower clearance of ADC and modestly higher ADC exposure in CTCL patients did not translate into higher MMAE exposure. In CTCL patients from the phase III ALCANZA study (n = 66), improved progression-free survival with brentuximab vedotin vs. controls was not related to ADC exposure. ADC exposure was a predictor of grade ≥3 treatment-emergent adverse events (TEAEs). Results support the consistent benefit observed with brentuximab vedotin 1.8 mg/kg every 3 weeks across the range of exposures in ALCANZA and support dose reductions in patients experiencing TEAEs at the starting dose.

Brentuximab vedotin, a CD30‐directed antibody‐drug conjugate (ADC), is approved for treating certain patients with CD30‐expressing hematologic malignancies. Its primary mechanism of action is the targeted delivery of a microtubule‐disrupting agent, monomethyl auristatin E (MMAE), to CD30‐expressing cells. A population pharmacokinetic (PopPK) analysis was conducted to characterize the PK of ADC and unconjugated MMAE in patients with CD30‐expressing hematologic malignancies by compartmental analysis and to evaluate the effects of covariates on PK of the ADC. A nonlinear mixed‐effects modeling approach was used to evaluate data from 314 patients in 5 clinical studies. ADC PK was described by a linear, 3‐compartment model with first‐order elimination. MMAE PK was described by a semimechanistic, linear, 2‐compartment model with first‐order elimination. The estimated typical values for a 75‐kg male patient were 1.56 L/d and 4.29 L for ADC systemic clearance (CL) and volume of central compartment (V1), respectively, with weight effect exponents of 0.698 and 0.503, respectively. Typical V1 in 75‐kg females was 87% of that in males, with no impact on systemic ADC exposure. Typical values of MMAE clearance (CLM) and volume of central compartment (V4) were 55.7 L/d and 79.8 L, respectively, with weight effect exponents fixed to 0.75 and 1.0, respectively. This is the first PopPK model of brentuximab vedotin to semimechanistically link the PK of ADC and that of the unconjugated small molecule MMAE. Both ADC and MMAE PK data were adequately described by the final integrated model, which supports weight‐based dosing of brentuximab vedotin in adult patients with CD30‐expressing hematologic malignancies.

Romosozumab (formerly AMG 785/CDP7851) is a monoclonal antibody that blocks sclerostin from inhibiting osteoblast maturation and function. This double-blind, placebo-controlled, randomized, ascending multiple-dose study enrolled 32 postmenopausal women and 16 healthy men with low bone mass. Women received six doses of 1 or 2 mg/kg once every 2 weeks (Q2W) or three doses of 2 or 3 mg/kg once every 4 weeks (Q4W) or placebo; and men received 1 mg/kg Q2W or 3 mg/kg Q4W or placebo. Mean serum romosozumab exposures increased approximately dose-proportionally. Romosozumab increased serum type 1 aminoterminal propeptide (PINP) by 66-147%, decreased serum C-telopeptide (sCTX) by 15-50%, and increased lumbar spine bone mineral density by 4-7%. Two subjects developed neutralizing antibodies without discernable effects on pharmacokinetics, pharmacodynamics, or safety. Adverse event rates were balanced between groups without any significant safety findings. These data support continued investigation of sclerostin inhibition in disorders that could benefit from increased bone formation.