LRRK2 Inhibition by BIIB122 in Healthy Participants and Patients with Parkinson's Disease.

BACKGROUND: Leucine-rich repeat kinase 2 (LRRK2) inhibition is a promising therapeutic approach for the treatment of Parkinson's disease (PD). OBJECTIVE: The aim of this study was to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of the potent, selective, CNS-penetrant LRRK2 inhibitor BIIB122 (DNL151) in healthy participants and patients with PD. METHODS: Two randomized, double-blind, placebo-controlled studies were completed. The phase 1 study (DNLI-C-0001) evaluated single and multiple doses of BIIB122 for up to 28 days in healthy participants. The phase 1b study (DNLI-C-0003) evaluated BIIB122 for 28 days in patients with mild to moderate PD. The primary objectives were to investigate the safety, tolerability, and plasma pharmacokinetics of BIIB122. Pharmacodynamic outcomes included peripheral and central target inhibition and lysosomal pathway engagement biomarkers. RESULTS: A total of 186/184 healthy participants (146/145 BIIB122, 40/39 placebo) and 36/36 patients (26/26 BIIB122, 10/10 placebo) were randomized/treated in the phase 1 and phase 1b studies, respectively. In both studies, BIIB122 was generally well tolerated; no serious adverse events were reported, and the majority of treatment-emergent adverse events were mild. BIIB122 cerebrospinal fluid/unbound plasma concentration ratio was ~1 (range, 0.7-1.8). Dose-dependent median reductions from baseline were observed in whole-blood phosphorylated serine 935 LRRK2 (≤98%), peripheral blood mononuclear cell phosphorylated threonine 73 pRab10 (≤93%), cerebrospinal fluid total LRRK2 (≤50%), and urine bis (monoacylglycerol) phosphate (≤74%). CONCLUSIONS: At generally safe and well-tolerated doses, BIIB122 achieved substantial peripheral LRRK2 kinase inhibition and modulation of lysosomal pathways downstream of LRRK2, with evidence of CNS distribution and target inhibition. These studies support continued investigation of LRRK2 inhibition with BIIB122 for the treatment of PD. © 2023 Denali Therapeutics Inc and The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Preclinical and clinical evaluation of the LRRK2 inhibitor DNL201 for Parkinson's disease.

Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic risk factors for Parkinson's disease (PD). Increased LRRK2 kinase activity is thought to impair lysosomal function and may contribute to the pathogenesis of PD. Thus, inhibition of LRRK2 is a potential disease-modifying therapeutic strategy for PD. DNL201 is an investigational, first-in-class, CNS-penetrant, selective, ATP-competitive, small-molecule LRRK2 kinase inhibitor. In preclinical models, DNL201 inhibited LRRK2 kinase activity as evidenced by reduced phosphorylation of both LRRK2 at serine-935 (pS935) and Rab10 at threonine-73 (pT73), a direct substrate of LRRK2. Inhibition of LRRK2 by DNL201 demonstrated improved lysosomal function in cellular models of disease, including primary mouse astrocytes and fibroblasts from patients with Gaucher disease. Chronic administration of DNL201 to cynomolgus macaques at pharmacologically relevant doses was not associated with adverse findings. In phase 1 and phase 1b clinical trials in 122 healthy volunteers and in 28 patients with PD, respectively, DNL201 at single and multiple doses inhibited LRRK2 and was well tolerated at doses demonstrating LRRK2 pathway engagement and alteration of downstream lysosomal biomarkers. Robust cerebrospinal fluid penetration of DNL201 was observed in both healthy volunteers and patients with PD. These data support the hypothesis that LRRK2 inhibition has the potential to correct lysosomal dysfunction in patients with PD at doses that are generally safe and well tolerated, warranting further clinical development of LRRK2 inhibitors as a therapeutic modality for PD.

Population Pharmacokinetics of Revefenacin in Patients with Chronic Obstructive Pulmonary Disease.

BACKGROUND AND OBJECTIVES: Revefenacin is a lung-selective, long-acting muscarinic antagonist indicated for the maintenance treatment of patients with chronic obstructive pulmonary disease. The objectives of this analysis were to evaluate the pharmacokinetics of revefenacin and its major metabolite (THRX-195518) in patients with chronic obstructive pulmonary disease, and identify significant covariates affecting revefenacin disposition using a population pharmacokinetic approach based on plasma concentration-time data obtained after single- and repeated-dose once-daily administration in three phase II and two phase III studies. METHODS: Plasma concentrations of revefenacin and THRX-195518 following once-daily administration via nebulization at a dose levels ranging from 22-700 µg in 935 patients (488 men, 447 women; age 41-88 years) were analyzed using nonlinear mixed-effects modeling. RESULTS: Plasma revefenacin pharmacokinetics was best described by a two-compartment model with first-order absorption and elimination. Pharmacokinetic parameters for THRX-195518 were estimated using a sequential approach, where the concentration-time profiles were fit to a combined model. The formation of the metabolite in each subject was estimated to be a fixed fraction of the individually estimated (post-hoc) clearance rate of revefenacin. Four statistically significant covariates were identified: for revefenacin, age on apparent clearance and body weight on apparent intercompartment clearance, for THRX-195518, age on apparent clearance and body weight on the fraction of revefenacin apparent clearance that was metabolized to THRX-195518. CONCLUSIONS: None of the identified statistically significant covariates were associated with a clinically meaningful effect on revefenacin or THRX-195518 exposure in patients with chronic obstructive pulmonary disease. REGISTRATION: ClinicalTrials.gov identifier number NCT03064113, NCT01704404, NCT02040792, NCT02459080, and NCT02512510.

Revefenacin Absorption, Metabolism, and Excretion in Healthy Subjects and Pharmacological Activity of Its Major Metabolite.

Revefenacin inhalation solution is an anticholinergic indicated for the maintenance treatment of patients with chronic obstructive pulmonary disease. Mass balance, pharmacokinetics, and metabolism of revefenacin were evaluated after intravenous and oral administration of [14C]-revefenacin in healthy subjects. Pharmacological activity of the major revefenacin metabolite was also assessed. Adult males (n = 9) received 20 µg intravenously of approximately 1 µCi [14C]-revefenacin and/or a single 200-µg oral solution of approximately 10 µCi [14C]-revefenacin. Mean recovery of radioactive material was 81.4% after intravenous administration (54.4% in feces; 27.1% in urine) and 92.7% after oral dosing (88.0% in feces, 4.7% in urine). Mean absolute bioavailability of oral revefenacin was low (2.8%). Intact revefenacin accounted for approximately 52.1% and 13.1% of the total radioactivity in plasma after intravenous and oral administration, respectively. Two main circulating metabolites were observed in plasma. After an intravenous dose, a hydrolysis product, THRX-195518 (M2) was observed that circulated in plasma at 14.3% of total radioactivity. After an oral dose, both THRX-195518 and THRX-697795 (M10, N-dealkylation and reduction of the parent compound) were observed at 12.5% of total circulating radioactivity. THRX-195518 was the major metabolite excreted in feces and comprised 18.8% and 9.4% of the administered intravenous and oral dose, respectively. The major metabolic pathway for revefenacin was hydrolysis to THRX-195518. In vitro pharmacological evaluation of THRX-195518 indicated that it had a 10-fold lower binding affinity for the M3 receptor relative to revefenacin. Receptor occupancy analysis suggested that THRX-195518 has minimal contribution to systemic pharmacology relative to revefenacin after inhaled administration. SIGNIFICANCE STATEMENT: The major metabolic pathway for revefenacin was hydrolysis to the metabolite THRX-195518 (M2), and both revefenacin and THRX-195518 underwent hepatic-biliary and fecal elimination after oral or intravenous administration with negligible renal excretion. Pharmacological evaluation of THRX-195518 indicated that it had a 10-fold lower binding affinity for the M3 muscarinic receptor relative to revefenacin and that THRX-195518 has minimal contribution to systemic pharmacology after inhaled administration.

Revefenacin, a Long-Acting Muscarinic Antagonist, Does Not Prolong QT Interval in Healthy Subjects: Results of a Placebo- and Positive-Controlled Thorough QT Study.

Revefenacin is a novel once-daily, lung-selective, long-acting muscarinic antagonist developed as a nebulized inhalation solution for the maintenance treatment of chronic obstructive pulmonary disease. In a randomized, 4-way crossover study, healthy subjects received a single inhaled dose of revefenacin 175 µg (therapeutic dose), revefenacin 700 µg (supratherapeutic dose), and placebo via standard jet nebulizer, and a single oral dose of moxifloxacin 400 mg (open-label) in separate treatment periods. Electrocardiograms were recorded, and pharmacokinetic samples were collected serially after dosing. The primary end point was the placebo-corrected change from baseline QT interval corrected for heart rate using Fridericia's formula, analyzed at each postdose time. Concentration-QTc modeling was also performed. Following administration of revefenacin 175  and 700 µg, placebo-corrected change from baseline QTcF (ΔΔQTcF) values were close to 0 at all times, with the largest mean ΔΔQTcF of 1.0 millisecond (95% confidence interval [CI], -1.2 to 3.1 milliseconds) 8 hours postdose and 1.0 millisecond (95%CI, -1.1 to 3.1 milliseconds) 1 hour postdose after inhalation of revefenacin 175 and 700 µg, respectively. Revefenacin did not have a clinically meaningful effect on heart rate (within ±5 beats per minute of placebo), or PR and QRS intervals (within ±3 and ±1 milliseconds of placebo, respectively). Using concentration-QTc modeling, an effect of revefenacin > 10 milliseconds can be excluded within the observed plasma concentration range of up to ≈3 ng/mL. Both doses of revefenacin were well tolerated. These results demonstrate that revefenacin does not prolong the QT interval.

Pharmacokinetics and safety of revefenacin in subjects with impaired renal or hepatic function.

Purpose: Revefenacin, a long-acting muscarinic antagonist for nebulization, has been shown to improve lung function in patients with chronic obstructive pulmonary disease. Here we report pharmacokinetic (PK) and safety results from two multicenter, open-label, single-dose trials evaluating revefenacin in subjects with severe renal impairment (NCT02578082) and moderate hepatic impairment (NCT02581592). Subjects and methods: The renal impairment trial enrolled subjects with normal renal function and severe renal impairment (estimated glomerular filtration rate <30 mL/min/1.73 m2). The hepatic impairment trial enrolled subjects with normal hepatic function and moderate hepatic impairment (Child-Pugh class B). Subjects received a single 175-µg dose of revefenacin through nebulization. PK plasma samples and urine collections were obtained at multiple time points for 5 days following treatment; all subjects were monitored for adverse events. Results: In the renal impairment study, the maximum observed plasma revefenacin concentration (Cmax) was up to 2.3-fold higher and area under the concentration-time curve from time 0 to infinity (AUCinf) was up to 2.4-fold higher in subjects with severe renal impairment compared with those with normal renal function. For THRX-195518, the major metabolite of revefenacin, the corresponding changes in Cmax and AUCinf were 1.8- and 2.7-fold higher, respectively. In the hepatic impairment study, revefenacin Cmax and AUCinf were 1.03- and 1.18-fold higher, respectively, in subjects with moderate hepatic impairment compared with those with normal hepatic function. The corresponding changes in THRX-195518 Cmax and AUCinf were 1.5- and 2.8-fold higher, respectively. Conclusion: Systemic exposure to revefenacin increased modestly in subjects with severe renal impairment but was similar between subjects with moderate hepatic impairment and normal hepatic function. The increase in plasma exposure to THRX-195518 in subjects with severe renal or moderate hepatic impairment is unlikely to be of clinical consequence given its low antimuscarinic potency, low systemic levels after inhaled revefenacin administration, and favorable safety profile.

Onartuzumab with or without bevacizumab in combination with weekly paclitaxel does not prolong QTc or adversely affect other ECG parameters in patients with locally recurrent or metastatic triple-negative breast cancer.

PURPOSE: The potential effect of onartuzumab, when administered with or without bevacizumab in combination with weekly paclitaxel, on the corrected QT interval (QTc) and other electrocardiogram (ECG) parameters, was investigated in a randomized, phase 2 study OAM4861g of first- or second-line therapy in patients with locally recurrent or metastatic triple-negative breast cancer. METHODS: Triplicate 12-lead ECGs were recorded at screening, pre- and post-dose on day 1 of cycles 1, 2, and 4, and at the study drug discontinuation visit (SDDV). Onartuzumab serum samples were collected pre- and post-dose on day 1 of cycles 1-4 and at the SDDV. Fridericia's correction was applied to QT recordings (QTcF), and change from baseline (ΔQTcF) was calculated. Post-baseline measurements were reported as baseline-adjusted control arm (placebo plus bevacizumab plus paclitaxel)-corrected values (ΔΔQTcF). Categorical ECG findings were noted. Linear mixed effects modeling evaluated a potential concentration-ΔQTcF relationship. RESULTS: Out of 185 enrolled patients, 165 patients had ECG-evaluable data for analyses. Similar ΔQTcF and ΔΔQTcF values were observed across all treatment arms, with mean increase <10 and <7 ms, respectively, across all time points. Similar changes in heart rate, PR interval, and QRS duration were noted across all treatment arms. Incidences of abnormal ECG findings of clinical interest were comparable in the onartuzumab-containing arms and the control arm. No concentration-ΔQTcF relationship was evident at onartuzumab serum concentrations up to 1,200 µg/ml. CONCLUSIONS: These data suggest that onartuzumab, at the dose and exposures studied in this clinical trial, does not meaningfully affect the QTcF interval.

Single and multiple dose intravenous and oral pharmacokinetics of the hedgehog pathway inhibitor vismodegib in healthy female subjects.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: While recent publications have suggested the pharmacokinetics (PK) of vismodegib appear to be non-linear, there has not been a report describing the mechanisms of non-linearity. WHAT THIS STUDY ADDS: This study provides evidence that two separate processes, namely, solubility-limited absorption and concentration-dependent plasma protein binding, can explain the non-linear PK of vismodegib. This study provides quantitative results which can account for the lower than expected accumulation of vismodegib with continuous daily dosing. AIM: Vismodegib has demonstrated clinical activity in patients with advanced basal cell carcinoma. The pharmacokinetics (PK) of vismodegib are non-linear. The objective of this study was to determine whether vismodegib PK change following repeated dosing by administering a tracer intravenous (i.v.) dose of (14) C-vismodegib with single and multiple oral doses. METHODS: Healthy post menopausal female subjects (n= 6/group) received either a single or daily 150 mg vismodegib oral dose with a (14) C-labelled 10 µg i.v. bolus dose administered 2 h after the single or last oral dose (day 7). Plasma samples were assayed for vismodegib by LC-MS/MS and for (14) C-vismodegib by accelerator mass spectrometry. RESULTS: Following a single i.v. dose, mean clearance, volume of distribution and absolute bioavailability were 43.4 ml h(-1) , 16.4 l and 31.8%, respectively. Parallel concentration-time profiles following single oral and i.v. administration of vismodegib indicated elimination rate limited PK. Following i.v. administration at steady-state, mean clearance and volume of distribution were 78.5 ml h(-1) and 26.8 l, respectively. Comparison of i.v. PK parameters after single and multiple oral dosing showed similar half-life, increased clearance and volume of distribution (81% and 63% higher, respectively) and decreased bioavailability (77% lower) after repeated dosing. Relative to single dose, the unbound fraction of vismodegib increased 2.4-fold with continuous daily dosing. CONCLUSION: Vismodegib exhibited a long terminal half-life after oral and i.v. administration, moderate absolute bioavailability and non-linear PK after repeated dosing. Results from this study suggest that the non-linear PK of vismodegib result from two separate, non-linear processes, namely solubility limited absorption and high affinity, saturable plasma protein binding.

Pharmacokinetics and safety of single and multiple doses of ACHN-490 injection administered intravenously in healthy subjects.

ACHN-490 is an aminoglycoside with activity against multidrug-resistant pathogens, including those resistant to currently used aminoglycosides. Two randomized, double-blind, placebo-controlled clinical studies investigated the pharmacokinetics (PK), safety, and tolerability of ACHN-490 injection in healthy subjects. Study 1 used a parallel-group design with escalating single (SD) and multiple doses (MD). Study 2 explored a longer duration of the highest dose tolerated in the first study. Subjects were randomly assigned to receive either ACHN-490 injection or a placebo administered by a 10-min intravenous infusion. Study 1 enrolled 39 subjects (30 active and 9 placebo) and consisted of a single dose of 1 mg/kg body weight followed by ascending SD and MD cohorts of 4, 7, 11, and 15 mg/kg for 10, 10, 5, and 3 days, respectively. Study 2 enrolled 8 subjects (6 active and 2 placebo) who received 15 mg/kg for 5 days. Safety was assessed from adverse event (AE) reporting, standard clinical laboratory procedures, and testing for renal, cochlear, and vestibular function. ACHN-490 exhibited linear and dose-proportional PK, with agreement between the studies for PK parameters assessed. The 15-mg/kg dose did not accumulate with repeated dosing over 5 days. Mean steady-state (±standard deviation) area under the concentration-time curve from 0 to 24 h (AUC(0-24)), maximum concentration of drug in serum (C(max)), half-life (t(1/2)), clearance, and volume of distribution at steady state (V(ss)) for the 15-mg/kg, day 5 dose were 239 ± 45 h·mg/liter, 113 ± 17 mg/liter, 3 ± 0.3 h, 1.1 ± 0.1 ml/min/kg, and 0.24 ± 0.04 liters/kg, respectively. AEs were mild to moderate and rapidly resolved. No evidence of nephrotoxicity or ototoxicity was observed.