Longitudinal Meta-Analysis of Historical Parkinson's Disease Trials to Inform Future Trial Design.

BACKGROUND: The outcome of clinical trials in neurodegeneration can be highly uncertain due to the presence of a strong placebo effect. OBJECTIVES: To develop a longitudinal model that can enhance the success of future Parkinson's disease trials by quantifying trial-to-trial variations in placebo and active treatment response. METHODS: A longitudinal model-based meta-analysis was conducted on the total score of Unified Parkinson's Disease Rating Scale (UPDRS) Parts 1, 2, and 3. The analysis included aggregate data from 66 arms (observational [4], placebo [28], or investigational-drug-treated [34]) from 4 observational studies and 17 interventional trials. Inter-study variabilities in key parameters were estimated. Residual variability was weighted by the size of study arms. RESULTS: The baseline total UPDRS was estimated to average at 24.5 points. Disease score was estimated to worsen by 3.90 points/year for the duration of the treatments; whilst notably, arms with a lower baseline progressed faster. The model captured the transient nature of the placebo response and sustained symptomatic drug effect. Both placebo and drug effects peaked within 2 months; although, 1 year was needed to observe the full treatment difference. Across these studies, the progression rate varied by 59.4%, the half-life for offset of placebo response varied by 79.4%, and the amplitude for drug effect varied by 105.3%. CONCLUSION: The longitudinal model-based meta-analysis describes UPDRS progression rate, captures the dynamics of the placebo response, quantifies the effect size of the available therapies, and sets the expectation of uncertainty for future trials. The findings provide informative priors to enhance the rigor and success of future trials of promising agents, including potential disease modifiers. © 2023 GSK. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Opportunities and Challenges of Disease Progression Modeling in Drug Development - An IQ Perspective.

Disease progression modeling (DPM) represents an important model-informed drug development framework. The scientific communities support the use of DPM to accelerate and increase efficiency in drug development. This article summarizes International Consortium for Innovation & Quality (IQ) in Pharmaceutical Development mediated survey conducted across multiple biopharmaceutical companies on challenges and opportunities for DPM. Additionally, this summary highlights the viewpoints of IQ from the 2021 workshop hosted by the US Food and Drug Administration (FDA). Sixteen pharmaceutical companies participated in the IQ survey with 36 main questions. The types of questions included single/multiple choice, dichotomous, rank questions, and open-ended or free text. The key results show that DPM has different representation, it encompasses natural disease history, placebo response, standard of care as background therapy, and can even be interpreted as pharmacokinetic/pharmacodynamic modeling. The most common reasons for not implementing DPM as frequently seem to be difficulties in internal cross-functional alignment, lack of knowledge of disease/data, and time constraints. If successfully implemented, DPM can have an impact on dose selection, reduction of sample size, trial read-out support, patient selection/stratification, and supportive evidence for regulatory interactions. The key success factors and key challenges of disease progression models were highlighted in the survey and about 24 case studies across different therapeutic areas were submitted from various survey sponsors. Although DPM is still evolving, its current impact is limited but promising. The success of such models in the future will depend on collaboration, advanced analytics, availability of and access to relevant and adequate-quality data, collaborative regulatory guidance, and published examples of impact.

Selective expansion of regulatory T cells by NKTR-358 in healthy volunteers and patients with systemic lupus erythematosus.

Objective: To evaluate NKTR-358, a polyethylene glycol-interleukin-2 conjugate composition designed to selectively induce regulatory T cells (Tregs), in first-in-human studies. Methods: Healthy volunteers and patients with systemic lupus erythematosus (SLE) received single- or multiple-dose (biweekly) NKTR-358 or placebo in two sequential, randomized, phase 1 studies (single ascending dose [SAD; NCT04133116] and multiple ascending dose [MAD; NCT03556007]). Primary objectives were safety and tolerability; secondary objectives included pharmacokinetics (PK) and immune effects of NKTR-358; exploratory objectives included effects on SLE disease activity. Results: There were eight ascending dose cohorts in the SAD study (0.3-28.0 µg/kg: n = 76; placebo: n = 24) and four in the MAD study (3-24.0 µg/kg: n = 36; placebo: n = 12). Most adverse events (AEs) were grade 1-2 injection-site reactions, with no treatment-related serious or severe AEs, or deaths. PK data showed dose proportionality and prolonged exposure (mean half-life: 7.4-12.9 days). Dose-dependent, selective, and sustained increases in percentages and absolute numbers of total CD4+ Tregs and CD25bright Tregs were observed, with no significant changes in conventional CD4+ and CD8+ T cells, and low-level increases in natural killer cells. At the highest doses tested, administration of NKTR-358 resulted in a 12-17-fold increase in CD25bright Tregs over baseline that was sustained for 20-30 days. Conclusion: NKTR-358 was well tolerated, had a suitable PK profile for biweekly dosing, and led to marked and selective dose-dependent increases in CD25bright Tregs, with no significant changes in conventional T cells. These results provide strong support for further testing in SLE and other inflammatory diseases.

A Disease Progression Model to Quantify the Nonmotor Symptoms of Parkinson's Disease in Participants With Leucine-Rich Repeat Kinase 2 Mutation.

Leucine-rich repeat kinase 2 (LRRK2) inhibitors are currently in clinical development as interventions to slow progression of Parkinson's disease (PD). Understanding the rate of progression in PD as measured by both motor and nonmotor features is particularly important in assessing the potential therapeutic effect of LRRK2 inhibitors in clinical development. Using standardized data from the Critical Path for Parkinson's Unified Clinical Database, we quantified the rate of progression of the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part I (nonmotor aspects of experiences of daily living) in 158 participants with PD who were carriers and 598 participants with PD who were noncarriers of at least one of three different LRRK2 gene mutations (G2019S, R1441C/G, or R1628P). Age and disease duration were found to predict baseline disease severity, while presence of at least one of these three LRRK2 mutations was a predictor of the rate of MDS-UPDRS Part I progression. The estimated progression rate in MDS-UPDRS Part I was 0.648 (95% confidence interval: 0.544, 0.739) points per year in noncarriers of a LRRK2 mutation and 0.259 (95% confidence interval: 0.217, 0.295) points per year in carriers of a LRRK2 mutation. This analysis demonstrates that the rate of progression based on MDS-UPDRS Part I is ~ 60% lower in carriers as compared with noncarriers of LRRK2 gene mutations.

Determination of Benznidazole in Human Dried Blood Spots by Liquid Chromatography-Mass Spectrometry to Monitor Adherence to Trypanosoma cruzi Infection Treatment in Infants and Children.

Medication adherence is critical to the effectiveness of benznidazole (BZ) therapy for the treatment of Chagas disease. Assessing BZ adherence using traditional plasma sampling methods presents numerous challenges in resource-limited settings. Dried blood spot (DBS) sampling of BZ can be used to overcome logistical barriers and provides a less invasive method for assessing BZ levels. A BZ DBS assay using liquid chromatography-tandem mass spectrometry was developed and applied to a clinical study of infants and children being treated with BZ for Trypanosoma cruzi infection in Argentina. The assay was validated over a concentration range of 9.8-5,000 ng/mL. Inter-assay and intra-assay measures ranged from -2.9% to 2.7% and 0.5% to 8.3% for accuracy and from 3.5% to 12% and 1.6% to 13.6% for precision, respectively. The mean recovery of BZ was greater than 91%. Partitioning ratios for DBSs/plasma ranged from 0.95 to 1.02. A cohort of 10 infants and six children with T. cruzi infection being treated with BZ had median BZ concentrations of 1.2 (IQR 0.29, 2.14) µg/mL with seven of 65 (11%) samples above the BZ treatment goal of 3 µg/mL for adults. The reported DBS assay is a simple and accurate method for the quantitative measurement of BZ that can be applied to facilitate urgently needed clinical studies of BZ for the treatment of Chagas disease and assess BZ adherence in resource-limited settings.

Sertraline Pharmacokinetics in HIV-Infected and Uninfected Children, Adolescents, and Young Adults.

Objective: Due to potential disease and drug interactions, the appropriate sertraline starting dose and titration range may require adjustment in pediatric patients living with HIV. This is the first report of sertraline pharmacokinetics in HIV-infected youth. Methods: IMPAACT P1080 was a multicenter pilot study describing psychiatric medication pharmacokinetics in HIV-infected and uninfected youth. Participants were stable on sertraline, >6 to <25 years old, and (1) HIV-uninfected (HIV(-)), (2) HIV-infected taking efavirenz (EFV), or (3) HIV-infected taking boosting ritonavir/protease inhibitor (PI/r). Sampling occurred at pre-dose, 2, 4, 6, 12, and 24-h post-dose. Analyses were performed for sertraline and N-desmethylsertraline, and CYP2D6 phenotyping was completed with dextromethorphan. Results: Thirty-one participants (16 HIV(-), 12 PI/r, and 3 EFV) had median (range) weight, age, and dose of 69.5 (31.5-118.2) kg, 21.8 (9.1-24.7) years, and 75.0 (12.5-150.0) mg once daily. Sertraline exposure was highest for HIV(-) and lowest for EFV cohorts; median dose-normalized AUC 0-24 was 1176 (HIV(-)), 791 (PI/r) and 473 (EFV) ng*hr/mL, and C24 was 32.7 (HIV(-)), 20.1 (PI/r), and 12.8 (EFV) ng/mL. The urinary dextromethorphan/dextrorphan (DXM/DXO) ratio was higher in HIV(-) vs. PI/r cohorts (p = 0.01). Four HIV(-) participants were CYP2D6 poor metabolizers (ln(DXM/DXO) of >-0.5). Conclusions: HIV(-) cohort had the highest sertraline exposure. Sertraline exposure was ~40% lower in the PI/r cohort than in HIV(-); the need to alter sertraline dose ranges for PI/r participants is not clear. The impact of efavirenz on sertraline needs further investigation due to limited numbers of EFV participants.

Marijuana Use by Breastfeeding Mothers and Cannabinoid Concentrations in Breast Milk.

: media-1vid110.1542/5799877373001PEDS-VA_2018-1076Video Abstract BACKGROUND AND OBJECTIVE: Marijuana is the most commonly used recreational drug among breastfeeding women. With legalization of marijuana in several US states and a 1990 study in which authors documented psychomotor deficits in infants breastfed by mothers using marijuana, there is a need for information on potential exposure to the breastfed infant. Our objective with this study was to quantify cannabinoids in human milk after maternal marijuana use. METHODS: Between 2014 and 2017, 50 breastfeeding women who reported marijuana use provided 54 breast milk samples to a research repository, Mommy's Milk. Concentrations of Δ-9-tetrahydrocannabinol (∆9-THC), 11-hydroxy-Δ-9-tetrahydrocannabinol, cannabidiol, and cannabinol were measured by using liquid chromatography mass spectrometry electrospray ionization. RESULTS: ∆9-THC was detectable in 34 (63%) of the 54 samples up to ∼6 days after last reported use; the median concentration of ∆9-THC was 9.47 ng/mL (range: 1.01-323.00). Five samples had detectable levels of 11-hydroxy-Δ-9-tetrahydrocannabinol (range: 1.33-12.80 ng/mL) or cannabidiol (range: 1.32-8.56 ng/mL). The sample with the highest concentration of cannabidiol (8.56 ng/mL) did not have measurable ∆9-THC. Cannabinol was not detected in any samples. The number of hours since last use was a significant predictor of log ∆9-THC concentrations (-0.03; 95% confidence interval [CI] -0.04 to -0.01; P = .005). Adjusted for time since last use, the number of daily uses and time from sample collection to analysis were also significant predictors of log ∆9-THC concentrations (0.51; 95% CI 0.03 to 0.99; P = .039; 0.08; 95% CI 0.00 to 0.15; P = .038, respectively). CONCLUSIONS: ∆9-THC was measurable in a majority of breast milk samples up to ∼6 days after maternal marijuana use.

Modeling nikkomycin Z dosing and pharmacology in murine pulmonary coccidioidomycosis preparatory to phase 2 clinical trials.

Nikkomycin Z (NikZ) is a chitin synthase inhibitor with activity against Coccidioides species that is being developed as a first-in-class orphan product for treatment of coccidioidomycosis. It has previously been shown to reduce lethal respiratory infections in mice to undetectable levels when treatment is begun 48 hours after infection. The studies described here focus on bracketing NikZ doses for phase 2 and 3 clinical trials, using an established mouse respiratory infection as a model and starting treatment 120 hours after infection. A dose of 80 mg/kg/day, divided into 2 doses, nearly eradicated infection, and larger doses did not improve fungal clearance. Increasing the duration of treatment from 1 week to 3 weeks resulted in a greater percentage of culture-negative mice. Comparative data show that plasma levels of NikZ that nearly eradicate Coccidioides in mice are achievable in patients and provide a plausibly effective dose range for initial phase 2 clinical studies.

Synthesis, characterization and sol-gel entrapment of a crown ether-styryl fluoroionophore.

The synthesis and initial evaluation of a new dye-functionalized crown-ether, 2-[2-(2,3,5,6,8,9,11,12,14,15-decahydro-1,4,7,10,13,16-benzohexaoxacyclooctadecin)ethenyl]-3-methyl benzothiazolium iodide (denoted BSD), are reported. This molecule contains a benzyl 18-crown-6 moiety as the ionophore and a benzothiazolium to spectrally transduce ion binding. Binding of K(+) to BSD in methanol causes shifts in the both absorbance and fluorescence emission maxima, as well as changes in the molar absorptivity and the emission intensity. Apparent dissociation constants (K(d)) in the range 30-65 microm were measured. In water and neutral buffer, K(d) values were approximately 1 mm. BSD was entrapped in sol-gel films composed of methyltriethoxysilane (MTES) and tetraethylorthosilicate (TEOS) with retention of its spectral properties and minimal leaching. K(+) binding to BSD in sol-gel films immersed in pH 7.4 buffer causes significant fluorescence quenching, with an apparent response time of approximately 2 min and an apparent K(d) of 1.5 mm.