Molnupiravir: Mechanism of action, clinical, and translational science.

Molnupiravir is an oral prodrug of the broadly active, antiviral ribonucleoside analog N-hydroxycytidine (NHC). The primary circulating metabolite NHC is taken up into cells and phosphorylated to NHC-triphosphate (NHC-TP). NHC-TP serves as a competitive substrate for viral RNA-dependent RNA polymerase (RdRp), which results in an accumulation of errors in the viral genome, rendering virus replication incompetent. Molnupiravir has demonstrated activity against SARS-CoV-2 both clinically and preclinically and has a high barrier to development of viral resistance. Little to no molnupiravir is observed in plasma due to rapid hydrolysis to NHC. Maximum concentrations of NHC are reached at 1.5 h following administration in a fasted state. The effective half-life of NHC is 3.3 h, reflecting minimal accumulation in the plasma following twice-daily (Q12H) dosing. The terminal half-life of NHC is 20.6 h. NHC-TP exhibits a flatter profile with a lower peak-to-trough ratio compared with NHC, which supports Q12H dosing. Renal and hepatic pathways are not major routes of elimination, as NHC is primarily cleared by metabolism to uridine and cytidine, which then mix with the endogenous nucleotide pools. In a phase III study of nonhospitalized patients with COVID-19 (MOVe-OUT), 5 days of treatment with 800 mg molnupiravir Q12H significantly reduced the incidence of hospitalization or death compared with placebo. Patients treated with molnupiravir also had a greater reduction in SARS-CoV-2 viral load and improved clinical outcomes, compared with those receiving placebo. The clinical effectiveness of molnupiravir has been further demonstrated in several real-world evidence studies. Molnupiravir is currently authorized or approved in more than 25 countries.

Population pharmacokinetics of molnupiravir in adults with COVID-19: Lack of clinically important exposure variation across individuals.

Effective antiviral treatments for coronavirus disease 2019 (COVID-19) are needed to reduce the morbidity and mortality associated with severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) infection, particularly in patients with risk factors for severe disease. Molnupiravir (MK-4482, EIDD-2801) is an orally administered, ribonucleoside prodrug of ß-D-N4-hydroxycytidine (NHC) with submicromolar potency against SARS-CoV-2. A population pharmacokinetic (PopPK) analysis for molnupiravir exposure was conducted using 4202 NHC plasma concentrations collected in 1207 individuals from a phase I trial in healthy participants, a phase IIa trial in non-hospitalized participants with COVID-19, a phase II trial in hospitalized participants with COVID-19, and a phase II/III trial in non-hospitalized participants with COVID-19. Molnupiravir pharmacokinetics (PK) was best described by a two-compartment model with a transit-compartment absorption model and linear elimination. Molnupiravir apparent elimination clearance increased with body weight less-than-proportionally (power 0.412) and was estimated as 70.6 L/h in 80-kg individuals with a moderate interindividual variability (43.4% coefficient of variation). Additionally, effects of sex and body mass index on apparent central volume and food status and formulation on the absorption mean transit time were identified as statistically significant descriptors of variability in these PK parameters. However, none of the identified covariate effects caused clinically relevant changes in the area under the NHC concentration versus time curve between doses, the exposure metric most closely related to clinical response. Overall, the PopPK model indicates that molnupiravir can be administered in adults without dose adjustment based on age, sex, body size, food, and mild-to-moderate renal or mild hepatic impairment.

Factors Influencing COVID-19 Risk: Insights From Molnupiravir Exposure-Response Modeling of Clinical Outcomes.

Molnupiravir (MOV) is an oral antiviral for the treatment of coronavirus disease 2019 (COVID-19) in outpatient settings. This analysis investigated the relationship between ß-D-N4-hydroxycytidine (NHC) pharmacokinetics and clinical outcomes in patients with mild to moderate COVID-19 in the phase III part of the randomized, double-blind, placebo-controlled MOVe-OUT trial. Logistic regression models of the dependency of outcomes on exposures and covariates were constructed using a multistep process. Influential covariates were identified first using placebo arm data, followed by assessment of exposure-dependency in drug effect using data from both the placebo and MOV arms. The exposure-response (E-R) analysis included 1,313 participants; 630 received MOV and 683 received placebo. Baseline viral load, baseline disease severity, age, weight, viral clade, active cancer, and diabetes were identified as significant determinants of response using placebo data. Absolute measures of viral load on days 5 and 10 were strong on-treatment predictors of hospitalization. An additive area under the curve (AUC)-based maximum effect (Emax ) model with a fixed Hill coefficient of 1 best represented the exposure-dependency in drug effect and the AUC50 was estimated to be 19,900 nM hour. Patients at 800 mg achieved near maximal response, which was larger than for 200 or 400 mg. The final E-R model was externally validated and predicted that the relative reduction in hospitalization with MOV treatment would vary with patient characteristics and factors in the population. In conclusion, the E-R results support the MOV dose of 800 mg twice daily to treat COVID-19. Many patient characteristics and factors impacted outcomes beyond drug exposures.

Measurement of cervical softness before cerclage placement with an aspiration-based device.

BACKGROUND: An abnormally soft cervix could contribute to the pathophysiology of cervical shortening and cervical insufficiency. Multiple techniques to measure cervical softness have been developed but none are used routinely in clinical practice. A clinically acceptable technique to measure cervical softness could improve identification of patients at risk for cervix-related preterm birth. OBJECTIVE: This study aimed to measure cervical softness in patients with cervical insufficiency and in normal controls using a novel, aspiration-based device. We hypothesized that the cervix is softer in patients with cervical insufficiency. STUDY DESIGN: This was a cross-sectional study of patients presenting for cerclage at a single academic medical center. Cervical softness was measured using a noninvasive, aspiration-based device placed on the anterior lip of the cervix during a speculum examination. The device measured the aspiration pressure required to displace cervical tissue to a predefined deformation level. Stiff tissue required increased aspiration pressure, whereas soft tissue required lower pressure values. Cerclage patients were subdivided into 3 groups, namely history-indicated, ultrasound-indicated, and examination-indicated cerclage. Controls were healthy volunteers between 12+0 weeks and 23+6 weeks of gestation without a history of cervical insufficiency and were matched by gestational age to the patients in the cerclage groups. Women with a cerclage in place, multiple gestations, active genital infection, or previous cervical excision procedures were excluded. Delivery information was subsequently recorded as well. RESULTS: Data from 133 women were analyzed; of those, 54 patients were in the cerclage group (23 history-indicated, 12 ultrasound-indicated, and 19 examination-indicated participants) and 79 were controls (40 in the first trimester and 39 in the second trimester groups). Patients who presented for ultrasound-indicated cerclage had significantly softer cervices (median; interquartile range) than second trimester controls (62 mbar; 50.5-114 vs 81 mbar; 75-101; P=.042). The difference in cervical softness was not significantly different between the history-indicated and examination-indicated cerclage groups and their respective control groups. CONCLUSION: Patients presenting for ultrasound-indicated cerclage had significantly softer cervices than normal controls as measured by an aspiration-based device. Quantitative measurement of cervical softness with the aspiration-based device is a promising technique for objective measurement of cervical softness during pregnancy.

Accelerating model-informed decisions for COVID-19 vaccine candidates using a model-based meta-analysis approach.

BACKGROUND: The COVID-19 pandemic has increased the need for innovative quantitative decision tools to support rapid development of safe and efficacious vaccines against SARS-CoV-2. To meet that need, we developed and applied a model-based meta-analysis (MBMA) approach integrating non-clinical and clinical immunogenicity and protection data. METHODS: A systematic literature review identified studies of vaccines against SARS-CoV-2 in rhesus macaques (RM) and humans. Summary-level data of 13 RM and 8 clinical trials were used in the analysis. A RM MBMA model was developed to quantify the relationship between serum neutralizing (SN) titres after vaccination and peak viral load (VL) post-challenge in RM. The translation of the RM MBMA model to a clinical protection model was then carried out to predict clinical efficacies based on RM data alone. Subsequently, clinical SN and efficacy data were integrated to develop three predictive models of efficacy - a calibrated RM MBMA, a joint (RM-Clinical) MBMA, and the clinical MBMA model. The three models were leveraged to predict efficacies of vaccine candidates not included in the model and efficacies against newer strains of SARS-CoV-2. FINDINGS: Clinical efficacies predicted based on RM data alone were in reasonable agreement with the reported data. The SN titre predicted to provide 50% efficacy was estimated to be about 21% of the mean human convalescent titre level, and that value was consistent across the three models. Clinical efficacies predicted from the MBMA models agreed with reported efficacies for two vaccine candidates (BBV152 and CoronaVac) not included in the modelling and for efficacies against delta variant. INTERPRETATION: The three MBMA models are predictive of protection against SARS-CoV-2 and provide a translational framework to enable early Go/No-Go and study design decisions using non-clinical and/or limited clinical immunogenicity data in the development of novel SARS-CoV-2 vaccines. FUNDING: This study was funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

Integrating Patient-generated Digital Health Data into Electronic Health Records (EHRs) in Ambulatory Care Settings: EHR Vendor Survey and Interviews.

Data traditionally collected in a clinic or hospital setting is now collected electronically in everyday environments from patients, known as patient-generated health data (PGHD). We conducted informal interviews and collected survey data from major ambulatory care EHR vendors that serve the majority of the U.S. market to collect information on how their clients are integrating PGHD into EHRs. Of the 9 EHR vendors contacted, 6 completed the survey and 5 participated in a 45-minute interview. Feedback from the vendors included how PGHD use has steadily risen over the past decade and how the COVID-19 pandemic accelerated PGHD use. Pathways for data from devices or surveys to be brought securely into the EHR are increasing. While promising, adoption of health IT systems has its challenges. There are disparities in EHRs, devices, and applications. We concluded that more supportive policies are needed to advance PGHD integration.

A Model-Based Approach to Bridging Plasma and Dried Blood Spot Concentration Data for Phase 3 Verubecestat Trials.

In-clinic venous dried blood spot (DBS) pharmacokinetic (PK) sampling was incorporated into two phase 3 studies of verubecestat for Alzheimer's disease (EPOCH [NCT01739348] and APECS [NCT01953601]), as a potential alternative to plasma PK sampling. Initially, plasma and DBS PK samples were collected concurrently to better understand the DBS-plasma verubecestat concentration relationship, with the intention of discontinuing DBS or plasma sampling following interim analysis. Following initial analyses and comparison of results with prespecified selection criteria, plasma PK sampling was discontinued; however, a stability issue resulting in generally lower DBS verubecestat concentrations with longer collection-to-assay times was subsequently discovered (associated with non-compliance in DBS sample handling), prompting reintroduction of plasma sampling. To enable inclusion of DBS data in population PK analyses, a conversion algorithm for calculating plasma-equivalent concentrations (accounting for DBS sample instability) was developed using paired (time-matched) plasma and DBS data from the EPOCH study. Verubecestat population PK models developed from pooled phase 1/1b and EPOCH data using either (1) plasma-only data or (2) plasma and plasma-equivalent concentrations (calculated from non-paired DBS samples) yielded similar results. The algorithm robustness was demonstrated using DBS data from paired samples from the APECS study and comparison between plasma and plasma-equivalent concentrations. The population PK model was updated with APECS data (both plasma and, if no plasma sample available, plasma equivalents). The results demonstrated similar PK in the two phase 3 populations and exposures consistent with expectations from phase 1 data. This case study illustrates challenges with employing new sampling techniques in large, global trials and describes lessons learned.

An Investigation of Instability in Dried Blood Spot Samples for Pharmacokinetic Sampling in Phase 3 Trials of Verubecestat.

In-clinic dried blood spot (DBS) pharmacokinetic (PK) sampling was incorporated into two phase 3 studies of verubecestat for Alzheimer's disease (EPOCH [NCT01739348] and APECS [NCT01953601]), as a potential alternative to plasma PK sampling for improved logistical feasibility and decreased blood volume burden. However, an interim PK analysis revealed verubecestat concentrations in DBS samples declined with time to assay in both trials. An investigation revealed wide variation in implementation practices for DBS sample handling procedures resulting in insufficient desiccation which caused verubecestat instability. High-resolution mass spectrometry evaluations of stressed and aged verubecestat DBS samples revealed the presence of two hydrolysis degradants. To minimize instability, new DBS handling procedures were implemented that provided additional desiccant and minimized the time to analysis. Both verubecestat hydrolysis products were previously discovered and synthesized during active pharmaceutical ingredient stability characterization. A liquid chromatography-mass spectrometry assay to quantitate the dominant verubecestat degradant in DBS samples was developed and validated. The application of this method to stressed and aged verubecestat DBS samples confirmed that degradant concentrations accounted for the observed decreases in the verubecestat concentration. Furthermore, after increasing desiccant amounts, degradant concentrations accounted for approximately 7% of the verubecestat concentration in DBS clinical samples, indicating that issues with sample handling were minimized with new storage and shipping conditions. This case study illustrates the challenges with employing new sampling techniques in large, global trials, and the importance of anticipating and mitigating implementation risks.

Personalized Research on Diet in Ulcerative Colitis and Crohn's Disease: A Series of N-of-1 Diet Trials.

INTRODUCTION: Evidence about specific carbohydrate diet (SCD) for inflammatory bowel disease (IBD) is limited. We conducted 54 single-subject, double-crossover N-of-1 trials comparing SCD with a modified SCD (MSCD) and comparing each with the participant's baseline, usual diet (UD). METHODS: Across 19 sites, we recruited patients aged 7-18 years with IBD and active inflammation. Following a 2-week baseline (UD), patients were randomized to 1 of 2 sequences of 4 alternating 8-week SCD and MSCD periods. Outcomes included fecal calprotectin and patient-reported symptoms. We report posterior probabilities from Bayesian models comparing diets. RESULTS: Twenty-one (39%) participants completed the trial, 9 (17%) completed a single crossover, and 24 (44%) withdrew. Withdrawal or early completion occurred commonly (lack of response [n = 11], adverse events [n = 11], and not desiring to continue [n = 6]). SCD and MSCD performed similarly for most individuals. On average, there was <1% probability of a clinically meaningful difference in IBD symptoms between SCD and MSCD. The average treatment difference was -0.3 (95% credible interval -1.2, 0.75). There was no significant difference in the ratio of fecal calprotectin geometric means comparing SCD and MSCD (0.77, 95% credible interval 0.51, 1.10). Some individuals had improvement in symptoms and fecal calprotectin compared with their UD, whereas others did not. DISCUSSION: SCD and MSCD did not consistently improve symptoms or inflammation, although some individuals may have benefited. However, there are inherent difficulties in examining dietary changes that complicate study design and ultimately conclusions regarding effectiveness.

Fetal gastric area ratio to predict severe neonatal opioid withdrawal syndrome.

OBJECTIVE: Neonatal opioid withdrawal syndrome (NOWS) can occur in newborns exposed to opioids in pregnancy. Opioids delay gastric emptying and inhibit gastric motility in adults, but little is known about their effect in the fetus. We sought to assess gastric area ratio (GAR) in opioid-exposed fetuses. STUDY DESIGN: Retrospective cohort study including opioid-exposed maternal-neonatal dyads between 2007-2017. Primary outcome: severe NOWS (three consecutive Finnegan scores ≥8 or three scores totaling ≥24 within 96 h of life). GAR: (gastric area)/(transverse abdominal area) × 100. Data analysis was by descriptive, parametric, and non-parametric tests. RESULTS: Forty-nine maternal-neonatal dyads were included, 67% (n = 33) with severe NOWS. GAR <95th percentile for gestational age was seen in 80% of neonates (n = 39). However, GAR was not different between groups (p = .90) and did not predict severe NOWS. CONCLUSION: Fetal GAR was <95th percentile in 80% of opioid-exposed neonates. However, fetal GAR may not predict NOWS treatment.

Exposure-Response Analyses of Letermovir Following Oral and Intravenous Administration in Allogeneic Hematopoietic Cell Transplantation Recipients.

The cytomegalovirus (CMV) viral terminase inhibitor letermovir is approved for prophylaxis of CMV infection and disease in adult CMV-seropositive allogeneic hematopoietic stem cell transplantation recipients. In a phase III trial (NCT02137772), letermovir significantly reduced clinically significant CMV infection (CS-CMVi) rate vs. placebo through Week 24 (primary end point) and Week 14 (secondary end point) post transplantation. Here, exposure-response relationships were investigated using efficacy and selected safety end points from the phase III trial to inform the proposed clinical dose. Post hoc exposure estimates were derived from a population pharmacokinetic model. No significant exposure dependencies were found for CS-CMVi through Week 24 or Week 14 among letermovir-treated participants. Evaluated covariates had no impact on exposure-efficacy relationships and letermovir plasma exposure did not affect time of CS-CMVi onset. There was no dependence between adverse event incidence and letermovir exposure. These results support current dosing recommendations in several countries and regions, including the United States and European Union.

Immune-viral dynamics modeling for SARS-CoV-2 drug development.

Coronavirus disease 2019 (COVID-19) global pandemic is caused by severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) viral infection, which can lead to pneumonia, lung injury, and death in susceptible populations. Understanding viral dynamics of SARS-CoV-2 is critical for development of effective treatments. An Immune-Viral Dynamics Model (IVDM) is developed to describe SARS-CoV-2 viral dynamics and COVID-19 disease progression. A dataset of 60 individual patients with COVID-19 with clinical viral load (VL) and reported disease severity were assembled from literature. Viral infection and replication mechanisms of SARS-CoV-2, viral-induced cell death, and time-dependent immune response are incorporated in the model to describe the dynamics of viruses and immune response. Disease severity are tested as a covariate to model parameters. The IVDM was fitted to the data and parameters were estimated using the nonlinear mixed-effect model. The model can adequately describe individual viral dynamics profiles, with disease severity identified as a covariate on infected cell death rate. The modeling suggested that it takes about 32.6 days to reach 50% of maximum cell-based immunity. Simulations based on virtual populations suggested a typical mild case reaches VL limit of detection (LOD) by 13 days with no treatment, a moderate case by 17 days, and a severe case by 41 days. Simulations were used to explore hypothetical treatments with different initiation time, disease severity, and drug effects to demonstrate the usefulness of such modeling in informing decisions. Overall, the IVDM modeling and simulation platform enables simulations for viral dynamics and treatment efficacy and can be used to aid in clinical pharmacokinetic/pharmacodynamic (PK/PD) and dose-efficacy response analysis for COVID-19 drug development.

A phase 1 pooled PK/PD analysis of bone resorption biomarkers for odanacatib, a Cathepsin K inhibitor.

To develop a framework for evaluating the resorption effects of Cathepsin K (CatK) inhibitors and to inform dose regimen selection, a pharmacokinetic/pharmacodynamic (PK/PD) model for odanacatib (ODN) was developed based upon data from Phase 1 studies. Pooled PK/PD data from 11 studies (N = 249) were fit reasonably to a population inhibitory sigmoid Emax model. Body weight on E0 (baseline uNTx/Cr, urinary N-terminal telopeptide normalized by creatinine) and age on Emax (fractional inhibition of the biomarker response) were significant covariates for biomarker response. Simulations of typical osteoporosis patients (by age, sex and weight) indicated minimal differences between sexes in concentration-uNTx/Cr relationship. There was no evidence that regimen (daily vs. weekly dosing) influenced the PK/PD relationship of resorption inhibition for odanacatib. PK/PD models based on data from odanacatib (ODN) Phase 1 studies demonstrated that uNTx/Cr was an appropriate bone resorption biomarker for assessment of the effects of a CatK inhibitor. The models also identified the determinants of response in the PK/PD relationship for ODN (body weight on E0 and age on Emax).

Population Pharmacokinetic Analysis of the Cathepsin K Inhibitor Odanacatib: Insights Into Intrinsic and Extrinsic Factor Effects on Exposure in Postmenopausal and Elderly Women.

This analysis developed a population pharmacokinetic (PK) model for odanacatib, characterized demographic and concomitant medication covariates effect, and provided odanacatib exposure estimates for subjects in phase 2/3 studies. Data from multiple phase 1 (P005, P025, and P014), phase 2b (P004 and P022), and phase 3 (Long-Term Odanacatib Fracture Trial; P018) studies were pooled to create a data set of 1280 postmenopausal women aged 45 to 91 years (102 from phase 1, 514 from phase 2b, and 664 from phase 3) who received weekly oral odanacatib doses ranging from 3 to 100 mg. A 1-compartment model with first-order absorption, dose-dependent relative bioavailability (F1), and first-order elimination best described odanacatib PK. F1 decreased from the 100% reference bioavailability for a 3-mg oral dose to 24.5% for a 100-mg dose. Eight statistically significant covariates were included in the final PK model: body weight, age, race, and concomitant cytochrome P450 (CYP)3A inhibitors on apparent clearance; body weight on apparent central volume of distribution; and concomitant hydrochlorothiazide, high-fat breakfast, and a study effect on F1. All fixed- and random-effects parameters were estimated with good precision (%standard error of the mean ≤29.5%). This population PK analysis provides insights into intrinsic- and extrinsic-factor effects on odanacatib exposure in postmenopausal and elderly women with osteoporosis. The magnitude of the intrinsic-factor effects was generally modest (odanacatib exposure geometric mean ratios, 0.80-1.21) even in subjects aged >80 years, or in subsets with multiple combinations of factors.

Hippocampal Neuroimaging-Informed Clinical Trial Enrichment Tool for Amnestic Mild Cognitive Impairment Using Open Data.

Our goal was to assess the enrichment utility of hippocampal volume (HV) as an enrichment biomarker in amnestic mild cognitive impairment (aMCI) clinical trials, and, hence, develop an HV neuroimaging-informed clinical trial enrichment tool. Modeling of integrated longitudinal patient-level data came from open-access natural history studies in patients diagnosed with aMCI-the Alzheimer's Disease Neuroimaging Initiative (ADNI)-1 and ADNI-2-and indicated that a decrease of 1 cm3 with respect to the analysis dataset median baseline intracranial volume-adjusted HV (ICV-HV; ~ 5 cm3 ) is associated with > 50% increase in disease progression rate as measured by the Clinical Dementia Rating Scale-Sum of Boxes. Clinical trial simulations showed that the inclusion of aMCI subjects with baseline ICV-HV below the 84th or 50th percentile allowed an approximate reduction in trial size of at least 26% and 55%, respectively. This clinical trial enrichment tool can help design more efficient and informative clinical trials.

Replens prevents preterm birth by decreasing type I interferon strengthening the cervical epithelial barrier.

PROBLEM: A breakdown of the cervical epithelial barrier has been associated with preterm cervical remodeling. It is unknown if Replens, the vehicle for vaginal progesterone, alters cervical epithelial junctional proteins impacting cervical remodeling and preterm birth. METHOD OF STUDY: E17 CD-1 pregnant mice received an intrauterine injection of saline or lipopolysaccharide (LPS). Effect of intravaginal Replens given on day E16 and on E17 coincident with LPS was tested. A second experiment determined if an antibody to the interferon receptor (IFNaR) blocked the effects of LPS. Mice were killed after six hours, the preterm birth rate was recorded, and the serum and cervices were collected for analysis. Additionally, the epithelial cell barrier was assessed using an in vitro permeability assay. RESULTS: Replens decreased the rate of LPS-induced preterm birth within six hours, from 87.5% to 37.5% (P < .005). LPS + IFNaR antibody decreased the rate of preterm birth or vaginal bleeding compared to LPS + control antibody mice, 43.8% vs 87%, respectively (P < .01). E-Cadherin in the mouse serum was increased by LPS, an effect mitigated by treatment with Replens (P < .0001) or the IFNaR antibody (P < .01). Replens + LPS decreased the expression of IFN-ß (P < .01). The anti-IFNaR, as well as Replens, decreased the expression of MMP13 (P < .05) compared to LPS mice. Replens also prevented the LPS-induced increase in permeability (P < .001). CONCLUSION: Replens prevents preterm birth by decreasing the interferon-induced upregulation of MMP13 and the degradation of the cell adhesion protein E-Cadherin. Further studies are needed to determine if Replens can be useful as treatment for preterm birth.

Development of a Disease Progression Model for Leucine-Rich Repeat Kinase 2 in Parkinson's Disease to Inform Clinical Trial Designs.

A quantitative assessment of Parkinson's disease (PD) progression is critical for optimizing clinical trials design. Disease progression model was developed using pooled data from the Progression Marker Initiative study and the Incidence of Cognitive Impairment in Cohorts with Longitudinal Evaluation in Parkinson's Disease study. Age, gender, concomitant medication, and study arms were predictors of baseline. A mutation in the leucine-rich repeat kinase 2 (LRRK2) encoding gene was associated with the disease progression rate. The progression rate in subjects with PD who carried LRRK2 mutation was slightly slower (~0.170 points/month) than that in PD subjects without the mutation (~0.222 points/month). For a nonenriched placebo-controlled clinical trial, approximately 70 subjects/arm would be required to detect a drug effect of 50% reduction in the progression rate with 80% probability, whereas 85, 93, and 100 subjects/arm would be required for an enriched clinical trial with 30%, 50%, and 70% subjects with LRRK2 mutations, respectively.

Maternal genetic diseases: potential concerns for mother and baby.

With advances in medical care, many women with genetic conditions previously known to decrease life expectancy are reaching childbearing age. Thus, it is important to understand the management of patients in the preconception, antepartum, and postpartum periods as they pose a unique challenge to the obstetrician. Most rare disorders lack well-established clinical guidelines for management in pregnancy. Existing data stem from case reports, case series, and expert opinion. We aim to summarize these recommendations and develop a clinical reference for managing reproductive age women with these conditions. We review recommendations for women with inborn errors in metabolism, connective tissue disorders, skeletal dysplasia, and selected single gene disorders. In all cases, it is crucial to employ a multidisciplinary team to optimize care for patients with rare disease before, during, and immediately after their pregnancies. The emphasis on expert consensus recommendations in the guidance of obstetric care is a signal that more studies are needed to determine best practices.

Evaluating the Comparative Effectiveness of Two Diets in Pediatric Inflammatory Bowel Disease: A Study Protocol for a Series of N-of-1 Trials.

Inflammatory bowel disease (IBD) affects 3 million children and adults in the US. Treatment involves medications with considerable risk profiles. Dietary modification, such as the specific carbohydrate diet (SCD), may be helpful in treating IBD, but there is insufficient evidence of its effectiveness. N-of-1 trials are ideal for addressing this important research question. The Personalized Research on Diet in Ulcerative Colitis and Crohn's Disease (PRODUCE) study employs a series of 50 individual N-of-1 trials that compare the SCD to a modified SCD. Treatment periods are assigned in blocks of two, with each patient completing two balanced treatment blocks. Patients are randomized to start with the SCD or modified SCD and alternate between conditions for four eight-week periods. A mobile app guides collecting and viewing data, transitioning diets, and reviewing personal results. Primary outcomes include patient reported outcomes (PROs) of stool frequency, stool consistency, pain interference, and gastrointestinal (GI) symptom severity. We examine changes in inflammation via fecal calprotectin. Participants will receive a personalized answer regarding comparative effectiveness between the SCD and a less restrictive diet option (modified SCD), as well as compared to their baseline diet. We will aggregate the results of completed N-of-1 trials across patients to estimate population level comparative effectiveness of these treatments and the effectiveness of each diet.

Immunogenicity of pembrolizumab in patients with advanced tumors.

BACKGROUND: Pembrolizumab is a potent, humanized, monoclonal anti-programmed death 1 antibody that has demonstrated effective antitumor activity and acceptable safety in multiple tumor types. Therapeutic biologics can result in the development of antidrug antibodies (ADAs), which may alter drug clearance and neutralize target binding, potentially reducing drug efficacy; such immunogenicity may also result in infusion reactions, anaphylaxis, and immune complex disorders. Pembrolizumab immunogenicity and its impact on exposure, safety, and efficacy was assessed in this study. PATIENTS AND METHODS: Pembrolizumab immunogenicity was assessed in 3655 patients with advanced or metastatic cancer treated in 12 clinical studies. Patients with melanoma, non-small cell lung cancer, head and neck squamous cell carcinoma, colorectal cancer, urothelial cancer, and Hodgkin lymphoma were treated with pembrolizumab at 2 mg/kg every 3 weeks, 10 mg/kg every 2 weeks, 10 mg/kg every 3 weeks, or 200 mg every 3 weeks. An additional study involving 496 patients with stage III melanoma treated with 200 mg adjuvant pembrolizumab every 3 weeks after complete resection was analyzed separately. RESULTS: Of 3655 patients, 2000 were evaluable for immunogenicity analysis, 36 (1.8%) were treatment-emergent (TE) ADA-positive; 9 (0.5%) of these TE-positive patients had antibodies with neutralizing capacity. The presence of pembrolizumab-specific ADAs did not impact pembrolizumab exposure, nor did pembrolizumab immunogenicity affect the incidence of drug-related adverse events (AEs) or infusion-related reactions. There was no clear relationship between the presence of pembrolizumab-specific ADAs and changes in tumor size across treatment regimens. Of the 496 patients treated with pembrolizumab as adjuvant therapy, 495 were evaluable, 17 (3.4%) were TE ADA-positive; none had neutralizing antibodies. CONCLUSIONS: The incidence of TE (neutralizing positive) ADAs against pembrolizumab was low in patients with advanced tumors. Furthermore, immunogenicity did not appear to have any clinically relevant effects on the exposure, safety, or efficacy of pembrolizumab. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01295827 (February 15, 2011), NCT01704287 (October 11, 2012), NCT01866319 (May 31, 2013), NCT01905657 (July 23, 2013), NCT02142738 (May 20, 2014), NCT01848834 (May 8, 2013), NCT02255097 (October 2, 2014), NCT02460198 (June 2, 2015), NCT01953692 (October 1, 2013), NCT02453594 (May 25, 2015), NCT02256436 (October 3, 2014), NCT02335424 (January 9, 2015), NCT02362594 (February 13, 2015).