Safety, tolerability, and antiviral effect of RG-101 in patients with chronic hepatitis C: a phase 1B, double-blind, randomised controlled trial.

BACKGROUND: miR-122 is an important host factor for hepatitis C virus (HCV) replication. The aim of this study was to assess the safety and tolerability, pharmacokinetics, and antiviral effect of a single dose of RG-101, a hepatocyte targeted N-acetylgalactosamine conjugated oligonucleotide that antagonises miR-122, in patients with chronic HCV infection with various genotypes. METHODS: In this randomised, double-blind, placebo-controlled, multicentre, phase 1B study, patients were randomly assigned to RG-101 or placebo (7:1). We enrolled men and postmenopausal or hysterectomised women (aged 18-65 years) with chronic HCV genotype 1, 3, or 4 infection diagnosed at least 24 weeks before screening who were either treatment naive to or relapsed after interferon-α based therapy. Patients with co-infection (hepatitis B virus or HIV infection), evidence of decompensated liver disease, or a history of hepatocellular carcinoma were excluded. Randomisation was done by an independent, unblinded, statistician using the SAS procedure Proc Plan. The first cohort received one subcutaneous injection of 2 mg/kg RG-101 or placebo; the second cohort received one subcutaneous injection of 4 mg/kg or placebo. Patients were followed up for 8 weeks (all patients) and up to 76 weeks (patients with no viral rebound and excluding those who were randomised to the placebo group) after randomisation. The primary objective was safety and tolerability of RG-101. This trial was registered with EudraCT, number 2013-002978-49. FINDINGS: Between June 4, 2014, and Oct 27, 2014, we enrolled 32 patients with chronic HCV genotype 1 (n=16), 3 (n=10), or 4 (n=6) infections. In the first cohort, 14 patients were randomly assigned to receive 2 mg/kg RG-101 and two patients were randomly assigned to receive placebo, and in the second cohort, 14 patients were randomly assigned to receive 4 mg/kg RG-101 and two patients were randomly assigned to receive placebo. Overall, 26 of the 28 patients dosed with RG-101 reported at least one treatment-related adverse event. At week 4, the median viral load reduction from baseline was 4·42 (IQR 3·23-5·00) and 5·07 (4·19-5·35) log10 IU/mL in patients dosed with 2 mg/kg RG-101 or 4 mg/kg RG-101. Three patients had undetectable HCV RNA levels 76 weeks after a single dose of RG-101. Viral rebound at or before week 12 was associated with the appearance of resistance associated substitutions in miR-122 binding regions in the 5' UTR of the HCV genome. INTERPRETATION: This study showed that one administration of 2 mg/kg or 4 mg/kg RG-101, a hepatocyte targeted N-acetylgalactosamine conjugated anti-miR-122 oligonucleotide, was well tolerated and resulted in substantial viral load reduction in all treated patients within 4 weeks, and sustained virological response in three patients for 76 weeks. FUNDING: Regulus Therapeutics, Inc.

Results and evaluation of a first-in-human study of RG7342, an mGlu5 positive allosteric modulator, utilizing Bayesian adaptive methods.

AIM: The objectives of this first-in-human study were to evaluate the safety and tolerability, pharmacokinetics and pharmacodynamics, and maximum tolerated dose (MTD) of single ascending oral doses of RG7342, a positive allosteric modulator (PAM) of the metabotropic glutamate receptor 5 (mGlu5) for the treatment of schizophrenia, in healthy male subjects. METHODS: This was a single-centre, randomized, double-blind, adaptive study of 37 subjects receiving single ascending oral doses of RG7342 (ranging from 0.06-1.2 mg, n = 27) or placebo (n = 10). A modified continual reassessment method, with control for the probability of overdosing based on the occurrence of dose-limiting events (DLEs), was applied to inform the subsequent dose decisions for RG7342. RESULTS: DLEs consisted of dizziness, nausea and vomiting, and the incidence and severity of these adverse events increased in a concentration-dependent manner. RG7342 doses of 1.2 mg under fasting conditions, which reached a mean maximum plasma concentration (Cmax ) of 10.2 ng ml-1 , were not tolerated (four out of six subjects experienced DLEs). RG7342 showed dose-proportional pharmacokinetics, with rapid absorption and a biphasic decline, and a mean terminal half-life estimated to be >1000 h. CONCLUSIONS: Single oral doses of RG7342 were generally tolerated up to 0.6 mg under fasting and 0.9 mg under fed conditions in healthy subjects. Bayesian adaptive methods describing the probability of DLEs were applied effectively to support dose escalation. MTDs (fasting, fed) were associated with a Cmax of 6.5 ng ml-1 . The development of RG7342 was discontinued owing to the potential challenges associated with a long half-life in context of the observed adverse events.

Bioavailability and bioequivalence comparison of brivaracetam 10, 50, 75, and 100 mg tablets and 100 mg intravenous bolus.

OBJECTIVE: To determine the bioequivalence of brivaracetam oral tablet formulations (10, 75, and 100 mg) versus 50 mg oral tablet and to compare the bioavailability of brivaracetam 100 mg intravenous (i.v.) bolus versus 50 and 100 mg tablets, in healthy participants. METHODS: Phase 1, randomized, open-label, five-period crossover study. Participants received five single doses of brivaracetam: 10, 50 (reference), 75, and 100 mg oral tablets; 100 mg, i.v., bolus injection. Pharmacokinetic parameters (maximum plasma concentration [Cmax ], area under the plasma concentration-time curve from time zero to the time of last quantifiable concentration [AUCt ], area under the plasma concentration-time curve extrapolated to infinity [AUCinf ]) were compared using analysis of variance (ANOVA) following dose normalization and logarithmic transformation. Bioavailability comparisons were based on the 90% confidence intervals (CIs) around the geometric least squares mean ratios (test: reference). RESULTS: Twenty-five participants were randomized. The 90% CIs around Cmax , AUCt , and AUCinf ratios for brivaracetam 10, 75, and 100 mg tablets versus 50 mg tablet were entirely contained within the bioequivalence limits (0.8000-1.2500). For brivaracetam 100 mg, i.v., bolus, bioequivalence versus 50 and 100 mg tablets was met for AUCt and AUCinf , but Cmax was partly outside the limits (90% CI: 1.1867-1.3863 and 1.1222-1.3136, respectively). SIGNIFICANCE: Brivaracetam 10, 75, and 100 mg tablets were bioequivalent to the 50 mg tablet. Brivaracetam 100 mg, i.v., bolus had bioavailability similar to that of 50 and 100 mg tablets.

A First-in-Human Randomized Study to Assess the Safety, Tolerability, Pharmacokinetics, and Neutralization Profile of Two Investigational Long-Acting Anti-SARS-CoV-2 Monoclonal Antibodies.

INTRODUCTION: COVID-19 remains a significant risk for the immunocompromised given their lower responsiveness to vaccination or infection. Therefore, passive immunity through long-acting monoclonal antibodies (mAbs) offers a needed approach for pre-exposure prophylaxis (PrEP). Our study evaluated safety, anti-SARS-CoV-2 neutralizing activity, nasal penetration, and pharmacokinetics (PK) of two half-life-extended investigational mAbs, AER001 and AER002, providing the first demonstration of upper airway penetration of mAbs with the LS-modification. METHODS: This randomized, double-blind, placebo-controlled phase I study enrolled healthy adults (n = 80) who received two long-acting COVID mAbs (AER001 and AER002), AER002 alone, or placebo. The dose ranged from 100 mg (mg) to 1200 mg per mAb component. The primary objective was to describe the safety and tolerability following intravenous (IV) administration. Secondary objectives were to describe PK, anti-drug antibodies (ADA), neutralization activity levels, and safety evaluation through 6 months of follow-up. RESULTS: The majority (97.6%) of the reported adverse events (AE) post administration were of grade 1 severity. There were no serious adverse events (SAE) or ADAs. AER001 and AER002 successfully achieved an extended half-life of 105 days and 97.5 days, respectively. Participants receiving AER001 and AER002 (300 mg each) or AER002 (300 mg) alone showed 15- and 26-fold higher neutralization levels against D614G and omicron BA.1 than the placebo group 24 h post-administration. Single 300 or 1200 mg IV dose of AER001 and AER002 resulted in nasal mucosa transudation of approximately 2.5% and 2.7%, respectively. CONCLUSION: AER001 and AER002 showed an acceptable safety profile and extended half-life. High serum neutralization activity was observed against D614G and Omicron BA.1 compared to the placebo group. These data support that LS-modified mAbs can achieve durability, safety, potency, and upper airway tissue penetration and will guide the development of the next generation of mAbs for COVID-19 prevention and treatment. TRIAL REGISTRATION: EudraCT Number 2022-001709-35 (COV-2022-001).

Safety, pharmacokinetics and target engagement of novel RIPK1 inhibitor SAR443060 (DNL747) for neurodegenerative disorders: Randomized, placebo-controlled, double-blind phase I/Ib studies in healthy subjects and patients.

RIPK1 is a master regulator of inflammatory signaling and cell death and increased RIPK1 activity is observed in human diseases, including Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS). RIPK1 inhibition has been shown to protect against cell death in a range of preclinical cellular and animal models of diseases. SAR443060 (previously DNL747) is a selective, orally bioavailable, central nervous system (CNS)-penetrant, small-molecule, reversible inhibitor of RIPK1. In three early-stage clinical trials in healthy subjects and patients with AD or ALS (NCT03757325 and NCT03757351), SAR443060 distributed into the cerebrospinal fluid (CSF) after oral administration and demonstrated robust peripheral target engagement as measured by a reduction in phosphorylation of RIPK1 at serine 166 (pRIPK1) in human peripheral blood mononuclear cells compared to baseline. RIPK1 inhibition was generally safe and well-tolerated in healthy volunteers and patients with AD or ALS. Taken together, the distribution into the CSF after oral administration, the peripheral proof-of-mechanism, and the safety profile of RIPK1 inhibition to date, suggest that therapeutic modulation of RIPK1 in the CNS is possible, conferring potential therapeutic promise for AD and ALS, as well as other neurodegenerative conditions. However, SAR443060 development was discontinued due to long-term nonclinical toxicology findings, although these nonclinical toxicology signals were not observed in the short duration dosing in any of the three early-stage clinical trials. The dose-limiting toxicities observed for SAR443060 preclinically have not been reported for other RIPK1-inhibitors, suggesting that these toxicities are compound-specific (related to SAR443060) rather than RIPK1 pathway-specific.

Ewing sarcoma outcomes in a country with limited resources: Egypt as an example.

As the scarcity of published research that comprehensively and meticulously analyzed the patient, disease, and treatment factors of prognostic significance in Ewing sarcoma (EWS) in Egypt; This study aimed at assessing survival outcomes of EWS in Upper Egypt, delineating factors of prognostic significance in comparison to other leading oncology centers in Egypt and internationally. By retrospectively reviewing medical records of 85 patients with a verified diagnosis of EWS in the period from 2001 to 2015 at Pediatric and Medical Oncology Departments at South Egypt Cancer Institute; We gathered data relevant to the patient, disease, and treatment variables of the study. Survival was estimated using the Kaplan Meier method and differences between various groups were determined by log rank test. Univariable and multivariable analyses were performed using Cox regression. With a median follow-up period of 62.7 months (95% CI 52.2-73.2, SE=5.4) for the study patients, the estimates of event-free survival (EFS) and overall survival (OS) at 3 and 5 years were 42.1% and 50.6%, and 40.8% and 48.5%, respectively. Metastatic disease at initial presentation (HR=8.91, 95% CI, 4.00-19.9; P<0.0001) stood as the most powerful predictor of OS in the multivariable analysis, followed by surgery used as a local modality (HR=0.16, 95% CI, 0.06-0.44; P=0.0004). Response to neoadjuvant chemotherapy (HR=2.61, 95% CI, 1.11-6.13; P=0.028), primary tumor size (HR=2.49, 95% CI, 1.03-6.03; P=0.044) were also shown to be significantly associated with OS. Radiotherapy as a local modality, whose effect, apparently shown to increase the hazard of events occurrence in the univariable analysis, an effect that was reversed to reveal EFS advantage (HR=0.41, 95% CI, 0.18-0.95; P=0.036) after control of other variables. With 5-year OS of 48.5%, our survival results were comparable to those previously published from Egypt; however, differences still exist between centers due to varied representative study samples. However, outcomes in Egypt in general are still inferior to internationally published studies.