A Phase 1a Study to Evaluate Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of RO7303509, an Anti-TGFß3 Antibody, in Healthy Volunteers.

INTRODUCTION: Transforming growth factor beta (TGFß) cytokines (TGFß1, TGFß2, and TGFß3) play critical roles in tissue fibrosis. However, treatment with systemic pan-TGFß inhibitors have demonstrated unacceptable toxicities. In this study, we evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of RO7303509, a high-affinity, TGFß3-specific, humanized immunoglobulin G1 monoclonal antibody, in healthy adult volunteers (HVs). METHODS: This phase 1a, randomized, double-blind trial included six cohorts for evaluation, with each cohort receiving single doses of placebo or RO7303509, administered intravenously (IV; 50 mg, 150 mg, 240 mg) or subcutaneously (SC; 240 mg, 675 mg, 1200 mg). The frequency and severity of adverse events (AEs) and RO7303509 serum concentrations were monitored throughout the study. We also measured serum periostin and cartilage oligomeric matrix protein (COMP) by immunoassay and developed a population pharmacokinetics model to characterize RO7303509 serum concentrations. RESULTS: The study enrolled 49 HVs, with a median age of 39 (range 18-73) years. Ten (27.8%) RO7303509-treated subjects reported 24 AEs, and six (30.8%) placebo-treated subjects reported six AEs. The most frequent AEs related to the study drug were injection site reactions and infusion-related reactions. Maximum serum concentrations (Cmax) and area under the concentration-time curve from time 0 to infinity (AUC0-inf) values for RO7303509 appeared to increase dose-proportionally across all doses tested. Serum concentrations across cohorts were best characterized by a two-compartment model plus a depot compartment with first-order SC absorption kinetics. No subjects tested positive for anti-drug antibodies (ADAs) at baseline; one subject (2.8%; 50 mg IV) tested positive for ADAs at a single time point (day 15). No clear pharmacodynamic effects were observed for periostin or COMP upon TGFß3 inhibition. CONCLUSION: RO7303509 was well tolerated at single SC doses up to 1200 mg in HVs with favorable pharmacokinetic data that appeared to increase dose-proportionally. TGFß3-specific inhibition may be suitable for development as a chronic antifibrotic therapy. TRIAL REGISTRATION: ISRCTN13175485.

The HER2-directed antibody-drug conjugate DHES0815A in advanced and/or metastatic breast cancer: preclinical characterization and phase 1 trial results.

Approved antibody-drug conjugates (ADCs) for HER2-positive breast cancer include trastuzumab emtansine and trastuzumab deruxtecan. To develop a differentiated HER2 ADC, we chose an antibody that does not compete with trastuzumab or pertuzumab for binding, conjugated to a reduced potency PBD (pyrrolobenzodiazepine) dimer payload. PBDs are potent cytotoxic agents that alkylate and cross-link DNA. In our study, the PBD dimer is modified to alkylate, but not cross-link DNA. This HER2 ADC, DHES0815A, demonstrates in vivo efficacy in models of HER2-positive and HER2-low cancers and is well-tolerated in cynomolgus monkey safety studies. Mechanisms of action include induction of DNA damage and apoptosis, activity in non-dividing cells, and bystander activity. A dose-escalation study (ClinicalTrials.gov: NCT03451162) in patients with HER2-positive metastatic breast cancer, with the primary objective of evaluating the safety and tolerability of DHES0815A and secondary objectives of characterizing the pharmacokinetics, objective response rate, duration of response, and formation of anti-DHES0815A antibodies, is reported herein. Despite early signs of anti-tumor activity, patients at higher doses develop persistent, non-resolvable dermal, ocular, and pulmonary toxicities, which led to early termination of the phase 1 trial.

Pharmacokinetic and exploratory exposure-response analysis of pertuzumab in patients with operable HER2-positive early breast cancer in the APHINITY study.

PURPOSE: To characterize the pharmacokinetics (PK) of, and perform an exploratory exposure-response (E-R) analysis for, pertuzumab in patients with HER2-positive early breast cancer (EBC) within the APHINITY study (NCT01358877, BIG 4-11/BO25126/TOC4939G). METHODS: A previously developed pertuzumab two-compartment linear population pharmacokinetic (popPK) model was subjected to external validation to examine appropriateness for describing pertuzumab concentrations from the APHINITY study. Pharmacokinetic drug-drug interactions (DDIs) between pertuzumab, trastuzumab, and chemotherapy were assessed by comparing observed serum or plasma Cmax, Cmin, and AUClast geometric mean ratios with 90% CIs. Predictions of pertuzumab Cmax,ss, Cmin,ss, and AUCss were derived from individual parameter estimates and used in an exploratory E-R analysis. RESULTS: Using data from 72 patients, based on goodness-of-fit, the popPK model was deemed appropriate for predictions of individual exposures for subsequent comparisons to historical data, assessment of DDIs, and E-R analyses. No evidence of DDIs for pertuzumab on trastuzumab, trastuzumab on pertuzumab, or pertuzumab on chemotherapy PK was observed. Analyses of differences in exposure between patients with and without invasive disease-free survival events did not indicate improved efficacy with increased exposure. Overall Grade ≥ 3 diarrhea prevalence was higher with pertuzumab versus placebo, but was not greater with increasing pertuzumab exposure. No apparent E-R relationship was suggested with respect to other grade ≥ 3 AEs. CONCLUSION: Overall, the limited available data from this exploratory study suggest that no dose adjustments are needed for pertuzumab when administered in combination with trastuzumab and an EBC chemotherapy regimen.

Incidence of Gastrointestinal Perforations in Patients with Rheumatoid Arthritis Treated with Tocilizumab from Clinical Trial, Postmarketing, and Real-World Data Sources.

INTRODUCTION: The aim of this study was to use multiple data sources to update information on gastrointestinal perforations (GIPs) during tocilizumab (TCZ) treatment in patients with rheumatoid arthritis (RA). METHODS: Reporting rates of GIP events were estimated from three distinct patient data sets: a TCZ-IV RA clinical trial all-exposure population, a global TCZ postmarketing safety database population, and a US healthcare claims database population of patients with RA, including patients who received TCZ, anti-tumor necrosis factor (aTNF) agents, or abatacept. RESULTS: The clinical trial, global postmarketing, and healthcare claims populations provided 17,906, 382,621, and 3268 patient-years (PYs) of TCZ exposure, respectively. GIP incidence rates [95% confidence interval (CI)] were 1.9 (1.3-2.7), 1.2 (1.1-1.3), and 1.8 (0.7-4.0; specific definition) to 2.8 (1.3-5.2; sensitive definition) per 1000 PYs for the clinical trial, postmarketing, and healthcare claims populations, respectively. The GIP incidence rate (95% CI) for the comparator aTNF healthcare claims population ranged from 0.6 (0.3-1.2) to 0.9 (0.5-1.5) per 1000 PYs, for an absolute rate difference between TCZ and aTNFs of 1.2 (-0.3 to 2.5) to 1.9 (0.0-3.7) per 1000 PYs, corresponding to a number needed to harm between 533 and 828. CONCLUSION: The TCZ GIP event rates from multiple data sources were consistent with previously reported rates, did not increase over time, and were significantly associated with the number of prior biologics. Comparison of GIP incidence rates among patients with prior biologic exposure suggests that, for every 1000 patients treated with TCZ per year, an additional 1-2 GIP events might occur compared with patients treated with aTNFs. FUNDING: Roche.

The role of the WDR36 gene on chromosome 5q22.1 in a large family with primary open-angle glaucoma mapped to this region.

OBJECTIVE: To determine whether mutations in the WD40-repeat 36 (WDR36) gene are responsible for primary open-angle glaucoma (POAG) that maps to the GLC1G locus in a family with 16 affected family members. METHODS: Ninety-two family members underwent clinical evaluation for POAG on the basis of intraocular pressures, cupping of discs, and visual fields after informed consent was obtained. All 23 exons of WDR36 were sequenced in DNA from 5 affected and 2 unaffected family members. RESULTS: Sixteen family members showed evidence of POAG. A number of sequence variations were identified in family members; most of the variations were previously described single-nucleotide polymorphisms also present in the general population. The 3 new sequence changes were all intronic; 2 were found in only 1 of the family members undergoing screening. CONCLUSIONS: Several polymorphisms, including known single-nucleotide polymorphisms, were identified; however, none of these were consistent with disease-causing mutations. A mutation in a noncoding region of WDR36 may be responsible for POAG in this family, or another gene in this region may be the actual cause of glaucoma in this family. CLINICAL RELEVANCE: The finding that the WDR36 gene is probably not the responsible gene in this family further documents the genetic heterogeneity of POAG.

Identification of a novel adult-onset primary open-angle glaucoma (POAG) gene on 5q22.1.

Glaucoma is a leading cause of blindness in virtually every country. Development of an accurate diagnostic test for presymptomatic detection of individuals at risk is an urgent requisition for this condition. Herein, we report mapping of a new adult-onset primary open-angle glaucoma (POAG) locus on 5q22.1 (GLC1G) and identification of its defective gene. Mutation screening of seven candidate genes from the GLC1G critical region (approximately 2 Mb between D5S1466 and D5S2051) identified only one significant alteration in the WDR36 (WD40-repeat 36) gene. This mutation (i.e. D658G) was segregated in all affected members of our first GLC1G-linked family but it was absent in 476 normal control chromosomes. Further screening of WDR36 in a total of 130 POAG families revealed 24 DNA variations. Overall, four mutations (N355S, A449T, R529Q and D658G) were identified in 17 (5.02-6.92%) unrelated POAG subjects, 11 with high-pressure and six with low-pressure glaucoma. These mutations were absent in a minimum of 200 normal control chromosomes and, further they were conserved between WDR36 orthologues in mouse, rat, dog, chimp and human. WDR36 is a novel gene with 23 exons, which encodes for 951 amino acids and a protein with multiple G-beta WD40 repeats. By northern blotting, two distinct mRNA transcripts of 5.9 and 2.5 kb were observed in human heart, placenta, liver, skeletal muscle, kidney and pancreas. WDR36 gene expression in lens, iris, sclera, ciliary muscles, ciliary body, trabecular meshwork, retina and optic nerve were established by RT-PCR. In mouse, two transcripts of 3.5 and 2.9 kb showed analogous expression patterns to human. mRNA expressions were detected in 7-, 11-, 15- and 17-day-old developing mouse embryos. In summary, WDR36 is a novel causative gene for adult-onset POAG at the GLC1G locus. Specific ocular expressions and observed mutations are consistent with WDR36 role in etiology of both high- and low-pressure glaucoma.