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.
IntroductionThe 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).MethodsReporting 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.ResultsThe 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.ConclusionThe 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.FundingRoche.
1023 Background: GDC-9545 is a potent, orally available, selective estrogen receptor degrader developed for the treatment of ER-positive (ER+) breast cancer alone or combined with CDK4/6 inhibitors. A first-in-human study evaluated 10-250 mg GDC-9545; tolerability, pharmacokinetic (PK), pharmacodynamic (PD), and clinical results support expansion cohorts at ≥30 mg (Jhaveri et al., 2019). Methods: This study evaluated PK, PD, and efficacy of GDC-9545 alone and combined with palbociclib, ± LHRH agonist. Eligible patients (pts) had ER+ (HER2-) metastatic breast cancer (MBC) with ≤ 2 prior therapies in the advanced or metastatic setting. No prior treatment with CDK4/6 inhibitor was allowed in pts receiving palbociclib. Results: Eight-five pts were enrolled in 2 cohorts: GDC-9545 100 mg given once daily ± LHRH agonist (Cohort A), and GDC-9545 100 mg +125 mg palbociclib on a 21 day on/7 day off schedule ± LHRH agonist (Cohort B). Of the 39 pts in Cohort A, adverse events (AE) occurring in ≥10% of pts were fatigue, cough, back pain, pain in extremity, and arthralgia. Related AEs were generally Grade (G) 1-2; there were 3 related G3 AEs of fatigue, transaminase increased, and diarrhea. Two pts had GDC-9545 reduced, one due to G3 diarrhea and another due to G3 transaminitis. Of the 46 pts in Cohort B, AEs in ≥10% of pts were neutropenia, fatigue, bradycardia, diarrhea, constipation, dizziness, nausea, anemia, asthenia, thrombocytopenia, pruritus, and visual impairment. Twenty-six (57%) pts had G≥3 AEs. G≥3 neutropenia was reported in 23 (50%) pts. One pt had palbociclib reduced due to G3 febrile neutropenia. Eleven (13%) of 85 pts had G1 asymptomatic bradycardia considered related to GDC-9545. No pts in either cohort discontinued study treatment due to AEs. PK analysis and clinical data demonstrate no clinically relevant drug-drug interactions between GDC-9545 and palbociclib. Reduced ER, PR, and Ki67 levels, and an ER activity signature, were observed in paired pre- and on-treatment biopsies (n = 12). Eighteen of 33 pts in Cohort A had either confirmed partial responses or were on study 24 weeks (clinical benefit rate 55%). Clinical benefit was observed in pts with prior fulvestrant treatment and with detectable ESR1 mutations at enrollment. Clinical benefit data for both cohorts are anticipated to be mature in April 2020. Conclusions: GDC-9545 was well-tolerated as a single agent and in combination with palbociclib with encouraging PK, PD, and anti-tumor activity in ER+ MBC to support Phase III development. Clinical trial information: NCT03332797 .
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 C max , C min , and AUC last geometric mean ratios with 90% CIs. Predictions of pertuzumab C max,ss , C min,ss , and AUC ss 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. Electronic supplementary material The online version of this article (10.1007/s00280-019-03826-1) contains supplementary material, which is available to authorized users.
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
Background: Modulation of estrogen activity and/or synthesis is a mainstay therapeutic strategy for ER+ breast cancer (BC). However, despite the effectiveness of available endocrine therapies, many patients ultimately relapse or develop resistance to these agents via estrogen-dependent and estrogen-independent mechanisms, including mutations in ESR1 affecting the ER ligand-binding domain, that drive ER-dependent transcription and proliferation in the absence of estrogen. ER antagonists that robustly suppress ER signaling in both ESR1 wild-type and mutant tumors may be of substantial therapeutic benefit. GDC-9545 is a novel, potent, non-steroidal, orally bioavailable, selective ER antagonist/ER degrader (SERD) that induces tumor regression in ER+ BC patient-derived xenograft models. Methods: A phase I dose escalation study with 3+3 design was conducted in postmenopausal women with ER+ (HER2−) advanced or metastatic BC (mBC). Patients were eligible if they had advanced or mBC that had progressed while being treated with adjuvant endocrine therapy for ≥ 24 months and/or endocrine therapy in the advanced or mBC setting for ≥ 6 months. No more than 2 prior treatments for advanced or mBC. Primary objective was to determine the safety, pharmacokinetics (PK) and the recommended Phase 2 dose (RP2D) of GDC-9545. Pharmacodynamic (PD) activity was assessed with [18F]-fluoroestradiol (FES)-PET scans and, when feasible, by performing biomarker analysis of pre- and on-study tumor biopsies. Plasma samples were collected for PK analyses and imaging for response assessment (CT and bone scans) were repeated every 8 weeks. Results: From November 27 2017 to February 1 2019 patients (n = 29) with a median age of 58 years (range 42-75) and a median number of prior therapies for mBC of 2 (range 1-4) were enrolled at 4 total daily dose levels (10, 30, 90 and 250 mg) given once daily (QD) while fasting. Increases in GDC-9545 exposure were approximately dose proportional and t1/2 was ~30 hours. Treatment related adverse events (AEs) were all Grade 1 or 2. The most common treatment-related AEs in ≥10% of patients were fatigue (21%, n=6), nausea (21%, n=6), hot flushes (17%, n=5), diarrhea (17%, n=5), arthralgia (17%, n=5), constipation (10%, n=3) and dyspepsia (10%, n=3). No dose-limiting toxicities, treatment-related serious adverse events (SAEs), Grade ≥ 3 events, or fatal events have been reported. Treatment interruption was required for 3 patients: one patient for a short episode of dyspepsia, vomiting, diarrhea, and dizziness; and two patients due to unrelated SAEs. In 14 patients with FES-PET avid disease at baseline and post-baseline scans, 11 (78%) showed complete or near complete (> 90%) suppression of FES uptake to background levels, including patients with ESR1 mutations. Evidence of reduced ER, PR, and Ki67 IHC values and an ER activity signature was observed in paired pre- and on-treatment biopsies (n = 7). Twelve of 27 patients (10 mg [n=2], 30 mg [4], 90 mg [4], 250 mg [2]) had either confirmed partial responses (n = 3) or were on study ≥ 24 weeks (CBR = 44%), including patients pretreated with CDK4/6i, fulvestrant or harboring baseline ESR1 mutations. The R2PD was 100 mg QD and was selected for dose-expansion in post- and pre/peri-menopausal women with and without palbociclib, which is ongoing. Updated results will be presented. Conclusions: GDC-9545 is well-tolerated to date with PK exposure supporting QD dosing, evidence of robust PD target engagement, and encouraging anti-tumor activity in patients with advanced or ER+ mBC, including patients with ESR1 mutations. Dose expansion cohorts of GDC-9545 with or without palbociclib in post-menopausal and pre/peri-menopausal women with mBC are ongoing. Citation Format: Komal Jhaveri, Eric Paul Winer, Elgene Lim, Jose AlejandroPerez Fidalgo, Meritxell Bellet, Ingrid Alina Mayer, Valentina Boni, Jaymin M Patel, Aditya Bardia, Jose Manuel Garcia, Peter Kabos, Mary Gates, Ya-Chi Chen, Jill Fredrickson, Xiaojing Wang, Lori Sickels Friedman, Jill Spoerke, Steven Gendreau, Ciara Metcalfe, Lichuan Liu, Ching-Wei Chang, Sharareh Monemi, Monica Gonzalez, Ursula McCurry, Sandra Milan, Eric William Humke, Sherene Loi. A first-in-human phase I study to evaluate the oral selective estrogen receptor degrader (SERD), GDC-9545, in postmenopausal women with estrogen receptor-positive (ER+) HER2-negative (HER2-) metastatic breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD7-05.
Background: Despite the success of multiple HER2-targeted agents in HER2+ breast cancer (BC), resistance remains a challenge and novel therapies are needed. DHES0815A is a THIOMABTM antibody-drug conjugate consisting of a humanized IgG1 anti-HER2 monoclonal antibody (mAb) conjugated to the DNA alkylating agent PBD-MA. The reduced potency of PBD-MA compared to PBD dimers and the stability of the conjugation site and linker were designed to improve tolerability, whereas the binding of the mAb to a HER2 epitope distinct from trastuzumab and pertuzumab was designed to enable combination therapy with existing HER2 therapies. Methods: This first-in-human, Phase I, open-label, multicenter, dose escalation study used a 3+3 dose escalation design to assess the safety, pharmacokinetics (PK), and preliminary anti-tumor activity of DHES0815A in patients with metastatic HER2-positive BC refractory to established therapies (NCT03451162). DHES0815A (0.6-6.0 mg/kg) was administered intravenously every 3 weeks (Q3W) until intolerable toxicity or disease progression. Results: A total of 14 patients were treated with DHES0815A; all had ≥3 prior lines of therapy. Thirteen patients discontinued treatment due to progressive disease (43%), adverse events (AE; [29%]) symptomatic deterioration (14%) or other (7%); 1 patient remains on treatment. DHES0815A was initially well-tolerated for doses up to 2.4 mg/kg. At 4.0 mg/kg and 6.0 mg/kg, the first dose was also well-tolerated with no dose limiting toxicities, however, following 3 or more cycles at 4.0 mg/kg or 2 or more cycles at 6.0 mg/kg, safety events involving skin, eyes, and lung emerged. Skin events were reported in 50% of patients (all doses) and related events occurring in n≥2 patients included pruritus (36%), rash (36%), and skin hyperpigmentation (21%). Ocular toxicities were reported in 57% and related events occurring in n≥2 patients included photophobia (21%), conjunctivitis, eye pain, and dry eye (each 14%). Lung toxicities were reported in 36% of patients; events occurring in n≥2 included pneumonitis (14%). Other related skin, ocular, and pulmonary events occurring in 1 patient (7%) included palmar-plantar erythrodysaesthesia, macular rash, blurred vision, eyelid edema, periorbital edema, blepharitis, punctate keratitis, wheezing, allergic rhinitis, and pneumothorax. Most events were grade 1 or 2 although 3 patients experienced grade 3 ocular events (blepharitis, eye pain, photophobia). Due to these AEs, DHES0815A dose was decreased to 2.4 mg/kg Q3W for all enrolled patients and accrual was stopped. All 5 patients receiving doses of 4.0 mg/kg and 6.0 mg/kg discontinued due to AEs. At lower doses, 1 patient receiving 2.4 mg/kg developed grade 2 rash at Cycle 21 and 1 patient receiving 1.2 mg/kg developed grade 1 rash, pruritis, and skin hyperpigmentation between Cycles 28-30. Nonlinear PK of antibody-conjugated PBD-MA (acPBD-MA) was observed due to target mediated drug disposition at 0.6, 1.2, and 2.4 mg/kg; PK approached linear at 4.0 mg/kg. Minimal systemic exposure of unconjugated PBD-MA was observed. Overall, 1 patient (7%) in the 1.2 mg/kg cohort achieved a confirmed complete response. As of 10Jun21, this patient remains on study after more than 32 months on treatment. Ten patients (86%) showed a confirmed best overall response of stable disease (86%). Conclusion: Despite some anti-tumor activity observed with DHES0815A, development in HER2-positive BC has been discontinued due to safety concerns and the narrow therapeutic window. Toxicities observed in skin, lung, and eyes are clinically apparent only after repeated dose administration. If future exploration of PBD-MA-based constructs is performed in the clinic, close monitoring for delayed toxicities is warranted. Citation Format: Ian Krop, Erika Hamilton, Kyung Hae Jung, Shanu Modi, Kevin M Kalinsky, Gail Phillips, Rong Shi, Sharareh Monemi, Michael Mamounas, Ola Saad, Voleak Choeurng, Renee Commerford, Eunpi Cho, Alexander Ungewickell, Patricia LoRusso. A phase I dose-escalation study of DHES0815A, a HER2-targeting antibody-drug conjugate with a DNA monoalkylator payload, in patients with HER2-positive breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-13-25.
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