Pharmacological inhibition of MERTK induces in vivo retinal degeneration: a multimodal imaging ocular safety assessment

The receptor tyrosine kinase, MERTK, plays an essential role in homeostasis of the retina via efferocytosis of shed outer nuclear segments of photoreceptors. The Royal College of Surgeons rat model of retinal degeneration has been linked to loss-of-function of MERTK, and together with the MERTK knock-out mouse, phenocopy retinitis pigmentosa in humans with MERTK mutations. Given recent efforts and interest in MERTK as a potential immuno-oncology target, development of a strategy to assess ocular safety at an early pre-clinical stage is critical. We have applied a state-of-the-art, multi-modal imaging platform to assess the in vivo effects of pharmacological inhibition of MERTK in mice. This involved the application of mass spectrometry imaging (MSI) to characterize the ocular spatial distribution of our highly selective MERTK inhibitor; AZ14145845, together with histopathology and transmission electron microscopy to characterize pathological and ultra-structural change in response to MERTK inhibition. In addition, we assessed the utility of a human retinal in vitro cell model to identify perturbation of phagocytosis post MERTK inhibition. We identified high localized total compound concentrations in the retinal pigment epithelium (RPE) and retinal lesions following 28 days of treatment with AZ14145845. These lesions were present in 4 of 8 treated animals, and were characterized by a thinning of the outer nuclear layer, loss of photoreceptors (PR) and accumulation of photoreceptor outer segments at the interface of the RPE and PRs. Furthermore, the lesions were very similar to that shown in the RCS rat and MERTK knock-out mouse, suggesting a MERTK-induced mechanism of PR cell death. This was further supported by the observation of reduced phagocytosis in the human retinal cell model following treatment with AZ14145845. Our study provides a viable, translational strategy to investigate the pre-clinical toxicity of MERTK inhibitors but is equally transferrable to novel chemotypes.

Rapid resolution of choroidal metastatic tumour secondary to lung cancer following treatment with alectinib

A 64-year-old man presented with reduced vision in the right eye (visual acuity of 6/24 Snellen). The patient reported having a chronic cough and recent weight loss with difficulty in swallowing and abnormal liver function test 8 months prior to his presentation. He was a chronic smoker for 45 years, having quit a year earlier. Fundus examination showed a unifocal large yellow–brown subretinal mass involving the posterior segment of the eye and associated with subretinal fluid. The patient was diagnosed with a choroidal metastasis and was referred urgently to the oncology team who confirmed the presence of non-small cell lung cancer with distant metastases. He started treatment with alectinib (second-generation tyrosine kinase inhibitor). A few weeks later, his vision improved and, on examination, there was complete resolution of the choroidal mass and the associated subretinal fluid. Alectinib led to rapid resolution of his choroidal secondary and has excellent ocular safety profile.

Evaluation of the ocular safety associated with the exhalation delivery system with fluticasone

Background: Intranasal corticosteroids (INCS) are the cornerstone of treatment for chronic rhinosinusitis. Although INCS are generally considered safe and effective, there is a concern that chronic use may lead to ocular adverse effects.Objective: To assess ocular safety of the exhalation delivery system with fluticasone propionate (EDS-FLU) in patients with chronic rhinosinusitis with nasal polyps.Methods: Ocular safety data were collected during two randomized, double-blind, placebo controlled studies with open label extensions. Ophthalmologists performed tonometry, slit-lamp, and visual acuity examinations to assess intraocular pressure (IOP) and the presence of cataracts. Ocular examinations were conducted before double-blind treatment, at the end of the 16-week double-blind phase, and at the end of the 8-week open-label phase. The results of pooled data from patients who received EDS-FLU 186 mcg (n = 160), EDS-FLU 372 mcg (n = 161), and EDS-placebo (n = 161) twice daily are reported here.Results: At the end of the double-blind phase, six patients developed elevated average IOP > 21 mm Hg: two patients(1.2%) in the EDS-placebo group, three patients (1.9%) in the EDS-FLU 186 mcg group, and one patient (0.6%) in the EDSFLU 372 mcg group. In addition, 6 of 482 patients developed cataracts: 3 patients in the EDS-placebo group, 2 patients in the EDS-FLU 186 mg group, and 1 patient in the EDS-FLU 372 mg group. At the end of the open-label phase, two additional patients showed IOP > 21 mm Hg and two additional patients developed cataracts.Conclusion: No increased risk of elevated IOP was detected with EDS-FLU; the rate of cataract development was similar to EDS-placebo and to that reported with other INCS.

Intraoperative Applications of Topical Corticosteroid Therapy for Chronic Rhinosinusitis

Objectives: To provide an overview of recent techniques and technologies for the application of topical corticosteroid therapy immediately following endoscopic sinus surgery (ESS) for chronic rhinosinusitis (CRS). Methods: A comprehensive search in the PubMed and Google Scholar databases was conducted to identify publications between January 2000 and December 2019 detailing clinical trials that have evaluated the efficacy and safety of intraoperative applications of topical corticosteroids for CRS. Results: A total of 21 articles, all of which highlight a variety of corticosteroid-infused products, including Propel corticosteroid-eluting stents, NasoPore, Merocel, SinuBand, calcium alginate, and bioresorbable gel-type products, are included for review. Propel stents are the only devices that have achieved level 1A evidence in terms of efficacy and have data to support their safety. The remaining products have shown mixed results in terms of efficacy and safety. Conclusion: A wide range of techniques and technologies have been introduced to enhance the topical delivery of corticosteroids into the neosinuses after ESS for CRS. Regarding efficacy, there is level 1A evidence to support the use of Propel stents. Most of the remaining strategies show some degree of efficacy. Direct comparisons across the different strategies are limited owing to the varied uses of delivery vectors, corticosteroid choices, and doses of corticosteroids. Propel stents and SinuBand have sufficient data to support systemic and ocular safety, whereas the remaining products have limited data to support their safety.

Exposure-Response (E-R) for Ocular Safety Endpoints for Belantamab Mafodotin (Belamaf), a B-Cell Maturation Antigen (BCMA)-Targeting Agent, in Patients with Relapsed/Refractory Multiple Myeloma (RRMM) in the DREAMM-2 Study

Introduction: Belamaf (GSK2857916) is a first-in-class BCMA-targeting antibody-drug conjugate (ADC) with a humanized afucosylated anti-BCMA mAb conjugated to a cytotoxic payload mafodotin (MMAF) by a protease-resistant maleimidocaproyl linker (mc). This ADC binds to BCMA and eliminates MM cells by a multimodal mechanism. It delivers MMAF to MM cells, which inhibits microtubule polymerization, resulting in apoptosis; enhances antibody-dependent cellular cytotoxicity and phagocytosis; and induces release of markers characteristic of immunogenic cell death. This analysis assessed the E-R relationships for ocular safety endpoints in the DREAMM-2 study (NCT03525678; Lonial et al. Lancet Oncol 2020). Methods: Heavily pretreated patients with RRMM were administered belamaf 2.5 or 3.4 mg/kg intravenously every 3 weeks in the pivotal Phase II study, DREAMM-2 (N=218; Lonial et al., Lancet Oncol 2020). Population pharmacokinetic (PK) models of belamaf and cys-mcMMAF were developed and used to predict individual Cycle 1 exposure measures (Ferron-Brady et al., AACR 2020; presentation CT196). Exposure-safety analyses evaluated the probability of Grade ≥2 or ≥3 corneal adverse event (CAE; based on ocular examination and graded using a study-specific keratopathy and visual acuity [KVA] scale), or ocular events including Grade ≥1 or ≥2 blurred vision or dry eye (graded with Common Terminology Criteria for Adverse Events [CTCAE] v4.03), definite worsening in best corrected visual acuity (BCVA) in the better-seeing eye, and unilateral or bilateral worsening in BCVA to 20/50 or worse (BCVA measured with Snellen scale). The time to first occurrence of these events was also evaluated. Generalized linear models were used to assess event probabilities, while Cox proportional hazard models were used to assess time to event endpoints. Baseline patient characteristics, including serum levels of free soluble BCMA (sBMCA), a marker of disease burden, and history of eye conditions (Popat et al., ASH 2020; presentation TBD), were also evaluated for association with these endpoints. Results: Higher belamaf Ctau (the predicted concentration on Day 21 at the end of the first cycle) was associated with greater probability of developing Grade ≥2 or ≥3 CAE as well as an earlier onset of these events. History of dry eye was associated with an increased probability of Grade ≥2 CAE; lower baseline sBCMA level was associated with higher probability of Grade ≥2 or ≥3 CAE. Higher belamaf Ctau was not found to be associated with probability of occurrence or timing of first occurrence of blurred vision, dry eye (Ferron-Brady et al. AACR 2020; presentation CT196), definite worsening in BCVA, and unilateral or bilateral worsening in BCVA to 20/50 or worse.Lower baseline sBCMA level was associated with higher probability of occurrence for most of these endpoints, with some showing an earlier occurrence. History of dry eye was associated with higher probability of any grade of blurred vision, while presence of keratopathy at baseline increased the probability of a Grade ≥2 blurred vision with an earlier occurrence of any grade and Grade ≥2 blurred vision. Conclusions: After accounting for patient and disease factors, higher belamaf exposure (Ctau) was associated with an increased probability of corneal AEs (KVA scale) but not with other ocular events (e.g., blurred vision, dry eye, or worsening in visual acuity) in integrated E-R safety analyses of DREAMM-2. Funding: GSK (Study 205678); drug linker technology licensed from Seattle Genetics; mAb produced using POTELLIGENT Technology licensed from BioWa. Disclosures Ferron-Brady: GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Rathi:GSK: Current Employment, Current equity holder in publicly-traded company. Collins:GSK: Current Employment, Current equity holder in publicly-traded company. Struemper:GSK: Current Employment, Current equity holder in publicly-traded company. Opalinska:GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Jewell:GSK: Current Employment, Current equity holder in publicly-traded company; Novartis: Current equity holder in publicly-traded company.