Our evolving prescribing practice: inhaled medication prescription changes over 5 years at the West Midlands Adult Cystic Fibrosis Centre

Background: Highly effective modulator therapy (HEMT) is now available for ∼90% of adults with CF with Kaftrio® licenced for use in the UK from August 2020. Despite continuation of routine CF treatments in randomised controlled trials, real-world evidence suggests a reduction in prescribed inhaled medication for people with CF on HEMT.1 Alongside the introduction of Kaftrio®, additional factors have impacted upon our inhaled medication prescribing practice including the COVID-19 pandemic and the introduction of CFHealthHub, which allows us to monitor nebulised treatment adherence. Objective: To examine how and to what extent our inhaled medication prescribing practice has changed over the past 5 years. Method: A retrospective audit of our prescribed inhaled medication databases from 2016, 2019 and 2021. Results: See table 1. Table 1. Number of CF patients prescribed inhaled mucolytics and long term inhaled therapy for Pa. (Table Presented) Conclusion: Despite an increasing rate of Pa infection,we have observed an overall reduction in prescribing of inhaled antibiotics and mucolytics. HEMTs, particularly Kaftrio®, have improved the health of our patients and, despite our caution, many have requested a reduction of inhaled therapy in line with their improved well-being. Assessment of adherence via CFHealthHub has often led to rationalisation of inhaled treatments in order to support improved adherence. During the COVID-19 pandemic, drug response assessments, the gateway to accessing a change in inhaled medication, have frequently been delayed as we have had to redesign our service in response to changing circumstances.

Trends in intravenous antibiotic prescriptions pre- and postintroduction of Kaftrio® in a large UK adult cystic fibrosis centre

Background: Since the introduction of Kaftrio® in 2020, people with CF (pwCF) have reported significant health improvements. Real-world experiences over the last 2 years suggest that pwCF are using fewer antibiotics. Evidence has confirmed this is the case with nebulised antibiotics, however it is unclear what the impact has been on intravenous antibiotics (IVABx). Objective: To investigate IVABx use in pwCF, in our centre, pre and post Kaftrio® commencement. Method: Retrospective data was collected from our internal pharmacy database on number of IVABx dose units issued pre and post the widespread use of Kaftrio®. Results: Since Jan 2020, 282 pwCF, 81% of our cohort, have commenced on Kaftrio®;initially via clinical trials and compassionate use programmes, then more widely from August 2020 following its UK licence. (Table Presented) Pharmacy data shows overall IVABx prescriptions have reduced consistently since 2019 with a trend towards less inpatient therapy. Conclusion: Data suggests that the use of IVABx has reduced in our centre since the introduction of Kaftrio®. Other factors which may have influenced IVABx usage during this period include the COVID-19 pandemic, which led to pwCF “shielding” for several months during 2020, providing protection from community acquired infections and potentially increasing anxiety levels around seeking in-patient healthcare. CFHealthHub has also been vital during this time, supporting pwCF to increase their adherence to longterm nebulised treatments. Further work is needed to investigate the trends of antibiotic usage (nebulised and IV) beyond the pandemic and the effect on the long-term health outcomes of pwCF.

Bispecific CART cells in the treatment of relapsed and refractory multiple myeloma: A review of literature

Background: Chimeric antigen receptor T cells (CART) have shown promising results in the treatment of relapsed and refractory multiple myeloma (RRMM). Recently, bispecific-CART cells targeting 2 antigens are being evaluated in various clinical trials. Methods: A comprehensive literature search was done of Pubmed, Embase, and Cochrane. Data presented at annual hematology and oncology conferences were also included. Results: We included 4 phase I clinical trials with a total of 77 RRMM patients between the ages of 18 to 71 years. The median follow-up duration ranged from 1 month to 27.5 months. All were lymphodepleted with Cyclophosphamide and Fludarabine before receiving CAR-T cell therapy. The CAR-T cell targets include BCMA and CD38 (dose range 0.5 x 10∧6 - 4 x 10∧6 cells/kg), BCMA and TACI (dose range 15 - 900 x 10e6 CAR-T cells), BCMA and CD19 (1 x 10e5/kg - 3 x 10e5 CAR-T cells/kg), and BCMA and CD19 (dose 1 x 10e6 cells/kg). Overall response rate (ORR) was reported by 4 trials (87.5%, 43%, 93.8%, 95%). Complete response (CR) was also reported in 4 trials as 50%, 64%, 56.3% and 14% and partial response (PR) reported as 25%, 28%, 16.6%, 14%, 18% in 5 trials (table). The most common grade 3-4 adverse effects that were reported include cytokine release syndrome, neurotoxicity, neutropenia, lymphopenia, anemia, thrombocytopenia, diarrhea, increased LDH, lower respiratory tract infections (LRTI), dehydration, renal failure (table). Yan et al. reported one death due to cerebral hemorrhage which was considered unrelated to treatment. Jiang et al. reported one death from unknown cause of a patient who presented with fever during the COVID- 19 pandemic.Conclusions: Bispecific CART cells have shown promising results in the treatment of RRMM. However, the clinical trials are ongoing, and a longer follow-up is needed.

Drug repurposing approach against novel coronavirus disease (COVID-19) through virtual screening targeting SARS-CoV-2 main protease

Novel coronavirus disease (COVID-19) was identified from China in December 2019 and spread rapidly through human-to-human transmission, affecting so many people worldwide. Until now, there has been no specific treatment against the disease and repurposing of the drug. Our investigation aimed to screen potential inhibitors against coronavirus for the repurposing of drugs. Our study analyzed sequence comparison among SARS-CoV, SARS-CoV-2, and MERS-CoV to determine the identity matrix using discovery studio. SARS-CoV-2 M^pro was targeted to generate an E-pharmacophore hypothesis to screen drugs from the DrugBank database having similar features. Promising drugs were used for docking-based virtual screening at several precisions. Best hits from virtual screening were subjected to MM/GBSA analysis to evaluate binding free energy, followed by the analysis of binding interactions. Furthermore, the molecular dynamics simulation approaches were carried out to assess the docked complex's conformational stability. A total of 33 drug classes were found from virtual screening based on their docking scores. Among them, seven potential drugs with several anticancer, antibiotic, and immunometabolic categories were screened and showed promising MM/GBSA scores. During interaction analysis, these drugs exhibited different types of hydrogen and hydrophobic interactions with amino acid residue. Besides, 17 experimental drugs selected from virtual screening might be crucial for drug discovery against COVID-19. The RMSD, RMSF, SASA, Rg, and MM/PBSA descriptors from molecular dynamics simulation confirmed the complex's firm nature. Seven promising drugs for repurposing against SARS-CoV-2 main protease (M^pro), namely sapanisertib, ornidazole, napabucasin, lenalidomide, daniquidone, indoximod, and salicylamide, could be vital for the treatment of COVID-19. However, extensive in vivo and in vitro studies are required to evaluate the mentioned drug's activity.