Preliminary safety of Bcl-2 inhibitor BGB-11417 in relapsed/refractory multiple myeloma Harbouring t(11,14): Phase 1b/2 study

Background: B-cell lymphoma-2 (Bcl-2) proteins play an important role in multiple myeloma (MM) cell survival and represent an attractive therapeutic target. In prior trials, a subgroup analysis of patients with t(11;14)-positive relapsed/refractory (R/R) MM showed the combination of a Bcl-2 inhibitor, a proteasome inhibitor, and dexamethasone improved progression-free survival with no increased mortality. BGB-11417, a Bcl-2 inhibitor, is more potent and selective than venetoclax. BGB-11417- 105 (NCT04973605) is a phase 1b/2 study assessing the safety and efficacy of BGB-11417 monotherapy, in combination with dexamethasone, or with dexamethasone+carfilzomib in patients with t(11;14)-positive R/R MM. Preliminary safety results for the combination of BGB-11417 + dexamethasone are presented. Method(s): Eligible patients had t(11;14)-positive R/R MM and had been exposed to a proteasome inhibitor, immunomodulatory agent, and anti-CD38 therapy. Patients received 80-, 160-, 320-, or 640-mg BGB-11417 daily with 40-mg dexamethasone weekly until death, intolerability, or disease progression. Dose escalation was guided by a mTPI-2 design and overall review by a safety monitoring committee. Pharmacokinetics (PK) were also assessed. Result(s): As of 1 July 2022, 10 patients were enrolled in the 80-, 160-, and 320-mg (3 patients each) and 640-mg (1 patient) dose-escalation cohorts of BGB-11417 + dexamethasone. The median age was 69 years (range, 52-81) and median prior lines of therapy was 3 (range, 1-5). The median treatment duration was 3.2 months (range, 0.5-6.5). No patients experienced dose-limiting toxicity at any dose level. Three patients died whilst on study: 1 due to COVID-19 complications 157 days after treatment discontinuation (day 208), 1 due to progressive disease 50 days after treatment discontinuation (day 89), and 1 due to COVID-19 whilst on study treatment (day 78). No deaths were associated with study treatment. Two patients experienced Grade >= 3 treatment-emergent adverse events (TEAEs). One patient in the 160-mg cohort experienced Grade 3 increase in liver enzymes and lymphopenia. One patient in the 320-mg cohort experienced Grade 3 lymphopenia. The most common TEAEs were insomnia (50%), fatigue (30%), arthralgia (20%), back pain (20%), lymphopenia (20%), and nausea (20%). BGB-11417 exposure increased dose-dependently from 80 mg to 320 mg with high interpatient PK variability. BGB-11417 exposures after single and multiple doses appeared similar, indicating limited accumulation. Conclusion(s): BGB-11417 plus dexamethasone was generally well-tolerated in patients with R/R MM harbouring t(11;14) at doses <=640 mg. Efficacy data are forthcoming. Recruitment is ongoing in the US, Australia, and New Zealand;the BGB-11417, dexamethasone, and carfilzomib combination arm will open in the future.

Effect of the capsid assembly modulator (CAM) ALG-000184 on HBsAg Levels in subjects with HBeAg positive chronic hepatitis B (CHB)

Background: ALG-000184 is a prodrug of ALG-001075, a novel, potent, pan-genotypic Class II CAM. CAMs are thought to have two mechanisms of action (MoA). The primary MoA affects pgRNA encapsidation resulting in inhibition of HBV DNA/RNA replication, as confirmed in CHB subjects receiving ALG-000184. The secondary MoA, which occurs at higher concentrations, regulates the establishment and replenishment of cccDNA, resulting in lowering of HBsAg, an effect that has not been reported to date with ALG- 000184. Method(s): ALG-000184-201 is a multi-part, multicenter, doubleblind, randomized, placebo-controlled study. In healthy volunteers (HVs), single doses up to 500 mg and multiple doses up to 250 mg were well tolerated with linear PK (Gane E., HBV TAG and APASL 2021). In treatment naive (TN) subjects with CHB, daily oral doses of 10-100 mg ALG-000184 for 28 days were well tolerated with linear PK and were associated with profound reductions of DNA/RNA regardless of HBeAg status or dose (Yuen MF, EASL 2022). Plasma exposures required to engage the secondary MoA are expected to be achieved at the 300 mg dose level. Data from a 300 mg cohort treated for 28 days are described here. Data from another ongoing cohort treated with 300 mg for 12 weeks will be presented at the conference. Result(s): Ten subjects were randomized to 300 mg ALG-000184 for 28 days and two to placebo. Two subjects randomized to ALG- 000184 were replaced due to missing data due to Covid-19 lockdown. Subjects were Asian, HBeAg positive, and genotype B or C. Mean baseline HBV DNA and RNA levels were 8.4 log10 IU/mL and 7.3 log10 copies/mL, respectively. One subject experienced a serious adverse event (AE) of pneumothorax>8 weeks after last dose which was considered unlikely related to study drug. No subjects prematurely discontinued study drug. All treatment emergent AEs were Grade <= 2 except for 4 Grade >= 3 alanine aminotransferase (ALT) elevations, which an independent ALT Flare Committee assessed as not related to study drug toxicity. PK was similar to HBeAg negative and HV cohorts following body weight adjustment. Subjects dosed with 300 mg ALG-000184 experienced mean declines of 4.0 log10 IU/mL and 2.6 log10 copies/mL in HBV DNA and RNA levels, respectively, at Day 28. Three of 7 evaluable subjects who received ALG-000184 had HBsAg declines>0.2 log10 IU/mL (0.23-0.78 log10 IU/mL). One subject receiving ALG-000184 had unquantifiable HBsAg throughout the study. Additionally, one HBeAg positive subject in a prior 100 mg cohort had plasma exposures equivalent to the 300 mg dose level and experienced a 0.5 log10 IU/mL HBsAg decline. Conclusion(s): In TN HBeAg positive CHB subjects, 300 mg ALG- 000184 for 28 days was well tolerated, exhibited predictable PK and resulted in rapid and substantial declines in HBV DNA and RNA. Notably, 3 of 7 evaluable subjects from this cohort experienced HBsAg declines of up to 0.78 log10 IU/mL. These data suggest that ALG-000184 can engage the secondary MoA of CAM II. Cohorts evaluating 300 mg over longer durations are planned or ongoing.

Tolerance of ETD001, a long-acting inhaled epithelial sodium channel blocker, in humans

Background: To assess the safety, tolerability, and pharmacokinetic (PK) profile in humans of the novel inhaled epithelial sodium channel blocker ETD001. Method(s): Inhaled ETD001 or placebo, delivered via nebulizer, have been administered in a 3:1 ratio to 96 healthy subjects in a blinded, first-inhuman clinical trial (ClinicalTrials.gov Identifier: NCT04926701). The study consisted of two parts. Part A evaluated single ascending doses (SADs) up to 10.8 mg, and Part B evaluated multiple ascending doses (MADs) up to 3.1 mg once daily (QD) for 7 days and 4.65 mg twice daily (BID) for 14 days. Safety was assessed by monitoring for adverse events (AEs), laboratory safety tests (including blood potassium monitoring), vital signs, 12-lead electrocardiogram (ECG), and spirometry. Systemic exposurewas assessed using serial pharmacokinetic blood draws. Result(s): Therewere no serious AEs. Twenty-four subjects reported 38 AEs, all of mild to moderate intensity and all resolved. There were no clinically relevant changes in laboratory safety tests, vital signs, ECGs, or spirometry measurements. All blood potassium assessments were within normal range at all doses. Three subjects withdrew in Part B;all withdrawals were considered unrelated to study drug: one on day 6 from the 3.1-mg QD cohort for personal reasons, one after the first dose of the 3.1-mg BID cohort because of vasovagal syncope at time of venipuncture triggering atrial fibrillation that spontaneously resolved, and one on Day 4 of the 3.1- mg BID cohort because of a positive COVID-19 test. Pharmacokinetic parameters were approximately dose proportional in Part A, with peak concentrations 1 to 2 hours after dose and exposure out to 12 to 24 hours at all doses, indicating good lung retention. Part B plasma concentrations displayed dose-independent kinetics and showed minimal accumulation, with a mean of 1.11-fold observed over 14 days. Conclusion(s): ETD001 was well tolerated at single doses up to 10.8 mg and multiple doses of 3.1 mg QD for 7 days and 4.65 mg BID for 14 days. The wide safety margin is predicted to enable doses capable of durable target engagement in the lung, which are expected to enhance mucociliary clearance in people with cystic fibrosis.Copyright © 2022, European Cystic Fibrosis Society. All rights reserved

Pharm Aco Kin Etics, Safety, and Tolerability of Upadacitinib in Children with Atopic Dermatitis

BACKGROUND: Upadacitinib is a Janus kinase inhibitor that has been approved for the treatment of adults and adolescents with moderate to severe atopic dermatitis (AD). The objective of this study was to characterize the pharmacokinetics (PK), safety, and tolerability of upadacitinib in children with severe atopic dermatitis. METHOD(S): This is an open-label, multiple-dose study. AD patients (n = 35) were enrolled into four cohorts (Cohort 1, 6 to <12 years, low dose;Cohort 2, 6 to <12 years, high dose;Cohort 3, 2 to <6 years, low dose;Cohort 4, 2 to <6 years, high dose). The low and high doses were selected based on body weight to provide comparable plasma exposure in pediatrics to 15 mg and 30 mg QD doses in adults, respectively. All patients continued on the low dose after the PK assessment on Study Day 7. Safety and exploratory efficacy parameters are assessed in the study. RESULT(S): Geometric mean Cmax and AUC over 0-24 hours at steady state were 33.1 ng/mL and 249 ng.h/mL, respectively, in Cohort 1, 95.5 ng/mL and 523 ng.h/mL, respectively, in Cohort 2, 35.2 ng/mL and 264 ng.h/mL, respectively, in Cohort 3, and 101 ng/mL and 625 ng.h/mL, respectively, in Cohort 4. Upadacitinib was generally safe and well tolerated. The most common AEs were COVID infection, headache, and abdominal discomfort. No new safety risks were identified compared to the known safety profile for upadacitinib. In the 29 subjects with available interim efficacy results at week 12, 34.5% achieved validated Investigator's Global Assessment scale for AD score of 0 or 1 and 69.0% achieved Eczema Area and Severity Index by at least 75% at Week 12 with treatment of upadacitinib. CONCLUSION(S): The findings supported the use of current dosing regimens for further investigation of upadacitinib in upcoming phase 3 clinical trials in pediatric AD patients.

Covid-19 Vaccination and Covid 19 Infection in Atypical Hemolytic Uremic Syndrome: One Single Center Study in Taiwan

Introduction: Acute kidney injury, microangiopathic hemolytic anemia and thrombocytopenia with multiple organ thrombotic microangiopathy (TMA) are typical characteristic presentation of Atypical hemolytic uremic syndrome(aHUS). Infection, pregnancy, operation, and some medication can be a trigger factor to induce the complement system over activation and induce atypical hemolytic uremic syndrome unstable to a life-threatening condition. Both SARS-CoV-2(Severe Acute Respiratory Syndrome Coronavirus 2) infection and COVID 19 vaccination are reported to be the trigger factors for aHUS. There are no clinical trial enrolled aHUS cases to COVID 19 vaccine or anti SARS-CoV2 agent. Therefore, aHUS became a tough medical issue in this pandemic status. In this study, we evaluate the efficacy and disease activity of aHUS after COVID 19 vaccination. Meanwhile, we analysis the severity of COVID 19 infection in our 21 aHUS cases. Method(s): There are 21 aHUS cases enrolled this study from April 2022 to September 2022. Each cases with regular blood sampling which include hemolysis markers (Hemoglobin, Platelet count, LDH, CH50, haptoglobin, Blood smear), renal function and urine analysis every months. While them had COVID 19 vaccination or COVID 19 infection, the above blood sampling and urine analysis should be followed up two weeks later. Once the aHUS cases became severe condition and need hospitalization, our medical team must visit these cases closely and monitor if any new critical issue happen. We confirmed the serum SARS-CoV-2 Spike IgG and Interferon-gamma (IFNgamma) release assay testing for the vaccination efficacy analysis. Result(s): 21 aHUS cases all had COVID 19 vaccination, 2 cases received 1 dose vaccine, 6 cases received 2 doses vaccine and 13 cases received 3 doses vaccine. Only one case with aHUS unstable after Moderna vaccine injection which is self-limited gradually and didn't need extra dose of anti-complement therapy. Interestingly, this case with stable aHUS disease activity while he switches to Pfizer-BioNTech vaccine as his 2nd dose. The SARS CoV-2 Spike IgG level and IFNgamma level are corelated to the dosage of COVID 19 vaccination, the higher doses with the higher level. The SARS-CoV2 spike IgG and IFNgamma level without lower response to the group with regular anti-C5 treatment. For those complete three dose vaccination cases, mix type of COVID-19 vaccination (AZ/mRNA) with better efficacy trend to fix type of mRNA. During this study period, there are 4 cases with COVID 19 infection. One case (already had 2 doses COVID 19 vaccination) needed hospitalization and improved after remdesivir and dexamethasone treatment who with mild aHUS disease activity progression. Two cases (complete three doses COVID 19 vaccination) with stable aHUS disease activity after Molnupiravir treatment. One case (complete three doses COVID 19 vaccination) refused Molnupiravir treatment and had mild aHUS disease activity progression. Conclusion(s): According to our study, we recommend the aHUS patient to have COVID 19 vaccination and multiple doses are more protective for them. aHUS disease activity should be close monitor especially after COVID 19 vaccination, during COVID 19 infection and after COVID 19 infection. Remdesivir and Molmupiravir are relative safe to use for aHUS cases. No conflict of interestCopyright © 2023

Potential cost of not vaccinating against COVID19 in the United States

Introduction: As of April 2022, the COVID19 global pandemic has resulted in over six million deaths globally, and over 81 million cases of COVID19 in the United States. Objective(s): The objective of the presentation is to share estimated direct and indirect costs due to COVID19 infection juxtaposed with the costs of COVID19 vaccine administration in the United States. Method(s): A literature review was conducted to identify potential cost savings from being immunized against COVID19. The costs of COVID19 vaccinations, direct costs related to healthcare and types of indirect costs were noted. Result(s): After reviewing over 40 resources, several costs were identified. The cost of COVID19 vaccine series, as defined by the Centers of Medicare and Medicaid Services (CMS), is currently USD40 for single-dose and USD40 per dose in a multiple-dose series. It is estimated that the average hospitalisation stay of an uninsured inpatient was ~USD7000-USD10,000 per day. The average cost of 12 major metropolitan cities in the United States were estimated for primary care facilities, urgent care facilities, and emergency room visits at USD195, USD239, USD1,425, respectively. As of April 2, 2022, 77% of the US have received at least one dose of COVID19 vaccine and 66% are considered to be fully vaccinated against COVID19 primary series. Conclusion(s): According to the data, the cost reduction in healthcare is consequential and cost-effective in vaccinating the population. This analysis contributes to the limited reports of a national cost-benefit analysis.

Evaluation of drug-drug interaction potential of ensitrelvir for CYP3A by clinical studies and physiologically-based pharmacokinetic model

Background. Ensitrelvir is a new drug candidate to treat COVID-19 disease. According to the in vitro drug-drug interaction (DDI) study, time-dependent inhibition by ensitrelvir was observed on cytochrome P450 3A (CYP3A). The purpose of this study was to evaluate the effect of ensitrelvir on the pharmacokinetics (PK) of CYP3A substrates by clinial DDI studies and physiologically-based pharmacokinetic (PBPK) analyses. Methods. Clinical studies: The effect of once daily multiple-doses of ensitrelvir with the loading dose on Day 1/ maintenance dose (750/250 mg) for 6 days on the PK of midazolam (MDZ) was assessed. MDZ was administered on Days -2 and 6. The effects of once daily multiple-doses of ensitrelvir with 750/250 mg for 5 days on the PK of dexamethasone (DXS) and prednisolone (PLS) were also assessed because these corticosteroids were also CYP3A substrates. DXS and PLS were administered on Days -2, 5 (co-administration with ensitrelvir), 9 and 14 to evaluate the effects after the last dose of ensitrelvir. PBPK analyses: The effects of once daily multiple-doses of ensitrelvir with another dose regimen (the loading dose/mentenance dose [375/125 mg] for 5 days) on the PK of CYP3A substrates were predicted using Simcyp PBPK Simulator (Version 20, Certara UK Limited, UK). Results. The AUC0-inf of MDZ co-administered with ensitrelvir was increased by 8.80-fold compared to those of MDZ alone, indicating that ensitrelvir is a strong CYP3A inhibitor with 750/250 mg for 6 days. The AUC0-inf of DXS on Day 5 was increased 3.47-fold and the effect of ensitrelvir on the PK of DXS was diminished over time after the last dose of ensitrelvir. The AUC0-inf of PLS on Day 5 was increased 1.25-fold and no clinically meaningful effect of ensitrelvir on the PK of PLS was observed. The PBPK analyses predicted that the co-administration of ensitrelvir increased the AUC of MDZ by 3.83-fold and the AUC of DXS by 2.49-fold following ensitrelvir at 375/125 mg for 5 days. A clinical study with MDZ under the analyses conditions is underway to confirm the PBPK results. Conclusion. The clinical study revealed that ensitrelvir affects the PK of CYP3A substrates with 750/250 mg for 5 or 6 days. The PBPK analyses suggests that ensitrelvir is expected to a moderate inhibitor of CYP3A with 375/125 mg for 5 days.

COVID-19 Vaccines

COVID-19 episode was and is a devastating pandemic. The morbidity and mortality have skyrocketed at its peak. In the initial phase it was challenging to restrain the outcome of the disease and then in finding a suitable and effective control measure (a vaccine) to prevent further spread and occurrences. The production of the vaccine was fast tracked and a number of vaccines was the outcome of the global effort. Four major types of vaccines were made - whole virus vaccines, protein based vaccines, viral vector vaccines and nucleic acid vaccines. The outcome of these vaccines have been inconstant and at present emphasis in on the protection levels achieved due to the vaccines. Although there have been sporadic aftereffects of COVID vaccines, which is common outcome of vaccination, excessive limitations have been perceived as exceptions. On the whole there has been some amount of control of the viral infection, even if not for the expected long duration. As the protective levels are not as expected and due to the occurrence of many variants of SARS-CoV-2 and other reasons, multiple doses of the same or combination of the different vaccines is advocated at this present situation. In addition, antivaxxers have hindered or tried to hinder the vaccination process in many countries around the world. There are other aspects, such as non-availability of vaccines, non-compliance and others to be taken note in regards to COVID vaccines. Time will tell the factual outcome of the COVID vaccines. Get protected against COVID infection through COVID vaccines for whatever the outcome of the vaccination may be.

A Single Center Study of SARS-CoV-2 Spike Antibody Response to Vaccination in Renal Transplant Recipients

Background: Kidney transplant recipients are at high risk of mortality and complications related to COVID-19. Vaccination remains the most important strategy to prevent severe disease in this vulnerable population. The goal of this study was to evaluate the antibody response to mRNA vaccines in kidney transplant recipients. Method(s): We studied anti-spike IgG response to mRNA vaccines (BNT162b2 and mRNA-1273) against SARS-CoV-2 in adult kidney transplant recipients in a single center. Preserved blood samples of kidney transplant patients undergoing routine monitoring were used. The LABScreen COVID Plus Assay (One Lambda) was used to detect SARSCoV-2 antibody response. Categorical variables were compared using the Fisher's exact test, and continuous variables were compared using a t-test. Result(s): Among 120 subjects receiving two doses of vaccines, only 74 (61.7%) elicited a positive response with anti-Spike antibody. After a third dose/first booster vaccine, 35 out of 43 (81.4%) kidney subjects had a positive response. There was no statistically significant difference between the responders and non-responders in terms of age, gender, race, blood group, time since transplant, vaccine type. A third dose vaccine produced statistically significant increase in antibody response compared to 2 doses only. A third dose induced a serological response in 7 out of 8 subjects (87.5%) who did not respond after 2 doses of vaccine. None of the patients developed donor specific HLA antibody in response to COVID-19 infection or the vaccine. Conclusion(s): In this single center retrospective study, we demonstrated that the antibody response to SARS-CoV-2 mRNA vaccine was most prevalent after 4 months since the second dose. In addition, a third dose induced an antibody response in a larger number of kidney transplant recipients (81.3% vs 61.67%, p value 0.018), suggesting that this patient population may benefit from receiving multiple doses of mRNA vaccines.

IGG4-RELATED PLEURAL DISEASE: A CAUSE OF RECURRENT PLEURAL EFFUSION AFTER COVID-19 VACCINATION

SESSION TITLE: Challenging Disorders of the Pleura SESSION TYPE: Rapid Fire Case Reports PRESENTED ON: 10/18/2022 01:35 pm - 02:35 pm INTRODUCTION: Great effort went into finding a vaccine to decrease the impact of COVID-19 virus. Pfizer vaccine which is a part of mRNA of the virus wrapped with lipid nanoparticles is one of them. Though its side effects are benign, rarely it can lead to IgG4 related lung disease (IgG4-RLD). Therefore, having a high degree of suspicion is important for early diagnosis and effective treatment. CASE PRESENTATION: The patient is a 71-year-old male with COPD, CAD, and prostate cancer developed dyspnea after receiving 2 doses of Pfizer vaccine. CT chest revealed a new left pleural effusion, 1.4L fluid was removed which was negative for malignant cells with lymphocytic predominance. After 10 days, his symptoms worsened and repeat CT scan revealed large left pleural effusion. Thoracoscopy was done with drainage of 2.5L pleural fluid followed by pleural biopsy and chemical pleurodesis with insertion of an indwelling tunneled catheter. Pleural biopsy revealed chronic organizing pleuritis with lymphoid and mesothelial hyperplasia. The tunneled catheter stopped draining after 3 months but oxygen requirement increased. A repeat CT scan revealed loculated pleural effusions and only 40 ml was drained due to bloody output. Thoracoscopy revealed multiloculated effusions with visceral pleural thickening and partial decortication was done. Pathology revealed pleural thickening and fibrosis with increased IgG4-positive plasma cells in pulmonary parenchyma. Blood IgG4 level was 268 mg/dl. He was diagnosed with IgG4-related disease (IgG4-RD) affecting lungs and pleura. DISCUSSION: Although IgG4 related nephritis after Pfizer vaccine has been reported(1), this is the 1st reported case of IgG4-RLD. Autoimmunity is a trigger for pathogenesis with involvement of Th-2 cell. The vaccine stimulates robust antigen-specific T-cell responses leading to antibody production that trigger autoimmune reactions due to molecular mimicry. Four patterns are observed including mediastinal, parenchymal, pleural, and airway involvement. Mediastinal and hilar lymphadenopathy is the commonest patterns(2). Our patient had loculated pleural effusion complicated by pleural thickening and fibrosis. For diagnosis of IgG4-RD, 3 criteria need to be fullfilled: consistent organ involvement;serum IgG4 level >135 mg/dL;histopathology showing marked lymphoplasmacytic infiltration(2). Our case fulfilled all 3 criteria and involved lungs;thus, diagnosed with IgG4-RLD. Most patients have a favorable response with corticosteroid therapy in 2 weeks. For steroid-refractory cases, immunosuppressants can be used(3). CONCLUSIONS: With increased COVID-19 vaccination, more autoimmune events including IgG4-RLD can happen. As multiple doses are offered, close observation is needed for prompt diagnosis and management of such diseases. Ultimately, theoretical risks must be balanced against known benefits, and discussion between providers and patients is important. Reference #1: Christophe M, Delphine K, Christine K A, Aurélie F, Gilles B, Mohamed H. Relapse of IgG4-related nephritis following mRNA COVID-19 vaccine. Kidney International. Vol 100, Issue 2, P465-466, August, 2021. DOI: https://doi.org/10.1016/j.kint.2021.06.002 Reference #2: Ryu JH, Sekiguchi H, Yi ES. Pulmonary manifestations of immunoglobulin G4-related sclerosing disease. Eur Respir J 2012;39:180–6 Reference #3: Campbell SN, Rubio E, Loschner AL. Clinical review of pulmonary manifestations of IgG4-related disease. Ann Am Thorac Soc 2014;11:1466–75. DISCLOSURES: no disclosure on file for Ola Al-Jobory;No relevant relationships by Ahmad Hallak No relevant relationships by Manish Patel No relevant relationships by Saria Tasnim

Long-term safety and efficacy of sepofarsen in a Ph1b/2 INSIGHT extension trial in CEP290-associated Leber congenital amaurosis (LCA10)

Purpose : Autosomal recessive CEP290-LCA (LCA10) is a severe inherited retinal disease resulting in early vision loss and currently has no treatment. Sepofarsen is an RNA antisense oligonucleotide targeting the most common c.2991+1655A>G disease-causing variant in the CEP290 gene. Long-term safety and efficacy of sepofarsen in the first eye treated (FE) and safety and efficacy in the second eye treated (SE) in this extension trial (Insight;NCT03913130) were evaluated. Methods : Subjects who completed the Ph1b/2 sepofarsen trial could enroll in the extension trial for continued dosing in the FE and initiation in the SE with the 160/80μg loading/maintenance dose. Frequency and severity of adverse events, and change in best-corrected visual acuity (BCVA) and full-field stimulus testing (FST) threshold were assessed. Baseline was defined as the value measured within the same month of-or last measurement prior to-the first dosing for each eye. Due to covid-19, some participants have missed scheduled injections. As such data up to-or available measurement prior to-6 months after the last dosing have been included in the analysis for each eye. Results : At data cut-off in mid-October 2021, 9 subjects (of 11 from the Ph1b/2 trial) aged 15-45 years were followed up to 46 months, 5 of them received at least one intravitreal injection of sepofarsen in the SE. Three subjects developed cataracts in the FE and 2 in the SE, of which 2 recovered following cataract surgery. Time to onset since initial dose was 13 months or later. Between 35-46 months after the 1 injection, long term BCVA improvement was reported in 4/6 FE ranging from-0.20 to-0.54 logMAR and 5/5 FE improved in either blue FST, red FST or both ranging from-0.21 to-2.06 log cd/m2. The SE showed a similar trend as the FE in BCVA (3/5 SE showed a change ranging from-0.06 to-2.50 logMAR) and in blue and red FST (4/4 SE showed improvement ranging from-0.27 to-4.57 log cd/m2). st Conclusions : The longer-term sepofarsen safety profile is consistent with that observed in the Ph1b/2. Meaningful BCVA and FST improvements observed in the Ph1b/2 continued up to 46 months. The responses in the SE were similar to the responses seen in the FE in both visual acuity and retinal sensitivity improvements. A Phase 2/3 (ILLUMINATE;NCT03913143), multiple dose, double-masked, randomized, sham-controlled trial is ongoing.

Respiratory Safety of Lemborexant in Adult and Elderly Subjects with Moderate to Severe Obstructive Sleep Apnea: A Randomized, Double-blind, Placebo-controlled, Crossover study

Introduction: A safety risk of some commonly prescribed sleep-promoting drugs, including benzodiazepines and nonbenzodiazepine receptor agonists, is central respiratory depression. Subjects with coexisting respiratory disease such as obstructive sleep apnea (OSA), and/or the elderly, are particularly at risk. Lemborexant (LEM) is a dual orexin receptor antagonist (DORA) approved in multiple countries for the treatment of adults with insomnia. In study 102 (E2006-A001-102;NCT03471871), no differences between LEM 10 mg (LEM10) and placebo (PBO) were found on peripheral oxygen saturation (SpO2) and the apnea-hypopnea index (AHI) in adult and elderly subjects with mild OSA following a single dose and multiple doses. Study 113 (E2006-A001-113;NCT04647383) is the first to investigate the effect of LEM on respiratory safety in adults and elderly subjects with moderate to severe OSA. Materials and Methods: This was a multicenter, multiple-dose, randomized, double-blind, PBO-controlled, 2-period crossover study in adult (age ≥45 to <65y) and elderly (age ≥65 to ≤90y) subjects with moderate (15≤AHI<30) to severe (AHI≥30) OSA. Subjects were randomized to two 8-night treatment periods (separated by a washout ≥14d) with either LEM10 or PBO. In-lab polysomnography and transmissive pulse oximetry were performed at screening, on Day 1 (after a single dose) and Day 8 of study drug during both treatment periods. Treatment-emergent adverse events (TEAEs) were recorded throughout the study. Results: Forty-eight subjects were screened;33 (68.8%) were randomized;of these n=13 had moderate OSA and n=20 had severe OSA. Mean age was 60.6y;22/33 subjects (66.7%) were age ≥45 to <65y and 11/33 (33.3%) were ≥65 to ≤90y. During total sleep time, mean baseline SpO2 was 93.5% and mean AHI for moderate OSA and severe OSA groups together (n=33) was 44.2. No significant difference was found in AHI (least squares mean [LSM]) after a single dose or multiple doses of LEM10 versus PBO in subjects with moderate (single: LEM10, 31.49;PBO, 32.41, P=0.818;multiple: LEM10, 34.66;PBO, 37.16, P=0.442) or severe (single: LEM10, 48.22;PBO, 52.69, P=0.172;multiple: LEM10, 51.48;PBO, 51.15, P=0.902) OSA. LEM10 versus PBO was also not significantly different for SpO2 (LSM with moderate [single: LEM10, 93.68;PBO, 93.86, P=0.696;multiple: LEM10, 93.74;PBO, 93.86%, P=0.784] or severe [single: LEM10, 92.57;PBO, 92.65, P=0.841;multiple: LEM10, 92.63;PBO, 93.02, P=0.283] OSA). Furthermore, no significant difference was found in percentage of total sleep time during which SpO2 was below the thresholds of <90%, <85%, <80% for LEM10 vs PBO following a single dose (P=0.694, P=0.134, P=0.195, respectively) or multiple doses (P=0.481, P=0.711, P=0.699, respectively) in subjects with moderate or severe OSA. TEAEs were higher with LEM10 (18.2%) versus PBO (9.1%). One subject did not complete treatment due to an adverse event unrelated to LEM10 (COVID-19). Overall, LEM was well tolerated, and most TEAEs were mild. Conclusion: As objectively measured by AHI and SpO2 during TST, LEM, a DORA, demonstrated respiratory safety with single and multiple dosing in subjects with moderate and severe OSA, and was well tolerated. Acknowledgements: Supported by Eisai, Inc.

COVID-19 Vaccine Acceptance among the Residents of Pakistan

Background: Despite the major developments in the vaccination, world health organization due to sudden rise in vaccine-preventable diseases has identified vaccine hesitancy as a major threat. Vaccine hesitancy gets stimulated by the health-related information acquired from various sources, hence is a major problem for health care authorities. Objectives: The main objective of the study was to assess the acceptance of COVID-19 vaccines and its predictors along with the attitude towards these vaccines by the public of Pakistan. Method: This cross-sectional survey was conducted from Jan-March 2022 in Pakistan. The survey from the current study was adopted from a previously conducted research. Male and female participants over the age of 18 were included for the current survey. Participants who declined to participate and providing incomplete details were excluded from the study. Institutional ethical approval for the research was obtained. Chi square test was conducted to assess association between the variable while descriptive statistics were used in form of frequencies. Results: From a total of 1194 participants, there were 232 (19.4%) males and 962 (80.6%) females. When enquired regarding finding vaccines to be safe, 69% of females and 75% of the males both agreed. In response to finding single dose of vaccine better than the multiple dose most of the females (38.5%) and males (47.4%) disagreed. Likewise, majority of females (81%) and males (84.5%) agreed that immunisation will protect against corona virus. In response to pharmaceutical companies being able to develop efficient COVID-19 vaccine, majority of the study participants agreed. When enquired about getting worried on hearing news of side effects, 61% females and 56% males stated not getting worried. Conclusion: An efficient and safe vaccine against COVID-19 is a vital factor in managing and bringing an end to the COVID-19 pandemic, however, wide acceptability of the vaccine is necessary. Public health policy developers must address the wide misinformation spreading regarding the COVID-19 vaccines. Moreover, government should aim to disseminate adequate information about the efficacy and safety of vaccine that will increase the trust of general public on government and will be beneficial in future.

Safety and Tolerability of the Toll-Like Receptor (TLR)2/6 Agonist INNA- 051 in Healthy Adults

RATIONALE: INNA-051 is a Toll-like receptor (TLR) 2/6 agonist delivered via intranasal spray, being developed for treatment of respiratory viral diseases. Pre-clinical studies demonstrate that INNA-051 and analogues are effective against a variety of respiratory viruses including SARS-CoV- 2, influenza, and rhinovirus. INNA-051 induces a tissue-localized innate immune response with cytokine expression and infiltration of innate immune cells into the nasal epithelium that play a key role in viral clearance. The primary objective of this study (ACTRN12621000607875p) was evaluation of safety and tolerability in healthy adults. METHODS: This was a randomized, doubleblind, placebo-controlled, Phase 1 study of single and multiple ascending INNA-051 intranasal doses, with the total dose split evenly across both nostrils. Sixty-four participants ages 18-55 were enrolled, with 5 cohorts (6 active:2 placebo/cohort) receiving single doses of 20μg, 60μg, 150μg, 300μg, or 600μg, and 3 cohorts (6 active:2 placebo/cohort) receiving 4 total doses of 60μg, 150μg, and 300μg administered every third day. Assessments included adverse events, clinical laboratories, peak inspiratory nasal flow (PINF), and peak expiratory flow (PEF).RESULTS: Sixtyfour participants (36 males:28 females) ages 19-55 years were enrolled. Preliminary blinded results demonstrate that INNA-051 was well tolerated across all single and multiple dose cohorts. Adverse events were predominantly mild, limited to the nasopharynx, and resolved within 24-48 hours. Across single dose cohorts, the most frequent events were nasal congestion/blockage (n=20), nasal erythema/inflammation (n=19), rhinorrhea (n=13) and headache (n=11). Except for the 20-μg cohort with only 2 reports of rhinorrhea, all other single dose cohorts had a similar incidence of the other adverse events with no obvious dose relationship. Across all 3 multiple dose cohorts, nasal erythema/inflammation (n=42) was most frequently reported, followed by nasal congestion/blockage (n=26), rhinorrhea (n=9), and headache (n=9), with no dose-dependent relationship. No participants withdrew from the study due to adverse events. There were no clinically significant changes in clinical chemistry and hematology laboratories across all single and multiple dose cohorts. No consistent decrease in post-dose PNIF assessments were observed, and there were no changes in PEF assessments to suggest lower respiratory tract airway response to intranasal INNA- 051.CONCLUSIONS: Intranasal INNA-051 was well tolerated up to single doses of 600μg and multiple doses of 300μg. Mild, self-limited nasal adverse events as described are possible indicators of tissue-localized innate immune response by INNA-051. Investigation of cytokine levels and gene expression of the intranasal epithelium are needed to specifically determine TLR2/6 engagement by INNA-051.

Real-World Crizanlizumab Treatment Patterns of Patients with Sickle Cell Disease

Background: Sickle cell disease (SCD) is an inherited blood disorder characterized by vaso-occlusive crises (VOCs). Crizanlizumab infusion was FDA approved in 2019 to reduce VOCs in patients with SCD ≥16 years old. There is little real-world evidence (RWE) regarding crizanlizumab use. Objective: To describe real-world crizanlizumab utilization. Methods: Using IQVIA’s US-based Longitudinal Pharmacy and Medical Claims Databases, patients with an SCD diagnosis between 01-November-2018 and 30-April-2021, ≥1 crizanlizumab claim (index date=first crizanlizumab claim) between 01-November-2019 and 31-January-2021, aged ≥16-years at index, ≥12-months of pre-index, and ≥6-months of post-index data were identified. Crizanlizumab treatment patterns were characterized by doses received, gap-days between doses (days between end of days-supply of one dose to the next administration), discontinuation (≥60-day gap), days on therapy prior to discontinuation, and restarts. Results: In total 262 patients were included. Of these patients, 235(87%) received dose #2, 204(78%) received dose #3, and 174(66%) received ≥4 doses with a median(interquartile range [IQR]) of 125(43-180) days on therapy prior to discontinuation. In the 6-months post-index, 150(57%) patients discontinued crizanlizumab. Of those patients who discontinued crizanlizumab, 46(31%) restarted. Among the 112 patients that did not discontinue, the median(IQR) gap-days between doses 1&2=2(1-15) days, between doses 2&3=1(1-7) days, between doses 3&4=1(1-5) days, and between doses 4&5=1(1-6) days. At the end of the 6-months of follow-up, 88 patients (34% of all patients) appeared to be on crizanlizumab. Conclusions: This RWE suggests that 66% of patients who receive crizanlizumab receive ≥4 doses within 6-months, patients receiving multiple doses appear to have a reduction in gap-days with each subsequent dose, and that of those who discontinue treatment, 31% restart crizanlizumab within 6-months post-index. Due to the nature of claims data, the reasons for discontinuation or gaps between doses are unknown. The impact of COVID-19 restrictions or other access barriers on crizanlizumab use is also unknown.

Quality Improvement Developments Following Pediatric Resuscitation and VA Extracorporeal Membrane Oxygenation Support due to a Massive Intentional Antidepressant Overdose

Introduction: The COVID-19 pandemic caused a significant increase in suicide attempts in teenagers. Fluoxetine and Wellbutrin have been prescribed to adolescents to treat depression. Overdosing on these medications can cause seizures, arrhythmias, and cardiogenic shock. We report on a patient who presented with a normal physical assessment following a massive antidepressant drug overdose, but quickly deteriorated, and required VA Extracorporeal Membrane Oxygenation (ECMO). Gaps identified in this case prompted us to assess our ECPR protocol, which led to areas for quality improvement. Case Review: A teenage male presented to our ED after intentionally ingesting Fluoxetine, Wellbutrin, and Hydroxyprogesterone. Fluid boluses, vasopressor infusions and multiple doses of epinephrine were administered, but his hemodynamic instability persisted. Concerns regarding cannulation, team activation and coordination of care during ECPR were areas identified as requiring improvement during a case review. The team was activated and cannulated the patient for VA ECMO. At hour eighty-five, he was hemodynamically stable, including normal sinus rhythm and resolved hypotension, and was removed from ECMO. He was successfully extubated, weaned to room air, and discharged with plans for outpatient therapy. Quality Improvement: An updated process for notifying team members for ECPR cannulation was implemented. Simulation scenarios, which are held quarterly, were developed, with clearly delineated roles, and emphasis on timing of chest compressions with minimal pauses during cannulation. Annual ECPR web-based education is mandatory. Improvements in the time to cannulation and team member interactions were noted during subsequent ECPR scenarios. Timing of team notification and cannulations continues to be tracked.

TIME IN RANGE AFTER 1 YEAR USING TELEHEALTH IN TYPE 1 DIABETES TREATED WITH HYBRID CLOSE LOOP THERAPY DURING THE COVID-19 PANDEMIC

Background and Aims: Literature supports efficacy and safety of Hybrid Close loop (HCL) system in type 1 diabetes (T1D) patients. Limited data are available showing the short and long-term outcomes of telehealth. Our study described efficacy and safety of HCL system at one year of follow-up through telehealth during COVID-19 pandemic. Methods: A prospective observational cohort study including T1D patients previously treated with multiple doses of insulin or sensor augmented pump therapy started on HCL system during COVID-19 pandemic. Virtual training and follow-up were done through telehealth. CGM data were analyzed to compare the time in range (TIR), time below range (TBR) and glycemic variability, GMI at base line, 3,6,9 and 12 months of virtual follow-up. Use of automatic mode (AM) was also evaluated. Results: 134 patients were included (54.9% female, baseline A1c 7.66% ± 1.15). 48.8% hypoglycemia was the main indication of HCL therapy. 32.6% had hypoglycemia unawareness and 40.5% had ≥1 severe hypoglycemia event in the last year. TIR at the end of the virtual training was 78 ± 0.14%. After 3,6,9 and 12 months of follow-up TIR was 78.5%, 77.6%, 76.8% and 77%, respectively. Coefficient of variation was 31.4 ± 6.05% at 12 months. TBR <70mg/dl and <54mg/dl was 2.39 ± 0.14% and 0.54 ± 0.07%, respectively. Use of AM was 80.7 ± 24.7% and percentage of use of sensor was 90.3 ± 7.3%. No severe adverse events were reported. Conclusions: HCL systems allows T1D patients to improve TIR, TBR and glycemic variability independently of previous treatment. Long term follow-up through virtual modality allows to maintain TIR with low TBR and adherence to AM of 80%.

PBI-0451 AN ORALLY ADMINISTERED 3CL PROTEASE INHIBITOR of SARS-CoV-2 for COVID-19

Background: The 3CL protease (3CLpro) of coronaviruses (CoV) is responsible for essential & early steps of viral replication. Early treatment of SARS-CoV2 infection with a 3CLpro inhibitor has shown to substantially reduce the rate of hospitalization & death from COVID-19. There is a need for a protease inhibitor that can be used as a stand-alone agent to treat and prevent SARS-CoV-2 infection globally, in the setting of remote testing & healthcare delivery, and as unsupervised outpatient use by a significant number of people who take other medications. Methods: PBI-0451 was assessed in cultures of inducible pluripotent stem cell-derived alveolar type II (iPS-AT2) cells, in nonclinical PK and toxicity studies, and an ongoing randomized, double-blind first-in-human (FIH) study evaluating the tolerability, safety, and PK of single and multiple doses administered as an oral suspension to healthy adult subjects. The effect of food and the potential for a drug-drug interaction (DDI) with ritonavir were also explored. Results: PBI-0451 potently inhibited SARS-CoV-2 replication in iPS-AT2 cells with multi-log reductions in viral titer and mean (SD) IC50 & EC90 values of 32 (25) & 106 (90) nM, respectively. No clinically relevant adverse effects of PBI-0451 were observed in 14-day GLP toxicity studies in mice and dogs, including on the cardiovascular, CNS, or respiratory systems. PBI-0451 was not genotoxic in Ames and micronucleus tests. In the ongoing FIH study to date, study treatments were generally well tolerated with no study drug or study discontinuations. No Grade 2, 3, 4, or severe adverse events were reported. Preliminary single-dose concentration-time profile of PBI-0451 following administration with food demonstrated a 2-compartment PK profile with a median terminal elimination t1/2 ranging from 11-14 hours. PBI-0451 demonstrated good oral bioavailability and a linear increase in exposure over a 10-fold dose range when administered with food, achieving concentrations >1-, 3-& 10-fold the plasma protein binding-adjusted EC90 value (374 ng/mL) against SARS-CoV-2 at doses of 100, 300 & 1050 mg, respectively. The PK of PBI-0451 was unaffected by coadministration with ritonavir. Conclusion: PBI-0451 has shown favorable nonclinical properties and early clinical safety & PK that supports its continued evaluation as a stand-alone agent. Ongoing multiple-dose evaluation will further elucidate its clinical profile and inform the dose & dosing regimen selection for potential Phase II/III studies.

Risk of infections with BCMA-directed immunotherapy in multiple myeloma

Introduction: B cell maturation antigen (BCMA) is a novel target for T cell immunotherapy in MM including bispecific antibody (bsAb) and chimeric antigen receptor therapy (CAR-T). BCMA is critical for survival of the long-lived plasma cell, responsible for generation of protective antibodies. Impaired immune reconstitution, cytopenias, B cell aplasia and hypogammaglobinemia can compound preexisting MM-induced immunosuppression. In the case of bsAb, potential redirection/activation of T regulatory cells can create an immunosuppressive milieu. Herein, we describe the clinically relevant infectious complications observed across different BCMA-directed therapies used across multiple clinical trials at our center. Methods: Infections confirmed by microbiologic or histopathologic evidence were captured from the D1 C1 of bsAb and D 1 of lymphodepleting chemotherapy of autologous BCMA CAR-T therapies. The NCI CTCAE v5 was used to describe the site and grade of infections. Hypogammaglobinemia and severe hypogammaglobinemia were defined as ≤700 mg/dl and ≤400 mg /dl, respectively. Standard antimicrobial prophylaxis included herpes zoster prophylaxis for all MM patients with antibacterial (levofloxacin) / antifungal (fluconazole) during periods of neutropenia and IVIG supplementation as per the treating physician's discretion. PCP prophylaxis was prescribed to CAR T recipient per institutional guidelines. Descriptive statistics and comparisons were performed using two-sample t-test for continuous variables and chi-square goodness of fit test for categorical variables. Results: We identified 62 patients who received BCMA-directed bsAb (n=36) or CAR-T (n=26) between 2019-2021(table 1). The median age was 66 (range 48-84) years with % females and 14.8% of patients belonging to Black race. The median time to bsAb and CAR-T use from diagnosis were 6.6 (range 0.83-15.5) and 2.6 (range 0.35-14.4) years, respectively. The median lines of prior therapy were 6 (range 1-11) with BCMA CAR-T recipients receiving fewer prior lines of therapy (4 vs 6, p=<0.001). The baseline lymphocyte count was higher in the CAR-T (14.71 vs 0.84;p=<0.001). Baseline severe hypogammaglobulinemia and lymphopenia were present in 30% and 26.7% of all patients, respectively. Tocilizumab was used in 40.9% (bsAb -30.8% versus CAR-T 55.6%) patients for CRS. IVIG was used in 25% of patients. The median study duration for bsAb was 4 (range 0.03- 24) months across multiple dose levels. Median follow up among CAR-T recipients was 3.9 (range 0.3 - 22.3) months. Among recipients of bsAb, 41.2% of patients experienced at least one episode of infection vs. 23.1% with CAR-T (p=0.141). The cumulative incidence of infection with bsAb and CAR-T were 22 and 8, respectively. The spectrum of infections with bsAb was predominantly bacterial (64.3% While gram negative infection (Escherichia coli and Klebsiella pneumoniae bacteremia, Proteus mirabilus and Psuedomonas aeroginosa urinary tract infections) were seen in 6 patients, skin infection including cellulitis occurred in 4 patients, with 1 case of necrotizing cellulitis. Bacteremia with rare opportunistic pathogens - Rhizobium radiobacter and recurrent Ochrobacterium anthropi were also observed . Viral infections included rhinovirus, cytomegalovirus, and parvovirus B19 reactivation, and COVID-19. About 50% of infections were ≥ grade 3 with 2 grade 5 events (Pseudomonas aeruginosa bacteremia and COVID-19). In the CAR-T group, we observed more viral infections (66.7% vs 35.7%;p=0.028) and fewer bacterial infections (33.3% vs 64.3%;p=0.028) . Common viral infections included rhinovirus, RSV, and herpes simplex virus reactivation. In this group 25% of infections were ≥grade 3. Conclusion: BCMA-targeted therapies seem to be associated with clinically significant bacterial and viral infections. Repetitive dosing with bsAb therapies could be the reason for the propensity to serious bacterial infections compared to CAR-T recipients and may need novel prophylaxis strategies. (Figure Presented).

Methylene blue and hydroxocobalamin in a severely vasoplegic lung transplant recipient

INTRODUCTION: Vasoplegia is defined as a refractory shock state with profound hypotension in the setting of reduced systemic vascular resistance and high cardiac output. Lung transplantation is an arduous surgery often requiring cardiopulmonary bypass, which ultimately predisposes to vasoplegia. We detail the treatment of a patient with end-stage lung disease secondary to COVID-19 pneumonia undergoing lung transplant who developed vasoplegia. DESCRIPTION: The patient is a 36-year-old female who was admitted with profound hypoxemic respiratory failure secondary to COVID-19 pneumonia. Despite initial therapy, she remained ventilator-dependent with need for extracorporeal membrane oxygenation (ECMO) support. Given her single organ failure status - lungs being solely affected - she was promptly considered for lung transplant evaluation upon resolution of her active SARS-CoV-2 infection. She was ultimately deemed appropriate for listing and underwent subsequent transplant. The surgery required the use of cardiopulmonary bypass, given the extensive adhesions of the native COVID-19-infected lungs. The lungs were, unfortunately, quite necrotic, with multiple purulent pockets. She was profoundly hypotensive throughout the surgery and required massive fluid resuscitation, as well as multiple vasopressors. In the setting of this vasoplegia, she received multiple doses of methylene blue at 2 mg/kg, with only marginal improvement in blood pressure. Decision was made to add high-dose (5 g) hydroxocobalamin in an attempt to synergistically stabilize blood pressure. Intraoperatively, her blood pressure stabilized within hours;she remained on ECMO support and was transferred to the ICU postoperatively. Eventually, she was slowly weaned from her vasopressors, with stable blood pressure. DISCUSSION: Methylene blue mechanistically inhibits inducible nitric oxide synthase and guanylyl cyclase, while hydroxycobalamin acts as a nitric oxide scavenger. Both agents have been used independently to treat vasoplegia during cardiopulmonary bypass. Together, they may be used as a salvage therapy to improve blood pressure in refractory cases of shock seemingly exacerbated by the cytokine milieu promoted by recent SARS-CoV-2 infection.