Repurposing of poly-gamma-glutamic acid, immunotherapeutic drug for cervical intraepithelial neoplasia 1, as covid-19 treatment

Covid-19 virus variants identified so far are due to viral genetic diversity, genetic evolution, and variable infectivity, suggesting that high infection rates and high mortality rates may be contributed by these mutations. And it has been reported that the targeting strategies for innate immunity should be less vulnerable to viral evolution, variant emergence and resistance. Therefore, the most effective solution to Covid-19 infection has been proposed to prevent and treat severe exacerbation of patients with moderate disease by enhancing human immune responses such as NK cell and T cell. In previous studies, we demonstrated for the first time that gamma-PGA induced significant antitumor activity and antiviral activity by modulating NK cell-mediated cytotoxicity. Especially intranasal administration of gamma-PGA was found to effectively induce protective innate and CTL immune responses against viruses and we found out that gamma-PGA can be an effective treatment for cervical intraepithelial neoplasia 1 through phase 2b clinical trial. In this study, the possibility of gamma-PGA as a Covid-19 immune modulating agent was confirmed by animal experiments infected with Covid-19 viruses. After oral administration of gamma-PGA 300mug/mouse once a day for 5 days in a K18-hACE2 TG mouse model infected with SARS-CoV-2 (NCCP 43326;original strain) and SARS-CoV-2 (NCCP 43390;Delta variant), virus titer and clinical symptom improvement were confirmed. In the RjHan:AURA Syrian hamster model infected with SARS-CoV-2 (NCCP 49930;Delta variant), 350 or 550 mug/head of gamma-PGA was administered orally for 10 days once a day. The virus for infection was administered at 5 x 104 TCID50, and the titer of virus and the improvement of pneumonia lesions were measured to confirm the effectiveness in terms of prevention or treatment. In the mouse model infected with original Covid-19 virus stain, the weight loss was significantly reduced and the survival rate was also improved by the administration of gamma-PGA. And gamma-PGA alleviated the pneumonic lesions and reduced the virus titer of lung tissue in mice infected with delta variant. In the deltavariant virus infected hamster model, gamma-PGA showed statistically significant improvement of weight loss and lung inflammation during administration after infection. This is a promising result for possibility of Covid-19 therapeutics along with the efficacy results of mouse model, suggesting gammaPGA can be therapeutic candidate to modulate an innate immune response for Covid-19.

Hematopoietic Stem/Progenitor Cells and Engineering: HEMATOPOIETIC STEM/PROGENITOR CELLS (HPC-A) CRYOPRESERVATION PROCESS VALIDATION USING CRYOSTOR CS10 FREEZE MEDIA

Background & Aim: During the COVID-19 pandemic, we performed HPC-A cryopreservation process validation using the CryoStor CS10 freeze media to replace the current 10% DMSO cryoprotectant (Control), which encountered severe backorder. Methods, Results & Conclusion(s): This process validation included phase I, phase II, and follow-up studies. Ten HPC-A collection cell product samples were cryopreserved in the phase I study using CS10 and Control (1:1) post-plasma depletion. Post-thaw viability tests using the 7-AAD method were performed on the cryopreserved samples for parallel comparison. In phase II, each of three patient HPC-A cell products was split evenly into CS10 and Control cryopreservation. The CS10 cryopreserved HPC-A cell products only were used for infusion. The recipients' engraftment outcomes of white blood cells (WBC), granulocytes (ANC), and platelets (Plts) were monitored. Post-thaw viability test was performed on the quality control samples from both groups. In the follow-up study, engraftment outcomes of WBC, ANC, and Plts were evaluated from ten recipients who received the CS10 cryopreserved HPC-A. In the phase I study, the post-thaw viability of the CS10 group was significantly higher than the Control group (p=0.002). All post-thaw viability results were above 60%, the current lab release criteria. In the phase II study, all cryopreserved cell products met cell product release criteria (> 60%). All engraftment results were within our center-established ranges except for the Pt b's platelet engraftment. Three recipients had not had any cell product infusion-related adverse events post infusion. Both CD34 and CD45 post-thaw viability results in the CS10 group were remarkably higher than the Control group, except for the patient c's CD34 viability. In the follow-up study, the total infused cell product volume ranged from 60 ml to 118 ml, and the WBC concentration in the cryopreserved cell products ranged from 134 to 440 (x10

Immunotherapy: FAMILIAL CD45RA DEPLETED T CELLS TO TREAT SEVERE REFRACTORY INFECTIONS IN IMMUNOCOMPROMISED PATIENTS

Background & Aim: Immunocompromised patients are susceptible to high-risk opportunistic infections and malignant diseases. If available, most antiviral and antifungal drugs are quite toxic, relatively ineffective, and induce resistance in the long term. Methods, Results & Conclusion(s): We have previously demonstrated the safety of adoptive cell therapy for COVID-19 patients with CD45RA negative cells containing SARS-CoV-2-specific T cells from a donor, chosen based on HLA compatibility and cellular response to SARS-CoV-2 peptide pools. After finishing a Phase 2 randomized multicenter clinical trial (RELEASE, NCT04578210), we concluded that the infusion is safe, effective, accelerates lymphocyte recovery and shows hallmarks of an immune response. To use adoptive cell therapy to treat COVID-19 it would be necessary to develop a biobank of living drugs. For that, we examined the immune evolution performing a longitudinal analysis from previously SARS-CoV-2 infected and infection- naive individuals covering 21 months from infection. Cellular responses were maintained over time while humoral responses increased after vaccination but were gradually lost. Therefore, the best donors would be recovered individuals and two months after vaccination. We also evaluated the effect of dexamethasone (current standard of care treatment for COVID-19 and other infections involving lymphopenia) and Interleukin-15 (cytokine involved in T-cell maintenance and survival) on CD45RA negative. Dexamethasone did not alter cell functionality, proliferation or phenotype at a clinical-practice concentration, while interleukin-15 increased the memory T-cell and T-regulatory cell activation state, and interferon gamma release. Furthermore, we applied the adoptive passive transfer of CD45RA negative cells containing pathogen-specific memory T-cells to other infectious diseases characterized by sustained lymphopenia. We infused six immunocompromised patients with Cytomegalovirus, BK virus, Aspergillus, and Epstein-Barr virus lymphoproliferative disease. Patients experienced pathogen clearance, resolution of symptoms and lymphocyte increase. Transient microchimerism was detected in three patients. The use of CD45RA negative cells containing specific memory T cells of a third-party donor for treating severe pathogenic diseases in immunocompromised patients is feasible, safe, and effective, and has an advantage over other cell therapies such as lower costs and a less complex regulatory environment.Copyright © 2023 International Society for Cell & Gene Therapy

GRAd-COV2 vaccine provides potent and durable humoral and cellular immunity to SARS-CoV-2 in randomized placebo-controlled phase 2 trial.

The ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic and heterologous immunization approaches implemented worldwide for booster doses call for diversified vaccine portfolios. GRAd-COV2 is a gorilla adenovirus-based COVID-19 vaccine candidate encoding prefusion-stabilized spike. The safety and immunogenicity of GRAd-COV2 is evaluated in a dose- and regimen-finding phase 2 trial (COVITAR study, ClinicalTrials.gov: NCT04791423) whereby 917 eligible participants are randomized to receive a single intramuscular GRAd-COV2 administration followed by placebo, or two vaccine injections, or two doses of placebo, spaced over 3 weeks. Here, we report that GRAd-COV2 is well tolerated and induces robust immune responses after a single immunization; a second administration increases binding and neutralizing antibody titers. Potent, variant of concern (VOC) cross-reactive spike-specific T cell response peaks after the first dose and is characterized by high frequencies of CD8s. T cells maintain immediate effector functions and high proliferative potential over time. Thus, GRAd vector is a valuable platform for genetic vaccine development, especially when robust CD8 response is needed.

Cuban Vaccines Abdala and Mambisa against Covid-19

Intro: With the first case of COVID-19 in Cuba on March 11, 2020, the Center for Genetic Engineering and Biotechnology in Havana began an extensive vaccine program. Two vaccines based on RBD recombinant protein were developed, one for systemic administration "Abdala" and one mucosal vaccine "Mambisa". Abdala received the EUA in July 2021 and "Mambisa" completed its clinical development as a booster dose for convalescent subjects. Method(s): Two doses (25 and 50 microg) and two schedules (0-14-28 and 1-28-56 days) were evaluated in phase I clinical trials with volunteers 19 to 54 years old. The phase II and III clinical trials were also double-blind, randomized, and placebo-controlled, and included respectively 660 and 48,000 volunteers from 19 to 80 years. The anti-RBD titers were evaluated using a quantitative ELISA system developed at the Center for Immunoassay, Havana Cuba, and ELECSYS system from Roche. The RBD to ACE2 plate-based binding competitive ELISA was performed to determine the inhibitory activity of the anti-RBD polyclonal sera on the binding of the hFc-ACE2 coated plates. The neutralization antibody titers were detected by a traditional virus microneutralization assay (MN50). Finding(s): The Abdala vaccine reached 92.28% efficacy. The epidemic was frankly under control in Cuba after the vaccine introduction having reached the highest levels of cases and mortality in July 2021 with the dominance of the Delta strain. The peak of the Omicron wave, unlike other countries, did not reach half of the cases of the Delta wave with a significant reduction in mortality. The mucosal vaccine candidate "Mambisa" completed its clinical development as a booster dose for convalescent subjects reaching the trial end-point. Conclusion(s): Vaccine composition based on RBD recombinant antigen alone is sufficient to achieve high vaccine efficacy comparable to mRNA and live vaccine platforms. The vaccine also protects against different viral variants including Delta and Omicron strains.Copyright © 2023

QUASAR Induction Study 1 Cumulative Response to Guselkumab in Patients With Moderately to Severely Active Ulcerative Colitis

Introduction: Guselkumab (GUS), an IL-23p19 antagonist, had greater efficacy than placebo (PBO) in achieving clinical response and clinical remission atWeek (Wk) 12 in the randomized, controlled Phase 2b QUASAR Induction Study 1 (NCT04033445) in patients with moderately to severely active ulcerative colitis (UC).1 Patients who were not in clinical response at Wk 12 received GUS treatment through Wk 24. Here, we report GUS cumulative efficacy and safety results for Induction Study 1. Method(s): Eligible patients had moderately to severely active UC (modified Mayo score of 5 to 9 with a Mayo endoscopy subscore >=2) at baseline. Patients were randomized 1:1:1 to IV GUS 200mg, 400mg, or PBO at Wks 0, 4, and 8. Patients who were not in clinical response to IV induction at Wk 12 received GUS treatment (PBO IV->GUS 200mg IV;GUS 200mg IV->GUS 200mg SC;GUS 400mg IV->GUS 200mg SC) at Wks 12, 16, and 20 and were evaluated at Wk 24 (Figure). Matching IV or SC PBO was administered to maintain the blind. Result(s): Three hundred thirteen patients were randomized and treated at baseline. Demographic and disease characteristics at baseline were similar among the treatment groups, and approximately 50% had a prior inadequate response or intolerance to advanced UC therapy. AtWk 12, clinical response was achieved by 61.4% (62/101) and 60.7% (65/107) of patients randomized to GUS 200mg and GUS 400mg IV vs 27.6 % (29/105) of patients randomized to PBO IV (both p< 0.001). Of the patients in the GUS groups who were not in clinical response at Wk 12, 54.3% (19/35) in the GUS 200mg IV->200mg SC group and 50.0% (19/38) in the GUS 400mg IV->200mg SC group achieved clinical response at Wk 24. Clinical response atWk 12 or 24 was achieved by 80.2% of patients who were randomized to GUS 200mg IV and 78.5% of patients who were randomized to GUS 400mg IV. For patients who received PBO IV->GUS 200mg IV, clinical response at Wk 24 (65.2%) was similar toWk 12 clinical response following GUS 200mg IV induction (61.4%). The most frequent adverse events among all GUS-treated pts (n=274) were anemia (7.7%), headache (5.1%), worsening UC (4.4%), COVID-19 (3.6%), arthralgia (2.9%) and abdominal pain (2.6%) which are consistent with Wk 12 results. Conclusion(s): Overall, approximately 80% of patients randomized to receive GUS achieved clinical response at Wk 12 or 24. Continued treatment with SC GUS allowed 50-54.3% of IV GUS Wk 12 clinical nonresponders to achieve clinical response at Wk 24. No new safety concerns for GUS were identified. (Figure Presented).

Cilta-Cel Efficacy and Safety in Patients with Progressive Multiple Myeloma after Exposure to Non-Cellular Anti-BCMA Immunotherapy

Introduction: CARTITUDE-2 (NCT04133636) is a phase 2, multicohort study evaluating cilta-cel, an anti-BCMA CAR-T therapy, in several multiple myeloma (MM) patient (pt) populations. Objective(s): To report updated results with longer follow-up on cohort C pts with previous exposure to a non-cellular anti- BCMA immunotherapy. Method(s): Cohort C pts had progressive MM after treatment (tx) with a proteasome inhibitor, immunomodulatory drug, anti-CD38 antibody, and non-cellular BCMA-targeting agent. A single cilta-cel infusion (target dose 0.75x106 CAR+ viable T cells/kg) was administered 5-7 days post lymphodepletion. Primary endpoint was minimal residual disease (MRD) negativity at 10-5. Secondary endpoints included overall response rate (ORR), duration of response (DOR), and adverse events (AEs). Result(s): As of June 1, 2022, 20 pts (13 ADC exposed;7 BsAb exposed) were treated with cilta-cel;4 pts did not receive cilta-cel due to either low cellular yield (n=2, 1 in each group) or death due to progressive disease (PD) prior to dosing (n=2, 1 in each group) and 6 pts received anti-BCMA tx as their last line of therapy (n=4 ADC, n=2 BsAb). During prior anti-BCMA tx, best responses included VGPR (ADC: 2 pts;BsAb: 1 pt), sCR (ADC: 1 pt), and CR (BsAb: 1 pt);the rest had best response of stable disease or PD (1 pt not evaluable). Baseline characteristics are presented in Figure 1A. Median time from last anti- BCMA agent to cilta-cel infusion was 195 d;median administered dose of cilta-cel was 0.65x106 CAR+ viable T cells/kg. At a median follow-up of 18.0 mo, 7/10 evaluable pts (70%) were MRD negative at 10-5 (ADC: 5/7 [71.4%], BsAb: 2/3 [66.7%]). ORR: full cohort, 60%;ADC, 61.5%;BsAb, 57.1% (Figure 1B). Median DOR: full cohort, 12.8 mo;ADC, 12.8 mo;BsAb, 8.2 mo. Median PFS: full cohort, 9.1 mo;ADC, 9.5 mo;BsAb, 5.3 mo. Cilta-cel responders had a shorter median duration of last anti- BCMA agent exposure (29.5 d) compared with non-responders (63.5 d). Responders also had a longer median time from last anti-BCMA tx exposure to apheresis (161.0 d) than non-responders (56.5 d). Most common AEs were hematologic. CRS: n=12 (60%;all Gr1/2), median time to onset 7.5 d, median duration 6.0 d. ICANS: n=4 (20%, 2 Gr3/4), median time to onset 9.0 d, median duration 7.0 d. No patient had movement or neurocognitive tx emergent AE/parkinsonism. There were 12 deaths (PD: 8;COVID-19 pneumonia: 2 [not tx related];subarachnoid hemorrhage: 1 [not tx related];C. difficile colitis: 1 [tx related]). (Figure Presented)(Figure Presented)Conclusions: Pts with heavily pretreated MM and previous exposure to a non-cellular anti-BCMA therapy had favorable responses to cilta-cel. However, depth and DOR appear lower than that seen in anti-BCMA-naive pts treated with cilta-cel (at 27.7 mo, median DOR was not reached in heavily pre-treated but anti-BCMA naive CARTITUDE-1 pts). These data may inform tx plans, including sequencing and washout period between BCMA-targeting agentsCopyright © 2023 American Society for Transplantation and Cellular Therapy

The First Reported Case of Lorlatinib-Associated Diabetic Ketoacidosis

Introduction: Lorlatinib is a third-generation tyrosine kinase inhibitor that inhibits anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1). Although 2-10% of patients with non-small cell lung cancer developed hyperglycemia in phase 2 and 3 studies of lorlatinib, only one case has subsequently reported hyperglycemia >500 mg/dL, and no cases of diabetic ketoacidosis (DKA) have been previously reported. Phase 1 trials in neuroblastoma are ongoing. Case Description: A 34-year-old woman with ALK-mutated paraspinal neuroblastoma presented with DKA 14 months after initiation of lorlatinib. Prior to starting lorlatinib, her hemoglobin A1c had been 5.0% (n: < 5.7%). After 12 months of therapy, her A1c increased to 7.8%, prompting the initiation of metformin 500 mg daily. However, two months later she was admitted for DKA with a blood glucose of 591 mg/dL (n: 65-99 mg/dL), CO2 17 mmol/L (n: 20-30 mmol/L), anion gap 18 (n: 8-12), moderate serum ketones, and 3+ ketonuria. Her A1c was 14.8%, C-peptide was 1.2 ng/mL (n: 1.1-4.3 ng/mL), and her glutamic acid decarboxylase-65 and islet antigen-2 autoantibodies were negative. She was also found to be incidentally positive for COVID-19 but was asymptomatic without any oxygen requirement. The patient's DKA was successfully treated with IV insulin infusion, and she was discharged after 3 days with insulin glargine 27 units twice daily and insulin aspart 16 units with meals. One month later, her hemoglobin A1c had improved to 9.4%, and the patient's oncologist discontinued lorlatinib due to sustained remission of her neuroblastoma and her complication of DKA. After stopping lorlatinib, her blood glucose rapidly improved, and she self-discontinued all her insulin in the following 3 weeks. One month later, she was seen in endocrine clinic only taking metformin 500 mg twice daily with fasting and post-prandial blood glucose ranging 86-107 mg/dL. Discussion(s): This is the first reported case of DKA associated with lorlatinib. This case highlights the importance of close glucose monitoring and the risk of severe hyperglycemia and DKA while on lorlatinib therapy. Discontinuation of lorlatinib results in rapid improvement of glycemic control, and glucose-lowering treatments should be promptly deescalated to avoid hypoglycemia.Copyright © 2023

Safety and tolerability of losmapimod for the treatment of FSHD

Evaluate the safety and tolerability of losmapimod in the treatment for FSHD. FSHD is a relentless, variably progressive disease leading to accumulation of disability over decades. Fulcrum is developing losmapimod, a small molecule p38 alpha/beta MAPK inhibitor, to treat FSHD. Losmapimod has been generally well-tolerated in more than 3,600 subjects across multiple clinical studies, including >100 subjects with FSHD. Fulcrum has assessed losmapimod in FSHD in one completed phase 1 study (FIS 001-2018) and two ongoing Phase 2 studies in the open label extension period (FIS 001-2019 and FIS 002-2019). Subjects aged 18-65 years with genetically confirmed FSHD1, clinical severity score 2-4, and MRI-eligible muscles for biopsy were exposed to losmapimod 7.5 or 15 mg twice daily PO for 14 days and up to 76 weeks. In study FIS 001-2018, 6 subjects were exposed to 7.5 mg and 11 subjects to 15 mg twice daily dosing for 14 consecutive days. In studies FIS 001-2019 and FIS 002-2019, 14 and 77 subjects respectively, received at least one dose of losmapimod 15 mg twice daily for up to 76 weeks. A total of 108 subjects with FSHD1 have been exposed to losmapimod, with approximately 131 patient-years of exposure. Fifty-seven subjects have been exposed to losmapimod for 12 to 18 months, and 30 have been exposed for over 18 months. Most adverse events (AEs) observed during the studies were considered of mild to moderate in severity. The most common AEs were alanine aminotransferase (ALT) increase, headache, dizziness, dry skin, eczema and gastrointestinal disorders. The majority of AEs resolved with continued dosing. Dosing has been paused for 14 days in four subjects (3 in FIS 001-2019 and 1 in FIS 002-2019) subjects due to COVID-19 infection. There were no reported drug related SAEs, deaths, discontinuations due to AEs, or clinically significant changes in vital signs, clinical laboratory results, or ECG parameters. Losmapimod given as up to 15 mg twice daily in >100 subjects with FSHD1 for up to 76 weeks has been generally well-tolerated, consistent with that previously reported in other patient populations. Therefore, the benefit-risk profile of losmapimod for the treatment of FSHD remains favorable.Copyright © 2022

Long-Term Efficacy and Safety of Zanubrutinib in Patients with Relapsed/Refractory (R/R) Marginal Zone Lymphoma (MZL): Final Analysis of the Magnolia (BGB-3111-214) Trial

Introduction: Advanced MZL is generally incurable, with periods of remission and relapse. Zanubrutinib (BGB-3111), a potent and highly specific next-generation Bruton tyrosine kinase (BTK) inhibitor, was approved in the US and Canada for R/R MZL based on the MAGNOLIA primary analysis (BGB- 3111-214;NCT03846427);here, the final MAGNOLIA analysis is presented. Method(s): This was a phase 2, multicenter, single-arm study of adult patients (pts) with R/R MZL (>=1 prior CD20-directed therapy). Zanubrutinib (160 mg twice daily) was given until disease progression or unacceptable toxicity. The primary endpoint was overall response rate (ORR) by independent review committee (IRC) per Lugano classification. Secondary endpoints were investigator-assessed ORR, duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Efficacy was assessed by positron emission tomography (PET)-based Lugano criteria for IRC-confirmed fluorodeoxyglucose (FDG)-avid disease at baseline;non-avid disease was assessed by computed tomography (CT)-based criteria. Result(s): As of May 4, 2022, 68 pts were treated (median age=70 y [range 37-95];>=75 y=27.9%). MZL subtypes included extranodal (38.2%), nodal (38.2%), splenic (17.6%), and unknown (5.9%). The median number of prior therapies was 2 (range 1-6);32.4% of pts had disease refractory to last therapy, most (89.7%) had prior chemoimmunotherapy, and 7 (10.3%) had rituximab monotherapy as their only prior treatment. Sixty-one pts (89.7%) had FDG-avid disease. After a median follow-up of 28.0 mos (range 1.6-32.9) and a median treatment duration of 24.2 mos (range 0.9-32.9), 66 pts were efficacy- evaluable. IRC-assessed ORR (complete response [CR]+partial response [PR]) was 68.2% (CR=25.8%). By subtype, (Figure Presented)(Figure Presented)ORR/CR rates were 64.0%/40.0% (extranodal), 76.0%/20.0% (nodal), 66.7%/8.3% (splenic), and 50.0%/25.0% (unknown). Median DOR, PFS, and OS were not reached. Over 70.0% of pts were alive or progression-free after 2 years (Figure). Sensitivity analysis using only CT-based criteria (n=66) showed an ORR of 66.7% and CR of 24.2%. The most common treatment-emergent AEs were bruising (23.5%), diarrhea (22.1%), and constipation (17.6%). Neutropenia (8.8%) and COVID-19 pneumonia (5.9%) were the most common Grade >=3 AEs. Five pts (7.4%) died due to unrelated AEs: COVID-19 pneumonia=2, acute myeloid leukemia=1, myocardial infarction=1, septic encephalopathy=1. Hypertension occurred in 3 pts (4.4%), atrial fibrillation and atrial flutter in 1 pt (1.5%) each;none led to treatment withdrawal. One pt (1.5%) had a Grade 3 gastrointestinal hemorrhage while receiving rivaroxaban. None of the pts required dose reduction. Conclusion(s): In this final analysis with over 2 years of median follow-up, zanubrutinib continues to demonstrate durable disease control and was generally well tolerated, with no new safety signals observedCopyright © 2023 American Society for Transplantation and Cellular Therapy

NAFAMOSTAT AS NASAL CHEMOPROPHYLAXIS FOR SARS-CoV-2 IN HAMSTERS

Background: Chemoprophylaxis is a critical tool for many infectious diseases, and in COVID-19 may have particular benefit for vulnerable patients that do not maximally benefit from vaccination. Nafamostat inhibits TMPRSS2, which catalyses a critical cell entry pathway for SARS-CoV-2. This study sought to assess efficacy of intranasal nafamostat against airborne transmission of SARSCoV-2 in Syrian Golden hamsters. Method(s): Male hamsters were intranasally administered water or 5 mg/kg nafamostat in water twice daily for 5 days (sentinels). One day after treatment initiation, sentinels were co-housed with an untreated hamster that was intranasally inoculated with 1 x 104 PFU of Wuhan SARS-CoV-2 (donor). Sentinels were separated from the donor by a perforated divider, allowing airflow between zones but not contact. Hamsters were weighed and throat-swabbed throughout. At day 4, all animals were culled, and lung and nasal turbinates were harvested. N-RNA was quantified relative to 18S-RNA by qPCR. A 2-way ANOVA with Bonferroni correction was applied to compare weight changes in the nafamostat group to those in controls. An unpaired t-test was used to compare viral RNA in lung and nasal turbinate between groups. Result(s): SARS-CoV-2 viral RNA was significantly lower in the nasal turbinates of nafamostat-treated hamsters compared to water-treated controls (P = 0.012;Figure 1). Within the lung, SARS-CoV-2 RNA was undetectable in the nafamostat-treated hamsters, but was detectable in the water-treated controls. Viral RNA was undetectable in the swabs of the nafamostat-treated hamsters at all timepoints, but was quantifiable in the water-treated control group from day 3. Body weight of the nafamostat-treated hamsters was significantly lower (P = < 0.001) than in the water-treated animals throughout. SARS-CoV-2 viral RNA was detectable in the donor hamsters lung, nasal turbinate and swab samples confirming validity of the experiment. Conclusion(s): This study demonstrated a protective effect of intranasal nafamostat against airborne SARS-CoV-2 transmission in Syrian golden hamsters. A phase IIa study of intravenously administered nafamostat yielded no evidence of clinical efficacy in hospitalised patients, but further investigation of intranasally administered nafamostat in a prophylactic setting may be warranted.

SAFETY AND EFFICACY OF INHALED INTERFERON-beta1A (SNG001) IN OUTPATIENTS WITH COVID-19

Background: SARS-CoV-2 variants resistant to monoclonal antibodies, and drug-drug interactions and potential mutagenicity of direct acting antivirals, heightens the need for additional therapeutics to prevent progression to severe COVID-19. Exogenous interferon beta is a promising therapeutic option against SARS-CoV-2 given its broad-spectrum antiviral activity and data suggesting impaired endogenous IFN production in individuals with severe disease. Method(s): The safety and efficacy of orally inhaled nebulized interferon-beta1a (SNG001) was evaluated in a Phase II randomized controlled trial on the ACTIV-2/ A5401 platform (NCT04518410). Adult outpatients with confirmed SARS-CoV-2 infection within 10 days of symptom onset were randomized to SNG001 once daily for 14 days or blinded pooled placebo. Primary outcomes included treatment-emergent Grade >=3 adverse event (TEAE) through day 28;time to symptom improvement of 13 targeted COVID-19 symptoms collected by daily study diary through day 28;and SARS-CoV-2 RNA < lower limit of quantification (LLoQ) from nasopharyngeal (NP) swabs at days 3, 7, and 14. All-cause hospitalization or death through day 28 was a key secondary outcome. Result(s): Of 221 participants enrolled at 25 US sites between February and August 2021, 220 (110 SNG001, 110 placebo) initiated study intervention, with a median age of 40 years, 55% female, and 20% SARS-CoV-2 vaccinated. There was no significant difference between SNG001 and placebo in Grade >=3 TEAEs (4% vs 8%, Fisher's exact test p=0.25). Median time to symptom improvement was 13 days for SNG001 and 9 days for placebo (Gehan-Wilcoxon test p=0.17). There was no difference in the proportion of participants with SARS-CoV-2 RNA < LLoQ at day 3, 7 or 14 (SNG001 vs placebo, Day 3: 28% vs. 39%;Day 7: 65% vs. 66%;Day 10: 91% vs. 91%;joint Wald test p=0.41). There were fewer hospitalizations with SNG001 (n=1;1%) compared with placebo (n=7;6%), but this difference was not statistically significant (Fisher's exact test p=0.07;Figure). All hospitalizations were due to COVID-19 and occurred among unvaccinated participants without protocol-defined high-risk factors. Conclusion(s): Inhaled nebulized SNG001 was safe and well tolerated but did not reduce SARS-CoV-2 RNA levels in the nasopharynx nor decrease time to improvement of COVID-19 symptoms in outpatients with mild-to-moderate COVID-19. The non-statistically significant decrease in hospitalizations among SNG001 participants warrants further investigation in a phase 3 clinical trial. Cumulative incidence of hospitalization or death comparing SNG001 vs. placebo.

Ensitrelvir for Mild-to-Moderate Covid-19: Phase 3 Part of Phase 2/3 Study

Background: Ensitrelvir is a SARS-CoV-2 3CL protease inhibitor approved in Japan under emergency regulatory approval system as an oral treatment for COVID-19. Here we report the key analysis results of 125 mg group of phase3 part (SCORPIO-SR). Method(s): This study was a multicenter, randomized, double-blind, placebocontrolled study. Regardless of SARS-CoV-2 vaccination status and presence of risk factors for severe disease, patients with mild-to-moderate COVID-19 within 120 hours from onset were randomized to oral administration of ensitrelvir 125 mg (375 mg loading dose on Day1), ensitrelvir 250 mg (750 mg loading dose on Day1), and placebo once daily, for 5 days. The primary endpoint was time to resolution of 5 symptoms of COVID-19 (stuffy or runny nose, sore throat, cough, feeling hot or feverish, and low energy or tiredness), and the key secondary endpoints include change from baseline on Day4 in the amount of SARS-CoV-2 viral RNA and time to first negative of viral titer. The primary population for the primary and key secondary endpoints was patients with <72 hours from onset to randomization. Result(s): Median time to resolution of 5 symptoms was significantly shorter in 125 mg group (n=336, 167.9 hours) than placebo group (n=321, 192.2 hours) (p=0.0407). Mean change of viral RNA levels from baseline (log10 copies/mL) on Day4 was significantly greater in 125 mg group (-2.48) than in placebo group (-1.01) (p< 0.0001). The time to first negative of viral titer was significantly shorter in 125 mg group (n=199, 36.2 hours) compared to placebo group (n=211, 65.3 hours) (p< 0.0001). Mean changes from baseline in viral titers [log10(TCID50)/mL] were significantly greater in 125mg group on Day2 (-0.807, n=196) and Day4 (-1.108, n=197) than in the placebo group (-0.395, n=208 and -0.850, n=207, respectively) (p< 0.0001). (Table Presented) In the patients randomized within 120 hours of onset, median time to resolution of 5 symptoms was 189.7 hours in 125 mg group (n=582) and 200.3 hours in placebo group (n=572) (p=0.4352). No deaths or serious adverse drug reactions were reported in either group, and the incidence of serious adverse events between the two groups was comparable. Conclusion(s): Ensitrelvir demonstrated a significant reduction in the time to resolution of 5 typical symptoms of COVID-19, robust antiviral effects and good tolerability.

Bimekizumab safety in patients with moderate-to-severe plaque psoriasis: Analysis of pooled data from up to three years of treatment in Phase 2 and 3 clinical trials

Background: Bimekizumab (BKZ) is a monoclonal IgG1 antibody used in the treatment of psoriasis which selectively inhibits interleukin (IL)-17F in addition to IL-17A.1,2 Data pooled over two years have indicated that BKZ is generally well-tolerated.3 We report three-year BKZ pooled safety data in patients with moderate-to-severe plaque psoriasis. Method(s): Safety data were evaluated for all patients who received one or more dose BKZ in four Phase 3 trials (BE SURE [NCT03412747], BE VIVID [NCT03370133], BE READY [NCT03410992], and their ongoing open-label extension BE BRIGHT open-label extension [NCT03598790;data cut-off : 10/23/2021]) and four Phase 2 trials (BE ABLE 1 [NCT02905006], BE ABLE 2 [NCT03010527], PS0016 [NCT03025542], PS0018 [NCT03230292]). Safety data were evaluated separately for patients receiving BKZ dosed 320mg every four weeks (Q4W) or every eight weeks (Q8W). Exposureadjusted incidence rates (EAIRs) for treatmentemergent adverse events (TEAEs) are the incidence of new cases per 100 patient-years (PY). Result(s): Total BKZ exposure was 4,245.3 PY (N=1,789) across Phase 2/3 trials, and 3,876.4 PY (N=1,495) in Phase 3 trials. TEAEs occurred at a rate of 186.1 across Phase 2/3 trials, serious TEAEs at 5.6, and TEAEs leading to discontinuation at 3.5. Eighteen deaths occurred (0.4/100 PY), all unrelated to study treatment except one (relationship unknown). TEAEs occurred less frequently in Q8W- than Q4W-treated patients in Phase 3 trials. Consistent with previous reports, most common TEAEs (EAIR) in Phase 2/3 trials were nasopharyngitis (15.3), oral candidiasis (10.2), and upper respiratory tract infection (7.1).3 EAIR of serious infections was 1.2. Most frequently reported were serious coronavirus infections (0.2). There were no cases of active tuberculosis. EAIR of oral candidiasis was 10.2, decreased vs two-year data (12.6),3 and was less common with BKZ Q8W vs Q4W. The vast majority of oral candidiasis events were mild or moderate (99.4%);none were serious. EAIRs of hepatic events (4.0) and elevated liver enzymes (3.4) were decreased vs. two-year data (4.3 and 3.6, respectively).3 EAIRs for inflammatory bowel disease (0.1), adjudicated major adverse cardiac events (0.6), and adjudicated suicidal ideation and behavior (0.1) were low. EAIRs for other safety topics of interest were also low and were similar to or lower than two-year EAIRs.3 Conclusion(s): BKZ was well-tolerated over three years. No safety signals were identified;EAIRs of TEAEs did not increase compared with data from two years.3.

A Multi-Center, Randomized, Placebo-Controlled, Double-Blinded Trial of Efficacy and Safety of Riluzole in Acute Spinal Cord Injury Study (RISCIS)

INTRODUCTION: Riluzole, a sodium-glutamate antagonist which is FDA approved for ALS has shown promising pre-clinical results and is clinically safe in SCI patients. METHOD(S): The RISCIS trial is an international, multi-center, prospective, double-blinded, randomized, placebo-controlled Phase II/ III trial. Patients with ASIA A-C, C4-C8 SCI and <12 hours from injury were randomized between Riluzole, at an oral dose of 100mg BID for the first 24 hours followed by 50mg BID for the following 13 days, and placebo control. RESULT(S): Due to the impact of the global COVID-19 pandemic this trial was terminated prior to completion. 193 patients were randomized with a follow-up rate of 82.7% at 180-days. No statistical difference was noted in the demographics and baseline injury characteristics between the two groups. At 6 months there was a median gain in total motor scores (TOTM) of 30.0 in the Riluzole group compared to 20.0 for the Placebo group. The improved motor outcomes did not reach statistical significance. Given the decreased sample size, additional sensitivity analyses were conducted. In the ASIA-C population, Riluzole was a significant improver of total motor scores (coefficient estimate: 14.10, p = 0.020) and upper motor scores (CE: 7.68, p = 0.040) at 6 months. ASIA B patients had higher reported independence, as measured by the SCIM score (45.3 vs. 27.3;p = 0.071) and change in mental health scores as measured by the SF-36 mental health domain (2.01 vs. -11.58;p: 0.0205) at 180 days. CONCLUSION(S): Despite the premature termination of the RISCIS trial due to the COVID-19 pandemic, 193 subjects were recruited into this trial. Primary analysis showed a 10-motor point gain in riluzoletreated subjects which did not reach significance. However, on secondary analysis, incomplete cervical SCI subjects (AIS B and C) showed significant gains in functional recovery.

Immune-Viral Dynamics Modeling of the Basis for Individual Variation in Covid-19

Background: Viral dynamics models provide mechanistic insights into viral disease and therapeutic interventions. A detailed, mechanistic model of COVID-19 was developed and fit to data from molnupiravir (MOV) trials to characterize the SARS-CoV-2 viral dynamics in MOV-treated and untreated participants and describe the basis for variation across individuals. Method(s): An Immune-Viral Dynamics Model (IVDM) incorporating mechanisms of viral infection, viral replication, and induced innate and adaptive immune response described the dynamics of viral load (VL) from pooled data from MOV Phase 2 and 3 trials (N=1958). Population approaches were incorporated to estimate variation across individuals and to conduct an extensive covariate analysis. Nineteen parameters in a system of five differential equations described SARS-CoV-2 viral dynamics in humans. Six population parameters were successfully informed through fitting to observed trial data while the remaining parameters were fixed based on literature values or calibrated via sensitivity analysis. Result(s): Final viral dynamics and immune response parameters were all estimated with high certainty and reasonable inter-individual variabilities. The model captured the viral load profiles across a wide range of subpopulations and predicted lymphocyte dynamics without using this data to inform the parameters, suggesting inferred immune response curves from this model were accurate. This mechanistic representation of COVID-19 disease indicated that the processes of cellular infection, viral production, and immune response are in a time-varying, non-equilibrium state throughout the course of infection. MOV mechanism of action was best described as an inhibitory process on the infectivity term with estimated AUC50 of 10.5 muM*hr. Covariates identified included baseline viral load on infectivity and age, baseline disease severity, viral clade, baseline viral load, and diabetes on immune response parameters. Greater variation was identified for immune parameters than viral kinetic parameters. Conclusion(s): These findings show that the variation in the human response (e.g., immune response) is more influential in COVID-19 disease than variations in the virus kinetics. The model indicates that immunocompromised patients (due to HIV, organ transplant, active cancer, immunosuppressive therapies) develop an immune response to SARS-CoV-2, albeit more slowly than in immunocompetent, and MOV is effective in further reducing viral loads in the immunocompromised.

Anti-IL17A, Ixekizumab, for treatment-resistant chronic venous leg ulcers: A phase II randomized, double-blind, placebo-controlled pilot trial

Chronic venous leg ulcers cause significant morbidity in patients and the majority reoccur after resolution. The current standard of care, double layer compression, is not effective in all patients. Interleukin 17A (IL17) antagonist therapy has been shown to promote healing in murine models of chronic wounds. This has not previously been explored in humans. Therefore, we aim to undertake a phase II randomized, double-blinded, placebo-controlled pilot trial to assess whether Ixekizumab, an anti-IL17A therapy, is effective at reducing chronic venous ulcer size. In addition, to determine the feasibility and safety of undertaking a randomized control trial. Patients with a venous leg ulcer not responsive to 4 weeks of compression therapy were recruited. Participant were randomized to receive either Ixekizumab (80mg) or placebo injected subcutaneously every fortnight for 12 weeks while continuing standard of care. From 30 eligible, 4 patients consented, were enrolled and randomized. Initially, COVID-19 risk, medical history and distance from recruiting site were the main causes of exclusion or refusal to participate. All participants completed the 12-week treatment period. At completion, two participants in the Ixekizumab group reduced by >40% and one completely resolved their ulcer. Ulcers in the Ixekizumab group reduced by an average size of 955mm2 to 529mm2at baseline to final review respectively (p-value 0.12). The placebo group reduced in size by <5%.There were no adverse events related to the intervention. This pilot clinical trial investigated a novel treatment for chronic venous ulcers and showed IL17 inhibition does not impede and may improve chronic wound healing. It also showed a lack of major safety issues in using anti-IL17A therapy in this population. Moreover, the findings reinforce the feasibility of a larger trial to more accurately evaluate anti-inflammatory strategies in chronic wounds.Copyright © 2023

Investigation of the effect of the angiotensin II type 2 receptor (AT2R) agonist C21 on plasma NT-proBNP a diagnostic biomarker, in subjects hospitalised with COVID-19

The prohormone N-terminal pro-B-type natriuretic peptide (NT-proBNP) is released from stretched cardiac myocytes and is a diagnostic biomarker for heart failure and cardiac dysfunction as well as pulmonary embolism and pneumonia that are frequent complications to severe Coronavirus Disease 2019 (COVID-19). NT-proBNP is frequently elevated in COVID-19. In a recent publication, it was demonstrated that NT-proBNP was strongly associated with mortality in patients with COVID-19, and further investigation of its usefulness as a prognostic tool to predict disease outcomes in COVID-19 was suggested (1). In the recently completed phase 2 trial (angiotensin II type 2 receptor agonist COVID-19 trial [ATTRACT];NCT04452435) in subjects hospitalised with COVID-19, it was investigated whether treatment with the AT2R agonist C21 for 7 days affected the release of the plasma biomarker NTproBNP. ATTRACT was a randomised, double-blind, placebo-controlled, phase 2 trial that investigated the safety and efficacy of C21 treatment (100 mg twice daily) for 7 days in hospitalised subjects with COVID-19, not requiring mechanical ventilation. The results of the trial demonstrated that treatment with C21 on top of standard of care (vast majority of patients received glucocorticoids) significantly reduced the proportion of subjects requiring supplemental oxygen at Day 14, indicating faster recovery with C21 treatment compared to placebo. Blood samples for exploratory analysis were taken before and after 7 days of treatment with C21 or placebo. Plasma NT-proBNP was markedly elevated in both treatment groups before treatment, with average values of 357 and 438 pg/mL in the placebo and C21 groups, respectively, as compared to normal levels of approximately <100 pg/mL. After 7 days of treatment, the C21 group experienced a dramatic reduction in plasma NT-proBNP (by 259 pg/mL) as compared to the placebo group (63 pg/mL) (p=0.02). The results show that short-term C21 treatment decreased the release of NT-proBNP in subjects hospitalised with COVID-19. Further investigations are needed to elucidate whether this is related to effects on COVID-19- induced pulmonary damage or direct protective effects on the heart. We are currently conducting a global phase 3 trial (VP-C21-008) further investigating the effect of C21 in subjects hospitalised with COVID-19 including determination of NT-proBNP.

QUASAR Induction Study 1 Cumulative Response to Guselkumab in Patients With Moderately to Severely Active Ulcerative Colitis

Background: Guselkumab (GUS), an IL-23p19 antagonist, had greater efficacy than placebo (PBO) in achieving clinical response and clinical remission at Week (Wk) 12 in the randomized, controlled Phase 2b QUASAR Induction Study 1 (NCT04033445) in patients with moderately to severely active ulcerative colitis (UC).1 Patients who were not in clinical response at Wk 12 received GUS treatment through Wk 24. Here, we report GUS cumulative efficacy and safety results for Induction Study 1. Method(s): Eligible patients had moderately to severely active UC (modified Mayo score of 5 to 9 with a Mayo endoscopy subscore >=2) at baseline. Patients were randomized 1:1:1 to IV GUS 200mg, 400mg, or PBO at Wks 0, 4, and 8. Patients who were not in clinical response to IV induction at Wk 12 received GUS treatment (PBO IVGUS 200mg IV;GUS 200mg IV->GUS 200mg SC;GUS 400mg IV->GUS 200mg SC) at Wks 12, 16, and 20 and were evaluated at Wk 24 (Figure 1). Matching IV or SC PBO was administered to maintain the blind. Result(s): Three hundred thirteen patients were randomized and treated at baseline. Demographic and disease characteristics at baseline were similar among the treatment groups, and approximately 50% had a prior inadequate response or intolerance to advanced UC therapy. At Wk 12, clinical response was achieved by 61.4% (62/101) and 60.7% (65/107) of patients randomized to GUS 200mg and GUS 400mg IV vs 27.6% (29/105) of patients randomized to PBO IV (both p<0.001). Of the patients in the GUS groups who were not in clinical response at Wk 12, 54.3% (19/35) in the GUS 200mg IV->200mg SC group and 50.0% (19/38) in the GUS 400mg IV->200mg SC group achieved clinical response at Wk 24. Clinical response at Wk 12 or 24 was achieved by 80.2% of patients who were randomized to GUS 200mg IV and 78.5% of patients who were randomized to GUS 400mg IV. For patients who received PBO IV->GUS 200mg IV, clinical response at Wk 24 (65.2%) was similar to Wk 12 clinical response following GUS 200mg IV induction (61.4%). The most frequent adverse events among all GUS-treated pts (n=274) were anemia (7.7%), headache (5.1%), worsening UC (4.4%), COVID-19 (3.6%), arthralgia (2.9%) and abdominal pain (2.6%) which are consistent with Wk 12 results. Conclusion(s): Overall, approximately 80% of patients randomized to receive GUS achieved clinical response at Wk 12 or 24. Continued treatment with SC GUS allowed 50-54.3% of IV GUS Wk 12 clinical nonresponders to achieve clinical response at Wk 24. No new safety concerns for GUS were identified.

Impact of COVID-19 related alterations in circulating respiratory viruses on children and adult patients with recurrent wheeze and asthma

Introduction: The epidemiology of respiratory infections changed fundamentally during COVID-19 pandemic. While during lockdown periods numbers of respiratory infection were low, an increase of respiratory syncytial virus and rhinovirus infections was reported outside the natural season. Viral infections being the main trigger for asthma and wheeze episodes in children, we aimed to investigate the impact of this observation on children and adults. Method(s): Within the ALL Age Asthma Cohort (ALLIANCE), an observational, longitudinal multicenter asthma study, we assessed data regarding disease control, use of medication and etiology of exacerbations at three time points, during (pilot: Feb-Aug 2020: n= 280, phase 1: Oct-Apr 2020/21: n= 412) and after lockdown periods (phase 2: JunOct 2021: n= 327). Result(s): We observed high proportions of improvement in disease burden in preschool children (age 0-5.9 years) during lockdown periods in the pilot-phase (35%) and in phase 1 (32%). While after easing of hygiene measures none of the preschool children reported improvement (phase 1/phase 2;p = 0.02), 29% showed worsening of their condition (pilot/phase 2, p = 0.01) associated with viral infections and higher need for medication. Children aged 6-18 years showed a stable course over all phases. In contrast, adults reported worsening of their asthma (pilot, 19%, phase 1, 29%), but no significant change in phase 2 (23%). Conclusion(s): COVID-19 related measures caused a reduction and re-emerge of respiratory virus infections, which influenced the course of disease in preschool children with recurrent wheeze, but not in older children and adults with asthma.