ABSTRACT
Background: Zotatifin (eFT226) is a potent and selective inhibitor of eukaryotic initiation factor 4A (eIF4A), a host RNA helicase required for SARS-CoV-2 replication. In vitro, zotatifin demonstrates broad spectrum antiviral activity against all human coronaviruses tested. Zotatifin has physicochemical and pharmacokinetic (PK) properties suitable for convenient, single subcutaneous (sc) injection. This study assessed the safety, antiviral activity, and PK of zotatifin in non-hospitalized patients (pts) with mild/moderate COVID. Method(s): PROPEL is a randomized, placebo-controlled, double-blind study in non-hospitalized pts with mild/moderate COVID. At randomization, pts must have had a SARS-CoV-2 positive test within 7 days and at least 1 COVID symptom. Pts were randomized (3:1) to zotatifin or placebo sc in 3 cohorts of 12 pts each. Cohort 1, 2 and 3 received a single dose (SD) of zotatifin of 0.01. 0.02 and 0.035 mg/kg or matching placebo. Safety (adverse event (AE) and laboratory tests), antiviral activity (mid-turbinate nasal swabs and saliva), and plasma PK were collected over 30 days. The primary endpoint was safety;key secondary endpoints included SARS-CoV-2 viral load (VL) and PK. The study was not powered for statistical inferential testing. Result(s): 36 pts were enrolled across all three cohorts and completed a 30-day follow up. Data is currently available for pts in cohorts 1 and 2, 18 and 6 of whom received zotatifin and placebo, respectively. Baseline characteristics were comparable between groups. The most common AE was erythema at injection site in cohort 1 (44%) and cohort 2 (89%), vs. 0% in the zotatifin and pooled placebo groups, respectively. Other AE frequencies were comparable between zotatifin and placebo and no serious AEs were reported. The concentrationtime profile of zotatifin from cohorts 1 and 2 following sc administration was similar to that reported previously following IV administration, demonstrated a terminal elimination half-life (t1/2) of ~ 4 days, high steady-state volume of distribution (Vss) of 31 L/kg, and low plasma clearance (Cl) of 3.9 mL/min/kg. A faster time to viral RNA undetectability was observed with zotatifin vs. placebo (see Fig 1. Not statistically significant). Conclusion(s): Zotatifin was safe, well tolerated and demonstrated a trend in clinical antiviral activity in patients with mild to moderate COVID which supports further clinical development. Zotatifin sc route of administration supports a point of care treatment for COVID.
ABSTRACT
Background: Coronavirus 2019 was declared as a pandemic by the World Health Organization in March 2020. Bereft of specific treatment for the disease, vaccinations and COVID appropriate behavior have come to be the main approaches to combat the pandemic. A number of vaccines have been approved after clearing clinical trials. Hence, it is essential to evaluate the safety profile of each vaccine for ensuring optimum health of the general population. This study was conducted to evaluate the adverse events following CoviShield vaccination in a tertiary care center. Aims and Objectives: The aim of the study was to describe the pattern of adverse effects, treatment given, and comorbidities seen in healthcare workers (HCW) who reported to the adverse drug reaction (ADR) monitoring center in the department of pharmacology Government T.D. Medical College, Alappuzha, following CoviShield vaccination from January 2021 to October 2021. Material(s) and Method(s): A retrospective and descriptive study was carried out at Department of Pharmacology, GTDMCA involving all HCW who reported side effects following CoviShield vaccination in the ADR monitoring centre (AMC) in the Department of Pharmacology, GTDMCA from January 2021 to Oct 2021. Result(s): Out of 620 HCWs who reported adverse event following vaccination, majority (45%) were from the age group 21-30 years. About 83% of HCWs who reported adverse effect were women. Majority of the respondents (96%) experienced the adverse effects within 24 h. About 88% of respondents experienced these adverse effects after the initial dose alone. Commonly encountered adverse effects were fever (57%), headache (43%), myalgia (38%) etc. Hypertension (7%) was the most common comorbidity seen. Majority of the beneficiaries (70%) took paracetamol for the treatment of the adverse effect. Conclusion(s): Majority of the vaccinated HCWs experienced minor and self-limiting adverse event following immunization (AEFI) with Chimpanzee Adenovirus Oxford novel CoronaVirus-19. No serious AEFI were reported to the AMC. Despite the record speed at which the vaccine has been developed, it has shown to have a good safety profile considering the millions of doses that have been administered.Copyright © 2023 Sai Nathan R, et al.
ABSTRACT
Background and aims: To evaluate the safety, pharmacokinetics (PK) and antiviral activity of ALG-010133, a STOPS molecule designed to reduce hepatitis B S-antigen (HBsAg) in chronic hepatitis B (CHB) patients. Method: This was a 3-part, multicenter, double-blind, randomized, placebo-controlled study. In Parts 1 and 2, single and multiple subcutaneous (SC) doses of ALG-010133were generallywell tolerated in healthy volunteers (Gane et al, EASL 2021). Part 3 evaluatedweekly SC doses of ALG-010133 or placebo × 12 weeks in virologically suppressed Hepatitis B e-antigen (HBeAg) negative CHB subjects (N = 10/cohort;8 active:2 placebo). Reported here are preliminary blinded Part 3 safety, PK, and antiviral data;unblinded data will be presented at the conference. Results: 31 CHB subjects completed dosing and follow-up in Cohorts 1 (120 mg;N = 10), 2. (200 mg;N = 10), and 3 (400 mg;N = 11). Most subjects were male (61%) and 48% were white, with mean age 48 years, mean BMI 26.1 kg/m2 and baseline HBsAg across cohorts of 3.6 to 3.7 log10 IU/ ml. Therewas 1 unrelated serious treatment emergent adverse event (TEAE) (hospitalization for orchitis) and 1 unrelated TEAE (COVID-19 infection) resulting in premature study drug discontinuation. All TEAEs were Grade 1 or 2 in severity, except for 1 Grade 3 TEAE of injection site erythema (severity based only on surface area criteria of ≥100 cm2;required no treatment and resolved despite continued study drug dosing) and the aforementioned TEAE of orchitis (Grade 3). There was no dose relationship to severity or frequency for any TEAE. The most common (≥3 subjects) TEAEs were injection site erythema (n = 5), increased ALT (n = 4), injection site bruising (n = 4), increased AST (n = 3), and injection site pruritus (n = 3);none were assessed as clinically concerning. Although treatment-emergent ALT and AST elevations (n = 13) were observed, all were Grade 1 (<2.5x upper limit of normal [ULN]) or 2 (≥2.5 to <5x ULN) and none led to premature study drug discontinuation or were associated with symptoms or evidence of liver dysfunction. There were no other clinically significant lab abnormalities. No clinically significant physical examinations, vital signs, or ECG abnormalities were reported. Plasma ALG-010133 exposures increased more than dose proportionally between the 120 to 400 mg dose levels, with moderate variability and minimal accumulation. Compared to baseline, the magnitude of HBsAg decline at Week 12 was <0.1 log10 IU/ml for placebo and across all ALG-010133 dose levels, including the projected efficacious dose level of 400 mg (estimated to maintain total liver exposures >3x EC90 for HBsAg inhibition). Conclusion: ALG-010133 was safe and well tolerated with predictable PK properties when given to CHB subjects as multiple SC doses of up to 400 mg. No meaningful HBsAg reduction was observed across all cohorts. Further clinical development of ALG-010133 has been discontinued.
ABSTRACT
Background: Blinatumomab, a bispecific T-cell engager (BiTE ®) molecule that directs cytotoxic T-cells to lyse CD19-expressing B lineage cells, has been investigated in NHL (Goebeler JCO 2016, Viardot Blood 2016, Katz ASH 2019). Here, we evaluated subcutaneous (SC) blinatumomab, which may simplify administration, improve convenience, and potentially reduce adverse events (AEs). Methods: Patients (pts;≥18 y) had indolent NHL (follicular, marginal zone, lymphoplasmacytic, mantle cell, or small lymphocytic) that was primary refractory (1+ prior line), relapsed (within 1 y of first response), or that had responded to initial therapy for ≥1 y and relapsed after 2+ lines, including an anti-CD20 monoclonal antibody. Disease must not have been irradiated and was measurable (≥1.5 cm) on PET-CT or CT. Pts had a 3-wk continuous intravenous (cIV) run-in period followed by SC dosing in 5 cohorts, a further 2 wks of cIV dosing, and the option for a second cycle of cIV dosing (Figure). The primary objective was safety and tolerability of SC blinatumomab;secondary objectives included pharmacokinetics (PK), estimating the maximum tolerated dose (MTD), ie, the highest dose at which ≤1/6 pts had a dose-limiting toxicity (DLT), and efficacy (NCT 02961881). Results: Pts (n=29) had a median (range) age of 64 (42-75) y, 55% were male, 90% Caucasian, with follicular I-IIIA (76%), marginal zone (10%), mantle cell (10%) and lymphoplasmacytic lymphoma (3%) subtypes;no pts had prior allo-hematopoietic stem cell transplant (HSCT), 38% had prior auto-HSCT. Of the 29 pts, 5 discontinued (D/C) blinatumomab due to AEs (n=3;2 cIV, 1 SC), pt request (1), and disease progression (1);no pts D/C due to COVID-19 control measures;26 pts completed the study;pts received a median (range) of 5 (3-10) doses. AEs leading to D/C in SC treatment included neurologic events of aphasia and seizure. During SC dosing, 2 DLTs occurred (aphasia, n=1;seizure, n=1 ). MTD was not reached. Five pts had grade 3 (G3) AEs (thrombocytopenia, erosive esophagitis, asthenia, device-related infection, hyperglycemia, aphasia, seizure;pts may have had >1 G3 AE);there were no G4 AEs or fatal AEs. AEs of interest included neurologic events (all, n=15;G3, n=2), infection (2;1), and cytokine release syndrome (4;0). One pt had grade 1 injection site erythema. Anti-blinatumomab antibodies have not been detected to date. Preliminary PK results were consistent across the 5 SC cohorts and 3 different dosing regimens. Following the first dose, maximum concentrations (C max) were reached after ~5-12 hours and exposures (C max and area under concentration-time curve [AUC] from 0-12 hours) increased in a dose-related manner. At steady state, exposures (AUC over the dosing interval) increased in a dose-related manner for dosing intervals of once every 12, 24, and 48 hours across cohorts. Blinatumomab bioavailability and apparent terminal elimination half-life were favorable for extending the dosing interval to once every other day and potentially longer intervals. The steady-state concentrations during both cIV infusion periods were consistent with those previously reported in NHL pts. In all pts, the overall response rate (ORR, representative of cIV, 5 wks and SC, 1wk) per Cheson criteria was 69% (evaluable, n=23: complete response [CR], 21%;partial response [PR], 48%;cycle 1 [C1], n=22: ORR, 62%;CR, 14%;PR,48%;cycle 2 [C2], n=17: 45%;17%;28%;respectively);per Lugano criteria, the ORR was 52% (n=21: CR, 24%;PR, 28%;C1, n=18: 45%;17%;28%;C2, n=12: 31%;21%;10%);for follicular lymphoma, ORR was 77% per Cheson (n=19: CR, 23%;PR, 55%) and 55% per Lugano (n=15: CR, 23%;PR, 32%). Conclusions: In pts with R/R indolent NHL, SC blinatumomab had a favorable safety profile, with the caveat that pts who could not tolerate cIV blinatumomab did not advance to SC dosing. Efficacy was comparable with that seen for cIV dosing in prior blinatumomab NHL studies. In contrast to prior blinatumomab trials, no dose dependency in efficacy or toxicity was observed because SC dosi g was administered for only 1 wk, after 3 wks of cIV;pts not tolerating cIV did not receive SC dosing. Safety/tolerability of blinatumomab SC administration over the whole cycle is currently being evaluated in a phase 1 trial of pts with R/R acute lymphoblastic leukemia (NCT 04521231). SC blinatumomab PK, including bioavailability and half-life, showed promising features, warranting further investigation. [Formula presented] Disclosures: Rossi: Astellas: Membership on an entity's Board of Directors or advisory committees;Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees;Abbvie: Membership on an entity's Board of Directors or advisory committees;Alexion: Membership on an entity's Board of Directors or advisory committees;Sanofi: Honoraria;Takeda: Membership on an entity's Board of Directors or advisory committees;Celgene: Membership on an entity's Board of Directors or advisory committees;Daiichi Sankyo: Consultancy, Honoraria;Janssen: Membership on an entity's Board of Directors or advisory committees;Jazz: Membership on an entity's Board of Directors or advisory committees;Novartis: Membership on an entity's Board of Directors or advisory committees;Pfizer: Membership on an entity's Board of Directors or advisory committees. Prince: Takeda: Consultancy, Honoraria;Amgen: Honoraria, Research Funding;Novartis: Honoraria. Tam: Janssen: Consultancy, Honoraria, Research Funding;BeiGene: Consultancy, Honoraria;AbbVie: Consultancy, Honoraria, Research Funding;Loxo: Consultancy;Roche: Consultancy, Honoraria;Novartis: Honoraria;Pharmacyclics: Honoraria. Ku: Roche: Consultancy;Genor Biopharma: Consultancy;Antegene: Consultancy. Thieblemont: Gilead Sciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses;Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding;Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees;Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees;Kyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses;Bristol Myers Squibb/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses;Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses;Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees;Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses;Cellectis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses;Hospira: Research Funding;Bayer: Honoraria;Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses. Popplewell: Pfizer: Other: Travel;Hoffman La Roche: Other: Food;Novartis: Other: Travel. Wermke: Novartis, Roche, Pfizer, BMS: Consultancy, Honoraria, Research Funding. Haioun: Roche: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company);Janssen-Cilag: Consultancy;Celgene: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company);Novartis: Honoraria;Amgen: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company);Servier/Pfizer: Honoraria;Gilead Sciences: Consultancy, Honoraria;Takeda: Consultancy;Miltenyi Biotec: Consultancy. Viardot: Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees;Amgen: Membership on an entity's Board of Directors or advisory committees;Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees;Kite/Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees;F. Hoffmann-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees;University Hospital of Ulm: Current Employment. Ferreri: Pfizer: Research Funding;x Incyte: Membership on an entity's Board of Directors or advisory committees;Amgen: Research Funding;Genmab: Research Funding;BMS: Research Funding;Hutchison Medipharma: Research Funding;PletixaPharm: Membership on an entity's Board of Directors or advisory committees;Adienne: Membership on an entity's Board of Directors or advisory committees;ADC Therapeutics: Research Funding;Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding;Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding;Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding;Ospedale San Raffaele srl: Patents & Royalties;Beigene: Research Funding. Wong: Amgen: Current Employment;Amgen: Current equity holder in publicly-traded company. Kadu: IQVIA: Current Employment. Zugmaier: Amgen: Current Employment;Micromet/Amgen: Patents & Royalties: Patents 20190300609 and 20130323247 licensed;receives royalties of family members of international applications published as WO2010/052014;WO2010/052013;WO2011/051307;WO2012/055961;WO 2012/062596;WO2014/122251;and WO2015/181683;Amgen: Current equity holder in publicly-traded company. Zeng: Amgen: Current Employment, Current equity holder in publicly-traded company. Rambaldi: Celgene: Other: Travel, Accommodations, Expenses;Jazz Pharmaceuticals: Consultancy;Astellas Pharma: Consultancy;Novartis: Consultancy;Omeros: Consultancy, Honoraria;Amgen: Consultancy, Honoraria. OffLabelDisclosure: Blinatumomab is approved in the United States for administration as a continuous intravenous infusion. It has not been approved for subcutaneous administration.