scholarly journals 1045. Safety of the Synthetic Saponin Adjuvant TQL1055: Preliminary Results from a First-in-humans Trial

2021 ◽  
Vol 8 (Supplement_1) ◽  
pp. S614-S614
Author(s):  
Sean R Bennett ◽  
Tyler Martin
Keyword(s):  
Adverse Events ◽  
Injection Site ◽  
Dose Escalation ◽  
Large Scale ◽  
Phase 1 ◽  
Safety Data ◽  
Synthetic Analog ◽  
Injection Site Pain ◽  
The Mean ◽  
Site Pain

Abstract Background Saponin adjuvants reliably enhance immune response to a variety of antigens, but their use is hindered by dose-limiting toxicities and supply constraints. TQL1055 is a semi-synthetic analog of the natural saponin adjuvant QS-21, rationally modified to improve tolerability and enable large-scale manufacturing. We previously showed that the combination of acellular pertussis vaccine (aP) and TQL1055 was well-tolerated and increased anti-pertussis toxin (PT) antibody responses in mice and rabbits, with a no observed adverse effect level (NOAEL) > 2000 mcg/dose. Methods Here we report interim results from a Phase 1 first-in-humans dose-escalation study of TQL1055. Healthy adults 18 to 50 years of age were sequentially enrolled into 6 groups (n=12/group) and randomized 10:2 to receive one intramuscular dose of aP + TQL1055 or aP alone on Day 1. TQL1055 dose increased by group from 25 to 800 mcg (Figure 1). Local adverse events (AEs) (injection site pain, redness, swelling) and systemic AEs (fever, chills, headache, fatigue, myalgia, arthralgia, nausea, vomiting, diarrhea) were solicited through Day 8. Clinical laboratory panels (chemistry, hematology, coagulation) were performed on Days 1 (pre-dose), 8, and 29. Serious AEs were collected through Day 365. Antibodies to PT were assessed at all visits. Figure 1. Study Design Results Blinded safety data from the first four groups (n=48) through Day 8 were analyzed, including 2 subjects/group receiving aP alone. All solicited AEs were mild or moderate (Figure 2). Local AEs, mainly injection site pain, occurred in 75% of subjects (mild 65%, moderate 10%). The incidence of total local AEs increased with TQL1055 dose, from 50% at 25 mcg to 92% at 200 mcg. The mean duration of local AEs was 1.8 days and also increased with TQL1055 dose, from 1.3 days at 25 mcg to 2.1 days at 200 mcg. Systemic AEs, mostly fatigue, headache, and nausea, occurred in 63% of subjects (mild 40%, moderate 23%), with no fevers. The mean duration of systemic AEs was 1.4 days, with no association with TQL1055 dose. No severe or serious adverse events were reported. Figure 2. Solicited Adverse Events by Severity and TQL1055 Dose Conclusion In this early analysis, the safety profile of aP + TQL1055 appears similar to that of licensed aP vaccines, without severe or prolonged injection site pain. These data support further dose escalation and assessment of immunogenicity. Disclosures Sean R. Bennett, MD PhD, Adjuvance Technologies (Employee) Tyler Martin, MD, Adjuvance Technologies (Employee, Shareholder)

A Stromal Cell Derived Factor 1 (SDF-1) Agonist Stimulates Neutrophil Mobilization in Normal Humans after Subcutaneous Injection.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4262-4262
Author(s):  
Donald Wong ◽  
Walter Korz ◽  
Ahmed Merzouk ◽  
Hassan Salari ◽  
Bensinger I. William
Keyword(s):  
Stem Cells ◽  
Adverse Events ◽  
Injection Site ◽  
Neutrophil Count ◽  
Dose Escalation ◽  
Blood Cells ◽  
Stromal Cell ◽  
Injection Site Pain ◽  
Stromal Cell Derived Factor ◽  
Site Pain

Abstract Stromal cell-derived factor-1 (SDF-1) is a well known key signaling molecule in the proliferation, homing, engraftment and expansion of hematopoietic stem cells and leukocytes. CTCE-0214, a peptide produced by rational drug design, is an analog of SDF-1 and agonist of the SDF-1 receptor, CXCR4. In vitro and in vivo models have shown that CTCE-0214 mobilized blood and progenitor cells and enhanced the survival and expansion of cord blood cells (Letters in Drug Design and Discovery.1:126, 2004; Exp Hematol.32:470, 2004; Exp Hematol.32:300, 2004; Stem Cells. In press). In this first phase I clinical trial of CTCE-0214, the safety and tolerability of single doses of CTCE-0214 given subcutaneously to healthy subjects as well as the pharmacokinetic profile and the pharmacodynamic effects were studied. The randomized, double-blinded, placebo-controlled dose-escalation trial enrolled 24 subjects in six dose-escalation groups. Four healthy human subjects in each cohort received either CTCE-0214 or Placebo, randomized in a 3:1 ratio. The starting dose for CTCE-0214 was 0.2 mg/kg. Successive dose cohorts received 0.5 mg/kg, 0.8 mg/kg, 1.5 mg/kg, 2.0 mg/kg, and 3.0 mg/kg. CTCE-0214 was shown to be safe with no serious adverse events reported in any of the dose levels studied. The most common drug related adverse events were injection site pain and erythema which were transient and resolved without intervention. The severity of injection site pain appeared to have an association with the overall quantity of study drug administered. Moderate or severe pain was reported only in subjects who received at least 80 mg of CTCE-0214 per syringe. Dilution across more than one syringe appeared to be effective in reducing injection site pain. Pharmacokinetic analysis of CTCE-0214 plasma concentrations showed that Tmax was reached at 0.25 hours post-administration for all CTCE-0214 treated cohorts. The apparent terminal elimination half-life (t1/2) values were estimated to be 0.41 to 0.32 hours. CTCE-0214 administration was associated with significant dose-dependent increases in total white blood cell and neutrophil counts in treated subjects, peaking at around 6 hours post-injection. In the 3.0 mg/kg arm, the mean difference in neutrophil count from baseline was more than three times the corresponding figure in the Placebo arm. The same trend was apparent in the 2.0 and 1.5 mg/kg arms with a greater than two times and two times increases, respectively. These results suggest that SDF-1 agonists may potentially be used in patients with low neutrophil count receiving chemotherapy with or without the use of G-CSF. The potential for CTCE-0214 to mobilize neutrophils and other blood cells merits serious consideration.

scholarly journals Adverse events following immunization with Covi-shield tm vaccine: a descriptive cross-sectional study at a tertiary center, Nepal

2021 ◽  
pp. 163-163
Author(s):  
Gopal Lama ◽  
Runa Jha ◽  
Sagar K Rajbhandari ◽  
Jenish Neupane ◽  
Anup Bastola
Keyword(s):  
Adverse Events ◽  
Injection Site ◽  
Cross Sectional Study ◽  
Injection Site Pain ◽  
Sectional Study ◽  
Serious Adverse Events ◽  
Cross Sectional ◽  
Tertiary Center ◽  
National Public Health ◽  
Site Pain

Introduction: As the COVID-19 pandemic continues to unfold, rapid global efforts to develop and test vaccines against SARS-CoV-2 have started. Adverse events after immunization are a common issue seen in many vaccines. This study aims at finding the adverse events following the first dose of CovishieldTM vaccine administered to the staffs at two health institutions in Kathmandu. Methods: This was a descriptive cross sectional study conducted among the staffs at National Public Health Laboratory and Sukraraj Tropical and Infectious Disease Hospital, Kathmandu between February to April, 2021. It included 162 participants who had taken the first dose of CovishieldTM vaccine. Ethical approval was taken from Nepal Health Research Council. Statistical Package for the Social Sciences were used for analysis. Results: Various adverse events were seen in 139 (85.8%) participants which were all minor events. None of the participants developed serious adverse events. Very common adverse events experienced were Injection site pain 116 (71.6%), myalgia 76 (46.9%), chills 68 (42%), headache 65 (40.1%), fever 54 (33.3%), dizziness 43 (26.5%) and nausea 20 (12.4%). Similarly, the range of time period from onset to recovery of adverse event was different for different adverse reactions. Conclusions: The adverse events following first dose of CovishieldTM vaccine were all minor reactions with commonest being injection site pain followed by myalgia, chills, headache and fever.

DNA Demethylation Activity Over Time and Safety Of 3 Different Dose-Escalation Regimens Of SGI-110, a Novel Subcutaneous (SQ) Hypomethylating Agent (HMA), In The Treatment Of Relapsed/Refractory Patients With MDS and AML

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1548-1548
Author(s):  
Gail J. Roboz ◽  
Jean-Pierre Issa ◽  
David Rizzieri ◽  
Wendy Stock ◽  
Casey O'Connell ◽  
...  
Keyword(s):  
Injection Site ◽  
Dose Escalation ◽  
Research Funding ◽  
Injection Site Reaction ◽  
Dna Demethylation ◽  
Clinical Activity ◽  
Injection Site Pain ◽  
Clinical Responses ◽  
Previously Treated ◽  
Site Pain

Abstract Background SGI-110 is a second generation HMA formulated as a dinucleotide of decitabine (DAC) and deoxyguanosine. The compound is delivered as a small volume, pharmaceutically stable subcutaneous (SQ) injection which allows longer half-life and more extended DAC exposure than DAC intravenous infusion. This pharmacokinetic profile offers the potential for improved biological and clinical activity and safety over currently available HMAs (Kantarjian et al. ASH, 2012). Methods A randomized Phase 1-2 first-in-human PK/PD-guided, dose-escalation study was conducted in patients with relapsed or refractory intermediate or high-risk MDS or AML. Patients were initially randomized to one of two SQ regimens - Dailyx5 or Weeklyx3, for 28-day courses. Subsequently, a Twice Weeklyx3 regimen (Monday, Thursday) was added for evaluation based on emerging LINE-1 demethylation data from the Weeklyx3 regimen. Results 93 patients (74 AML, 19 MDS) were treated in the dose escalation phase: 44, 34, and 15 patients were treated in the Dailyx5, Weeklyx3, and the Twice Weeklyx3 regimens, respectively. Across the three regimens, median age was 70 years (range, 29–86), 68% male, and 87% had ECOG PS of 0-1. The median number of prior regimens was 3 (range, 1–9) and 68% of patients had prior HMA treatment (59% AML, and 100% MDS). Of the 74 AML patients treated, 31 (42%) had secondary AML including antecedent MDS. Patients received a median of 2 courses of SGI-110 (range, 1-20). LINE-1 demethylation data at the 2 highest dose levels which were well tolerated and evaluated for all 3 regimens (60 and 90 mg/m2) are shown in the figure below. The Dailyx5 regimen demonstrated the most potent average LINE-1 demethylation, while the Twice Weeklyx3 achieved the most prolonged LINE-1 demethylation. The least potent demethylation was seen with the Weeklyx3 regimen. There was no additional demethylation at the 90 mg/m2 dose compared to 60 mg/m2in all 3 regimens. Responses were reported according to the IWG Criteria 2006 (MDS)/2003 (AML). Complete remissions were observed in 5 AML patients (2CRs, 1CRp, and 2CRi). Clinical responses (2 mCR and 3 HI-E, 1 HI-N, 1 HI-P) were observed in 6 MDS patients, all of whom had been previously treated with HMA. All AML responses and both mCR in MDS patients achieved ≥10% LINE-1 demethylation. Safety is reported based on Adverse Events (AEs) as graded by the CTCAE v4 criteria. Across regimens, the Twice Weeklyx3 demonstrated an increased number of related AEs compared to the other regimens. The most commonly reported related AEs ≥ 10% in the Dailyx5 regimen (injection site pain, thrombocytopenia, neutropenia, anemia, fatigue), Weeklyx3 regimen (injection site pain and diarrhea), and Twice Weeklyx3 regimen (injection site pain, injection site reaction, fatigue, dizziness, febrile neutropenia, neutropenia, anemia, and thrombocytopenia). Conclusions SQ SGI-110 is a potent HMA using all 3 regimens evaluated. The most potent hypomethylation was achieved with Dailyx5 dosing and the most prolonged hypomethylation was achieved using the Twice Weeklyx3 regimen. All 3 regimens were well tolerated. Clinical responses were observed in heavily pretreated patients, including those with prior HMA exposure. These results support the ongoing Phase 2 expansion study investigating the Dailyx5 dosing schedule in patients with MDS and AML who are either HMA treatment naïve or previously treated with HMAs. Disclosures: Roboz: Astex Pharmaceuticals, Inc.: Honoraria, Research Funding. Issa:Astex Pharmaceuticals Inc.: Honoraria, Research Funding. Rizzieri:Astex Pharmaceuticals, Inc.: Research Funding. Stock:Astex Pharmaceuticals, Inc.: Research Funding. O'Connell:Astex Pharmaceuticals, Inc.: Research Funding. Yee:Astex Pharmaceuticals, Inc.: Research Funding. Tibes:Astex Pharmaceuticals, Inc.: Research Funding. Griffiths:Astex Pharmaceuticals, Inc.: Research Funding. Walsh:Astex Pharmaceuticals, Inc.: Research Funding. Feldman:Astex Pharmaceuticals, Inc.: Research Funding. Ritchie:Astex Pharmaceuticals, Inc.: Research Funding. Rao:Astex Pharmaceuticals, Inc.: Research Funding. Larson:Astex Pharmaceuticals, Inc.: Research Funding. Garcia-Manero:Astex Pharmaceuticals, Inc.: Research Funding. Ravandi:Astex Pharmaceuticals, Inc.: Research Funding. Jabbour:Astex Pharmaceuticals, Inc.: Research Funding. Cortes:Astex Pharmaceuticals, Inc.: Research Funding. Schimmer:Astex Pharmaceuticals, Inc.: Research Funding. Mesa:Astex Pharmaceuticals, Inc.: Research Funding. Blum:Astex Pharmaceuticals, Inc.: Research Funding. Chung:Astex Pharmaceuticals Inc.: Research Funding. Naim:Astex Pharmaceuticals, Inc.: Employment. Taverna:Astex Pharmaceuticals Inc.: Employment. Hao:Astex Pharmaceuticals Inc.: Employment. Choy:Astex Pharmaceuticals, Inc.: Employment. Azab:Astex Pharmaceuticals Inc.: Employment. Kantarjian:Astex Pharmaceuticals, Inc.: Research Funding.

POS1248 SAFETY PROFILE OF PFIZER-BIONTECH COVID-19 VACCINE IN PATIENTS WITH RHEUMATIC DISEASES: PRELIMINARY ASSESSMENT

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 907.2-908
Author(s):  
G. Cuomo ◽  
M. Atteno ◽  
C. Naclerio ◽  
L. E. Adinolfi ◽  
C. Romano
Keyword(s):  
Adverse Events ◽  
Injection Site ◽  
Rheumatic Diseases ◽  
Healthy Subjects ◽  
Vaccine Dose ◽  
Injection Site Pain ◽  
Multicenter Observational Study ◽  
Lymph Node Enlargement ◽  
Preliminary Study ◽  
Site Pain

Background:Efficacious vaccines are urgently needed to contain the ongoing coronavirus disease 2019 (Covid-19) pandemic of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). On December 11, 2020, the Food and Drug Administration (FDA) issued an Emergency Use Authorization (EUA) for Pfizer-BioNTech COVID-19 vaccine to prevent COVID-19, administered as 2 doses separated by 21 days (1)On December 27, 2020, Italy started use of Pfizer-BioNTech COVID-19 vaccine and initial doses were reserved for health care personnelObjectives:The primary end points were the safety of each administered dose in patients with Rheumatic diseases (RD’s)Methods:In this multicenter, observational study, we interviewed by phone 27 patients with rheumatic diseases (RDs) and 30 healthy subjects receiving the Pfizer-BioNTech vaccine (0.3 ml i.m. in two doses 21 days apart, time 0 and 3 weeks).Results:As of 30 January 2021, 57 subjects (27 patients and 30 healthy subjects) were interviewed. The epidemiological and clinical features of the 27 patients are reported in Table 1. Among the whole population, 35 subjects (16 patients and 19 healthy subjects) complained of an adverse event after the first vaccine dose, with symptom onset occurring within 1 day of vaccination. All adverse events (100%) were classified as nonserious and included: injection site pain (17), fatigue (5), headache (16), fever (3), tachycardia (2), and paresthesia (2).After 21 days, 6 patients and 11 healthy subjects received the second vaccine dose. Fifteen (5 patients and 10 healthy subjects) of them (88%) reported adverse events, again categorized as nonserious. Specifically, injection site pain (7), fatigue (10), headache (10), fever (10), paresthesia (1), cutaneous vasculitis (1), itchy and scratchy throat (1), diarrhea (4), lymph node enlargement (1) were recorded. No differences were noted between patients with RDs and healthy subjects in terms of adverse events.Conclusion:This preliminary study shows that the Pfizer-BioNTech COVID-19 vaccine is as safe in patients with RDs as in healthy subjects. Whether patients with RDs will develop protective titers of anti-SARS-CoV-2 antibodies as compared to healthy subjects will be evaluated in further, ongoing studies.References:[1]Dooling K et al. MMWR Morb Mortal Wkly Rep 2020; 69:1857Table 1.Acknowledgements:I thank the Italian League of Systemic Sclerosis for launching a survey for ssc patients.Disclosure of Interests:None declared

Results From the Dose Escalation Phase of a Randomized Phase 1–2 First-in-Human (FIH) Study of SGI-110, a Novel Low Volume Stable Subcutaneous (SQ) Second Generation Hypomethylating Agent (HMA) in Patients with Relapsed/Refractory MDS and AML

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 414-414 ◽  
Author(s):  
Hagop M. Kantarjian ◽  
Gail J. Roboz ◽  
David A. Rizzieri ◽  
Wendy Stock ◽  
Casey L. O'Connell ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Research Funding ◽  
Phase 1 ◽  
Clinical Activity ◽  
Daily Regimen ◽  
Injection Site Pain ◽  
Heavily Pretreated ◽  
Clinical Responses ◽  
Low Volume ◽  
Site Pain

Abstract Abstract 414 Background: SGI-110 is a dinucleotide of decitabine (DAC) and deoxyguanosine formulated as a low volume and pharmaceutically stable SQ injection allowing more extended decitabine exposure than DAC IV infusion. The anticipated differentiated PK profile offers the potential of improved biological and clinical activity and safety over currently available HMAs. Methods: A randomized Phase 1–2 FIH Pharmacokinetics/Pharmacodynamics (PK/PD)-guided, dose-escalation study has been conducted in patients with relapsed/refractory intermediate or high-risk MDS or AML. The objective of the first stage (dose escalation) is to determine safety and tolerability and to establish the Maximum Tolerated Dose (MTD) and Biologically Effective Dose (BED). Patients were randomized to one of two SQ regimens (dailyx5 or once weeklyx3, 28-day courses). PD is evaluated by LINE-1 global DNA hypomethylation. The second stage (dose expansion) is to determine the clinical activity and safety in AML and MDS using the established BED and MTD. We report here the results of the dose escalation phase which has completed enrolment. Results: 78 patients (64 AML, 14 MDS) were enrolled in the dose escalation phase: 44 patients in the dailyx5 regimen and 34 in the weeklyx3 regimen. Median age was 69 years (range 29–86), 65% were male, and 82% had ECOG PS of 0–1. Median number of prior regimens was 3 (range 1–9), 59% of patients had prior HMA treatment (50% of AML patients, and 100% of MDS patients). Six patients are still ongoing treatment. The PK profile demonstrated efficient conversion of SGI-110 to decitabine as predicted from the SGI-110 rational design, resulting in longer decitabine exposure window (beyond 8 hrs) compared to DAC IV (3–4 hrs). At SGI-110 dose range of 60–125 mg/m2, observed mean decitabine AUCs (88–231 ng*hr/mL) reach or exceed the therapeutic range seen with 20 mg/m2 DAC IV (115 ng*hr/mL) while achieving only a small fraction of the Cmax (26–64 ng/mL vs 146 ng/mL for DAC IV). The effective half-life for decitabine after SQ SGI-110 injection appeared to be prolonged (up to 4-fold or ∼2.4 hrs) compared to DAC IV (0.58 hrs). Decitabine exposures (AUC) increased in a dose-proportional manner regardless of the regimen and no accumulation was observed. Dose-related LINE-1 hypomethylation was observed in patients treated with the daily regimen between 18 and 60 mg/m2; a plateau in maximum average hypomethylation (∼25%) was evident at higher daily doses (90-125 mg/m2) and therefore the BED for the dailyx5 schedule is established at 60 mg/m2. The 25% average hypomethylation of LINE-1 compares favorably with that observed historically after DAC IV at the dose of 20 mg/m2 dailyx5. The extent of LINE-1 hypomethylation after weeklyx3 SGI-110 was inferior as the maximum average hypomethylation plateaued at ∼8% from baseline. Starting at 36 mg/m2 daily and 60 mg/m2 weekly (44 AML, and 7 MDS patients), clinical responses were observed: 2CRs, 1CRp, and 1CRi in heavily pretreated AML patients; 1 mCR and 1 HI in MDS patients previously treated with azacitidine. All responses were in patients who achieved >10% LINE-1 hypomethylation. The most common Adverse Events (AEs), regardless of relationship to SGI-110, were diarrhea (21%), febrile neutropenia (17%), fatigue/injection site pain/nausea at 15% each. The most common drug-related AEs were injection site pain (15%), fatigue (8%), nausea (6%), and thrombocytopenia (5%). MTD was not reached with the weekly regimen up to 125 mg/m2 weeklyx3. With the daily regimen, 125 mg/m2dailyx5 resulted in 2 Dose-Limiting Toxicities (DLTs) of febrile neutropenia in 3 MDS patients (1 associated with bacteremia, and the other with sepsis and thrombocytopenia Grade 4) while none of the 9 patients with AML had DLT at that dose. Conclusions: SGI-110 is well tolerated at doses higher than BED which is established at 60 mg/m2 dailyx5 where average hypomethylation of ∼25% was achieved. MTD estimated to be 90 mg/m2 dailyx5 for MDS and 125 mg/m2dailyx5 for AML patients. SQ administration of SGI-110 achieved efficient conversion to decitabine resulting in an improved PK profile over DAC IV. Clinical responses were observed in this heavily pretreated population and they seem to correlate with the extent of LINE-1 hypomethylation. Study is currently enrolling patients in the dose-expansion Phase 2 stage. Disclosures: Kantarjian: Astex Pharmaceuticals: Research Funding. Roboz:Astex Pharmaceuticals: Research Funding. Rizzieri:Astex Pharmaceuticals: Research Funding. Stock:Astex Pharmaceuticals: Research Funding. O'Connell:Astex Pharmaceuticals: Research Funding. Griffiths:Astex Pharmaceuticals: Research Funding. Yee:Astex Pharmaceuticals: Research Funding. Tibes:Astex Pharmaceuticals: Research Funding. Garcia-Manero:Astex Pharmaceuticals: Research Funding. Ravandi:Astex Pharmaceuticals: Research Funding. Walsh:Astex Pharmaceuticals: Research Funding. Feldman:Astex Pharmaceuticals: Research Funding. Ritchie:Astex Pharmaceuticals: Research Funding. Rao:Astex Pharmaceuticals: Research Funding. Decastro:Astex Pharmaceuticals: Research Funding. Schimmer:Astex Pharmaceuticals: Research Funding. Mesa:Astex Pharmaceuticals: Research Funding. Syed:Astex Pharmaceuticals: Research Funding. Choy:Astex Pharmaceuticals: Employment. Oganesian:Astex Pharmaceuticals: Employment. Taverna:Astex Pharmaceuticals: Employment. Azab:Astex Pharmaceuticals: Employment. Chung:Astex Pharmaceuticals: Research Funding. Issa:Astex Pharmaceuticals: Honoraria, Research Funding.

scholarly journals Phase 1 Safety and Immunogenicity Study of a Quadrivalent Seasonal Flu Vaccine Comprising Recombinant Hemagglutinin-Flagellin Fusion Proteins

2016 ◽  
Vol 3 (1) ◽  
Author(s):  
Lynda Tussey ◽  
Cynthia Strout ◽  
Matthew Davis ◽  
Casey Johnson ◽  
Gregg Lucksinger ◽  
...  
Keyword(s):  
Injection Site ◽  
Dose Level ◽  
Phase 1 ◽  
Injection Site Pain ◽  
Open Label ◽  
Seasonal Flu ◽  
Flu Vaccine ◽  
Systemic Symptoms ◽  
Dose Levels ◽  
Site Pain

Abstract Background.  We evaluated the safety and immunogenicity of VAX2012Q, a quadrivalent influenza vaccine comprising 4 hemagglutinin subunits fused to flagellin. Methods.  In this dose-ranging, open-label study, healthy adults (18–40 years) were divided into 7 cohorts for evaluation of 5 dose levels and 3 component ratios. Dose levels were as follows: (1) 1 mcg per component of VAX128C (H1N1), VAX181 (H3N2), VAX173 (B-YAM), and VAX172 (B-VIC), respectively; (2) 2 mcg per component, respectively; (3) 2, 4, 4, and 4 mcg of each component, respectively; (4) 2, 4, 6, and 6 mcg of each component, respectively; and (5) 3 mcg per component, respectively. Tolerability and immunogenicity data were analyzed. Results.  Three hundred sixteen subjects received VAX2012Q (309 per protocol). At all dose levels, 54% to 65% of subjects reported mild injection site pain, the most common local reaction. Moderate injection site pain increased at dose levels 2 through 5 (22%–42%, compared with 20% at dose level 1). Systemic symptoms were mostly mild to moderate with moderate symptoms increasing in dose levels 3 and 4. Three dose level 3 subjects (6%) reported severe, transient chills and or fever. Mean fold rises in hemagglutination inhibition titers ranged from 2.5 to 6.9 despite high baseline titers. Mean seroprotection rates were ≥90% and mean seroconversion rates were ≥40% for all strains in all groups postvaccination. Conclusions.  VAX2012Q elicited immune responses at all dose levels with no significant safety concerns. Doses of 2 or 3 mcg per component provided a favorable balance of tolerability and immunogenicity.

scholarly journals 1288. Phase 1 First-in-Human Single- and Multiple-Ascending Dose Trial Demonstrates Pharmacokinetics (PK) and Tolerability of SPR720, an Oral DNA GyrB Inhibitor for Mycobacterial Infections

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S659-S659
Author(s):  
Angela Talley ◽  
Archie Thurston ◽  
Grayson Moore ◽  
Myriah M Satterfield ◽  
Erika L Manyak ◽  
...  
Keyword(s):  
Adverse Events ◽  
Healthy Volunteers ◽  
Controlled Trial ◽  
Phase 1 ◽  
Safety Data ◽  
Elderly Subjects ◽  
Independent Contractor ◽  
Serious Adverse Events ◽  
Healthy Elderly ◽  
Dose Proportional

Abstract Background SPR720 (phosphate pro-drug of SPR719) is a novel aminobenzimidazole bacterial DNA gyrase (GyrB) inhibitor in development for non-tuberculous mycobacterial lung disease (NTM-LD) and pulmonary tuberculosis. SPR719 has broad-spectrum activity versus clinically relevant mycobacteria in vitro and in murine and hollow fiber (HF) infection models. In this first-in-human single ascending dose (SAD) /multiple ascending dose (MAD) study, the safety, tolerability and pharmacokinetics (PK) of SPR720/SPR719 were evaluated in healthy volunteers. Methods This was a Phase 1 randomized, double-blind, placebo-controlled trial with 7 SAD cohorts (including a food effect cohort) and 5 MAD cohorts. Healthy volunteers (n=8/cohort, 3:1 randomization) received SPR720 or placebo in single oral doses of ranging from 100 mg to 2000 mg or repeat total daily doses ranging from 500 mg to 1500 mg for 7 or 14 days. Safety monitoring and PK sampling occurred throughout the trial. Plasma and urine concentrations of SPR720/SPR719 were measured by validated LC-MS/MS methods. PK parameters were calculated using non-compartmental analysis. Results A total of 96 subjects (including 8 healthy elderly subjects, age ≥ 65 years) were randomized and received study drug. SPR720 was well-tolerated at daily doses up to 1000 mg for up to 14 days. Across SAD/MAD cohorts, the most common adverse events were gastrointestinal (nausea, vomiting and diarrhea) and headache, all of mild or moderate severity and dose dependent. No serious adverse events were reported. Across SAD cohorts, a dose proportional and greater-than-dose proportional increase in SPR719 plasma Cmax and AUC0-24, respectively were observed. SPR720 was rapidly absorbed with a mean SPR719 t1/2 of 2.9-4.5 h. Dosing with food decreased SPR719 plasma AUC by ~20%. No clinically meaningful effect of age on plasma AUC was observed. In the MAD cohorts, SPR719 plasma exposure declined approximately 40% between Day 1 and Day 7, suggesting induction of an elimination pathway. However, plasma AUC0-24 was similar at Days 7 and 14. Conclusion Together with HF pharmacodynamic data, human PK and safety data for SPR720 suggest that predicted therapeutic exposures can be attained with a well-tolerated once-daily dose. Further evaluation in a Phase 2 NTM-LD trial is planned. Disclosures Angela Talley, MD, Spero Therapeutics (Employee, Shareholder) Archie Thurston, Jr., PhD, Spero Therapeutics (Consultant) Grayson Moore, BA, RN, Spero Therapeutics, Inc. (Shareholder, Independent Contractor) Vipul Kumar, PhD, Spero Therapeutics (Employee, Shareholder) Suzanne Stokes, PhD, Spero Therapeutics (Employee, Shareholder) Aaron Dane, MSc, Spero theraputics (Consultant) David Melnick, MD, Spero Therapeutics (Employee)Spero Therapeutics (Employee)

scholarly journals AB1343-HPR A QUALITATIVE REVIEW ASSESSING THEMATIC OUTCOMES FROM THE PHARMACY-LED ADALIMUMAB BIOSIMILAR SWITCH PLAN ACROSS 3 SPECIALITIES; RHEUMATOLOGY, GASTROENTEROLOGY AND DERMATOLOGY AT UNIVERSITY HOSPITALS OF COVENTRY AND WARWICKSHIRE (UHCW)

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1959.1-1960
Author(s):  
S. Gohil
Keyword(s):  
Cost Saving ◽  
Injection Site ◽  
Cost Savings ◽  
Latex Allergy ◽  
Foot Drop ◽  
Injection Site Pain ◽  
Patient Counselling ◽  
Qualitative Review ◽  
Patient Reported ◽  
Site Pain

Background:The advent of biosimilars has heralded a new era for cost effective biologic prescribing in the NHS. As patents expire for originator biologics, less expensive versions are now widely available as biosimilars. Non-medical switches (for reasons unrelated to a patient’s health) ensure prescribing of best value medicines, and cost savings can be redirected to patient care.1This practice resonates with recommendations from Lord Carter’s 2016 report regarding reducing unwarranted variation in the NHS and adopting cost saving opportunities.2In 2018/19, following loss of patent exclusivity for the expensive adalimumab originator biologic, UHCW worked in accordance with national directives to drive forward one of the largest non-medical biosimilar switches.Objectives:This qualitative review aims to explore the success of the adalimumab biosimilar switch and key themes associated with switch backs/refusals across the Rheumatology (R), Gastroenterology (G) and Dermatology (D) specialities at UHCW.Methods:The switch plan occurred between April-December 2019. 403 patients (R;189, G;176, D; 38) were eligible for switch. Patients were informed of the plan in advance via a patient information leaflet/hospital clinic visits. Switch refusals, withheld treatments and cancellations were documented and patients were advised to contact the hospital pharmacy/clinical teams if they encountered any concerns, adverse effects or lack of efficacy post switch. The clinician would then advise on subsequent management.Results:During April-December 2019, 264/403 patients had been successfully switched (R;122, G;109, D;33). 33/403 patients switched back to the originator biologic (R;22, G;10; D;1). Of the 22 rheumatology switch back patients; 6 patients reported injection site pain and variably headache, fatigue, disease relapse, gastrointestinal (GI) upset, erythema; 10=reported lack of efficacy and variably influenza-type symptoms, relapse in associated psoriasis, difficulty in walking/sleeping, hair loss, excessive perspiration, facial cellulitis, foot drop and GI upset; 1=blepharitis;1=latex allergy before injection; 3=later declined switch; 1=damaged two devices and did not wish to continue biosimilar. Of the 10 gastroenterology switch back patients; 1=injection site pain; 2=lack of efficacy; 1=developed needle phobia; 1=latex allergy before injection; 1=switch detrimental to health; 2=unstable disease; 1=insomnia; 1=pregnancy. The 1 dermatology switch back patient reported injection site pain and bleeding.38/403 patients refused the switch and remained on the originator biologic (R;11, G;27, D;0). 29/403 patients had treatment cancellations and were switched to an alternative biologic (R;17, G;9, D;3). 32/403 patients stopped treatment (R;13, G;19, D;0). Treatment was withheld for 7/403 patients (R;4, G;2, D;1).Conclusion:The UHCW adalimumab biosimilar switch plan succeeded in switching a total of 66% of patients; thus an annual cost saving of £73,020. Injection site pain, most likely due to the biosimilar citrate content, and lack of efficacy according to patient perception and subsequent clinical review, were the most predominant causative themes for switch backs. Gastroenterology patients accounted for 71% (27/38) of the total switch refusals. Additional data regarding patient refusals, identifies future opportunities to improve patient counselling and drive further cost savings.References:[1]Azevedo V, et al. Biosimilars: considerations for clinical practice. Considerations in Medicine. 2017;1(1):13–8[2]Lord Carter of Coles. (2016) Operational productivity and performance in English NHS Acute Hospitals: Unwarranted variations [Online]Acknowledgments:Mark Easter, Chief Pharmacist, Hardeep Bagga, Deputy Chief Pharmacist, UHCW Pharmacy Homecare Team, UHCW Specialist Clinical Teams.Disclosure of Interests:None declared

405 CDX1140–01, a phase 1 dose-escalation/expansion study of CDX-1140 alone (Part 1) and in combination with CDX-301 (Part 2) or pembrolizumab (Part 3)

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A430-A430
Author(s):  
Rachel Sanborn ◽  
Ralph Hauke ◽  
Nashat Gabrail ◽  
Mark O’Hara ◽  
Nina Bhardwaj ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Metabolic Response ◽  
Phase 1 ◽  
Safety Data ◽  
Systemic Exposure ◽  
University Of Pennsylvania ◽  
Cancer Center ◽  
Low Grade ◽  
Metastatic Pancreatic Adenocarcinoma ◽  
Expansion Cohort

BackgroundCDX-1140 is an agonist anti-CD40 mAb selected to optimize systemic exposure and hence tumor microenvironment (TME) ingress. CDX-1140 activity may be enhanced by combining with CDX-301 (recombinant Flt3L), a dendritic cell growth factor, or with pembrolizumab, an anti-PD-1 mAb.MethodsPatients with advanced solid or hematologic (Part 1 only) tumors are enrolled. Part 1 dose-escalation results have been presented (SITC 2019). In Part 2, CDX-1140 dose-escalation (0.09–1.5 mg/kg q4w) is in combination with CDX-301 (75 mcg/kg sc QD x 5 for 2 cycles). In Part 3, CDX-1140 dose-escalation (0.72–1.5 mg/kg q3w) is in combination with pembrolizumab 200 mg q3w. Part 1 and 2 expansion cohorts are dosed at the CDX-1140 MTD, 1.5 mg/kg q4w. Part 3 expansion cohorts are planned. Peripheral blood and tumor biomarkers analysis are ongoing.Results92 patients have been treated (Part 1 n=57, Part 2 n=31, Part 3 n=4). Part 1 expansion cohorts in SCCHN (n=7) and RCC (n=5) are fully enrolled. Part 2 dose-escalation completed to the highest CDX-1140 dose and a SCCHN expansion cohort is ongoing. Part 3 dose-escalation recently initiated. Safety data is available for 23 and 10 patients at the MTD in Part 1 and 2, respectively. In general, the safety profiles were similar, with arthralgia (52% vs. 50%), pyrexia (44% vs 50%), fatigue (30% vs. 50%), chills (39% vs. 40%), vomiting (30% vs. 20%), nausea (26% vs 40%), myalgia (22% vs. 30%), increased ALT (22% vs. 20%), and increased AST (22% vs. 30%) being the most common drug related AEs at the MTD in Part 1 and 2, respectively. Most AEs were low grade. Across all cohorts, cytokine release syndrome (CRS) (G2 n=4, G3 n=2) occurred in 6 (Part 1 n=2; Part 2 n=4) and pneumonitis (G3) occurred in 5 (Part 1 n=4; Part 2 n=1) patients. Immune activation in the TME consistent with CD40 agonism and increases serum inflammatory cytokines were observed. Evidence of anti-tumor activity/clinical benefit include SD (n=13), tumor cavitation (n=2) and a uPR in solid tumors. A patient with follicular lymphoma has an ongoing durable complete metabolic response.ConclusionsThe CDX-1140 MTD dose of 1.5 mg/kg, a dose level expected to provide good systemic exposure and TME penetration, is generally well tolerated alone and with CDX-301. Transaminitis and CRS have generally been low grade and infrequent. A cohort combining CDX-1140 with chemotherapy will be initiated in patients with previously untreated metastatic pancreatic adenocarcinoma.Trial RegistrationNCT03329950Ethics ApprovalThe study was approved by the following: Providence St. Joseph Health IRB, approval number MOD2020001128; WIRB, approval number 1188814 (Hauke, Gabrail, Bordoni & Gordon); University of Pennsylvania IRB, approval number UPCC 18917; Mount Sinai School of Medicine IRB, approval number 18-00202; Memorial Sloan Kettering Cancer Center IRB, approval number 18-225A; Houston Methodist IRB, approval number MOD00000836

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