scholarly journals The Safety of Novel Drugs Targeting Factor XI and XII in Human Clinical Trials:a Systematic Review

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4966-4966
Author(s):  
Gillian E Mair ◽  
Sven Reid Olson ◽  
Joseph J Shatzel
Keyword(s):  
Monoclonal Antibody ◽  
Clinical Trials ◽  
Adverse Events ◽  
Dose Escalation ◽  
Phase 1 ◽  
Postoperative Bleeding ◽  
Phase 2 ◽  
Risk Of Bleeding ◽  
Novel Drugs ◽  
Contact Pathway

Introduction While effective at treating and preventing thrombosis, modern forms of anticoagulation universally increase the risk of hemorrhage. Data suggests that factors FXI and FXII could serve as druggable targets to provide anticoagulation without increasing the risk of bleeding. The purpose of this systematic review is to evaluate the safety of novel drugs targeting FXI and FXII in human clinical trials. Methods We performed a search in Ovid MEDLINE to identify published manuscripts describing administration of contact pathway-inhibiting drugs to humans. All human clinical trials evaluating a drug specific to FXI or FXII were included. Outcomes of interest collected for analysis included primarily bleeding events of any type, total adverse events (AEs)as well as other treatment-emergent adverse events (TEAE) and treatment-related adverse events (TRAE). Results A total of 338 published articles were identified from the original search. After screening, one phase 2 study of an antisense oligonucleotide (ISIS 416858) and three phase 1 trials of monoclonal antibodies (AB023, BAY1213790, MAA868) were included. A total of 465 patients across these 4 clinical trials were included. No patients experienced spontaneous bleeding. Postoperative bleeding occurred in 3% of patients treated with ISIS 416858 at each dose level and one patient experienced major bleeding. For comparison an 8% postoperative bleeding rate was seen in the arm treated with prophylactic low molecular weight heparin (LMWH). AB023, a monoclonal antibody inhibiting FXIIa-mediated activation of FXI to FXIa, was examined in a phase 1, dose-escalation trial in 21 healthy adults. Overall, there were no severe AEs. Minor AEs occurred in 10 of the 21 patients. 3 patients were deemed to possibly have TRAE. There was no statistical difference in bleeding time compared to placebo. activated thromboplastin time (aPTT) was prolonged for over a month after the highest dose level. BAY1213790 is a monoclonal antibody targeting the enzymatic active site of FXIa, and was studied in a phase 1 dose escalation trial in 83 healthy men. There were no severe AEs. Of the 54 subjects experiencing AEs, 34 were mild and 20 were moderate. TRAE were reported in 6 subjects. One subject had an infusion reaction and another subject requested the infusion be stopped. APTT showed a dose-dependent increase while bleeding times also did not increase compared to placebo. ISIS 416858 is an antisense oligonucleotide targeting FXI mRNA for degradation at its source within the hepatocyte. ISIS416858 was studied in a phase 2, randomized controlled trial in patients undergoing total knee arthroplasty. The safety and efficacy at preventing post-operative venous thromboembolism (VTE) was assessed at 200 mg or 300 mg doses compared to standard-of-care with LMWH. Bleeding occurred in 4 (3%), 2 (3%), and 6 (8%) patients in these three study groups, respectively. This was the only study drug where one patient experienced major bleeding. Mild AEs affected 219 subjects, with severe AEs occurring in 4 patients; only 2 discontinued ISIS416858. Patients in the 300 mg dose cohort of ISIS416858 experienced statistically fewer VTE events compared with LMWH; bleeding rates were numerically low compared to LMWH (3% vs 8%), though statistical significance was not reached. MAA868 is a monoclonal antibody targeting both the zymogen and active forms of FXI at the enzymatic active site, and was studied in a phase 1, dose-escalation clinical trial. MAA868 is unique due to its subcutaneous route of administration. Of the total 61 patient cohort, 34 patients experienced AEs and 9 TRAE. Only 2 severe, unrelated AEs occurred after the trial: one fatal cardiac arrest after elective surgery, and a gunshot wound requiring urgent surgery. MAA868 resulted in prolonged FXI suppression for up to four weeks. Conclusion Contact pathway-inhibiting drugs show promise as novel anticoagulation strategies that could significantly reduce the risk of bleeding seen with traditional anticoagulants. Additional studies are needed to further develop these drugs to test their efficacy at targeting the coagulation pathway in common settings of high risk for VTE, or existing thrombosis. The paradigm that anticoagulants cause bleeding could be broken in the near future based on this promising clinical data on contact pathway inhibition. Table Disclosures Shatzel: Aronora, Inc.: Consultancy.

scholarly journals Phase 1/2 Double-Blind, Placebo-Controlled, Dose Escalation, Safety, and Pharmacokinetic Study of Pagibaximab (BSYX-A110), an Antistaphylococcal Monoclonal Antibody for the Prevention of Staphylococcal Bloodstream Infections, in Very-Low-Birth-Weight Neonates

2009 ◽  
Vol 53 (7) ◽  
pp. 2879-2886 ◽  
Author(s):  
Leonard E. Weisman ◽  
Helen M. Thackray ◽  
Joseph A. Garcia-Prats ◽  
Mirjana Nesin ◽  
Joseph H. Schneider ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Birth Weight ◽  
High Risk ◽  
Adverse Events ◽  
Dose Escalation ◽  
Very Low Birth Weight ◽  
Phase 1 ◽  
Double Blind ◽  
Double Blind Placebo ◽  
Vlbw Infants

ABSTRACT Staphylococcal sepsis is a major cause of morbidity and mortality in very-low-birth-weight (VLBW) infants. A human chimeric monoclonal antibody, pagibaximab, was developed against staphylococcal lipoteichoic acid. We evaluated the safety, tolerability, and pharmacokinetics of pagibaximab in VLBW neonates. A phase 1/2, randomized, double-blind, placebo-controlled, dose escalation study was conducted in VLBW infants (700 to 1,300 g) 3 to 7 days old. Patients received two doses 14 days apart of intravenous pagibaximab (10, 30, 60, or 90 mg/kg of body weight) or placebo in a 2:1 ratio. Blood and urine samples were obtained pre- and postinfusion for analysis of safety and pharmacokinetics, and data on adverse events were gathered. Staphylococcal organisms causing sepsis were collected and evaluated. Fifty-three patients received at least one dose of pagibaximab or placebo. The average gestational age was 27.6 weeks; the average birth weight was 1,003 g. All serious adverse events were deemed unrelated or probably not drug related. Morbidity and mortality were similar across treatment groups. No evidence of immunogenicity of pagibaximab was detected. Pagibaximab pharmacokinetics was linear. The mean clearance (CL), volume of distribution, and elimination half-life of pagibaximab were independent of dose. The serum half-life was 20.5 ± 6.8 days. Pagibaximab enhanced serum opsonophagocytic activity. All staphylococci causing sepsis were opsonizable by pagibaximab. Two infusions of pagibaximab, administered 2 weeks apart to high-risk neonates appeared safe and tolerable, and pharmacokinetics were linear. Evaluation of more frequent doses, at the highest doses tested, in neonates at high-risk of staphylococcal sepsis, is warranted.

Phase 1 Clinical Trial of a Novel Proteasome Inhibitor (NPI-0052) in Patients with Lymphomas and Solid Tumors.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4504-4504
Author(s):  
Razelle Kurzrock ◽  
Paul Hamlin ◽  
Anas Younes ◽  
David Hong ◽  
Michael Gordon ◽  
...  
Keyword(s):  
Adverse Events ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Proteasome Inhibitor ◽  
Phase 1 ◽  
Proteasome Inhibition ◽  
Pharmacokinetic Data ◽  
Phase 2 ◽  
Phase 1 Study ◽  
Elimination Half

Abstract NPI-0052 is a novel proteasome inhibitor that produces prolonged inhibition of all three catalytic activities (C-L, T-L, CT-L) of the 20S proteasome. Preclinical data suggest NPI-0052 may demonstrate an improved therapeutic ratio, with activity in multiple myeloma, lymphoma, leukemia and solid tumor models. Phase 1 dose escalation studies are ongoing in patients with myeloma, lymphomas and solid tumors. Data from the Phase 1 study in patients with lymphomas or solid tumors are presented herein to examine the endpoints of pharmacodynamics (proteasome inhibition), pharmacokinetics and safety at doses below the MTD. Patients in this study were treated with NPI-0052 administered as a weekly IV bolus, for 3 weeks in 4-week cycles. The dose of NPI-0052 was escalated in cohorts of 3 patients dependent on observed adverse events utilizing a 3+3 design. In addition to weekly safety monitoring, proteasome inhibition and pharmacokinetics were assayed after the 1st and 3rd dose and with intrapatient dose escalations. Sixteen patients have been treated at doses ranging from 0.0125 mg/m2 to 0.112 mg/m2 for up to 7 cycles without reaching an MTD. Although, one SAE of MRSA sepsis and renal failure was reported at a dose of 0.1 mg/m2, drug related adverse events have not been reported at 0.112 mg/m2. Proteasome inhibition in whole blood has been assayed from 0.0125 mg/m2 through 0.075 mg/m2, with results ranging from no inhibition to 63% inhibition of CT-L activity and indication of a correlation of inhibition with dose, inclusive of intrapatient dose increases. Preliminary pharmacokinetic data demonstrate a rapid elimination half-life (estimated to be 3–4 minutes) with clearance between 8–21 mL/min and Vz of 44–99L. No responses have been confirmed, however, 4 patients have had stable disease for 4 or more months, including patients with hepatocellular carcinoma (6 months), adenoid cystic carcinoma (4 months and 4 months), and cervical carcinoma [7 months with investigator reported complete resolution of target (lymph node) lesion(s) to palpation]. These data suggest that NPI-0052 is affecting parameters relevant to pharmacodynamics, pharmacokinetics and potentially clinical benefit at doses below the MTD. Dose escalation continues to define a recommended phase 2 dose and further investigate the relevance of these outcomes in larger Recommended Phase 2 Dose Cohorts.

Multicenter Phase I Dose-Escalation Study of Lenalidomide in Patients with Relapsed Adult T-Cell Leukemia-Lymphoma (ATL) or Peripheral T-Cell Lymphoma (PTCL).

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2737-2737 ◽  
Author(s):  
Naokuni Uike ◽  
Michinora Ogura ◽  
Yoshitaka Imaizumi ◽  
Norio Asou ◽  
Atae Utsunomiya ◽  
...  
Keyword(s):  
Clinical Trials ◽  
T Cell ◽  
Board Of Directors ◽  
Dose Escalation ◽  
Research Funding ◽  
Phase 1 ◽  
Phase 2 ◽  
Advisory Committees ◽  
Phase 2 Study ◽  
Grade 3

Abstract Abstract 2737 Introduction: ATL is prevalent in Japan and has the worst prognosis among T-cell malignancies. PTCL also has a poor prognosis with currently available chemotherapeutic regimens, and both would benefit from better treatment modality. Lenalidomide is an immunomodulatory agent with direct tumoricidal and antiproliferative activity, and is approved for multiple myeloma (MM) in combination with dexamethasone after at least 1 prior therapy and for transfusion-dependent anemia due to low- or intermediate-1-risk myelodysplastic syndromes associated with 5q deletion. We conducted a phase 1 study of lenalidomide in patients with relapsed ATL or PTCL to establish the recommended dose and schedule for a subsequent phase 2 study. Patients and Methods: This multicenter, phase 1, dose-escalation study assessed the safety, maximum tolerated dose (MTD), pharmacokinetics, and efficacy in patients with relapsed advanced ATL or PTCL. Dose-escalation was conducted according to the standard 3+3 design. Up to one PTCL patient was allowed to be included in each cohort of 3 patients. Patients in Cohort 1 received oral lenalidomide 25 mg daily on Days 1–21 of a 28-day cycle. Patients in Cohorts 2 and 3 received 25 and 35 mg/day, respectively, on each day of the 28-day cycle. Dose-limiting toxicity (DLT) was defined as febrile neutropenia lasting 5 or more days; thrombocytopenia (platelets <10,000/uL or bleeding requiring platelet transfusion); ALT/AST elevation of Grade 4 or that of Grade 3 lasting 7 or more days; and/or clinically unacceptable Grade 3 or higher other non-hematological adverse events (AEs). Treatment was continued until the development of unacceptable toxicity or progressive disease (PD). Response was assessed by internationally accepted standard criteria for ATL and PTCL. Results: From July 2010–June 2012, 13 Japanese patients (9 ATL and 4 PTCL; age 32–74 years [median, 64]; 1–11 prior therapies [median, 1]) were enrolled: 3 in Cohort 1, 6 in Cohort 2, and 4 in Cohort 3. The 3 patients in Cohort 1 received lenalidomide for 21, 103, and 637 days, respectively, until PD with no instances of DLT. In Cohort 2, 1 patient experienced DLT (thrombocytopenia, platelets <10,000/uL) and 4 patients received lenalidomide for 37, 56, 138, and 387 days, respectively, until PD in 3 patients and unrelated death in one. The sixth patient is still receiving lenalidomide for 28+ days without a DLT. In Cohort 3, 2 patients had DLTs (thrombocytopenia, platelets <10,000/uL in one patient and Grade 3 prolongation of QTc interval in one patient on concomitant fluconazole with preexisting cardiac disease and grade 1 QTc prolongation at baseline), 1 patient received lenalidomide for 71 days before withdrawal of consent, and 1 patient is still receiving lenalidomide for 323+ days without a DLT. Based on these results, 25 mg daily per 28-day cycle was regarded as the MTD. Other Grade 3/4 non-DLT AEs occurring in 2 or more patients included neutropenia (n=8), lymphocytopenia (n=7), thrombocytopenia (n=3), skin rash (n=3), hyperbilirubinemia (n=2), and increased ALT/AST (n=2). Among the 9 ATL patients, 3 achieved partial responses (PR) with hematological complete response in 2 patients, including the disappearance of skin lesions in 1 patient. These responses occurred between 54 and 57 days, and lasted for 92, 279+ and 505 days. Among the 4 PTCL patients, 1 achieved a PR at day 106 with >75% reduction in lymph nodes, which lasted for 282 days. PK profiles of patients in the study were generally consistent with that observed in Japanese MM patients. Plasma exposure of lenalidomide increased with increasing dose with a mean Cmax on Day 1 for 25 mg and 35 mg of 493 ng/mL and 628 ng/mL, respectively, and a mean AUC24 of 2774 ng/mL and 3062 ng/mL, respectively. There was no evidence of accumulation following multiple dosing for 8 days. Conclusions: This phase 1 study identified lenalidomide 25 mg daily per 28-day cycle as the dose and schedule for a subsequent phase 2 study in patients with ATL or PTCL. Based on the preliminary evidence of antitumor activity in ATL and PTCL patients, a phase 2 study in patients with relapsed ATL in Japan is planned. Disclosures: Off Label Use: Lenalidomide (CC-5013) is an investigational agent in Japan; this abstract assesses its use in adult ATL patients. Tobinai:Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Mundipharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Zenyaku: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genzyme: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Symbio: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Eli Lilly: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kyowa-Kirin: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biomedics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Solasia Pharma: Clinical trials, Clinical trials Other, Research Funding; Novartis: Research Funding; Johnson & Johnson: Research Funding; Pfizer: Research Funding; GSK: Research Funding; Chugai/Roche: Research Funding; Takeda: Clinical trials, Clinical trials Other, Research Funding.

Results of a Phase 1/2 Study for KW-0761, a Monoclonal Antibody Directed Against CC Chemokine Receptor Type 4 (CCR4), In CTCL Patients

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 962-962 ◽  
Author(s):  
Madeleine Duvic ◽  
Lauren Pinter-Brown ◽  
Francine M Foss ◽  
Lubomir Sokol ◽  
Jeffrey Jorgensen ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Adverse Events ◽  
Chemokine Receptor ◽  
Dose Escalation ◽  
Research Funding ◽  
Phase 1 ◽  
Open Label ◽  
Serious Adverse Events ◽  
Cc Chemokine ◽  
Overall Response

Abstract Abstract 962 Introduction: KW-0761 is a defucosylated, humanized, monoclonal antibody with enhanced antibody dependent cellular cytotoxicity (ADCC; Potelligent®) that binds to CC chemokine receptor 4 (CCR4). CCR4 is over expressed in PTCL and CTCL, and is a potential target for anti-neoplastic therapy in these disorders. Study Design: This multicenter, open-label, dose escalation phase 1/2 study is in patients with previously treated PTCL and CTCL (including MF and SS). The study is composed of a dose escalation phase (Phase 1) and preliminary assessment of safety and efficacy (Phase 2). The phase 1 portion is a standard 3+3 design at doses of 0.1, 0.3, and 1 mg/kg. In the first treatment course, KW-0761 is administered i.v. once a week for four weeks, followed by a 2-week observation period. Subjects demonstrating a response or maintaining stable disease may receive additional infusions of KW-0761 every other week until progression or withdrawal from study. For CTCL patients, the overall global response score is a composite of response in all compartments (skin, lymph nodes, viscera). For subjects with Sezary Syndrome (SS), response in blood is also considered for overall response. For PTCL patients, the response is based on criteria defined by the International Working Group (IWG). Results: Forty-two patients who had received at least one prior systemic therapy (median 5; range 1–17) are enrolled. The median age is 67 (range: 35–85) years with more males (57%) than females (43%). A total of 40 patients received at least four doses of KW-0761 at 0.1 mg/kg (n=3), 0.3 mg/kg (n=3) and 1 mg/kg (n=34). There are no dose limiting toxicities (DLT) or drug-related serious adverse events (SAEs) reported in the dose escalation portion of the study. Most observed adverse events (AEs) are mild to moderate in severity. There does not appear to be any dose relationship with the incidence or severity of the AEs. The most frequent AEs are chills, headache, nausea, pyrexia, infusion related reactions and back pain. There does not seem to be an increase in the rate of infections associated with the use of this drug. Six of 42 patients who received at least one dose of KW-0761 developed a new skin eruption not consistent with the patients' underlying disease, including one grade 3 hypersensitivity rash with eosinophils. No significant hematologic AEs have been observed except for lymphopenia which is due to the pharmacologic effect of the drug. A total of 38 patients (23 with MF; 15 with SS) are evaluable for efficacy (only one subject with PTCL was enrolled and is not included in this analysis). A summary of all patients evaluable for efficacy to date is presented in the table belowa: Conclusions: KW-0761 is well tolerated at doses of 0.1–1.0 mg/kg. The MTD has not been reached in this study. The overall response rate is 39% for all patients in the phase 1/2 trial with a higher rate in SS patients (47%) versus MF patients (35%). Additionally, 12 of 15 SS patients had a response in the blood, including 7 CRs. These promising results warrant further clinical studies using KW-0761 in refractory or relapsed CTCL patients. Disclosures: Duvic: Kyowa-kirin-pharma.com: Consultancy, Research Funding. Pinter-Brown:Kyowa-Kirin: Consultancy, Research Funding. Foss:Kyowa-Kirin: Consultancy, Research Funding. Sokol:Kyowa-Kirin: Research Funding. Jorgensen:Kyowa Hakko Kirin Co, Ltd.: Research Funding. Spitalny:Kyowa-Kirin: Employment. Kim:Kyowa-Kirin: Consultancy, Research Funding.

Phase 1 Clinical Trial of NPI-0052, a Novel Proteasome Inhibitor in Patients with Multiple Myeloma

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2770-2770 ◽  
Author(s):  
Paul Richardson ◽  
Craig C. Hofmeister ◽  
Todd M. Zimmerman ◽  
Asher Alban Chanan-Khan ◽  
Matthew A. Spear ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Clinical Trials ◽  
Adverse Events ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Proteasome Inhibitor ◽  
Phase 1 ◽  
Proteasome Inhibition ◽  
Significant Activity ◽  
Potential Clinical Benefit

Abstract Background: NPI-0052 is a novel proteasome inhibitor that produces prolonged inhibition of all three catalytic activities (C-L, T-L, CT-L) of the 20S proteasome. Preclinical data suggest NPI-0052 may demonstrate an improved therapeutic ratio, with significant activity in hematologic and solid tumor malignancies including multiple myeloma (MM) resistant to bortezomib and other agents (Chauhan et al, Blood 2006). Studies have therefore been initiated in patients with multiple myeloma, lymphoma, leukemia and solid tumors. Materials and Methods: This Phase 1 dose escalation study evaluated NPI-0052 monotherapy in patients with relapsed and relapsed/refractory MM, including those that have received bortezomib and/or lenalidomide. Patients were assessed for safety, pharmacodynamics (including ex vivo proteasome inhibition), plasma pharmacokinetics (PK), and clinical activity (with response assessed by modified EBMT criteria). Patients were treated with NPI-0052 administered as a weekly IV injection on Days 1, 8 and 15 every 4 weeks with concomitant hydration. The dose of NPI-0052 was escalated in cohorts of 3 patients dependent on observed adverse events utilizing a 3+3 design. Proteasome inhibition and PK were assayed after the 1st and 3rd dose and upon any intra-patient dose escalation. Proteasome inhibition was also assessed in CD138 positive cells isolated from bone marrow aspirates obtained at baseline and after the 3rd dose in a subset of patients. Preliminary Results: To date, 10 patients have been treated at doses ranging from 0.025 mg/m2 to 0.075 mg/m2 without reaching an MTD. One patient experienced reversible elevation in serum creatinine that responded to drug cessation and steroids; this event may have been related to progression of his underlying light chain nephropathy (as interval worsening of renal function was noted prior to enrollment). Drug-related adverse events have been otherwise unremarkable at all dose levels tested. PK data demonstrate a rapid elimination half life (estimated to be 3–4 minutes) with clearance between 8–21 mL/min and Vz of 44–99L; no change in PK has been observed comparing the 1st and 3rd injection. Proteasome inhibition in whole blood suggests drug-dependent CT-L inhibition, with inhibition up to 28% observed (inhibition up to 100% at doses of up to 0.7 mg/m2 has been observed in other clinical trials with NPI-0052 without producing the profile of toxicity reported with standard doses of bortezomib). Whilst no responses have been confirmed, two patients with relapse/refractory MM remained on study for over 6 months and one year, respectively, with stable disease and no significant toxicity. Importantly, no peripheral neuropathy or myelosuppression has been seen in 41 treatment cycles in patients to date. Conclusions: In patients with relapsed and relapsed, refractory MM, NPI-0052 affects parameters relevant to pharmacodynamics, PK and demonstrated potential clinical benefit at doses well below the MTD anticipated from Phase 1 clinical trials with NPI-0052 in lymphoma and solid tumors. Drug administration to date has been well tolerated. Dose escalation continues to define DLT and MTD, and to recommend a phase 2 dose for further study in patients with advanced MM.

IMO-8400, an Antagonist of Toll-like Receptors 7, 8, and 9, in Development for Genetically Defined B-Cell Lymphomas: Safety and Activity in Phase 1 and Phase 2 Clinical Trials

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3101-3101 ◽  
Author(s):  
Louis Brenner ◽  
Robert D. Arbeit ◽  
Tim Sullivan
Keyword(s):  
Clinical Trials ◽  
Adverse Events ◽  
B Cell ◽  
Phase 1 ◽  
Phase 2 ◽  
B Cell Malignancies ◽  
Dna And Rna ◽  
Phase 2 Trial ◽  
Myd88 L265p Mutation ◽  
Myd88 L265p

Abstract Background. Toll-like receptors (TLRs) are pathogen-associated molecular pattern recognition receptors of the innate immune system. TLRs 7 and 9, which are expressed in human B-cells, respond to DNA- and RNA-based ligands by initiating a signaling cascade mediated through NF-κB, IRAK1/4, BTK, and JAK/STAT. DNA- and RNA-based ligands for TLRs 7 and 9 also are generated as damage-associated molecular patterns in certain autoimmune diseases and malignancies. MYD88 is a key adaptor molecule in TLR signaling. Recently, the oncogenic mutation MYD88 L265P mutation has been described and reported to occur in patients with activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL), Waldenström’s macroglobulinemia (WM), and other B-cell malignancies. MYD88 L265P drives over-expression of TLR 7 and 9 signaling, creating an anti-apoptotic microenvironment that promotes cancer cell survival and proliferation. Recent epidemiological data confirm a strong association between the presence of MYD88 L265P and poor outcomes in patients with DLBCL. Specific targeting of signaling initiated by TLRs 7 and 9 therefore is a novel approach to the treatment of B-cell lymphomas harboring the MYD88 L265P mutation. Preclinical data presented at AACR 2014, including from xenograft tumor studies, show that IMO-8400 inhibits cell signaling and reduces tumor growth in WM and DLBCL models harboring the MYD88 L265P mutation. Clinical data from 2 completed trials of IMO-8400 are presented here. Clinical Trial Designs. In a first-in-man Phase 1 trial in healthy subjects, IMO-8400 was administered by s.c. injection at single dosages of 0.1, 0.3, and 0.6 mg/kg and for four weeks at 0.3 and 0.6 mg/kg/week (each n=6). Goals of the Phase 1 trial included safety and tolerability evaluation through single- and multiple-dose escalation, and assessment of TLR engagement. Subsequently, a randomized, placebo-controlled Phase 2 trial was conducted with IMO-8400 in patients with moderate to severe plaque psoriasis at dosages of 0.075, 0.15, 0.3, and 0.6 mg/kg/week for 12 weeks (n=8 or 9 per dosage). Goals of the Phase 2 trial included safety and tolerability assessment over a 12-week treatment period, and evaluation of clinical proof of concept in a disease that involves TLR7 and 9 over-activation. Clinical Trial Results. IMO-8400 was well tolerated across all dose regimens in both studies, with no treatment-related severe or serious adverse events, no drug-related treatment discontinuations, and no pattern of systemic adverse events or laboratory changes. The only treatment-related adverse events in more than one subject were injection site reactions, comprised of generally mild erythema with occasional induration, pruritus, tenderness or pain. In neither trial were there adverse or consistent shifts in laboratory parameters. Specifically, any changes in white or red blood cell parameters, platelet numbers, and liver enzymes or other serum chemistry parameters were similar following IMO-8400 treatment or after placebo treatment. In the Phase 2 trial, clinical proof of mechanism was demonstrated by increased frequency of improvements in psoriasis disease activity in IMO-8400-treated patients across multiple dose levels relative to placebo-treated patients. Conclusion. Antagonism of TLRs 7 and 9 is a novel, scientifically-driven approach to the treatment of B-cell malignancies characterized by presence of the MYD88 L265P oncogenic mutation. IMO-8400, a clinical-stage drug candidate, was well tolerated in clinical trials conducted in healthy subjects and patients with psoriasis, having demonstrated no myelosuppression or any pattern of hematological or other toxicity in 12-week treatment regimens. The risk-benefit profile of IMO-8400 to date merits further clinical testing for genetically defined B-cell malignancies, as monotherapy and in combination with other agents. Based on the accumulated preclinical data, clinical safety, and demonstrated mechanism of action of IMO-8400, Phase 1/2 clinical trials of IMO-8400 are being conducted in both relapsed/refractory patients with WM and in patients with DLBCL and the MYD88 L265P mutation. Disclosures Brenner: Idera Pharmaceuticals : Employment, Equity Ownership. Arbeit:Idera Pharmaceuticals: Employment. Sullivan:Idera Pharmaceuticals: Employment.

scholarly journals Safety and Immunogenicity of Nanocovax, a SARS-CoV-2 Recombinant Spike Protein Vaccine

2021 ◽  
Author(s):  
Thuy P Nguyen ◽  
Quyet Do ◽  
Lan T Lan ◽  
Duc V Dinh ◽  
Hiep Khong ◽  
...  
Keyword(s):  
Adverse Events ◽  
Aluminum Hydroxide ◽  
Dose Escalation ◽  
Phase 1 ◽  
Vaccine Safety ◽  
Antibody Responses ◽  
Phase 2 ◽  
Serious Adverse Events ◽  
To Receive ◽  
Trial Phase

Background Nanocovax is a recombinant severe acute respiratory syndrome coronavirus 2 subunit vaccine composed of full-length prefusion stabilized recombinant SARS-CoV-2 spike glycoproteins (S-2P) and aluminum hydroxide adjuvant. Methods We conducted a dose-escalation, open label trial (phase 1) and a randomized, double-blind, placebo-controlled trial (phase 2) to evaluate the safety and immunogenicity of the Nanocovax vaccine (in 25 microgram (mcg), 50 mcg, and 75 mcg doses, aluminum hydroxide adjuvanted). In phase 1, 60 participants received two intramuscular injection of the vaccine following dose-escalation procedure. The primary outcomes were reactogenicity and laboratory tests to evaluate the vaccine safety. In phase 2 which involved in 560 healthy adults, the primary outcomes are vaccine safety; and anti-S IgG antibody response. Secondary outcomes were surrogate virus neutralization, wild-type SARS-CoV-2 neutralization, and T-cell responses by intracellular staining (ICS) for interferon gamma (IFNg). We performed primary analyses at day 35 and day 42. Results For phase 1 study, no serious adverse events (SAE) were observed for all 60 participants. Most adverse events (AE) were grade 1 and disappeared shortly after injection. For phase 2 study, after randomization, 480 participants were assigned to receive the vaccine with adjuvant, and 80 participants were assigned to receive placebo. Reactogenicity was absent or mild in the majority of participants and of short duration (mean, ≤3 days). Unsolicited adverse events were mild in most participants. There were no serious adverse events related to Nanocovax. Regarding the immunogenicity, Nanocovax induced robust anti-S antibody responses. There was no statistical difference in antibody responses among dose strengths on Day 42, in terms of anti S-IgG level and neutralizing antibody titer. Conclusions Up to 42 days, Nanocovax vaccine was safe, well tolerated and induced robust immune responses. We propose using Nanocovax 25 mcg for Phase 3 to evaluate the vaccine efficacy. (Research funded by Nanogen Pharmaceutical Biotechnology JSC., and the Ministry of Science and Technology of Vietnam; ClinicalTrials.gov number, NCT04683484.)

Clinical Drug Development for the Treatment of Pulmonary Arterial Hypertension: Collaboration With the Pharmaceutical Industry and Regulatory Agencies

2010 ◽  
Vol 9 (4) ◽  
pp. 214-219
Author(s):  
Robyn J. Barst
Keyword(s):  
Clinical Trials ◽  
Pulmonary Arterial Hypertension ◽  
Drug Development ◽  
Phase 1 ◽  
Preclinical Studies ◽  
Phase 2 ◽  
Phase 3 ◽  
Preclinical Testing ◽  
New Drug ◽  
Pulmonary Arterial

Drug development is the entire process of introducing a new drug to the market. It involves drug discovery, screening, preclinical testing, an Investigational New Drug (IND) application in the US or a Clinical Trial Application (CTA) in the EU, phase 1–3 clinical trials, a New Drug Application (NDA), Food and Drug Administration (FDA) review and approval, and postapproval studies required for continuing safety evaluation. Preclinical testing assesses safety and biologic activity, phase 1 determines safety and dosage, phase 2 evaluates efficacy and side effects, and phase 3 confirms efficacy and monitors adverse effects in a larger number of patients. Postapproval studies provide additional postmarketing data. On average, it takes 15 years from preclinical studies to regulatory approval by the FDA: about 3.5–6.5 years for preclinical, 1–1.5 years for phase 1, 2 years for phase 2, 3–3.5 years for phase 3, and 1.5–2.5 years for filing the NDA and completing the FDA review process. Of approximately 5000 compounds evaluated in preclinical studies, about 5 compounds enter clinical trials, and 1 compound is approved (Tufts Center for the Study of Drug Development, 2011). Most drug development programs include approximately 35–40 phase 1 studies, 15 phase 2 studies, and 3–5 pivotal trials with more than 5000 patients enrolled. Thus, to produce safe and effective drugs in a regulated environment is a highly complex process. Against this backdrop, what is the best way to develop drugs for pulmonary arterial hypertension (PAH), an orphan disease often rapidly fatal within several years of diagnosis and in which spontaneous regression does not occur?

scholarly journals Adverse events of special interest in clinical trials of rheumatoid arthritis, psoriatic arthritis, ulcerative colitis and psoriasis with 37 066 patient-years of tofacitinib exposure

RMD Open ◽  
2021 ◽  
Vol 7 (2) ◽  
pp. e001595
Author(s):  
Gerd R Burmester ◽  
Peter Nash ◽  
Bruce E Sands ◽  
Kim Papp ◽  
Lori Stockert ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Ulcerative Colitis ◽  
Clinical Trials ◽  
Psoriatic Arthritis ◽  
Adverse Events ◽  
Special Interest ◽  
Phase 1 ◽  
Incidence Rates ◽  
Study Data ◽  
System Organ Class

ObjectivesTo analyse adverse events (AEs) of special interest across tofacitinib clinical programmes in rheumatoid arthritis (RA), psoriatic arthritis (PsA), ulcerative colitis (UC) and psoriasis (PsO), and to determine whether the incidence rates (IRs; unique patients with events per 100 patient-years) of these events are consistent across diseases.MethodsThe analysis included data from patients exposed to ≥1 dose of tofacitinib in phase 1, 2, 3 or 3b/4 clinical trials and long-term extension (LTE) studies (38 trials) in RA (23 trials), PsA (3 trials), UC (5 trials) and PsO (7 trials). All studies were completed by or before July 2019, except for one ongoing UC LTE study (data cut-off May 2019). IRs were obtained for AEs of special interest.Results13 567 patients were included in the analysis (RA: n=7964; PsA: n=783; UC: n=1157; PsO: n=3663), representing 37 066 patient-years of exposure. Maximum duration of exposure was 10.5 years (RA). AEs within the ‘infections and infestations’ System Organ Class were the most common in all diseases. Among AEs of special interest, IRs were highest for herpes zoster (non-serious and serious; 3.6, 1.8, 3.5 and 2.4 for RA, PsA, UC and PsO, respectively) and serious infections (2.5, 1.2, 1.7 and 1.3 for RA, PsA, UC and PsO, respectively). Age-adjusted and sex-adjusted mortality ratios (weighted for country) were ≤0.2 across cohorts.ConclusionsThe tofacitinib safety profile in this analysis was generally consistent across diseases and with longer term follow-up compared with previous analyses.

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