A Subcutaneously Administered Investigational RNAi Therapeutic (ALN-CC5) Targeting Complement C5 for Treatment of PNH and Complement-Mediated Diseases: Interim Phase 1 Study Results

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2413-2413 ◽  
Author(s):  
Anita Hill ◽  
Jorg Taubel ◽  
Jim Bush ◽  
Anna Borodovsky ◽  
Noriyuki Kawahata ◽  
...  
Keyword(s):  
Healthy Volunteers ◽  
Phase 1 ◽  
Employment Equity ◽  
Double Blind ◽  
Therapeutic Targeting ◽  
Primary Endpoints ◽  
Study Results ◽  
Tolerability Data ◽  
Dose Study ◽  
Equity Ownership

Abstract Introduction: Uncontrolled complement activation plays a pivotal role in a variety of disorders such as PNH and aHUS. ALN-CC5 is a subcutaneous (SC) investigational RNAi therapeutic targeting complement C5 (C5). In preclinical studies, ALN-CC5 has demonstrated decreased terminal complement activity. Based on the literature, preventing the generation of the terminal complex protects against intravascular hemolysis and complement-mediated tissue damage. The purpose of this study is to evaluate the safety and tolerability of ALN-CC5 in normal healthy volunteers. Material and methods: A multi-centered, placebo controlled, double blind phase 1 clinical study in healthy volunteers is ongoing. Several cohorts of healthy volunteers in Part A, a single ascending dose study and Part B, a weekly multiple ascending dose study have been completed. Primary endpoints are safety and tolerability. Secondary endpoints are pharmacokinetics, reduction of circulating C5, reduction in hemolytic, CAP and CCP activity. Results: In Part A, 20 healthy volunteers were randomized (1:3) to placebo or single SC dose of 50, 200, 400, 600 or 900mg of ALN-CC5 and followed for at least 70 days. In Part B, 12 healthy volunteers were randomized (1:3) to placebo or 5 weekly doses of 100, 200 or 400mg of ALN-CC5. No SAEs or study discontinuations occurred and overall ALN-CC5 was considered safe and generally well tolerated. A dose dependent and 94% mean maximum C5 knockdown was achieved following weekly administration. Updated safety and tolerability data as well as C5 knockdown, and changes in CAP, CCP and hemolytic activity from the study will be presented. Conclusion: Collectively, these initial results suggest that the use of a novel RNAi therapeutic targeting C5 is a promising approach for inhibiting complement in PNH, aHUS and other complement-mediated diseases. The subcutaneous route of administration and infrequent dosing make this a potentially encouraging therapy. Disclosures Hill: Alnylam: Consultancy. Off Label Use: ALN-CC5 is an investigational RNAi therapeutic targeting complement C5.. Borodovsky:Alnylam Pharmaceuticals: Employment, Equity Ownership. Kawahata:Alnylam Pharmaceuticals: Employment, Equity Ownership. Mclean:Alnylam Pharmaceuticals: Employment, Equity Ownership. Powell:Alnylam Pharmaceuticals: Employment, Equity Ownership. Chaturvedi:Alnylam Pharmaceuticals: Employment, Equity Ownership. Warner:Alnylam Pharmaceuticals: Employment, Equity Ownership. Garg:Alnylam Pharmaceuticals: Employment, Equity Ownership. Sorensen:Alnylam Pharmaceuticals: Employment, Equity Ownership.

Initial Findings From the PACE Trial: A Pivotal Phase 2 Study of Ponatinib in Patients with CML and Ph+ ALL Resistant or Intolerant to Dasatinib or Nilotinib, or with the T315I Mutation

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 109-109 ◽  
Author(s):  
Jorge E. Cortes ◽  
Dong-Wook Kim ◽  
Javier Pinilla-Ibarz ◽  
Philipp D. Le Coutre ◽  
Charles Chuah ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Phase 1 ◽  
Initial Response ◽  
Employment Equity ◽  
Advisory Committees ◽  
Primary Endpoints ◽  
T315i Mutation ◽  
Equity Ownership ◽  
Grade 3

Abstract Abstract 109 Background: Despite progress in chronic myeloid leukemia (CML) therapy with tyrosine kinase inhibitors (TKIs), patients (pts) who fail dasatinib or nilotinib or pts with T315I mutation have no treatment options. Ponatinib is a potent, oral, pan-BCR-ABL inhibitor active against the native enzyme and all tested resistant mutants, including the uniformly resistant T315I mutation. Methods: The PACE trial (Ponatinib Ph+ALL and CML Evaluation) was initiated in September 2010. The objective of this international, single-arm, open-label, phase 2 trial is to establish the efficacy and safety of ponatinib. Pts with refractory CML in chronic, accelerated or blast phase (CP, AP or BP), or Ph+ acute lymphoblastic leukemia (ALL), resistant or intolerant (R/I) to dasatinib or nilotinib or with the resistant T315I mutation received 45 mg ponatinib orally once daily in one of 6 cohorts: CP R/I; CP T315I; AP R/I; AP T315I; BP/ALL R/I; BP/ALL T315I. The primary endpoints are major cytogenetic response (MCyR) for CP and major hematologic response (MaHR) for AP, BP or ALL. The trial is ongoing; projected enrollment is approximately 450. Data as of 18 July 2011 are reported. Results: At analysis, 403 pts were enrolled; 397 were treated and eligible. The median age was 59 (range, 18–94) years, 52% were male. Diagnoses were: CP R/I, n=188; CP T315I, 48; AP R/I, 52; AP T315I, 15; BP/ALL R/I, 51; BP/ALL T315I, 43. Median time from initial diagnosis to start of ponatinib was 6.2 years. Prior TKIs included imatinib (93%), dasatinib (85%), nilotinib (66%), and bosutinib (8%); 94% failed >2 prior TKIs, and 57% failed >3 prior TKIs. Overall, 88% had a history of resistance to dasatinib or nilotinib, and 12% were purely intolerant. Mutation status was determined centrally by MolecularMD. Overall, 106 pts had the T315I mutation. Of 291 R/I pts, 110 (38%) had non-T315I BCR-ABL mutations, most frequently F317L (10%), F359V (5%), E255K (4%), and G250E (4%). To date, 343 (85%) pts remain on therapy, 60 (15%) have discontinued (42 BP/ALL): 24 (6%) progressive disease (20 BP/ALL); 11 (3%) AE (3 pain, 3 thrombocytopenia, 1 each haemorrhage, loss of consciousness, enterocolitis, cytokine release syndrome, hepatotoxicity/pleuro-pericardial effusion after overdose); 8 (2%) died (3 related; 7 BP/ALL); 17 (4%) other. The most common drug-related AEs (≥10% any grade) were thrombocytopenia (19%; 15% grade 3/4), rash (18%), dry skin (13%), myalgia (12%), abdominal pain (11%; 3% grade 3/4), headache (11%), arthralgia (11%). Overall, 67 (17%) pts experienced at least 1 related SAE. The most common related SAEs (>5 cases) were pancreatitis 15 cases (3.7%), 5 cases each (1.2%) diarrhea, anemia, febrile neutropenia, and pyrexia. At the time of reporting, 159/397 eligible pts were evaluable for the primary endpoints. Median follow-up was 57 days. Of CP pts, 83 had an assessment at 3 months (10 at 6 months) or discontinued. In CP R/I, 25/60 (42%) attained MCyR (15 CCyR). In CP T315I, 13/23 (57%) had MCyR (11 CCyR). The overall CP MCyR rate was 38/83 (46%) (26 CCyR). Of AP, BP/ALL pts, 76 had an assessment at 1 month or later or discontinued. In AP, 17/23 (74%) R/I and 1/1 T315I pts achieved MaHR. In BP/ALL, 11/30 (37%) R/I and 6/22 (27%) T315I pts had MaHR. Conclusion: In this first analysis of the pivotal PACE trial, ponatinib has a favorable early safety profile, similar to that observed in phase 1, but with a lower incidence of pancreatitis. Initial response data after short follow-up indicate ponatinib has substantial anti-leukemic activity in this heavily pretreated population, and in pts with refractory T315I. These early efficacy signals replicate initial response results reported in the phase 1 setting. Updated data will be presented at the annual meeting. Disclosures: Cortes: Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding. Kim:BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; ARIAD: Research Funding. Pinilla-Ibarz:ARIAD: Membership on an entity's Board of Directors or advisory committees, Research Funding. Le Coutre:Novartis: Honoraria, Research Funding, Speakers Bureau; ARIAD: Research Funding. Paquette:ARIAD: Membership on an entity's Board of Directors or advisory committees. Apperley:Novartis: Honoraria, Research Funding; Bristol Myers Sqibb: Honoraria; Ariad: Honoraria; Chemgenex: Honoraria; Genzyme: Honoraria. DiPersio:Genzyme: Honoraria. Rea:Novartis: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Talpaz:ARIAD: Research Funding. Abruzzese:Novartis: Consultancy; BMS: Consultancy. Baccarani:Pfizer Oncology: Consultancy; Novartis: Consultancy; BMS: Consultancy; Ariad: Consultancy; Novartis: Research Funding; Pfizer Oncology: Honoraria; Novartis: Honoraria; BMS: Honoraria; Ariad: Honoraria; Novartis: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Ariad: Membership on an entity's Board of Directors or advisory committees. Wong:MolecularMD: Employment, Equity Ownership. Lustgarten:ARIAD: Employment. Turner:ARIAD: Employment, Equity Ownership. Rivera:ARIAD: Employment, Equity Ownership. Clackson:ARIAD: Employment, Equity Ownership. Haluska:ARIAD: Employment, Equity Ownership. Kantarjian:Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; BMS: Consultancy, Research Funding; ARIAD: Research Funding.

Safety, Tolerability and Pharmacokinetics of GMI-1070, a Pan-Selectin Inhibitor for Treatment of Vaso-Occlusive Crisis: Single and Multiple Dose Studies in Healthy Volunteers.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1526-1526 ◽  
Author(s):  
Yuli Xie ◽  
Rebecca Seufert ◽  
John L. Magnani ◽  
William Kramer ◽  
Helen M. Thackray
Keyword(s):  
Healthy Volunteers ◽  
Dose Regimen ◽  
Multiple Dose ◽  
Study Drug ◽  
Loading Dose ◽  
Employment Equity ◽  
Multiple Dose Study ◽  
Dose Study ◽  
Urine Concentrations ◽  
Equity Ownership

Abstract Abstract 1526 Poster Board I-549 Introduction GMI-1070 is a pan-selectin inhibitor which targets E-, P-, and L-selectin, and has demonstrated activity in multiple animal models of disease including sickle cell vaso-occlusive crisis, myocardial infarction, delayed-type hypersensitivity, and microcirculation in diabetes. These Phase 1 healthy volunteer studies evaluated the safety, tolerability and pharmacokinetics (PK) of intravenous (IV) GMI-1070 in single and multiple doses, using a dose-ranging design. Methods A total of 72 healthy volunteers were randomized to receive study drug (GMI-1070 or placebo) in two blinded studies. In the first study, subjects were enrolled in groups of 8 (at a 3:1 ratio), administered a single IV dose of the study drug, and evaluated for safety prior to a dose review by the investigator and medical monitor. After the safety data from each group of 8 was reviewed in a blinded fashion, the decision was made to advance to the next dose group. Doses evaluated in the study were 2, 5, 10, 20, and 40 mg/kg. In the second study, subjects were enrolled similarly in groups of 8 (at a 3:1 ratio), administered multiple IV doses of the study drug over the course of 2 to 4 days, and evaluated for safety and dose escalation in a similar fashion. Doses evaluated in the multiple dose study were: 5, 10, and 20 mg/kg q8 hours for 13 doses (4 days); and finally a loading dose regimen of 40 mg/kg followed by 20 mg/kg q8 hours for 6 doses (2 days). For both studies, safety parameters included adverse events (AEs), clinical lab results, vital signs, ECG, and physical exam. Plasma and urine concentrations of GMI-1070 were measured, and PK parameters were calculated using a non-compartmental analysis. Results All 72 randomized healthy volunteers were included in the safety analysis, and all 54 who received GMI-1070 were included in the PK analysis. There were no serious AEs in either study. All AEs in subjects receiving GMI-1070 were grades 1 or 2 (mild or moderate); no grade 3 (severe) AEs were seen in subjects receiving GMI-1070. One subject did exhibit a pruritic rash while receiving the loading dose regimen of the multiple dose study, and had to discontinue study drug after 3 doses. The rash resolved with treatment. All other AEs in all groups were either possibly related, probably not related, or unrelated to study drug. There was no treatment- or dose-related trend in the incidence of AEs. Overall, there also did not appear to be any clinically significant treatment- or dose-related trends in the clinical lab, vital sign, ECG, or physical exam data in either study. Analysis of the plasma and urine concentrations indicated linear PK over the range of doses tested. The elimination half life is 8 hours with the multiple dose regimen, with a minimum of 89% of the dose recovered in the urine. Conclusions GMI-1070, a pan-selectin inhibitor administered in single or multiple doses IV, at the doses used in these studies, appears to be safe and well-tolerated with linear PK. These studies support proceeding with evaluation of GMI-1070 in the treatment of sickle cell patients in vaso-occlusive crisis. Disclosures Xie: MDS Pharma Services: Employment. Seufert:GlycoMimetics, Inc.: Consultancy. Magnani:GlycoMimetics, Inc.: Employment, Equity Ownership. Kramer:GlycoMimetics, Inc.: Consultancy. Thackray:GlycoMimetics, Inc: Employment, Equity Ownership.

GMI-1070, a Pan-Selectin Inhibitor: Safety and PK In a Phase 1/2 Study In Adults with Sickle Cell Disease

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1632-1632 ◽  
Author(s):  
Lori Styles ◽  
Ted Wun ◽  
Laura M. De Castro ◽  
Marilyn J. Telen ◽  
William Kramer ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Steady State ◽  
Adverse Events ◽  
Healthy Volunteers ◽  
Phase 1 ◽  
Study Drug ◽  
Cell Disease ◽  
Employment Equity ◽  
The Past ◽  
Equity Ownership

Abstract Abstract 1632 GMI-1070 is a pan-selectin inhibitor that targets E-, P-, and L-selectins and has shown activity in multiple animal models of disease. Sickle cell disease (SCD) is characterized by periodic vaso-occlusive (VOC) episodes in which cell adhesion and aggregation play a crucial role. GMI-1070 has previously been shown to restore blood flow and improve survival in a mouse model of VOC, and safety and PK have been evaluated in normal, healthy volunteers in phase 1. Here we report clinical, safety, and PK results from the first study of GMI-1070 in individuals with SCD. Methods: An open-label phase 1/2 study was performed, enrolling adults with SCD at steady state. GMI-1070 was administered in two IV doses given on the same day: 20 mg/kg in the first dose, followed 10 hours later by 10 mg/kg. Patients were evaluated for safety on days 0, 1, 2, 7 and 28, including adverse events (AEs), routine clinical labs, and clinical exam. Plasma and urine concentrations of GMI-1070 were measured on days 0, 1, and 2, and PK parameters calculated and compared with those from healthy volunteers. Results: Fifteen adults were enrolled at three centers; 13 with HbSS, 2 with HbSB0thal. All were African-American, 9 were male, mean age was 32 years (range 18–50), mean weight was 64.7 kg; 4 were on hydroxyurea. In the past year, 6 had experienced VOC requiring medical care; 2 had ACS; 2 required transfusions; and 1 had an episode of priapism. Five were hospitalized in the past year; 12 were hospitalized in the past 5 years. All subjects received both doses of study drug; all but one were followed for 28 days. The PK in adults with SCD was in good agreement with that in the controls. The elimination half-life of GMI-1070 averaged 7.73 ± 2.45 hours (Figure). Renal clearance averaged 18.0 ± 7.93 mL/min and accounted for essentially all elimination. Physical exam parameters after dosing were unchanged, and all infusions were well tolerated. Four subjects reported headache within 24 hours of dosing, all of which were mild or moderate and resolved within 24 hours. Two subjects experienced VOC not requiring hospitalization, at 2 and 4 weeks after dosing. One subject had worsening anemia requiring transfusion 5 days after dosing. Other adverse events typical of SCD were reported without apparent association with study drug; none were serious adverse events. Routine labs demonstrated no changes from baseline (Hb, reticulocytes, platelets, electrolytes, glucose, ALT, LDH, BUN, Cr, bilirubin, urinalysis) with the exception of white blood cell counts (WBC) and absolute neutrophil counts (ANC). At 24 hours, mean WBC change from baseline was 1.9K/mm3, or 20% (p=0.076, using parametric test with mixed model); mean ANC change was 2.7, or 67% (p=0.019); all returned to baseline by 7 days. One individual had marked leukocytosis 24 hours after dosing (from 10.4 to 28K/mm3), returning to baseline by day 7; no other effects were observed in this subject. Mean C-reactive protein (CRP) increased at 24 and 48 hours, returning to baseline by day 7. Two subjects had marked increases in CRP: one exhibited leukocytosis with dosing and the other had a high baseline WBC count. There was otherwise no apparent correlation between PK, WBC/ANC, hydroxyurea use, or adverse events. In conclusion, GMI-1070, a pan-selectin inhibitor, when administered to adults with SCD at steady state, has a similar safety and PK profile to that in healthy volunteers. However, SCD patients had moderate WBC and ANC increases at 24–48 hours after dosing, which return to baseline without other observed symptomatic adverse events. This study supports further evaluation of GMI-1070 for the treatment of vaso-occlusive crisis. Disclosures: Styles: GlycoMimetics: Consultancy, clinical trial sponsorship. Wun:GlycoMimetics: Consultancy, clinical trial sponsorship. De Castro:GlycoMimetics: clinical trial sponsorship. Telen:GlycoMimetics: Consultancy, clinical trial sponsorship. Kramer:GlycoMimetics: Consultancy. Flanner:GlycoMimetics: Employment, Equity Ownership. Magnani:GlycoMimetics: Employment, Equity Ownership. Thackray:GlycoMimetics: Employment, Equity Ownership. Off Label Use: This drug (GMI-1070) has not been approved for any clinical indication.

A Phase 1 Trial of the Hematopoietic Growth Factor CDX-301 (rhuFlt3L) in Healthy Volunteers

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4124-4124
Author(s):  
Niroshana Anandasabapathy ◽  
Arlene Hurley ◽  
Marina Caskey ◽  
Christine Trumpfheller ◽  
Popi Sarma ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Healthy Volunteers ◽  
Phase 1 ◽  
Community Acquired Pneumonia ◽  
Employment Equity ◽  
Hematopoietic Stem ◽  
Phase 1 Trial ◽  
Biologic Activity ◽  
Equity Ownership

Abstract Abstract 4124 Fms-like tyrosine kinase-3 ligand (Flt3L) uniquely binds the Flt3 (CD135) receptor expressed on hematopoietic stem cells (HSC), early progenitor cells, immature thymocytes, and steady state dendritic cells and induces the proliferation, differentiation, development and mobilization of these cells in the bone marrow, peripheral blood, and lymphoid organs. Given its potential as a stem cell mobilizer and immunotherapeutic, the safety and biologic activity of recombinant human (rh) Flt3L were originally demonstrated in clinical studies conducted by Immunex Inc, but development had been halted. CDX-301 is a soluble, rhFlt3L composed of the identical amino acid sequence and comparable biologic activity as the Immunex product. A Phase 1 trial was initiated to assess the safety, pharmacokinetic, pharmacodynamic and immunologic profile of CDX-301. Using a standard 3+3 dose-escalating design, 18 healthy volunteers (HV) (51% male, median age = 32 years) received 5 daily subcutaneous injections of CDX-301 (at a dose of 1, 3, 10, 25 or 75 mcg/kg) followed by 28-day observation. All HV completed dosing and CDX-301 was well tolerated. Dose-escalation proceeded through the 25 mcg/kg dose level with no DLT (n=3 in each cohort). In the 75 mcg/kg cohort, one HV with a remote history of community acquired pneumonia developed community acquired pneumonia on study day 12; the event responded rapidly to antibiotic treatment and fully recovered within 2 weeks, but was considered a dose-limiting toxicity given the temporal association with CDX-301 administration. The cohort was expanded to a total of six HV, and no additional infections or DLT were reported. Transient Grade 1 lymphadenopathy was observed in 3 HV across multiple dose levels. No anti-CDX-301 antibodies were detected through end of study day 34 in any HV. White blood cell count (WBC) and monocytes increased in all HV; peak levels were observed around Day 10 and generally returned to baseline by Day 34. At doses above 3 mcg/kg, there was no clear dose response; mean maximum % change from baseline for the HV receiving 10 – 75 mcg/kg = 111% (range: 55–224%) for WBC and 800% (range: 450–1167%) for monocytes. In-depth phenotypic and/or functional analysis of hematopoietic stem cells and dendritic cell subsets are planned. Data from this current Phase 1 trial are consistent with previous studies showing that rhFlt3L can safely and effectively mobilize hematopoietic cell populations. Two additional cohorts will receive extended dosing (25 mcg/kg dose; 7 & 10 day durations) to further define an optimal dosing regimen for planned trials of CDX-301 in allogeneic hematopoietic stem cell transplantation (HSCT) and immunotherapy. Disclosures: Riggs: CelldexTherapeutics: Employment, Equity Ownership. Green:Celldex: Employment, Equity Ownership. Yellin:CelldexTherapeutics: Employment, Equity Ownership. Davis:CelldexTherapeutics: Employment, Equity Ownership. Keler:CelldexTherapeutics: Employment, Equity Ownership.

A Subcutaneously Administered RNAi Therapeutic (ALN-AT3) Targeting Antithrombin for Treatment of Hemophilia: Interim Phase 1 Study Results in Healthy Volunteers and Patients with Hemophilia a or B

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 693-693 ◽  
Author(s):  
Benny Sorensen ◽  
Tim Mant ◽  
Akin Akinc ◽  
Amy Simon ◽  
Lauren Melton ◽  
...  
Keyword(s):  
Factor Viii ◽  
Healthy Volunteers ◽  
Thrombin Generation ◽  
Hemophilia A ◽  
Thrombus Formation ◽  
Phase 1 ◽  
Study Drug ◽  
Relative Reduction ◽  
Employment Equity ◽  
Equity Ownership

Abstract Introduction: Hemophilia A and B are congenital bleeding disorders caused by insufficient thrombin generation due to deficiency in factor VIII or IX, respectively. In the presence of normal levels of endogenous anticoagulants, deficiency of factor VIII or IX results in an imbalance of the hemostatic system toward a bleeding phenotype. ALN-AT3 is a subcutaneously administered investigational RNAi therapeutic aimed at reducing the levels of antithrombin (AT) with the purpose of increasing thrombin generation and thereby restoring hemostatic balance in hemophilia. Material and methods: Preclinical studies in hemophilia mouse models were used to investigate the ability of ALN-AT3 to reduce AT, increase thrombin generation, restore thrombus formation after microvascular laser injury, and control traumatic bleeding after saphenous vein transection. A study in an induced hemophilia A model in non-human primates was used to investigate the ability of ALN-AT3 to enhance thrombin generation in the setting of inhibitors to factor VIII. A Phase 1 clinical study in healthy volunteers and severe/moderate hemophilia A or B is ongoing. Part A, a single ascending dose study in healthy volunteers, has been completed and Part B, a multiple ascending dose study in hemophilia patients, is currently ongoing. Primary endpoints are safety and tolerability. Secondary endpoints are pharmacokinetics, relative reduction in levels of AT and change in thrombin generation as measured by Calibrated Automated Thrombin (CAT) generation. Results: ALN-AT3 treatment resulting in residual AT levels of 20-40% in hemophilia A and B mouse models increased thrombin generation, restored real-time localized thrombus formation in the laser-injury model comparable to treatment with full-length recombinant factor VIII. ALN-AT3 controlled traumatic bleeding in the saphenous vein model with an increase in number of hemostatic events equivalent to that achieved with infusion of 25 IU/kg full-length recombinant factor VIII. ALN-AT3 treatment targeting 20% residual AT levels normalized thrombin generation in non-human primates with induced high titer inhibitor hemophilia A. In Part A of the phase 1 study, a total of 4 human volunteer subjects were randomized to receive a single subcutaneous dose of ALN-AT3 0.03 mg/kg or placebo (3:1) and were followed for at least 70 days. No serious adverse events (SAEs) were observed. A total of 5 mild AEs were recorded. Four out of 5 mild AEs were considered unlikely/not related to study drug. One mild AE of temporary self-limiting headache was considered possibly related to study drug. In Part A, per protocol, the maximum allowable level of AT relative reduction was set at 40%. Results in healthy volunteers show that a single, low subcutaneous dose of ALN-AT3 at 0.03 mg/kg resulted in an up to 28-32% knockdown of AT activity at nadir, and the treatment effect was statistically significant relative to placebo (p < 0.01 by ANOVA). This led to a statistically significant (p < 0.01) increase in peak thrombin generation, that was temporally associated and consistent with the degree of AT knockdown. The AT reduction was stable and durable for up to 70 days post single dose. In the ongoing Part B, cohorts of 3 hemophilia patients will receive 3 weekly doses of ALN-AT3, with dosing commenced at 0.015 mg/kg. Up-to-date results from Part B will be presented. Conclusion: Collectively, these data suggest that the use of a novel RNAi therapeutic targeting AT is a promising approach for restoring hemostatic balance in hemophilia, and potentially, other bleeding disorders. Further, the subcutaneous route of administration, infrequent dosing, and applicability to persons with hemophilia who have inhibitors, make this a particularly encouraging potential therapy. Disclosures Sorensen: Alnylam Pharmaceuticals: Employment, Equity Ownership. Off Label Use: ALN-AT3 is an investigational drug for potential treatment of hemophilia. The data represent phase 1/2 data. Mant:Quintiles phase 1 unit, London: Employment. Akinc:Alnylam Pharmaceuticals: Employment. Simon:Alnylam Pharmaceuticals: Employment, Equity Ownership. Melton:Alnylam Pharmaceuticals: Employment, Equity Ownership. Lynam:Alnylam Pharmaceuticals: Employment. Strahs:Alnylam Pharmaceuticals: Employment, Equity Ownership. Sehgal:Alnylam Pharmaceuticals: Employment, Equity Ownership. Hutabarat:Alnylam Pharmaceuticals: Employment, Equity Ownership. Chaturvedi:Alnylam Pharmaceuticals: Employment, Equity Ownership. Barros:Alnylam Pharmaceuticals: Employment, Equity Ownership. Vaishnaw:Alnylam Pharmaceuticals: Employment, Equity Ownership. Investigators:Alnylam Pharmaceuticals: Clinical investigators in phase 1/2 study Other, Consultancy.

Safety evaluation of an antimalarial herbal product from Andrographis paniculata (AS201-01) in healthy volunteers

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Aty Widyawaruyanti ◽  
Arijanto Jonosewojo ◽  
Hilkatul Ilmi ◽  
Lidya Tumewu ◽  
Ario Imandiri ◽  
...  
Keyword(s):  
Blood Glucose ◽  
Healthy Volunteers ◽  
Day Treatment ◽  
Phase 1 ◽  
Andrographis Paniculata ◽  
Control Group ◽  
Healthy Human ◽  
Double Blind ◽  
Random Blood Glucose ◽  
Significant Difference

Abstract Objectives Andrographis paniculata tablets (AS201-01) have previously been shown to have potent bioactivity as an antimalarial and to produce no unwanted side effects in animal models. Here, we present the phase 1 clinical trial conducted to evaluate the safety of AS201-01 tablets in healthy volunteers. Methods The study was a randomized, double-blind controlled cross-over, a placebo-controlled design consisting of a 4-day treatment of AS201-01 tablets. A total of 30 healthy human volunteers (16 males and 14 females) were divided into two groups, and each group was given 4 tablets, twice daily for 4 days. Group 1 received AS201-01, while group 2 received placebo tablets. Volunteers were given a physical examination before the treatment. The effects of AS201-01 on random blood glucose, biochemical, and hematological as well as urine profiles were investigated. Results There were no changes in observed parameters as a result of AS201-01 being administered. Statistical analysis showed no significant difference (p>0.05) between the test and control group regarding hematology profile, biochemical profile, and random blood glucose. Increased appetite and better sleep, which categorized as grade 1 adverse event was reported after treatment with AS201-01 tablet Conclusions The outcome supports our previous observation that the AS201-01 tablet, given twice a day for 4 days, is safe and nontoxic.

MO258SAFETY, TOLERABILITY, PHARMACOKINETICS AND PHARMACODYNAMICS OF VIS649, AN APRIL-NEUTRALIZING IGG2 MONOCLONAL ANTIBODY, IN HEALTHY VOLUNTEERS: PHASE 1, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, SINGLE ASCENDING DOSE STUDY

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Yusuke Suzuki ◽  
Mohit Mathur ◽  
Jonathan Barratt ◽  
Frank Engler ◽  
Jill Yarbrough ◽  
...  
Keyword(s):  
Phase 1 ◽  
Study Drug ◽  
Dependent Manner ◽  
Double Blind ◽  
Serum Iga ◽  
Dose Study ◽  
Dose Response Effect ◽  
Japanese Descent ◽  
Dose Dependent ◽  
Single Ascending Dose Study

Abstract Background and Aims Immunoglobulin A (IgA) nephropathy (IgAN) is a glomerulonephritis characterized by the presence of circulating and glomerular immune complexes containing galactose-deficient (Gd) IgA1. A proliferation-inducing ligand (APRIL), a member of the tumor necrosis factor superfamily of ligands, is thought to play a key role in the pathogenesis of IgAN by virtue of its role in class-switching to IgA production. VIS649, a humanized immunoglobulin G (IgG2) monoclonal antibody that binds to and blocks the biological actions of APRIL, is in clinical development as a potential treatment for IgAN. The primary objective of this first-in-human study was to evaluate the safety and tolerability of VIS649 in healthy volunteers. Secondary objectives included characterization of the pharmacokinetics (PK) and pharmacodynamics (PD) of VIS649. Method This was a Phase 1, randomized, double-blind, placebo-controlled, single ascending dose study of VIS649 in healthy adult male and female volunteers (ClinicalTrials.gov identifier: NCT03719443). The study was conducted in sequential dosing cohorts. The first four cohorts (0.5, 2.0, 6.0, and 12.0 mg/kg, respectively) each enrolled 9 participants (4 of Japanese descent and 5 of non-Japanese descent) who were randomized to VIS649 or placebo in a ratio of 7:2. In addition, a fifth cohort enrolled 15 adults randomized to receive VIS649 6.0 mg/kg or placebo (10:5), followed by tetanus/diphtheria vaccine challenge after 28 days (TENIVAC®, Sanofi Pasteur Limited; the effect of APRIL inhibition on vaccine response is described in a companion abstract). Participants received intravenous administration of study drug on Day 1, were discharged from the institution on Day 2, and were followed for 16–24 weeks on an outpatient basis. Standard safety assessments and blood sampling for PK and PD were performed at regular intervals. Results 51 participants were randomized and dosed with study drug, of whom 47 (92.2%) completed the study. VIS649 was well tolerated, with no serious adverse events (AEs) or AEs that led to study discontinuation. Most treatment-emergent AEs (TEAEs) were mild; the incidence and severity of TEAEs were not dose dependent. One participant in the 2.0 mg/kg group experienced a severe TEAE of syncope following phlebotomy that the investigator considered unlikely to be related to study drug. There was no clinically relevant effect of treatment on laboratory tests, vital signs, electrocardiogram parameters, or physical examinations. VIS649 had non-linear PK: half-life (t½) increased with dose, while drug exposure (AUC) increased in a greater than dose proportional manner. Serum IgA, Gd-IgA1, IgG, and IgM were reversibly suppressed in a dose-dependent manner following VIS649 administration. The maximum mean percentage reductions from baseline occurred at Week 12 for the 12.0 mg/kg dose: IgA, -57.2% (Figure); Gd-IgA1, -71.6% (Figure); IgG, -33.6%; and IgM, -67.2%. These reductions were reversible and showed a dose-response effect with respect to time-to-recovery. Mean free (non-VIS649 bound) serum APRIL levels decreased to the lower limit of quantification (50 pg/mL) for all VIS649 doses at Week 1, and also showed a dose-response effect with respect to time-to-recovery. No depletions in circulating lymphocyte populations were observed. There were no significant PK or PD differences between Japanese and non-Japanese participants. Conclusion A single dose of VIS649, up to 12.0 mg/kg, was safe and well tolerated in healthy adults and was able to suppress free serum APRIL to the lower level of quantification. Serum Gd-IgA1 decreased in parallel with total serum IgA and recovered in a dose-dependent manner following reappearance of free APRIL in serum. These data support the further clinical development of VIS649 as a potential treatment for IgAN.

Safety and pharmacokinetics of recombinant factor XIII in healthy volunteers. A randomized, placebo-controlled, double-blind, multi-dose study

2005 ◽  
Author(s):  
Jennifer E. Visich ◽  
Linda A. Zuckerman ◽  
Michael D. Butine ◽  
Kulasiri A. Gunewardena ◽  
Richard Wild ◽  
...  
Keyword(s):  
Healthy Volunteers ◽  
Factor Xiii ◽  
Double Blind ◽  
Dose Study
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