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.

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.

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A Randomized, Double-Blind, Placebo-Controlled Phase 1 Study of the Pharmacokinetics and Pharmacodynamics of REGN3918, a Human Antibody Against Complement Factor C5, in Healthy Volunteers

Blood ◽

10.1182/blood-2018-99-112262 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1039-1039 ◽

Cited By ~ 6

Author(s):

Jonathan Weyne ◽

Yan Ni ◽

Richard DelGizzi ◽

Stephen Godin ◽

Lori Morton ◽

...

Keyword(s):

Healthy Volunteers ◽

Hemolytic Activity ◽

Multiple Dose ◽

Complete Suppression ◽

Complement Factor ◽

Loading Dose ◽

Employment Equity ◽

Dose Cohort ◽

Equity Ownership ◽

Dose Dependent

Abstract INTRODUCTION: Blockade of complement factor C5 has demonstrated benefit in Paroxysmal Nocturnal Hemoglobinuria (PNH), atypical Hemolytic Uremic Syndrome and Generalized Myasthenia Gravis. We developed a human IgG4P antibody, REGN3918, that binds with high affinity to wild-type and variant (R885H/C) human C5. REGN3918 was well-tolerated in monkey toxicology studies with up to 26 weeks of dosing at up to 100 mg/kg/week. This finding was supportive of conducting this first-in-human study of REGN3918 in healthy volunteers. OBJECTIVE: The primary objective of this ongoing study is to evaluate the safety and tolerability of single ascending intravenous (IV) and subcutaneous (SC) doses and a multiple dose regimen consisting of an IV loading dose plus multiple weekly SC doses of REGN3918 administered in healthy volunteers. The secondary objectives of the study are to assess the pharmacokinetic (PK) and pharmacodynamic (PD) profile of REGN3918. METHODS: 56 subjects were randomized to 4 sequential ascending IV dose cohorts plus 2 sequential ascending SC cohorts followed by 1 multiple dose cohort (consisting of an IV loading dose and weekly SC doses). Each cohort consisted of 8 subjects randomized to receive REGN3918 or placebo (6 active: 2 placebo). An adaptive design was implemented to allow for dose level and dosing interval adjustment utilizing in-study PK and PD measures. The PD profile of REGN3918 was assessed utilizing a sheep red blood cell complement activity assay (CH50 assay) as well as serum concentrations of total C5. REGN3918 was administered as follows:Cohort 1: 1 mg/kg IV, single doseCohort 2a: 3 mg/kg IV, single doseCohort 2b: 300 mg SC, single doseCohort 3a: 10 mg/kg IV, single doseCohort 3b: 600 mg SC, single doseCohort 4: 30 mg/kg IV, single doseCohort 5: Loading dose of 15 mg/kg IV followed by 4 repeat SC doses of 400 mg administered once weekly for four weeks. RESULTS: REGN3918 was found to be well tolerated in single doses of up to 30 mg/kg IV and 600 mg SC. The multiple dose Cohort 5 has completed dosing in all subjects and is currently in safety follow-up. Thus far, there has been one SAE, salpingitis in a subject with an intra-uterine contraceptive device. The SAE occurred in a Cohort 5 subject after completion of dosing and has since resolved. REGN3918 exhibited dose-dependent increases in exposure in serum, with a trend toward prolonged serum concentrations at IV doses ≥10 mg/kg. Following SC administration, concentrations of REGN3918 in serum peaked at 4 to 8 days post dose and bioavailability was estimated as approximately 70%. REGN3918 exposure led to dose-dependent inhibition of CH50. In all 4 IV dosing cohorts, suppression of hemolysis was observed at 15 min post-injection. Complete suppression of hemolysis was achieved with ≥ 3mg/kg dosing. At 30 mg/kg, complete suppression of hemolysis was maintained for >6 weeks, consistent with observed prolonged REGN3918 concentrations following this dose. In the 2 SC cohorts, peak suppression of hemolysis was observed 3-7 days post dosing, again consistent with observed peak concentrations of REGN3918 in serum. In the multiple dose cohort 5, complete suppression of CH50 was observed over the four-week dosing period. CONCLUSIONS: REGN3918 was well tolerated and resulted in dose-dependent inhibition of hemolytic activity in normal healthy volunteers. A single IV infusion of R3918, at 30 mg/kg, blocked hemolytic activity completely for >6 weeks. Complete inhibition of hemolytic activity was maintained over a 4-week dosing period by a weekly SC regimen following an IV loading dose. Disclosures Weyne: Regeneron Pharmaceuticals: Employment, Equity Ownership. Ni:Regeneron Pharmaceuticals: Employment, Equity Ownership. DelGizzi:Regeneron Pharmaceuticals: Employment, Equity Ownership. Godin:Regeneron Pharmaceuticals: Employment. Morton:Regeneron Pharmaceuticals: Employment, Equity Ownership. Prasad:Regeneron Pharmaceuticals: Employment, Equity Ownership. Rankin:Regeneron Pharmaceuticals: Employment, Equity Ownership. Simek-Lemos:Regeneron Pharmaceuticals: Employment, Equity Ownership. Wang:Regeneron Pharmaceuticals: Employment, Equity Ownership. Rippley:Regeneron Pharmaceuticals: Employment, Equity Ownership. Harari:Regeneron Pharmaceuticals, Inc.: Employment.

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Safety, Tolerability, and Pharmacokinetics of GDC-0276, a Novel NaV1.7 Inhibitor, in a First-in-Human, Single- and Multiple-Dose Study in Healthy Volunteers

Clinical Drug Investigation ◽

10.1007/s40261-019-00807-3 ◽

2019 ◽

Vol 39 (9) ◽

pp. 873-887 ◽

Cited By ~ 6

Author(s):

Michael E. Rothenberg ◽

Michael Tagen ◽

Jae H. Chang ◽

Janel Boyce-Rustay ◽

Michel Friesenhahn ◽

...

Keyword(s):

Healthy Volunteers ◽

Multiple Dose ◽

Multiple Dose Study ◽

Dose Study

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Pharmacodynamic Effects of Steady-State Fingolimod on Antibody Response in Healthy Volunteers: A 4-Week, Randomized, Placebo-Controlled, Parallel-Group, Multiple-Dose Study

The Journal of Clinical Pharmacology ◽

10.1177/0091270011427908 ◽

2012 ◽

Vol 52 (12) ◽

pp. 1879-1890 ◽

Cited By ~ 32

Author(s):

Craig Boulton ◽

Karin Meiser ◽

Olivier J. David ◽

Robert Schmouder

Keyword(s):

Steady State ◽

Antibody Response ◽

Healthy Volunteers ◽

Multiple Dose ◽

Pharmacodynamic Effects ◽

Multiple Dose Study ◽

Parallel Group ◽

Dose Study

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Placebo-Controlled, Double-Blind, First-In-Human, Ascending Single Dose and Multiple Dose, Healthy Subject Study Of Intravenous-Administered SelG1, a Humanized Anti-P-Selectin Antibody In Development For Sickle Cell Disease

Blood ◽

10.1182/blood.v122.21.970.970 ◽

2013 ◽

Vol 122 (21) ◽

pp. 970-970 ◽

Cited By ~ 4

Author(s):

Jonathan W. Stocker ◽

Debra Mandarino ◽

Ziad Kawar ◽

Richard Alvarez ◽

David Falconer ◽

...

Keyword(s):

Single Dose ◽

Sickle Cell ◽

Multiple Dose ◽

Study Drug ◽

Cell Disease ◽

Employment Equity ◽

Double Blind ◽

Equity Ownership ◽

Clinically Significant ◽

Dose Dependent

Abstract SelG1 is a humanized anti-P-selectin monoclonal antibody being developed as a treatment for sickle cell disease (SCD). Extensive data have been published that suggest a pivotal role for P-selectin in the pathophysiology of SCD. Much of this work has been conducted in mice engineered to express human β hemoglobin S (sickle cell hemoglobin). These mice have a remarkably similar disease pathology to that observed in human SCD including vasoocclusion. Using these mice, investigators have demonstrated P-selectin interactions between the endothelium and sickled red blood cells, leukocytes and platelets. Additional studies have demonstrated direct P-selectin mediated binding of leukocytes with platelets. All of these cell-cell interactions have been implicated in SCD vasoocclusion. Further, blockade or genetic absence of P-selectin decreases or eliminates these cell-cell interactions and vasoocclusion. A Phase I clinical study was conducted to evaluate the safety, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of SelG1. This was a single-center, double-blind, placebo-controlled, first-in-human, ascending single dose and multiple dose study of intravenous (IV)-administered SelG1 in healthy adult male and female subjects. There were 5 dosing cohorts in the study (A through E): Ascending single dose cohorts: Cohort A:0.2 mg/kg IV dose of SelG1 (n=3) or placebo (n=1); Cohort B:0.5 mg/kg IV dose of SelG1 (n=3) or placebo (n=1); Cohort C:1.0 mg/kg IV dose of SelG1 (n=3) or placebo (n=1); Cohort D:5.0 mg/kg IV dose of SelG1 (n=6) or placebo (n=2). Multi-dose cohort: Cohort E:two 8.0 mg/kg IV doses of SelG1 (n=5) or placebo (n=2); the doses were given 2 weeks apart. In Cohorts A through D, SelG1 was slowly eliminated (mean t1/2 = 75.6 to 500 hours). Mean t1/2 values increased in a dose dependent manner. The exposure to SelG1 (mean Cmax, AUC0-t, and AUC0-∞) increased in a greater than proportional manner over the dose range. In Cohort E, SelG1 was slowly eliminated (mean t1/2 = 363 hours for the second infusion). The mean Cmax and AUC0-336values were 1.6- and 1.7-fold higher, respectively, after the second infusion relative to the first infusion. The PD data demonstrate that P-selectin function was completely blocked for a minimum of 28 days in Cohort D and at least 56 days in Cohort E. Twenty-six of the 27 subjects who received study drug completed the study, with 1 placebo subject in Cohort D withdrawing himself from the study due to the required travel commitment. There were no deaths, serious adverse events, or severe AEs reported in any subject. There were no increases in the number or severity of AEs with increasing dosages or with multi-dose administration. The percentage of subjects experiencing an AE was similar between the SelG1-treated subjects and the placebo-treated subjects; in Cohorts A-D, 66.7% of SelG1-treated subjects and 60.0% of placebo subjects reported at least 1 AE, while in Cohort E, 60.0% of SelG1-treated subjects and 50.0% of placebo-treated subjects reported at least 1 AE. Only 1 AE occurred in more than 1 subject; vessel puncture site hematoma occurred in 1 subject of Cohort A, 1 subject of Cohort C, and 2 subjects of Cohort E. All other AEs occurred in only 1 subject and were mild to moderate in severity. No AEs in any subject were deemed “related” to study drug. No clinically significant findings were noted from vital sign measurements, physical examinations, or 12-lead ECGs for this study. No biochemistry, hematology, or other laboratory data were reported as clinically significant or were reported as AEs; there were no trends that indicated increases or decreases in mean or median values over time, and there were no dose-dependent increases or decreases in mean or median values. There were no demonstrable changes in coagulation parameters or increased bleeding tendencies. No specific antibody response to SelG1 occurred in any of the subjects. In summary, the administration of SelG1 was well tolerated in this group of healthy male and female subjects. A Phase II clinical study to evaluate the clinical efficacy of SelG1 in SCD patients is currently underway. Disclosures: Stocker: Selexys Pharmaceuticals: Employment, Equity Ownership. Mandarino:Selexys Pharmaceuticals: CRO Other. Kawar:Selexys Pharmaceuticals: Employment, Equity Ownership, Patents & Royalties. Alvarez:Selexys Pharmaceuticals: Employment, Equity Ownership, Patents & Royalties. Falconer:Selexys Pharmaceuticals: Employment, Equity Ownership. Rollins:Selexys Pharmaceuticals: Employment, Equity Ownership, Membership on an entity’s Board of Directors or advisory committees. Rother:Selexys Pharmaceuticals: Employment, Equity Ownership.

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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 ◽

10.1182/blood.v126.23.2413.2413 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2413-2413 ◽

Cited By ~ 11

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.

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