EHA Library - The official digital education library of European Hematology Association (EHA)

CHARACTERIZATION OF ORALLY BIOAVAILABLE SMALL MOLECULE INHIBITORS OF COMPLEMENT C5
Author(s): ,
Alonso Ricardo
Affiliations:
Ra Pharmaceuticals, Inc.,CAMBRIDGE,United States
,
Michael Hale
Affiliations:
Ra Pharmaceuticals, Inc.,CAMBRIDGE,United States
,
Zhong Ma
Affiliations:
Ra Pharmaceuticals, Inc.,CAMBRIDGE,United States
,
Jorge Reyes
Affiliations:
Ra Pharmaceuticals, Inc.,CAMBRIDGE,United States
,
Camil Sayegh
Affiliations:
Ra Pharmaceuticals, Inc.,CAMBRIDGE,United States
,
Kate Sherry
Affiliations:
Ra Pharmaceuticals, Inc.,CAMBRIDGE,United States
,
Yili Sun
Affiliations:
Ra Pharmaceuticals, Inc.,CAMBRIDGE,United States
,
Yalang Tan
Affiliations:
Ra Pharmaceuticals, Inc.,CAMBRIDGE,United States
,
Douangsone Vadysirisack
Affiliations:
Ra Pharmaceuticals, Inc.,CAMBRIDGE,United States
Nanqun Zu
Affiliations:
Ra Pharmaceuticals, Inc.,CAMBRIDGE,United States
(Abstract release date: 05/17/18) EHA Library. Ricardo A. 06/17/18; 214586; S1581
Alonso Ricardo
Alonso Ricardo
Contributions
Abstract

Abstract: S1581

Type: Oral Presentation

Presentation during EHA23: On Sunday, June 17, 2018 from 08:15 - 08:30

Location: Room A8

Background
Abnormal activation of the complement cascade is implicated in the pathogenesis of many rare and common diseases. Complement C5 inhibition by intravenous administration of the monoclonal antibody eculizumab has demonstrated therapeutic benefit in paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS) and, most recently, in myasthenia gravis. Given the demonstrated and broad therapeutic utility of complement inhibition in these and other disorders, there is substantial interest in the development of an oral small molecule C5 inhibitor (C5SMi) as a treatment for autoimmune, hematological, renal, vascular and neurological diseases.

We recently described the discovery of orally bioavailable small molecule inhibitors of complement C5. Here, we describe their pharmacology in human whole blood-based assay models, pharmacokinetics in several preclinical species, and their ex vivo PK/PD relationships.

Aims
-Characterize the pharmacology of orally available C5SMi in human whole blood-based models of disease

-Determine the pharmacokinetic parameters of C5SMi in preclinical species (rodents and dog)

-Establish a PK/PD (ex vivo) relationship for orally available C5SMi in mice 

Methods
Pharmacokinetic studies of C5SMi were conducted in rodents and dogs following intravenous and oral administration. Non-compartmental analyses were applied to the plasma concentration versus time data (PK analysis).  Blood was drawn at multiple time points following administration to establish an ex-vivo PK/PD relationship by monitoring C5a formation after zymosan mediated complement activation (PD analysis). Potency in disease-relevant human whole blood studies was determined by ABO incompatibility reactions following mixing blood from a donor with serum from an incompatible recipient.  Finally, a human whole blood hemolysis assay was performed using a polyclonal anti-human RBC antibody and hemolysis monitored using spectrophotometric methods. 

Results
The pharmacokinetic data demonstrate that compounds within the lead series display dose proportional oral exposure and low clearance values in several preclinical species.  Ex vivo and in vitro assays, including in human whole blood assays, demonstrate the selective engagement of complement C5, and the mouse PK/PD relationship following oral dosing informs the level of exposure required to achieve therapeutic efficacy in humans.

Conclusion
The results presented in here confirm the feasibility of inhibiting complement C5 using small molecule inhibitors via oral dosing. The excellent drug-like properties exhibited by these compounds, their favorable pharmacokinetic behavior in different preclinical species, and the understanding of the PK/PD relationship informs the required therapeutic drug levels that will be necessary to evaluate their pharmacology in human disease.

Session topic: 11. Bone marrow failure syndromes incl. PNH – Biology & Translational Research

Keyword(s): Autoimmune disease, Complement, Hemolysis, PNH

Abstract: S1581

Type: Oral Presentation

Presentation during EHA23: On Sunday, June 17, 2018 from 08:15 - 08:30

Location: Room A8

Background
Abnormal activation of the complement cascade is implicated in the pathogenesis of many rare and common diseases. Complement C5 inhibition by intravenous administration of the monoclonal antibody eculizumab has demonstrated therapeutic benefit in paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS) and, most recently, in myasthenia gravis. Given the demonstrated and broad therapeutic utility of complement inhibition in these and other disorders, there is substantial interest in the development of an oral small molecule C5 inhibitor (C5SMi) as a treatment for autoimmune, hematological, renal, vascular and neurological diseases.

We recently described the discovery of orally bioavailable small molecule inhibitors of complement C5. Here, we describe their pharmacology in human whole blood-based assay models, pharmacokinetics in several preclinical species, and their ex vivo PK/PD relationships.

Aims
-Characterize the pharmacology of orally available C5SMi in human whole blood-based models of disease

-Determine the pharmacokinetic parameters of C5SMi in preclinical species (rodents and dog)

-Establish a PK/PD (ex vivo) relationship for orally available C5SMi in mice 

Methods
Pharmacokinetic studies of C5SMi were conducted in rodents and dogs following intravenous and oral administration. Non-compartmental analyses were applied to the plasma concentration versus time data (PK analysis).  Blood was drawn at multiple time points following administration to establish an ex-vivo PK/PD relationship by monitoring C5a formation after zymosan mediated complement activation (PD analysis). Potency in disease-relevant human whole blood studies was determined by ABO incompatibility reactions following mixing blood from a donor with serum from an incompatible recipient.  Finally, a human whole blood hemolysis assay was performed using a polyclonal anti-human RBC antibody and hemolysis monitored using spectrophotometric methods. 

Results
The pharmacokinetic data demonstrate that compounds within the lead series display dose proportional oral exposure and low clearance values in several preclinical species.  Ex vivo and in vitro assays, including in human whole blood assays, demonstrate the selective engagement of complement C5, and the mouse PK/PD relationship following oral dosing informs the level of exposure required to achieve therapeutic efficacy in humans.

Conclusion
The results presented in here confirm the feasibility of inhibiting complement C5 using small molecule inhibitors via oral dosing. The excellent drug-like properties exhibited by these compounds, their favorable pharmacokinetic behavior in different preclinical species, and the understanding of the PK/PD relationship informs the required therapeutic drug levels that will be necessary to evaluate their pharmacology in human disease.

Session topic: 11. Bone marrow failure syndromes incl. PNH – Biology & Translational Research

Keyword(s): Autoimmune disease, Complement, Hemolysis, PNH

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