Evaluation of avoralstat, an oral kallikrein inhibitor, in a Phase 3 hereditary angioedema prophylaxis trial: The OPuS-2 study

M A Riedl; E Aygören-Pürsün; J Baker; H Farkas; J Anderson; J A Bernstein; L Bouillet; P Busse; M Manning; M Magerl; M Gompels; A P Huissoon; H Longhurst; W Lumry; B Ritchie; R Shapiro; D Soteres; A Banerji; M Cancian; D T Johnston; T J Craig; D Launay; H H Li; M Liebhaber; T Nickel; J Offenberger; W Rae; R Schrijvers; M Triggiani; H J Wedner; S Dobo; M Cornpropst; D Clemons; L Fang; P Collis; W P Sheridan; M Maurer

doi:10.1111/all.13466

Evaluation of avoralstat, an oral kallikrein inhibitor, in a Phase 3 hereditary angioedema prophylaxis trial: The OPuS-2 study

Allergy. 2018 Sep;73(9):1871-1880. doi: 10.1111/all.13466. Epub 2018 Jun 17.

Authors

M A Riedl¹, E Aygören-Pürsün², J Baker³, H Farkas⁴, J Anderson⁵, J A Bernstein⁶, L Bouillet⁷, P Busse⁸, M Manning⁹, M Magerl¹⁰, M Gompels¹¹, A P Huissoon¹², H Longhurst¹³, W Lumry¹⁴, B Ritchie¹⁵, R Shapiro¹⁶, D Soteres¹⁷, A Banerji¹⁸, M Cancian¹⁹, D T Johnston²⁰, T J Craig²¹, D Launay²², H H Li²³, M Liebhaber²⁴, T Nickel²⁵, J Offenberger²⁶, W Rae²⁷, R Schrijvers²⁸, M Triggiani²⁹, H J Wedner³⁰, S Dobo³¹, M Cornpropst³¹, D Clemons³¹, L Fang³², P Collis³¹, W P Sheridan³¹, M Maurer³³

Affiliations

¹ Division of Rheumatology, Allergy & Immunology, University of California San Diego, San Diego, CA, USA.
² Department for Children and Adolescents, University Hospital Frankfurt, Frankfurt, Germany.
³ Baker Allergy Asthma Dermatology Research Center, Portland, OR, USA.
⁴ 3rd Department of Internal Medicine, Semmelweis University, Budapest, Hungary.
⁵ Clinical Research Center of Alabama, Birmingham, AL, USA.
⁶ Department of Internal Medicine, University of Cincinnati, Cincinnati, OH, USA.
⁷ Internal Medicine, National Reference Centre of Angioedema, Grenoble University Hospital, Grenoble, France.
⁸ Division of Clinical Immunology and Allergy, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁹ Medical Research of Arizona, Allergy, Asthma & Immunology Associates, Scottsdale, AZ, USA.
¹⁰ Dermatology, Venerology and Allergology, Charite - Universitätsmedizin Berlin, Berlin, Germany.
¹¹ Immunology, North Bristol NHS Trust, Bristol, UK.
¹² Department of Allergy and Immunology, Heartlands Hospital, Birmingham, UK.
¹³ Immunology, Addenbrookes Hospital, Cambridge University Hospitals, Cambridge, UK.
¹⁴ Allergy and Asthma Research Associates Research Center, Dallas, TX, USA.
¹⁵ Division of Hematology, Department of Medicine, University of Alberta, Edmonton, AB, Canada.
¹⁶ Immunology, Midwest Immunology Clinic, Plymouth, MN, USA.
¹⁷ Asthma and Allergy Associates PC, Colorado Springs, CO, USA.
¹⁸ Division of Rheumatology, Allergy& Immunology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
¹⁹ Department of Medicine, University of Padova, Padova, Italy.
²⁰ Asthma & Allergy Specialists, P.A., Charlotte, NC, USA.
²¹ Department of Medicine and Pediatrics, Penn State Hershey Allergy Asthma, and Immunology, Hershey, PA, USA.
²² Internal Medicine, CHRU Lille, France, France.
²³ Institute for Asthma and Allergy, Chevy Chase, MD, USA.
²⁴ Allergy and Immunology, Sansum Clinic, Santa Barbara, CA, USA.
²⁵ Allergy & Immunology, Allergy Clinic of Tulsa, Tulsa, OK, USA.
²⁶ Allergy and Asthma Relief Experts, Grenada Hills, CA, USA.
²⁷ Allergy & Clinical Immunology, University Hospital Southampton NHS Foundation Trust, Southampton, UK.
²⁸ Laboratory of Clinical Immunology, KU Leuven, Leuven, Belgium.
²⁹ Division of Allergy and Clinical Immunology, University of Salerno, Salerno, Italy.
³⁰ Division of Allergy and Immunology, Washington University School of Medicine, St. Louis, MO, USA.
³¹ Biocryst Pharmaceuticals, Durham, NC, USA.
³² Statistics, PharStat, Inc., Raleigh, NC, USA.
³³ Department of Dermatology and Allergy, Charité - Universitätsmedizin Berlin, Berlin, Germany.

Abstract

Background: Effective inhibition of plasma kallikrein may have significant benefits for patients with hereditary angioedema due to deficiency of C1 inhibitor (C1-INH-HAE) by reducing the frequency of angioedema attacks. Avoralstat is a small molecule inhibitor of plasma kallikrein. This study (OPuS-2) evaluated the efficacy and safety of prophylactic avoralstat 300 or 500 mg compared with placebo.

Methods: OPuS-2 was a Phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Subjects were administered avoralstat 300 mg, avoralstat 500 mg, or placebo orally 3 times per day for 12 weeks. The primary efficacy endpoint was the angioedema attack rate based on adjudicator-confirmed attacks.

Results: A total of 110 subjects were randomized and dosed. The least squares (LS) mean attack rates per week were 0.589, 0.675, and 0.593 for subjects receiving avoralstat 500 mg, avoralstat 300 mg, and placebo, respectively. Overall, 1 subject in each of the avoralstat groups and no subjects in the placebo group were attack-free during the 84-day treatment period. The LS mean duration of all confirmed attacks was 25.4, 29.4, and 31.4 hours for the avoralstat 500 mg, avoralstat 300 mg, and placebo groups, respectively. Using the Angioedema Quality of Life Questionnaire (AE-QoL), improved QoL was observed for the avoralstat 500 mg group compared with placebo. Avoralstat was generally safe and well tolerated.

Conclusions: Although this study did not demonstrate efficacy of avoralstat in preventing angioedema attacks in C1-INH-HAE, it provided evidence of shortened angioedema episodes and improved QoL in the avoralstat 500 mg treatment group compared with placebo.

Keywords: C1 inhibitor; hereditary angioedema; oral kallikrein inhibitor; prophylaxis.

Publication types

Clinical Trial, Phase III
Multicenter Study
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

MeSH terms

Administration, Oral
Adult
Angioedemas, Hereditary / diagnosis
Angioedemas, Hereditary / drug therapy
Angioedemas, Hereditary / prevention & control*
Disease Progression
Enzyme Inhibitors / administration & dosage
Enzyme Inhibitors / adverse effects
Enzyme Inhibitors / pharmacokinetics
Enzyme Inhibitors / therapeutic use*
Female
Humans
Male
Middle Aged
Plasma Kallikrein / antagonists & inhibitors*
Quality of Life
Recurrence
Treatment Outcome

Substances

Enzyme Inhibitors
Plasma Kallikrein