Publications by authors named "Ryan Iarrobino"

4 Publications

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Inhibiting Plasma Kallikrein for Hereditary Angioedema Prophylaxis.

N Engl J Med 2017 02;376(8):717-728

From the Division of Rheumatology, Allergy, and Immunology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston (A.B.), Dyax, Burlington (C. Soo, R.I., D.J.S., C.T., J.A.K., R.F., H.K., R.M., C. Stevens, J.C.B., Y.C., B.A.), and ICON Clinical Research, Marlborough (J.G.S.) - all in Massachusetts; the Division of Clinical Immunology and Allergy, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York (P.B.), and Winthrop University Hospital, Mineola (M.D.-L.) - both in New York; Triumpharma, Amman, Jordan (M.S., A.A.-G.); Asthma and Allergy Research Associates, Dallas (W.L.); the Division of Allergy and Immunology, Washington University School of Medicine, St. Louis (H.J.W.); Allergy and Asthma Medical Group, Walnut Creek (J.J.), and the Department of Rheumatology, Allergy, and Immunology, University of California, San Diego, San Diego (M.R.) - both in California; Baker Allergy, Asthma, and Dermatology, Lake Oswego, OR (J.B.); the Department of Internal Medicine-Allergy Section Cincinnati, University of Cincinnati College of Medicine, Cincinnati (J.A.B.); the Division of Allergy and Immunology, Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa (R.L.); the Institute for Asthma and Allergy, Chevy Chase, MD (H.H.L.); the Department of Medicine and Pediatrics, Penn State Hershey Allergy, Asthma, and Immunology, Hershey, PA (T.C.); and the Department of Biomedical and Clinical Sciences, Luigi Sacco, University of Milan, and Luigi Sacco Hospital Milan, Milan (M.C.).

Background: Hereditary angioedema with C1 inhibitor deficiency is characterized by recurrent, unpredictable swelling episodes caused by uncontrolled plasma kallikrein generation and excessive bradykinin release resulting from cleavage of high-molecular-weight kininogen. Lanadelumab (DX-2930) is a new kallikrein inhibitor with the potential for prophylactic treatment of hereditary angioedema with C1 inhibitor deficiency.

Methods: We conducted a phase 1b, multicenter, double-blind, placebo-controlled, multiple-ascending-dose trial. Patients with hereditary angioedema with C1 inhibitor deficiency were randomly assigned in a 2:1 ratio to receive either lanadelumab (24 patients) or placebo (13 patients), in two administrations 14 days apart. Patients assigned to lanadelumab were enrolled in sequential dose groups: total dose of 30 mg (4 patients), 100 mg (4 patients), 300 mg (5 patients), or 400 mg (11 patients). The pharmacodynamic profile of lanadelumab was assessed by measurement of plasma levels of cleaved high-molecular-weight kininogen, and efficacy was assessed by the rate of attacks of angioedema during a prespecified period (day 8 to day 50) in the 300-mg and 400-mg groups as compared with the placebo group.

Results: No discontinuations occurred because of adverse events, serious adverse events, or deaths in patients who received lanadelumab. The most common adverse events that emerged during treatment were attacks of angioedema, injection-site pain, and headache. Dose-proportional increases in serum concentrations of lanadelumab were observed; the mean elimination half-life was approximately 2 weeks. Lanadelumab at a dose of 300 mg or 400 mg reduced cleavage of high-molecular-weight kininogen in plasma from patients with hereditary angioedema with C1 inhibitor deficiency to levels approaching that from patients without the disorder. From day 8 to day 50, the 300-mg and 400-mg groups had 100% and 88% fewer attacks, respectively, than the placebo group. All patients in the 300-mg group and 82% (9 of 11) in the 400-mg group were attack-free, as compared with 27% (3 of 11) in the placebo group.

Conclusions: In this small trial, administration of lanadelumab to patients with hereditary angioedema with C1 inhibitor deficiency reduced cleavage of high-molecular-weight kininogen and attacks of angioedema. (Funded by Dyax; ClinicalTrials.gov number, NCT02093923 .).
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http://dx.doi.org/10.1056/NEJMoa1605767DOI Listing
February 2017

Ecallantide for the acute treatment of angiotensin-converting enzyme inhibitor-induced angioedema: a multicenter, randomized, controlled trial.

Ann Emerg Med 2015 Feb 30;65(2):204-13. Epub 2014 Aug 30.

Dyax Corp, Burlington, MA.

Study Objective: We compare the safety and efficacy of ecallantide with placebo in subjects undergoing assessment for acute angiotensin-converting enzyme inhibitor-induced angioedema (ACEIA) in an emergency department (ED).

Methods: This was a multicenter, phase 2, double-blind study with subjects randomized to receive a single subcutaneous dose of ecallantide (10, 30, or 60 mg) or placebo plus physician-directed conventional therapy. The primary endpoint was defined as meeting predetermined discharge eligibility criteria within 6 hours of study drug administration. Discharge criteria included improvement of edema, stable vital signs, absence of stridor, absence of dyspnea or use of accessory muscles during respiration, absence of drooling, and ability to drink without difficulty.

Results: An interim analysis showed that a high percentage of subjects met the primary endpoint, and the study was halted. Overall, 79 subjects were randomized and 76 had data for analysis. Most had mild (45%) or moderate (42%) ACEIA. The discharge eligibility endpoint was met by 72% of the placebo group and 85%, 89%, and 89% of the ecallantide 10-, 30-, and 60-mg groups, respectively. This difference in meeting discharge eligibility endpoint criteria between treatment groups was not statistically significant. The incidence of treatment-emergent adverse events was similar between placebo and active-treatment groups.

Conclusion: The addition of ecallantide to standard therapy does not appear to improve angioedema compared with placebo in ED patients with ACEIA. Our data suggest that most ED patients presenting with mild to moderate ACEIA are likely to meet our discharge eligibility criteria within 6 hours of treatment, regardless of intervention. Further studies to assess the utility of ecallantide in patients with more severe angioedema may be useful. No new safety signals related to ecallantide administration were identified.
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http://dx.doi.org/10.1016/j.annemergmed.2014.07.014DOI Listing
February 2015

A phase 1 study investigating DX-2930 in healthy subjects.

Ann Allergy Asthma Immunol 2014 Oct 26;113(4):460-6.e2. Epub 2014 Jun 26.

Dyax Corp, Burlington, Massachusetts.

Background: DX-2930 is a human monoclonal antibody inhibitor of plasma kallikrein under investigation for long-term prophylaxis of hereditary angioedema.

Objective: To assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of DX-2930 in healthy subjects.

Methods: A single-center, double-blinded study was performed in 32 healthy subjects randomized 3:1 to receive a single subcutaneous administration of DX-2930 or placebo within 1 of 4 sequential, ascending dose cohorts (n = 8 each): 0.1, 0.3, 1.0, or 3.0 mg/kg.

Results: No dose-limiting toxicity was observed. Headache was the most commonly reported treatment emergent adverse event (AE), occurring at a rate of 25% in the DX-2930- and placebo-treated groups; none were severe and all resolved. There were no serious AEs, discontinuations owing to an AE, or deaths. Two subjects had a severe AE reported as related to treatment by the blinded investigator; the 2 AEs were asymptomatic creatinine phosphokinase elevations of 902 U/L in 1 subject receiving 0.1 mg/kg DX-2930 and 1,967 U/L in 1 subject receiving placebo. For the 0.1-, 0.3-, 1.0-, and 3.0-mg/kg dose groups, respectively, mean maximum plasma concentrations were 0.6, 1.4, 5.6, and 14.5 μg/mL and mean elimination half-lives were 20.6, 16.8, 17.6, and 21.2 days. Exploratory biomarker assays, involving ex vivo activation of the kallikrein pathway, showed dose- and time-dependent inhibition of plasma kallikrein, with evidence of sustained bioactivity consistent with the pharmacokinetics profile.

Conclusion: A single administration of DX-2930 in healthy subjects up to doses of 3.0 mg/kg was well tolerated without dose-limiting toxicity. Pharmacokinetic and pharmacodynamic data provide evidence for a long-acting biological effect relevant to long-term prophylaxis for hereditary angioedema with C1-inhibitor deficiency.

Trial Registration: ClinicalTrials.gov identifier: NCT01923207.
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http://dx.doi.org/10.1016/j.anai.2014.05.028DOI Listing
October 2014

Efficacy and safety of ecallantide in treatment of recurrent attacks of hereditary angioedema: open-label continuation study.

Allergy Asthma Proc 2013 Mar-Apr;34(2):155-61

Allergy & Asthma Specialists, Dallas, Texas, USA.

Hereditary angioedema (HAE) is a rare disorder characterized by recurrent attacks of potentially life-threatening edema. The plasma kallikrein inhibitor ecallantide is approved for treatment of acute HAE attacks. This study evaluates the efficacy and safety of ecallantide for treatment of multiple HAE episodes in the DX-88/19 (continuation) study. Patients received 30 mg of subcutaneous ecallantide for acute HAE attack symptoms, with no limit on number of episodes treated. Primary end point was change in patient-reported mean symptom complex severity (MSCS) score at 4 hours. Additional end points included change in MSCS score at 24 hours, treatment outcome score (TOS) at 4 and 24 hours, and time to response. Safety parameters included adverse events. Statistical analyses were conducted on qualifying treatment episodes (those with ≥12 patients). One hundred forty-seven patients received treatment for 625 episodes; analyses were conducted through 13 treatment episodes. Across 13 episodes at 4 hours, mean change in MSCS score ranged from -1.04 to -1.36, and mean TOSs ranged from 56.2 to 79.8. Median time to onset of sustained improvement ranged from 59 to 113 minutes. There was no indication of reduced efficacy with repeated ecallantide use. No new safety signals were detected. Eight patients (5.4%) reported potential hypersensitivity reactions, six of whom met the definition of anaphylaxis based on National Institute of Allergy and Infectious Diseases criteria. Ecallantide is effective for acute recurrent HAE attacks and maintains its efficacy and safety during multiple treatment episodes in patients with HAE. Potential hypersensitivity reactions were consistent with prior reports.
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http://dx.doi.org/10.2500/aap.2013.34.3653DOI Listing
August 2013