Publications by authors named "Marc A Riedl"

67 Publications

Long-term health-related quality of life in patients treated with subcutaneous C1-inhibitor replacement therapy for the prevention of hereditary angioedema attacks: findings from the COMPACT open-label extension study.

Orphanet J Rare Dis 2021 Feb 15;16(1):86. Epub 2021 Feb 15.

University College Hospital, London, UK.

Background: Long-term prophylaxis with subcutaneous C1-inhibitor (C1-INH[SC]; HAEGARDA, CSL Behring) in patients with hereditary angioedema (HAE) due to C1-INH deficiency (C1-INH-HAE) was evaluated in an open-label extension follow-up study to the international, double-blind, placebo-controlled COMPACT study. The current analysis evaluated patient-reported health-related quality of life (HRQoL) data from 126 patients in the open-label extension study randomized to treatment with C1-INH(SC) 40 IU/kg (n = 63) or 60 IU/kg (n = 63) twice weekly for 52 weeks. HRQoL was evaluated at the beginning of the open-label study and at various time points using the European Quality of Life-5 Dimensions Questionnaire (EQ-5D), the Hospital Anxiety and Depression Scale (HADS), the Work Productivity and Activity Impairment Questionnaire (WPAI), and the Treatment Satisfaction Questionnaire for Medication. The disease-specific Angioedema Quality of Life Questionnaire (AE-QoL) and HAE quality of life questionnaire (HAE-QoL) instruments were administered in a subset of patients. Statistical significance was determined by change-from-baseline 95% confidence intervals (CIs) excluding zero. No adjustment for multiplicity was done.

Results: Mean baseline EQ-5D scores (Health State Value, 0.90; Visual Analog Scale, 81.32) were slightly higher (better) than United States population norms (0.825, 80.0, respectively) and mean HADS anxiety (5.48) and depression (2.88) scores were within "normal" range (0-7). Yet, patients using C1-INH(SC) 60 IU/kg demonstrated significant improvement from baseline to end-of-study on the EQ-5D Health State Value (mean change [95% CI], 0.07 [0.01, 0.12] and Visual Analog Scale (7.45 [3.29, 11.62]). In the C1-INH(SC) 60 IU/kg group, there were significant improvements in the HADS anxiety scale (mean change [95% CI], - 1.23 [- 2.08, - 0.38]), HADS depression scale (- 0.95 [- 1.57, - 0.34]), and WPAI-assessed presenteeism (mean change [95% CI], - 23.33% [- 34.86, - 11.81]), work productivity loss (- 26.68% [- 39.92, - 13.44]), and activity impairment (- 16.14% [- 26.36, - 5.91]). Clinically important improvements were achieved in ≥ 25% of patients for all domains except WPAI-assessed absenteeism (which was very low at baseline). Mean AE-QoL total score by visit ranged from 13.39 to 17.89 (scale 0-100; lower scores = less impairment). Mean HAE-QoL global scores at each visit (115.7-122.3) were close to the maximum (best) possible score of 135.

Conclusions: Long-term C1-INH(SC) replacement therapy in patients with C1-INH-HAE leads to significant and sustained improvements in multiple measures of HRQoL. Trial registration A Study to Evaluate the Long-term Clinical Safety and Efficacy of Subcutaneously Administered C1-esterase Inhibitor in the Prevention of Hereditary Angioedema, NCT02316353. Registered December 12, 2014, https://clinicaltrials.gov/ct2/show/NCT02316353 .
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13023-020-01658-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7885603PMC
February 2021

Androgen use in hereditary angioedema: A critical appraisal and approaches to transitioning from androgens to other therapies.

Allergy Asthma Proc 2021 01 21;42(1):22-29. Epub 2020 Dec 21.

Division of Rheumatology, Allergy and Immunology, Department of Medicine, University of California San Diego, La Jolla, California.

Hereditary angioedema (HAE) is a rare genetic disorder clinically characterized by recurrent attacks of subcutaneous and mucosal swelling. Attenuated androgens have been a prophylactic treatment option to reduce the frequency of HAE attacks for > 4 decades. However, the advent of effective on-demand treatments and highly effective, more tolerable, long-term prophylactic therapies has led to a decline in the use of attenuated androgens for the management of HAE in regions where newer therapies are available. A consensus about the best approach for discontinuing or tapering off attenuated androgen therapy does not exist. To develop a consensus on androgen tapering for patients with HAE. We sent an open-ended survey about androgen tapering to 21 physicians who treat HAE, 12 of whom responded. We reviewed the collective experience of the participating physicians in combination with results from a literature review on the topic. The survey and literature review underscored potential concerns related to rapid androgen withdrawal in patients with HAE, including physician and patient concerns that the frequency and severity of attacks would abruptly worsen. In addition, discontinuation of attenuated androgens may have the potential for transient adverse effects, such as an increase in the rate of attacks or effects related to hormone withdrawal. Our survey showed that physicians often taper androgens to prevent increases in HAE attacks and possible withdrawal complications. Based on both experiences of the physicians who responded to our survey and reports in the endocrine literature, we provided recommendations for androgen tapering. However, we noted that the likelihood of adverse effects due to androgen withdrawal in patients with HAE is poorly understood and requires further study.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2500/aap.2021.42.200106DOI Listing
January 2021

Impact of lanadelumab on health-related quality of life in patients with hereditary angioedema in the HELP study.

Allergy 2020 Nov 30. Epub 2020 Nov 30.

Dermatological Allergology, Allergie-Centrum-Charité, Department of Dermatology and Allergy, Charité - Universitätsmedizin Berlin, Berlin, Germany.

Background: An objective of the phase 3 HELP Study was to investigate the effect of lanadelumab on health-related quality of life (HRQoL) in patients with hereditary angioedema (HAE).

Methods: Patients with HAE-1/2 received either lanadelumab 150 mg every 4 weeks (q4wks; n = 28), 300 mg q4wks (n = 29), 300 mg every 2 weeks (q2wks; n = 27), or placebo (n = 41) for 26 weeks (days 0-182). The Angioedema Quality of Life Questionnaire (AE-QoL) was administered monthly, consisting of four domain (functioning, fatigue/mood, fears/shame, nutrition) and total scores. The generic EQ-5D-5L questionnaire was administered on days 0, 98, and 182. Comparisons were made between placebo and (a) all lanadelumab-treated patients and (b) individual lanadelumab groups for changes in scores (day 0-182) and proportions achieving the minimal clinically important difference (MCID, -6) in AE-QoL total score.

Results: Compared with the placebo group, the lanadelumab total group demonstrated significantly greater improvements in AE-QoL total and domain scores (mean change, -13.0 to -29.3; p < 0.05 for all); the largest improvement was in functioning. A significantly greater proportion of the lanadelumab total group achieved the MCID (70% vs 37%; p = 0.001). The lanadelumab 300 mg q2wks group had the highest proportion (81%; p = 0.001) and was 7.2 times more likely to achieve the MCID than the placebo group. Mean EQ-5D-5L scores at day 0 were high in all groups, indicating low impairment, with no significant changes at day 182.

Conclusion: Patients with HAE-1/2 experienced significant and clinically meaningful improvements in HRQoL measured by AE-QoL following lanadelumab treatment in the HELP Study.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/all.14680DOI Listing
November 2020

Current medical management of hereditary angioedema: Follow-up survey of US physicians.

Ann Allergy Asthma Immunol 2021 Mar 26;126(3):264-272. Epub 2020 Oct 26.

Department of Medicine, University of Washington, Spokane, Washington.

Background: Physician surveys on hereditary angioedema (HAE) management in 2010 and 2013 revealed important trends in HAE care.

Objective: To evaluate current HAE management and the impact of new treatment options on physician practice patterns over time.

Methods: During June and July 2019, 5382 physicians were contacted by means of postal mail to complete a 47-question survey; 177 responded (3%).

Results: Across the 3 surveys, the home replaced the emergency department as the most typically reported setting for HAE attack treatment (54.3% vs 11.6% in 2010 and 32.5% in 2013; P < .001). Physicians reported C1 esterase inhibitor (C1-INH) as the most typically prescribed long-term prophylactic treatment (LTP) (60.0% vs 20.4% in 2010 and 56.7% in 2013; P < .001). Subcutaneous LTP medications were most typically prescribed over intravenous (C1-INH, 41.4%; subcutaneous lanadelumab, 21%; intravenous C1-INH, 18.6%). Danazol, the most frequently prescribed LTP treatment, dropped to 6.4% (55.8% in 2010 and 23.4% in 2013; P < .001). The strongest nonefficacy factor influencing clinician treatment choice changed over time, with cost and (or) insurance coverage increasing to 43.7% (from 24.4% in 2010 and 40.5% in 2013; P = .001), whereas the concern over adverse effects dropped to 16.2% (from 55.8% in 2010 and 29.5% in 2013; P < .001). Physician-reported patient satisfaction remains high, with only 1.5% of physicians indicating patients are not satisfied with treatment.

Conclusion: The US physician survey data reflect improvements in the HAE management in recent years. Therapeutic advances in HAE have led to reported higher rates of home treatment of HAE attacks, reduced concern for adverse treatment effects, and high levels of patient satisfaction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.anai.2020.10.009DOI Listing
March 2021

Hereditary angioedema and shared decision making.

Allergy Asthma Proc 2020 11;41(Suppl 1):S55-S60

Division of Rheumatology, Allergy, and Immunology, University of California-San Diego, California.

Clinical decision-making in hereditary angioedema (HAE) management involves a high degree of complexity given the number of therapeutic agents that are available and the risk for significant morbidity and potential mortality attributable to the disease. Given this complexity, there is an opportunity to develop shared decision-making (SDM) aids and/or tools that would facilitate the interactive participation of practitioners and patients in the SDM process. This article reviews the general constructs of SDM, the unmet need for SDM in HAE, and the steps necessary to create a SDM tool specific for HAE, and outlines the challenges that must be navigated to guide the establishment and widespread implementation of SDM in the management of HAE.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2500/aap.2020.41.200057DOI Listing
November 2020

A roadmap for optimal care of the patient with hereditary angioedema.

Allergy Asthma Proc 2020 11;41(Suppl 1):S01-S02

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2500/aap.2020.41.200087DOI Listing
November 2020

Oral once-daily berotralstat for the prevention of hereditary angioedema attacks: A randomized, double-blind, placebo-controlled phase 3 trial.

J Allergy Clin Immunol 2020 Oct 21. Epub 2020 Oct 21.

University of California San Diego, San Diego, Calif.

Background: Berotralstat (BCX7353) is an oral, once-daily inhibitor of plasma kallikrein in development for the prophylaxis of hereditary angioedema (HAE) attacks.

Objective: Our aim was to determine the efficacy, safety, and tolerability of berotralstat in patients with HAE over a 24-week treatment period (the phase 3 APeX-2 trial).

Methods: APeX-2 was a double-blind, parallel-group study that randomized patients at 40 sites in 11 countries 1:1:1 to receive once-daily berotralstat in a dose of 110 mg or 150 mg or placebo (Clinicaltrials.gov identifier NCT03485911). Patients aged 12 years or older with HAE due to C1 inhibitor deficiency and at least 2 investigator-confirmed HAE attacks in the first 56 days of a prospective run-in period were eligible. The primary efficacy end point was the rate of investigator-confirmed HAE attacks during the 24-week treatment period.

Results: A total of 121 patients were randomized; 120 of them received at least 1 dose of the study drug (n = 41, 40, and 39 in the 110-mg dose of berotralstat, 150-mg of dose berotralstat, and placebo groups, respectively). Berotralstat demonstrated a significant reduction in attack rate at both 110 mg (1.65 attacks per month; P = .024) and 150 mg (1.31 attacks per month; P < .001) relative to placebo (2.35 attacks per month). The most frequent treatment-emergent adverse events that occurred more with berotralstat than with placebo were abdominal pain, vomiting, diarrhea, and back pain. No drug-related serious treatment-emergent adverse events occurred.

Conclusion: Both the 110-mg and 150-mg doses of berotralstat reduced HAE attack rates compared with placebo and were safe and generally well tolerated. The most favorable benefit-to-risk profile was observed at a dose of 150 mg per day.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jaci.2020.10.015DOI Listing
October 2020

US HAEA Medical Advisory Board 2020 Guidelines for the Management of Hereditary Angioedema.

J Allergy Clin Immunol Pract 2021 Jan 6;9(1):132-150.e3. Epub 2020 Sep 6.

Division of Rheumatology, Allergy, and Immunology, Department of Medicine, University of California San Diego, La Jolla, Calif; San Diego Veterans Administration Healthcare, San Diego, Calif. Electronic address:

Scientific and clinical progress together with the development of effective novel therapeutic options has engendered multiple important changes in the diagnosis and management of hereditary angioedema (HAE). We now update and extend the 2013 United States Hereditary Angioedema Association Medical Advisory Board guidelines for the treatment and management of HAE. The guidelines are based on a comprehensive literature review with recommendations indicating both the strength of our recommendation and the quality of the underlying evidence. Guidelines are provided regarding the classification, diagnosis, on-demand treatment, prophylactic treatment, special considerations for women and children, development of a comprehensive management and monitoring plan, and assessment of burden of illness for both HAE due to C1 inhibitor deficiency and HAE with normal C1 inhibitor. Advances in HAE treatment now allow the development of management plans that can help many patients with HAE lead a normal life. Achieving this goal requires that physicians be familiar with the diagnostic and therapeutic transformations that have occurred in recent years.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jaip.2020.08.046DOI Listing
January 2021

Association Between Self-Reported Dental Hygiene Practices and Dental Procedure-Related Recurrent Angioedema Attacks in HAE Subjects: A Multicenter Survey.

J Allergy Clin Immunol Pract 2020 Oct 10;8(9):3162-3169.e5. Epub 2020 Jun 10.

Division of Immunology/Allergy, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio. Electronic address:

Background: Hereditary angioedema (HAE) symptoms may be triggered by dental procedures, thereby complicating dental care in individuals affected by the condition.

Objective: This study investigated the self-perceived dental care needs, perceived susceptibility to acute angioedema (AE) attacks after dental procedures, and dental care behavior of patients with HAE.

Methods: A self-administered semistructured web-based questionnaire was distributed to 250 adult patients with HAE (type 1 or 2; 88% type 1) and 256 matched non-HAE controls. Data were analyzed using stratified χ tests, logistic regression, and classification trees.

Results: A total of 46.4% of HAE versus 55.5% of control patients had dental visits within 6 months (P = .04). Dental insurance was a barrier to seeking routine dental visits among both groups. However, significantly fewer patients with HAE had routine dental visits within 6 months despite having dental insurance compared with control patients (48% vs 60%, P = .01). Within the HAE group, a significantly greater number of patients with dental visits at intervals greater than 6 months had a history of recurrent postprocedural AE attacks (odds ratio [OR]: 3.9 [1.7, 8.8], P = .0005) and used antibacterial toothpaste more frequently than those without recurrent AE attacks (OR: 4.7 [1.5, 15.4], P = .005).

Conclusions: These data support the hypothesis that patients with HAE who are predisposed to having AE episodes in response to medical or physical trauma visit the dentist less and engage in specific oral hygiene practices more frequently than matched control patients and patients with HAE who reported that they were less likely to swell after a dental procedure.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jaip.2020.05.041DOI Listing
October 2020

Lanadelumab demonstrates rapid and sustained prevention of hereditary angioedema attacks.

Allergy 2020 11 6;75(11):2879-2887. Epub 2020 Jul 6.

Allergy and Asthma Research Associates, Dallas, TX, USA.

Background: Lanadelumab demonstrated efficacy in preventing hereditary angioedema (HAE) attacks in the phase 3 HELP Study.

Objective: To assess time to onset of effect and long-term efficacy of lanadelumab, based on exploratory findings from the HELP Study.

Methods: Eligible patients with HAE type I/II received lanadelumab 150 mg every 4 weeks (q4wks), 300 mg q4wks, 300 mg q2wks, or placebo. Ad hoc analyses evaluated day 0-69 findings using a Poisson regression model accounting for overdispersion. Least-squares mean monthly HAE attack rate for lanadelumab was compared with placebo. Intrapatient comparisons for days 0-69 versus steady state (days 70-182) used a paired t test for continuous endpoints or Kappa statistics for categorical endpoints.

Results: One hundred twenty-five patients were randomized and treated. During days 0-69, mean monthly attack rate was significantly lower with lanadelumab (0.41-0.76) vs placebo (2.04), including attacks requiring acute treatment (0.33-0.61 vs 1.66) and moderate/severe attacks (0.31-0.48 vs 1.33, all P ≤ .001). More patients receiving lanadelumab vs placebo were attack free (37.9%-48.1% vs 7.3%) and responders (85.7%-100% vs 26.8%). During steady state, the efficacy of lanadelumab vs placebo was similar or improved vs days 0-69. Intrapatient differences were significant with lanadelumab 300 mg q4wks for select outcomes. Lanadelumab efficacy was durable-HAE attack rate was consistently lower vs placebo, from the first 2 weeks of treatment through study end. Treatment emergent adverse events were comparable during days 0-69 and 70-182.

Conclusion: Protection with lanadelumab started from the first dose and continued throughout the entire study period.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/all.14416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7689768PMC
November 2020

Long-term safety and efficacy of subcutaneous C1-inhibitor in older patients with hereditary angioedema.

Ann Allergy Asthma Immunol 2020 09 20;125(3):334-340.e1. Epub 2020 May 20.

University of California, San Diego School of Medicine, La Jolla, California.

Background: Patients aged 65 years and older with hereditary angioedema (HAE) owing to C1-inhibitor (C1-INH) deficiency may have an altered response to treatment and are at higher risk for treatment-related adverse events (AEs) because of comorbidities and polypharmacy.

Objective: To investigate the safety and efficacy of subcutaneous C1 esterase inhibitor (C1-INH) in patients aged 65 years and older treated in an open-label extension of a phase 3 trial.

Methods: Eligible patients (≥4 attacks for more than 2 consecutive months) were randomized to receive twice-weekly subcutaneous C1-INH with a dosage of 40 IU/kg or 60 IU/kg for 52 to 140 weeks. Safety end points and efficacy outcomes were evaluated for patients aged 65 years and above and younger than 65 years.

Results: Of the 126 patients treated, 10 were 65 years and older (mean age [range], 68 [65-72 years]). A total of 8 of 10 patients had multiple comorbidities, and 6 of these 10 patients were taking more than 5 non-HAE-related drugs concomitantly. AEs occurring in more than 1 patient included injection site bruising (n = 2, related), injection site pain (n = 2, related), urinary tract infection (n = 2, unrelated), and diarrhea (n = 2, unrelated). No thromboembolic events or cases of anaphylaxis were reported. Two patients aged 65 years and older experienced unrelated serious AEs (dehydration and hypokalemia in 1 and pneumonia and an HAE attack leading to hospitalization in another). A total of 6 of 9 evaluable patients were responders, with a greater than or equal to 50% reduction in HAE attacks vs prestudy; 6 of 10 patients had less than 1 attack over 4 weeks and 3 were attack-free (median attack rate, 0.52 attacks per month).

Conclusion: Subcutaneous C1-INH was well-tolerated and effective in the management of HAE in patients aged 65 years and older with multiple comorbid conditions and polypharmacy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.anai.2020.05.015DOI Listing
September 2020

Experience with Intravenous Plasma-Derived C1-Inhibitor in Pregnant Women with Hereditary Angioedema: A Systematic Literature Review.

J Allergy Clin Immunol Pract 2020 06 3;8(6):1875-1880.e3. Epub 2020 Apr 3.

Department of Internal Medicine, Section of Allergy and Clinical Immunology, Yale University School of Medicine, New Haven, Conn.

Consensus guidelines recommend plasma-derived C1 inhibitor (C1-INH) as first-line treatment in pregnant women with hereditary angioedema (HAE). We conducted a systematic review of the literature that describes experience with plasma-derived C1-INH during pregnancy. A literature search of PubMed was conducted in November 2018 using variants of "hereditary angioedema" and "pregnancy." English language articles that presented original data about the use of plasma-derived C1-INH during pregnancy were selected for data extraction. The search returned 253 unique records, of which 40 described the use of C1-INH during pregnancy (91 patients, 136 pregnancies). When the number of doses was reported, a total of 1562 doses were administered ranging from 500 to 3000 IU. Infusions were administered during all 3 trimesters and were most commonly administered during the third trimester. Overall, 1,490,500 IU of plasma-derived C1-INH were administered during pregnancy. Of the 128 fetuses for which outcomes were reported, 3 (2%) resulted in spontaneous abortion, 1 (1%) was stillborn, and 1 (1%) was a vanishing twin. Use of plasma-derived C1-INH in women with HAE during pregnancy has been widely reported in the scientific literature and has a favorable safety profile, supporting treatment guideline recommendations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jaip.2020.03.009DOI Listing
June 2020

Definition, aims, and implementation of GA LEN/HAEi Angioedema Centers of Reference and Excellence.

Authors:
Marcus Maurer Werner Aberer Rosana Agondi Mona Al-Ahmad Maryam Ali Al-Nesf Ignacio Ansotegui Rand Arnaout Luisa Karla Arruda Riccardo Asero Emel Aygören-Pürsün Aleena Banerji Andrea Bauer Moshe Ben-Shoshan Alejandro Berardi Jonathan A Bernstein Stephen Betschel Carsten Bindslev-Jensen Mojca Bizjak Isabelle Boccon-Gibod Konrad Bork Laurence Bouillet Henrik Balle Boysen Nicholas Brodszki Sigurd Broesby-Olsen Paula Busse Thomas Buttgereit Anette Bygum Teresa Caballero Régis A Campos Mauro Cancian Ivan Cherrez-Ojeda Danny M Cohn Célia Costa Timothy Craig Paulo Ricardo Criado Roberta F Criado Dorottya Csuka Joachim Dissemond Aurélie Du-Thanh Luis Felipe Ensina Ragıp Ertaş José E Fabiani Claudio Fantini Henriette Farkas Silvia Mariel Ferrucci Ignasi Figueras-Nart Natalia L Fili Daria Fomina Atsushi Fukunaga Asli Gelincik Ana Giménez-Arnau Kiran Godse Mark Gompels Margarida Gonçalo Maia Gotua Richard Gower Anete S Grumach Guillermo Guidos-Fogelbach Michihiro Hide Natalia Ilina Naoko Inomata Thilo Jakob Dario O Josviack Hye-Ryun Kang Allen Kaplan Alicja Kasperska-Zając Constance Katelaris Aharon Kessel Andreas Kleinheinz Emek Kocatürk Mitja Košnik Dorota Krasowska Kanokvalai Kulthanan M Sendhil Kumaran José Ignacio Larco Sousa Hilary J Longhurst William Lumry Andrew MacGinnitie Markus Magerl Michael P Makris Alejandro Malbrán Alexander Marsland Inmaculada Martinez-Saguer Iris V Medina Raisa Meshkova Martin Metz Iman Nasr Jan Nicolay Chikako Nishigori Isao Ohsawa Kemal Özyurt Nikolaos G Papadopoulos Claudio A S Parisi Jonathan Grant Peter Wolfgang Pfützner Todor Popov Nieves Prior German D Ramon Adam Reich Avner Reshef Marc A Riedl Bruce Ritchie Heike Röckmann-Helmbach Michael Rudenko Andaç Salman Mario Sanchez-Borges Peter Schmid-Grendelmeier Faradiba S Serpa Esther Serra-Baldrich Farrukh R Sheikh William Smith Angèle Soria Petra Staubach Urs C Steiner Marcin Stobiecki Gordon Sussman Anna Tagka Simon Francis Thomsen Regina Treudler Solange Valle Martijn van Doorn Lilian Varga Daniel O Vázquez Nicola Wagner Liangchun Wang Christina Weber-Chrysochoou Young-Min Ye Anna Zalewska-Janowska Andrea Zanichelli Zuotao Zhao Yuxiang Zhi Torsten Zuberbier Ricardo D Zwiener Anthony Castaldo

Allergy 2020 08 27;75(8):2115-2123. Epub 2020 Apr 27.

HAE International (HAEi), Fairfax City, VA, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/all.14293DOI Listing
August 2020

Long-term efficacy and safety of subcutaneous C1-inhibitor in women with hereditary angioedema: subgroup analysis from an open-label extension of a phase 3 trial.

Allergy Asthma Clin Immunol 2020 4;16. Epub 2020 Feb 4.

7Allergy, Immunology and Angioedema Center, Barzilai Medical Center, Ashkelon, Israel.

Background: Women with hereditary angioedema due to C1-inhibitor deficiency (HAE-C1INH) experience more frequent and severe angioedema attacks compared with men. Fluctuations in female sex hormones can influence HAE attack frequency and severity. Subcutaneous C1-INH (C1-INH [SC]) is indicated as routine prophylaxis to prevent HAE attacks. In this post hoc subgroup analysis, we evaluated the efficacy and safety of C1-INH (SC) in female subjects with HAE-C1INH enrolled in an open-label extension of the pivotal phase III COMPACT trial.

Methods: In this multicenter, randomized, parallel-arm trial, eligible subjects (age ≥ 6 years with ≥ 4 attacks over 2 consecutive months) received C1-INH (SC) 40 IU/kg or 60 IU/kg twice weekly for 52 to 140 weeks. Analyses of efficacy endpoints were performed for all female subjects and those of childbearing age (age ≥ 15 to ≤ 45 years), including subjects who became pregnant during the evaluation period.

Results: Overall, 91% (69/76) of female subjects were classified as responders (≥ 50% reduction in HAE attacks relative to the pre-study period); 82% experienced < 1 attack/4 weeks. The median number of attacks/month was 0.10, with 96% median reduction in attacks relative to the pre-study period. Results were similar in the subgroup of subjects of childbearing age. Four women who became pregnant during the trial and were exposed to C1-INH (SC) during the first trimester delivered healthy babies with no congenital abnormalities.

Conclusions: C1-INH (SC) prophylaxis was safe and effective in women with HAE-C1INH, including those of childbearing age. Four women exposed to C1-INH (SC) during the first trimester had uneventful pregnancies and delivered healthy babies. Clinicaltrials.gov identifier NCT02316353 (Registered December 10, 2014); https://clinicaltrials.gov/ct2/show/NCT02316353.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13223-020-0409-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7001333PMC
February 2020

Subcutaneous C1 inhibitor for prevention of attacks of hereditary angioedema: additional outcomes and subgroup analysis of a placebo-controlled randomized study.

Allergy Asthma Clin Immunol 2019 28;15:49. Epub 2019 Aug 28.

13Department of Medicine and Pediatrics, Penn State University Allergy, Immunology and Respiratory Research, 500 University Drive H041, Hershey, PA 17033 USA.

Background: Hereditary angioedema (HAE) is a debilitating disorder resulting from C1-esterase inhibitor (C1-INH) deficiency. In the COMPACT phase 3 study the prophylactic use of a subcutaneous C1 inhibitor (C1-INH [SC], HAEGARDA, CSL Behring) twice weekly significantly reduced the frequency of acute edema attacks. Analysis of treatment effects by subgroups, onset of effect, and other exploratory analysis have not been reported.

Methods: This is a post hoc exploratory analysis on data from the randomized, placebo-controlled COMPACT study. 90 patients with C1-INH-HAE were randomized to 1 of 4 treatment sequences: C1-INH (SC) 40 or 60 IU/kg of body weight twice weekly for 16 weeks, preceded or followed by a placebo period. The pre-specified primary efficacy endpoint was the time-normalized number of HAE attacks, and pre-specified secondary efficacy endpoints were the percentage of patients with a certain treatment response (≥ 50% reduction on C1-INH (SC) versus placebo in the time-normalized number of attacks) and the time-normalized number of use of rescue medication. Pre-specified exploratory endpoints included severity of attacks, alone and combined with rescue medication use. Post hoc analyses included exploration of onset of effect and clinical assessment of patients with < 50% of response.

Results: Subgroup findings by various patient characteristics showed a consistent preventive effect of C1-INH (SC). In a post hoc analysis of attacks, the onset of the preventive effect within the first 2 weeks after treatment initiation in COMPACT showed that 10/43 patients (23%) experienced attacks of any severity with 60 IU/kg versus 34/42 patients (81%) with placebo. The need for rescue medication was tenfold lower with 60 IU/kg (35 treated attacks) versus placebo (358 treated attacks). A qualitative analysis of the 4 patients treated with 60 IU/kg and with < 50% reduction of attacks demonstrated a reduction in severity of attacks, rescue medication use, and symptom days which was considered a clinically meaningful treatment effect.

Conclusions: C1-INH (SC) prophylaxis demonstrated a preventive treatment effect with evidence of benefit within 2 weeks. A consistent treatment effect at recommended C1-INH (SC) dosing was evident in all subgroups of patients with type I/II HAE and by various measures of disease and treatment burden. EU Clinical Trials Register, 2013-000916-10, Registered 10 December 2013, https://www.clinicaltrialsregister.eu/ctr-search/trial/2013-000916-10; ClinicalTrials.gov Register, NCT01912456, Registered 31 July 2013, https://clinicaltrials.gov/ct2/show/NCT01912456.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13223-019-0362-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6714075PMC
August 2019

Fixed-Dose Subcutaneous C1-Inhibitor Liquid for Prophylactic Treatment of C1-INH-HAE: SAHARA Randomized Study.

J Allergy Clin Immunol Pract 2019 May - Jun;7(5):1610-1618.e4. Epub 2019 Jan 23.

Hungarian Angioedema Reference Center, Semmelweis University, Budapest, Hungary.

Background: Hereditary angioedema (HAE) with C1 inhibitor deficiency (C1-INH) is characterized by swelling of subcutaneous and/or submucosal tissues.

Objective: To evaluate efficacy/safety of fixed-dose subcutaneous plasma-derived C1-INH (pdC1-INH) liquid for HAE attack prevention (NCT02584959).

Methods: Eligible patients were ≥12 years with ≥2 monthly attacks prescreening or pre-long-term prophylaxis. In a partial crossover design, 80% of patients were randomized to placebo or pdC1-INH liquid for 14 weeks and crossed over from active to placebo or vice versa for another 14 weeks. The remainder were randomized to pdC1-INH liquid for 28 weeks. The primary efficacy endpoint was normalized number of attacks (NNA) versus placebo. Key additional endpoints were the proportion of patients achieving NNA reduction ≥50%, attack severity, number of attack-free days, and safety.

Results: Seventy-five patients were randomized and 58 (77%) completed the study. Mean age 41 years; 88% HAE type I. Least-squares means of NNA were reduced from 3.9 with placebo to 1.6 with pdC1-INH (from day 1; P < .0001). Most patients had ≥50% NNA reduction with pdC1-INH (from day 1, 78%). A total of 8.8% of placebo-treated patients were attack-free and 5.3%, 22.8%, and 63.2% had mild, moderate, and severe attacks, respectively; 37.5% of pdC1-INH-treated patients were attack-free and 8.9%, 26.8%, and 26.8% had mild, moderate, and severe attacks, respectively. Treatment-emergent adverse event rates were similar between groups (52% vs 56% for pdC1-INH crossover vs placebo, respectively).

Conclusions: Fixed-dose subcutaneous pdC1-INH liquid was superior to placebo in preventing HAE attacks and demonstrated a favorable safety profile.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jaip.2019.01.021DOI Listing
August 2020

Treatment effect of switching from intravenous to subcutaneous C1-inhibitor for prevention of hereditary angioedema attacks: COMPACT subgroup findings.

J Allergy Clin Immunol Pract 2019 Jul - Aug;7(6):2035-2038. Epub 2019 Jan 17.

Department of Immunology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jaip.2019.01.007DOI Listing
September 2020

Lanadelumab for the Prophylactic Treatment of Hereditary Angioedema with C1 Inhibitor Deficiency: A Review of Preclinical and Phase I Studies.

BioDrugs 2019 Feb;33(1):33-43

Division of Rheumatology, Allergy and Immunology, University of California, San Diego, 8899 University Center Lane, Suite 230, San Diego, CA, 92122, USA.

Hereditary angioedema (HAE) with C1 esterase inhibitor (C1-INH) deficiency (C1-INH-HAE) is a rare disease characterized by diminished levels or dysfunctional activity of C1-INH, leading to dysregulated plasma kallikrein activity within the kallikrein-kinin pathway. Symptoms manifest as painful, potentially life-threatening swelling of subcutaneous tissues throughout the body and/or submucosal edema in the upper airway or gastrointestinal tract. Attacks recur with unpredictable frequency, intensity, and duration, placing a heavy burden on patients' daily lives. Despite improved availability of medications for on-demand treatment during attacks and prophylaxis of future attacks, unmet needs remain. Lanadelumab, a fully human monoclonal antibody, may help address some of the limitations of existing prophylactic options (e.g., the need for intravenous administration or frequent dosing). Preclinical studies demonstrate that it is highly potent and specifically inhibits plasma kallikrein, and findings from phase Ia and Ib studies suggest this agent is well tolerated and provides sustained inhibition of plasma kallikrein, allowing for less frequent dosing. The phase III HELP Study (NCT02586805) evaluating the efficacy and safety of lanadelumab in preventing HAE attacks has been completed, and its open-label extension (NCT02741596) is ongoing. Lanadelumab is now approved in the USA and Canada for prophylaxis to prevent attacks of HAE in patients aged ≥ 12 years. This review provides an overview of the discovery and clinical development of lanadelumab, from preclinical through phase Ib studies, characterizing its safety/tolerability, efficacy, and pharmacokinetic and pharmacodynamic profiles. It also highlights how this agent may positively impact clinical care of patients with C1-INH-HAE.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s40259-018-0325-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6373397PMC
February 2019

Effect of Lanadelumab Compared With Placebo on Prevention of Hereditary Angioedema Attacks: A Randomized Clinical Trial.

JAMA 2018 11;320(20):2108-2121

Department of Dermatology and Allergy, Dermatological Allergology, Charité-Universitätsmedizin Berlin, Berlin, Germany.

Importance: Current treatments for long-term prophylaxis in hereditary angioedema have limitations.

Objective: To assess the efficacy of lanadelumab, a fully human monoclonal antibody that selectively inhibits active plasma kallikrein, in preventing hereditary angioedema attacks.

Design, Setting, And Participants: Phase 3, randomized, double-blind, parallel-group, placebo-controlled trial conducted at 41 sites in Canada, Europe, Jordan, and the United States. Patients were randomized between March 3, 2016, and September 9, 2016; last day of follow-up was April 13, 2017. Randomization was 2:1 lanadelumab to placebo; patients assigned to lanadelumab were further randomized 1:1:1 to 1 of the 3 dose regimens. Patients 12 years or older with hereditary angioedema type I or II underwent a 4-week run-in period and those with 1 or more hereditary angioedema attacks during run-in were randomized.

Interventions: Twenty-six-week treatment with subcutaneous lanadelumab 150 mg every 4 weeks (n = 28), 300 mg every 4 weeks (n = 29), 300 mg every 2 weeks (n = 27), or placebo (n = 41). All patients received injections every 2 weeks, with those in the every-4-week group receiving placebo in between active treatments.

Main Outcome And Measures: Primary efficacy end point was the number of investigator-confirmed attacks of hereditary angioedema over the treatment period.

Results: Among 125 patients randomized (mean age, 40.7 years [SD, 14.7 years]; 88 females [70.4%]; 113 white [90.4%]), 113 (90.4%) completed the study. During the run-in period, the mean number of hereditary angioedema attacks per month in the placebo group was 4.0; for the lanadelumab groups, 3.2 for the every-4-week 150-mg group; 3.7 for the every-4-week 300-mg group; and 3.5 for the every-2-week 300-mg group. During the treatment period, the mean number of attacks per month for the placebo group was 1.97; for the lanadelumab groups, 0.48 for the every-4-week 150-mg group; 0.53 for the every-4-week 300-mg group; and 0.26 for the every-2-week 300-mg group. Compared with placebo, the mean differences in the attack rate per month were -1.49 (95% CI, -1.90 to -1.08; P < .001); -1.44 (95% CI, -1.84 to -1.04; P < .001); and -1.71 (95% CI, -2.09 to -1.33; P < .001). The most commonly occurring adverse events with greater frequency in the lanadelumab treatment groups were injection site reactions (34.1% placebo, 52.4% lanadelumab) and dizziness (0% placebo, 6.0% lanadelumab).

Conclusions And Relevance: Among patients with hereditary angioedema type I or II, treatment with subcutaneous lanadelumab for 26 weeks significantly reduced the attack rate compared with placebo. These findings support the use of lanadelumab as a prophylactic therapy for hereditary angioedema. Further research is needed to determine long-term safety and efficacy.

Trial Registration: EudraCT Identifier: 2015-003943-20; ClinicalTrials.gov Identifier: NCT02586805.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jama.2018.16773DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6583584PMC
November 2018

Treatment patterns and healthcare resource utilization among patients with hereditary angioedema in the United States.

Orphanet J Rare Dis 2018 10 12;13(1):180. Epub 2018 Oct 12.

CSL Behring, King of Prussia, PA, USA.

Background: Real-world data on usage and associated outcomes with hereditary angioedema (HAE)-specific medications introduced to the United States (US) market since 2009 are very limited. The purpose of this retrospective study was to evaluate real-world treatment patterns of HAE-specific medications in the US and to assess their impact on healthcare resource utilization (HCRU). This analysis used IMS PharMetrics PlusTM database records (2006-2014) of patients with HAE, ≥1 insurance claim for an HAE-specific medication, and continuous insurance enrollment for ≥3 months following the first HAE prescription claim.

Results: Of 631 total patients, 434 (68.8%) reported C1-INH(IV) use; 396 (62.8%) reported using ecallantide and/or icatibant. There were 306 episodes of prophylactic use of C1-INH(IV) (defined by continuous refills averaging ≥1500 IU/week for ≥13 weeks) in 155 patients; use of ≥1 on-demand rescue medication was implicated during 53% (163/306) of those episodes. Sixty-eight (20.2%) of 336 C1-INH(IV) users eligible for the HCRU analysis were hospitalized at least once, and 191 (56.8%) visited the emergency department (ED). Eighteen patients (5.4%) had a central venous access device (CVAD); of these, 5 (27.7%) required hospitalization and 14 (77.7%) had an ED visit. The adjusted relative risk of hospitalization and/or ED visits for patients with a CVAD was 2.6 (95% CI: 0.17, 39.23) compared to C1-INH(IV) users without a CVAD.

Conclusions: Despite widespread availability of modern HAE medications in the US, we identified a subset of patients requiring long-term prophylaxis who continue to be burdened by frequent rescue medication usage and/or complications related to the use of CVADs for intravenous HAE medication.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13023-018-0922-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6186115PMC
October 2018

Long-term prophylaxis therapy in patients with hereditary angioedema with C1 inhibitor deficiency.

Ann Allergy Asthma Immunol 2018 12 27;121(6):673-679. Epub 2018 Jul 27.

Asthma and Allergy Associates PC, Colorado Springs, Colorado.

Objective: To review the criteria for long-term prophylaxis therapy in patients with hereditary angioedema due to C1 inhibitor deficiency (C1-INH-HAE), describe how these criteria have evolved over time, and anticipate how criteria may change in the future with the availability of new C1-INH-HAE treatment options.

Data Sources: Treatment guidelines, consensus statements, and expert reviews.

Study Selections: Manuscripts that described long-term prophylaxis therapy in patients with C1-INH-HAE were selected.

Results: Historically, patients with C1-INH-HAE were considered to be candidates for long-term prophylaxis therapy if they had at least 1 attack per month, had at least 5 days of disability per month because of C1-INH-HAE, or did not sufficiently respond to on-demand treatment. More recently, guidelines and reviews state that thresholds of number of attacks or days of disability are arbitrary and that treatment plans should be individualized to the patient's needs. Furthermore, all patients should have a comprehensive management plan that is reviewed periodically and should have at least 2 doses of on-demand treatment available. Prophylaxis therapy should be discussed as a potential treatment option for each patient; however, the decision for its use will depend on the patient's individual needs and the course of their symptoms.

Conclusion: The criteria for long-term prophylaxis therapy in C1-INH-HAE have changed with the recognition that treatments should be individualized to the patient's needs and with the availability of new medications that have more favorable benefit-risk profiles, are easier to use, and improve patients' quality of life.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.anai.2018.07.025DOI Listing
December 2018

Population pharmacokinetics of subcutaneous C1-inhibitor for prevention of attacks in patients with hereditary angioedema.

Clin Exp Allergy 2018 10 26;48(10):1325-1332. Epub 2018 Aug 26.

CSL Limited, Parkville, Melbourne, Australia.

Background: Long-term prophylaxis with subcutaneous (SC) administration of a highly concentrated plasma-derived C1-esterase inhibitor (C1-INH) formulation was recently approved by the Food and Drug Administration for hereditary angioedema (HAE) attack prevention.

Objective: To characterize the population pharmacokinetics of C1-INH (SC) (HAEGARDA ; CSL Behring) in healthy volunteers and HAE patients, and assess the variability and influence of covariates on pharmacokinetics.

Methods: C1-INH functional activity data obtained after administration of various C1-INH (intravenous; IV) and C1-INH (SC) doses from 1 study in healthy volunteers (n = 16) and 2 studies in subjects with HAE (n = 108) were pooled to develop a population pharmacokinetic model (NONMEM v7.2). Pharmacokinetic parameters derived from steady-state simulations based on the final model were also evaluated.

Results: C1-INH functional activity following C1-INH (SC) administration was described by a linear one-compartment model with first-order absorption and elimination, with inter-individual variability in all parameters tested. The mean population bioavailability of C1-INH (SC), and pharmacokinetic parameters for clearance (CL), volume of distribution, and absorption rate were estimated to be ~43%, 1.03 mL/hour/kg, 0.05 L/kg and 0.0146 hour , respectively. The effect of bodyweight on CL of C1-INH functional activity was included in the final model, estimated to be 0.74. Steady-state simulations of C1-INH functional activity vs time profiles in 1000 virtual HAE patients revealed higher minimum functional activity (C ) levels after twice-weekly dosing with 40 IU/kg (~40%) and 60 IU/kg (~48%) compared with 1000 IU IV (~30%). Based on the population pharmacokinetic model, the median time to peak concentration was ~59 hours and the median apparent plasma half-life was ~69 hours.

Conclusions And Clinical Relevance: Twice-weekly bodyweight-adjusted dosing of C1-INH (SC) exhibits linear pharmacokinetics and dose-dependent increases in C levels at each dosing interval. In this analysis, SC dosing led to maintenance of higher C levels than IV dosing.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/cea.13220DOI Listing
October 2018

Threshold-stimulated kallikrein activity distinguishes bradykinin- from histamine-mediated angioedema.

Clin Exp Allergy 2018 11 21;48(11):1429-1438. Epub 2018 Aug 21.

Division of Rheumatology, Allergy and Immunology, Department of Medicine, UC San Diego, La Jolla, California.

Background: The lack of specific biomarkers makes the diagnosis of hereditary angioedema (HAE) with normal levels of C1-inhibitor (C1INH) protein (HAE-nl-C1INH) and idiopathic non-histaminergic angioedema (INHA) difficult. Confirming or excluding these diagnoses is a significant challenge for clinicians evaluating patients with angioedema.

Objective: To develop a reliable biomarker that would aid the diagnosis of HAE-nl-C1INH and INHA.

Methods: A total of 154 consecutive patients referred for angioedema at a single centre were enrolled and evaluated. Subjects were clinically phenotyped based on clinical history and response to treatment by clinicians blinded to laboratory assay results. Plasma kallikrein activity was measured by the cleavage of the fluorometric substrate Z-Phe-Arg-AMC-HCL in plasma samples stimulated ex vivo with submaximal doses of dextran sulphate.

Results: Stimulated plasma kallikrein activity (mean relative fluorescence units/min ± SD) was significantly increased in both HAE-nl-C1INH (1804 ± 600) and INHA (1579 ± 371) subjects compared to non-swelling controls (171 ± 46) and histaminergic angioedema (133 ± 30) subjects. Using a threshold cut-off based on the normal controls, HAE-nl-C1INH and INHA subjects could be differentiated from histaminergic angioedema subjects with high sensitivity (negative predictive value 86%-89%) and specificity (positive predictive value 80%-100%).

Conclusion And Clinical Relevance: The stimulated kallikrein activity assay allows differentiation of bradykinin- from histamine-mediated angioedema. The assay could feasibly be considered as a potential clinical tool for the diagnosis of bradykinin-mediated angioedema.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/cea.13219DOI Listing
November 2018

Efficacy of recombinant human C1 esterase inhibitor across anatomic locations in acute hereditary angioedema attacks.

Allergy Asthma Proc 2018 Sep 28;39(5):359-364. Epub 2018 Jun 28.

Division of Rheumatology, Allergy, and Immunology, University of California-San Diego, San Diego, California.

Background: Hereditary angioedema (HAE) may occur at or spread to multiple anatomic locations during an acute attack. Recombinant human C1 esterase inhibitor (rhC1-INH) is approved for treating acute HAE attacks.

Objective: To examine the time to the beginning of symptom relief with rhC1-INH by attack location.

Methods: Data for patients ≥12 years of age with an acute HAE attack who received rhC1-INH 50 IU/kg or placebo were pooled from two double-blind clinical trials with open-label extensions. The time to the beginning of symptom relief was defined as the first time point that the visual analog scale severity score at an attack location decreased by ≥20 mm versus baseline, with persistence. Data were reported as median time values (95% confidence interval [CI]).

Results: For abdominal attacks, the median time to the beginning of symptom relief was 60.0 minutes (95% CI, 47.0-62.0 minutes; n = 194 attacks) with rhC1-INH versus 240.0 minutes (95% CI, 45.0-720.0 minutes; n = 15 attacks) with placebo. The median time to the beginning of symptom relief for peripheral attacks was 105.0 minutes (95% CI, 90.0-120.0 minutes; n = 169 attacks) with rhC1-INH versus 303.0 minutes (95% CI, 180.0-720.0 minutes; n = 17 attacks) with placebo. For oro-facial-pharyngeal-laryngeal attacks or urogenital attacks, the median time to the beginning of symptom relief with rhC1-INH was 64.5 minutes (95% CI, 60.0-120.0 minutes; n = 36 attacks) and 119.0 minutes (95% CI, 40.0-270.0 minutes; n = 13 attacks), respectively, versus 306.0 minutes (95% CI, 30.0-495.0 minutes; n = 6 attacks) and 320.0 minutes (n = 1 attack) with placebo.

Conclusion: In shortening the median time to the beginning of symptom relief of acute HAE attacks, rhC1-INH 50 IU/kg was efficacious, regardless of attack location.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2500/aap.2018.39.4151DOI Listing
September 2018

Hereditary angioedema from the patient's perspective: A follow-up patient survey.

Allergy Asthma Proc 2018 May;39(3):212-223

Department of Medicine, University of California San Diego, La Jolla, California.

Background: We conducted our first patient survey at the 2013 hereditary angioedema (HAE) patient summit and learned that, despite several novel therapies, the burden of disease was high.

Objective: To determine, from the patient's perspective, if any improvements in the current state of HAE care occurred over a two-year period between HAE patient summits.

Methods: A patient survey was conducted at the 2015 Hereditary Angioedema Association conference by using paper surveys that aimed at understanding the current state of HAE care. Questions included patient characteristics, burden of disease, and satisfaction with care and treatment options. Comparisons between patients with HAE with C1-inhibitor (HAE-C1INH) and patients with HAE with normal C1-inhibitor (HAE-nlC1INH), as well as between patients with HAE in 2013 and 2015, were performed by using χ2 tests.

Results: There were 232 surveys distributed, and 143 surveys were identified as complete for inclusion and analysis from patients with self-reported HAE. Most patients had type I or type II HAE (67.5% [n = 106]), with a smaller number of patients with HAE-nlC1INH (23.6% [n = 37]). In 2015, almost half of the patients with HAE-C1INH (47.1%) and 56.7% of the patients with HAE-nlC1INH experienced a delay of ≥10 years between initial symptoms and diagnosis. Among the patients with HAE-C1INH, 25% reported one or more attacks per week and another 48% reported experiencing one or more attacks per month (fewer than one attack per week). The patients with HAE-nlC1INH reported attacks more frequently than did the patients with HAE-C1INH (p = 0.002), with 59.5% who reported attacks at least once a week. Emergency care was reported one or more times per month in 5% of the patients with HAE-C1INH and in 24.3% of the patients with HAE-nlC1INH.

Conclusion: Similar to 2013, although significant progress has been made, there is still a high burden of disease that faces patients with HAE.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2500/aap.2018.39.4123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5911511PMC
May 2018

C1 esterase inhibitor concentrates and attenuated androgens - Authors' reply.

Lancet 2018 04;391(10128):1356

Dipartimento di Scienze Biomediche e Cliniche Luigi Sacco, Universita degli Studi di Milano, Milan, Italy.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S0140-6736(18)30573-7DOI Listing
April 2018

Health-Related Quality of Life with Subcutaneous C1-Inhibitor for Prevention of Attacks of Hereditary Angioedema.

J Allergy Clin Immunol Pract 2018 Sep - Oct;6(5):1733-1741.e3. Epub 2018 Jan 31.

CSL Behring, King of Prussia, Pa.

Background: Hereditary angioedema with C1-inhibitor deficiency (C1-INH-HAE) impairs health-related quality of life (HRQoL).

Objective: The objective of this study was to assess HRQoL outcomes in patients self-administering subcutaneous C1-INH (C1-INH[SC]; HAEGARDA) for routine prevention of HAE attacks.

Methods: Post hoc analysis of data from the placebo-controlled, crossover phase III COMPACT study (Clinical Studies for Optimal Management of Preventing Angioedema with Low-Volume Subcutaneous C1-Inhibitor Replacement Therapy). Ninety patients with C1-INH-HAE were randomized to 1 of 4 treatment sequences: C1-INH(SC) 40 or 60 IU/kg twice weekly for 16 weeks, preceded or followed by 16 weeks of twice weekly placebo injections. All HAE attacks were treated with open-label on-demand treatment as necessary. HRQoL assessments at week 14 (last visit) included the European Quality of Life-5 Dimensions Questionnaire (EQ-5D-3L), the Hospital Anxiety and Depression Scale (HADS), the Work Productivity and Activity Impairment Questionnaire (WPAI), and the Treatment Satisfaction Questionnaire for Medication (TSQM).

Results: Compared with placebo (on-demand treatment alone), treatment with twice weekly C1-INH(SC) (both doses combined) was associated with better EQ-5D visual analog scale general health, less HADS anxiety, less WPAI presenteeism, work productivity loss, and activity impairment, and greater TSQM effectiveness and overall treatment satisfaction. More patients self-reported a "good/excellent" response during routine prevention with C1-INH(SC) compared with on-demand only (placebo prophylaxis) management. For each HRQoL measure, a greater proportion of patients had a clinically meaningful improvement during C1-INH(SC) treatment compared with placebo.

Conclusions: In patients with frequent HAE attacks, a treatment strategy of routine prevention with self-administered twice weekly C1-INH(SC) had a greater impact on improving multiple HAE-related HRQoL impairments, most notably anxiety and work productivity, compared with on-demand treatment alone (placebo prophylaxis).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jaip.2017.12.039DOI Listing
November 2019

An open-label study to evaluate the long-term safety and efficacy of lanadelumab for prevention of attacks in hereditary angioedema: design of the HELP study extension.

Clin Transl Allergy 2017 6;7:36. Epub 2017 Oct 6.

Division of Clinical Immunology and Allergy, Department of Medicine, Icahn School of Medicine at Mount Sinai, 5 East 98th Street 11th Floor, New York, NY 10029 USA.

Background: Hereditary angioedema (HAE) is characterized by recurrent attacks of subcutaneous or submucosal edema. Attacks are unpredictable, debilitating, and have a significant impact on quality of life. Patients may be prescribed prophylactic therapy to prevent angioedema attacks. Current prophylactic treatments may be difficult to administer (i.e., intravenously), require frequent administrations or are not well tolerated, and breakthrough attacks may still occur frequently. Lanadelumab is a subcutaneously-administered monoclonal antibody inhibitor of plasma kallikrein in clinical development for prophylaxis of hereditary angioedema attacks. A Phase 1b study supported its efficacy in preventing attacks. A Phase 3, randomized, double-blind, placebo-controlled, parallel-arm study has been completed and an open-label extension is currently ongoing.

Methods/design: The primary objective of the open-label extension is to evaluate the long-term safety of repeated subcutaneous administrations of lanadelumab in patients with type I/II HAE. Secondary objectives include evaluation of efficacy and time to first angioedema attack to determine outer bounds of the dosing interval. The study will also evaluate immunogenicity, pharmacokinetics/pharmacodynamics, quality of life, characteristics of breakthrough attacks, ease of self-administration, and safety/efficacy in patients who switch to lanadelumab from another prophylactic therapy. The open-label extension will enroll patients who completed the double-blind study ("rollover patients") and those who did not participate in the double-blind study ("non-rollover patients"), which includes patients who may or may not be currently using another prophylactic therapy. Rollover patients will receive a single 300 mg dose of lanadelumab on Day 0 and the second dose after the patient's first confirmed angioedema attack. Thereafter, lanadelumab will be administered every 2 weeks. Non-rollover patients will receive 300 mg lanadelumab every 2 weeks regardless of the first attack. All patients will receive their last dose on Day 350 (maximum of 26 doses), and will then undergo a 4-week follow-up.

Discussion: Prevention of attacks can reduce the burden of illness associated with HAE. Prophylactic therapy requires extended, repeated dosing and the results of this study will provide important data on the long-term safety and efficacy of lanadelumab, a monoclonal antibody inhibitor of plasma kallikrein for subcutaneous administration for the treatment of HAE. NCT02741596.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13601-017-0172-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5629784PMC
October 2017

Vedolizumab in Patients With Common Variable Immune Deficiency and Gut Inflammation.

Am J Gastroenterol 2017 10;112(10):1621

Division of Gastroenterology, Inflammatory Bowel Disease Center, University of California San Diego, La Jolla, California, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ajg.2017.246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6389596PMC
October 2017

Recombinant human C1 esterase inhibitor for acute hereditary angioedema attacks with upper airway involvement.

Allergy Asthma Proc 2017 Nov 13;38(6):462-466. Epub 2017 Sep 13.

Background: Recombinant human C1 esterase inhibitor (rhC1-INH) is approved for treatment of hereditary angioedema (HAE) in adolescents and adults. HAE attacks that involve the upper airway can be life threatening, and data on the administration of rhC1-INH for these types of attacks are currently limited.

Objective: To evaluate the efficacy and safety of rhC1-INH for treatment of acute HAE attacks with upper airway involvement.

Methods: A pooled analysis of data from three clinical trials with open-label extensions examined rhC1-INH for treatment of acute HAE attacks with upper airway involvement. Patients with functional plasma C1 esterase inhibitor <50% of normal who had experienced an acute upper airway HAE attack and received rhC1-INH were identified retrospectively based on severity of breathing or swallowing symptoms. The primary end point was the time to beginning of relief (time at which the overall visual analog scale score [0-100 mm] decreased from baseline by ≥20 mm for two consecutive time points [persistence]).

Results: Of 683 acute HAE attacks treated with rhC1-INH, data for 45 attacks with upper airway involvement were included. The median time to the beginning of symptom relief was 67 minutes (95% confidence interval, 60-120 minutes) and did not differ by attack number or by baseline breathing or swallowing symptom severity. Most attacks (91.1%) achieved the beginning of relief within 4 hours of rhC1-INH treatment. All attacks resolved without the need for any additional medication, and no patients required intubation or tracheostomy. Treatment with rhC1-INH was well tolerated, with no adverse events reported in more than one patient (except HAE reported as an adverse event [n = 2]).

Conclusion: This pooled analysis of clinical trial data supports the efficacy of rhC1-INH for treatment of acute HAE attacks with upper airway involvement.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2500/aap.2017.38.4090DOI Listing
November 2017