Mark Davis-Lorton

US Hereditary Angioedema Association Medical Advisory Board 2013 Recommendations for the Management of Hereditary Angioedema Due to C1 Inhibitor Deficiency

BACKGROUND The treatment of hereditary angioedema (HAE) has undergone dramatic changes as newer medicines have become available in recent years. Optimal care of these patients requires a comprehensive management plan. Although several consensus papers have been published concerning the diagnosis and treatment of HAE, guidelines for a comprehensive management plan have not been developed. OBJECTIVE To develop state-of-the-art recommendations for the treatment and management of HAE due to C1 inhibitor (C1INH) deficiency in the United States. METHODS Members of the US Hereditary Angioedema Association Medical Advisory Board began by reviewing the literature concerning treatment of HAE. Preliminary recommendations were developed based on the literature review, discussions in a face-to-face meeting, and refinements in a series of drafts. Final recommendations reflect the unanimous consensus of the medical advisory board and the US Hereditary Angioedema Association leadership. RESULTS Recommendations are provided regarding a comprehensive care plan for HAE, including the following: development of an overall management plan, treatment of angioedema attacks, prophylactic treatment, and patient monitoring. CONCLUSION A comprehensive individualized management plan developed between an expert HAE physician and the patient, in collaboration with local medical providers and emergency departments, can provide patients with the best opportunity to lead a normal life.

Nanofiltered C1-Esterase Inhibitor for the Acute Management and Prevention of Hereditary Angioedema Attacks due to C1-Inhibitor Deficiency in Children

OBJECTIVES To evaluate the use of Cinryze (nanofiltered C1-esterase inhibitor [C1 INH-nf]) for the acute management and prevention of hereditary angioedema attacks in the subgroup of children and adolescents who participated in 2 placebo-controlled and 2 open-label extension studies. STUDY DESIGN In the acute-attack treatment studies, the efficacy of 1000 U of C1 INH-nf (with an additional 1000 U given 1 hour later if needed) was assessed based on the time to the start of symptomatic relief and the proportion of patients experiencing relief within 4 hours of therapy. In the prophylaxis studies, C1 INH-nf 1000 U was given twice weekly, and efficacy was based on the frequency of attacks. RESULTS Across 4 studies, 46 children received a total of 2237 C1 INH-nf infusions. The median time to the start of unequivocal relief in the acute-attack treatment study (n = 12) was 30 minutes with C1 INH-nf, compared with 2 hours for placebo. In the open-label extension (n = 22), clinical relief began within 4 hours of therapy in 89% of attacks. In the prophylaxis study (n = 4), the number of attacks was reduced by approximately 2-fold with C1 INH-nf compared with placebo. In the prophylaxis open-label extension (n = 23), the median monthly attack rate decreased from 3.0 before treatment to 0.39 with C1 INH-nf use. CONCLUSION In children, C1 INH-nf was well tolerated, provided relief from symptoms of hereditary angioedema attacks, and reduced the rate of attacks.

Inhibiting Plasma Kallikrein for Hereditary Angioedema Prophylaxis

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.)

Current state of hereditary angioedema management: a patient survey.

Hereditary angioedema (HAE) is a chronic disease with a high burden of disease that is poorly understood and often misdiagnosed. Availability of treatments, including C1 esterase inhibitor (C1INH) replacement, ecallantide, and icatibant, marks a significant advance for HAE patients. We aimed to better understand the current state of HAE care, from a patient perspective, after the introduction of several novel therapies. One session of the United States Hereditary Angioedema Association 2013 patient summit was devoted to data collection for this study. Patients attending the summit were self-selected, and HAE diagnosis was self-reported. Survey questions assessed patient characteristics, burden of disease, and treatment. Participant responses were captured using an audience response system. We surveyed 149 (80%) type I and II HAE (HAE-C1INH) and 37 (20%) HAE with normal C1INH (HAE-nlC1INH) patients. HAE-C1INH (72%) and HAE-nlCINH patients (76%) equally reported that HAE had a significant impact on quality of life (QOL). A third of HAE-C1INH patients were diagnosed within one year of their first HAE attack, but another third reported a delay of more than 10 years. Most HAE-C1INH (88%) and HAE-nlC1INH (76%) patients had on-demand treatment available. HAE-C1INH patients frequently had an individual treatment plan (76%) compared with 50% of HAE-nlC1INH patients. Most HAE-C1INH patients went to the emergency department (ED) or were hospitalized less than once every six months (80%). Our findings show that HAE management is improving with good access to on-demand and prophylactic treatment options. However, HAE patients still have a significant burden of disease and continued research and educational efforts are needed.

Escalating Doses of C1 Esterase Inhibitor (CINRYZE) for Prophylaxis in Patients With Hereditary Angioedema

BACKGROUND Nanofiltered C1 inhibitor (human) is approved in the United States for routine prophylaxis of angioedema attacks in patients with hereditary angioedema, a rare disease caused by a deficiency of functional C1 inhibitor. OBJECTIVE To assess the safety of escalating doses of nanofiltered C1 inhibitor (human) in patients who were not adequately controlled on the indicated dose (1000 U every 3 or 4 days). METHODS Eligible patients had >1 attack/month over the 3 months before the trial. Doses were escalated to 1500 U every 3 or 4 days for 12 weeks, at which point, the patients were evaluated. If treatment was successful (≤1 attack/mo) or at the investigators discretion, the patients entered a 3-month follow-up period. The patients with an average of >1 attack/month were eligible for further escalation to 2000 U and then 2500 U. RESULTS Twenty patients started at 1500 U; 13 were escalated to 2000 U, and 12 were escalated to 2500 U. Eighteen patients reported adverse events. Two patients reported 4 serious adverse events (cerebral cystic hygroma, laryngeal angioedema attack, anemia, and bile duct stone) that were considered by investigators to be unrelated to treatment. Notably, there were no systemic thrombotic events or discontinuations due to adverse events. Fourteen patients were treated successfully (70%), continued to the follow-up period at the investigators discretion, or experienced a reduction in attacks of >1.0/month. CONCLUSIONS Dose escalation of nanofiltered C1 inhibitor (human) up to 2500 U was well tolerated and reduced attack frequency in the majority of patients.

Hereditary Angioedema Caused By C1-Esterase Inhibitor Deficiency: A Literature-Based Analysis and Clinical Commentary on Prophylaxis Treatment Strategies

Hereditary angioedema (HAE) caused by C1-esterase inhibitor deficiency is an autosomal-dominant disease resulting from a mutation in the C1-inhibitor gene. HAE is characterized by recurrent attacks of intense, massive, localized subcutaneous edema involving the extremities, genitalia, face, or trunk, or submucosal edema of upper airway or bowels. These symptoms may be disabling, have a dramatic impact on quality of life, and can be life-threatening when affecting the upper airways. Because the manifestations and severity of HAE are highly variable and unpredictable, patients need individualized care to reduce the burden of HAE on daily life. Although effective therapy for the treatment of HAE attacks has been available in many countries for more than 30 years, until recently, there were no agents approved in the United States to treat HAE acutely. Therefore, prophylactic therapy is an integral part of HAE treatment in the United States and for selected patients worldwide. Routine long-term prophylaxis with either attenuated androgens or C1-esterase inhibitor has been shown to reduce the frequency and severity of HAE attacks. Therapy with attenuated androgens, a mainstay of treatment in the past, has been marked by concern about potential adverse effects. C1-esterase inhibitor works directly on the complement and contact plasma cascades to reduce bradykinin release, which is the primary pathologic mechanism in HAE. Different approaches to long-term prophylactic therapy can be used to successfully manage HAE when tailored to meet the needs of the individual patient.

Use of Ecallantide in Pediatric Hereditary Angioedema

OBJECTIVE: Hereditary angioedema (HAE) due to C1-inhbitor deficiency is a rare autosomal dominant disease that manifests as sudden unpredictable attacks of subcutaneous or submucosal edema affecting the skin, intestine, and upper airway. Ecallantide is a plasma kallikrein inhibitor indicated for treatment of HAE attacks in patients aged 16 years and older. This analysis examines safety and efficacy of ecallantide for treatment of HAE attacks in patients <18 years of age. METHODS: Data for patients aged 9 to 17 years treated subcutaneously with 30 mg ecallantide or placebo were pooled from 4 clinical studies (2 double-blind, placebo-controlled and 2 open-label). Efficacy end points included 2 HAE-specific patient-reported outcome measures: mean symptom complex severity (MSCS) score and treatment outcome score (TOS). Times to initial improvement, sustained improvement, and complete or near-complete symptom resolution were calculated. Treatment-emergent adverse events were examined. RESULTS: Overall, 29 pediatric patients were included; 25 of them received ecallantide for 62 total HAE attacks, and 10 received placebo for 10 total attacks. Ecallantide-treated attacks revealed clinically relevant reduction in symptom severity at 4 hours postdosing based on mean change in MSCS score (−1.4 ± 0.9 ecallantide versus −0.9 ± 0.6 placebo) and TOS (73.9 ± 35.50 ecallantide versus 45.0 ± 43.78 placebo). Patients treated with ecallantide showed rapid improvement in symptoms (median time to complete or near-complete symptom resolution: 181 minutes). No serious adverse events related to treatment were observed. CONCLUSIONS: Ecallantide appears effective for HAE attacks in adolescents, with rapid symptom improvement. No unexpected safety issues were identified.

Before and after, the impact of available on-demand treatment for HAE.

Availability of effective treatment for acute attacks is expected to transform the care of hereditary angioedema (HAE) patients. We felt that it would be of interest to test these assumptions by examining the perceptions of HAE patients regarding the impact that these therapies have had on their lives. Patients at a United States HAE Association summit meeting were asked to rate the burden of HAE currently and compare by recall with 2009 when these therapies were not available. Questions covered five domains: psychological/emotional status, ability to carry out daily activities, fear of suffocation, worry about their children inheriting HAE, and medication side effects. Data were analyzed using Wilcoxon signed-rank tests or analysis of variance. Responses were obtained from 134 self-identified HAE subjects: 85 type I, 21 type II, and 28 with normal C1 inhibitor (C1INH). Burden of disease showed significant improvement in all domains except worry about children inheriting HAE. With the introduction of newer therapies, subjects with the most severe burden of illness improved more than those with milder burdens. However, significant burden of illness remained. The availability of the current treatments has substantially improved the quality of life for HAE patients in the United States, similar to a survey of Danish HAE patients regarding the introduction of home treatment. Nevertheless, our study shows that a substantial burden of illness remains for HAE patients.

A multi-center, retrospective review of patch testing for contact dermatitis in allergy practices

BACKGROUND Studies assessing patch testing (PT) in allergy practices are limited. OBJECTIVES To determine whether PT results using a limited panel of allergens such as in the Thin-Layer Rapid-Use Epicutaneous Test (TT) as compared with an expanded panel, such as the addition of supplemental allergens (North American Contact Dermatitis [NACD] Panel, Dormer Cosmetics, hairdressing series, corticosteroid series, and personal products) will miss a significant number of positive PTs. To compare our PT results with published data from dermatology practices. METHODS This is a 5-year multicenter retrospective chart review of PT at 3 separate allergy practices. RESULTS Four hundred twenty-seven patients (mean age, 49.8 years) were patch tested. Eighty-two percent were female; 54% reported an atopic history. Of the standardized allergens, the 5 most common positives were nickel sulfate, fragrance mix I, p-phenylenediamine (PPD), thimerosal, and cobalt chloride. Two hundred eighteen (56.9%; 95% CI = 51.9-61.8%) patients were positive to at least 1 TT allergen. Ninety-eight (25.6%; 95% CI = 21.5-30.2%) patients were positive to both a TT and a supplemental allergen. Forty-eight (12.5%; 95% CI = 9.6-16.2%) patients were negative to a TT allergen but positive to a supplemental allergen. CONCLUSION Positive allergens would have been missed in 12.5% of patients when evaluating with TT allergens alone, whereas 25.6% would be partially evaluated. Patch test performance characteristics for these allergy practices appear to parallel that seen for dermatology. The TT remains an adequate screening tool in an allergy practice, but a more comprehensive panel may be needed to fully evaluate contact dermatitis.

Alterations in serum neopterin correlate with thrombolysis in myocardial infarction risk scores in acute coronary syndromes.

ObjectivesUsing serum neopterin as a marker of macrophage activation, we sought to examine the relationship between serum neopterin levels, thrombolysis in myocardial infarction (TIMI) risk scores, and how different treatments of acute coronary syndromes affect change in neopterin. MethodsWe examined serum neopterin concentrations at presentation and 72 h after treatment in 70 patients with acute coronary syndromes (35 with medical therapy, 25 with uncoated coronary stents, and 10 received rapamycin-eluting stents) using a commercially available immunoassay. Serum neopterin levels were determined for 36 patients with stable coronary artery disease. TIMI risk scores were calculated when appropriate (n=58). ResultsSerum neopterin had a strong correlation with the TIMI risk score on admission (P<0.0001). The mean baseline neopterin levels in patients with acute coronary syndromes stratified with TIMI scores between 1 and 7 were the following: patients with TIMI 1 scores had a level of 3.3±0.4 nmol/l, TIMI 2 patients 4.6±0.6 nmol/l, TIMI 3 patients 5.5±1.4 nmol/l, TIMI 4 patients 7.5±2.4 nmol/l, TIMI 5 patients 10.8±3.3 nmol/l, TIMI 6 patients 17.5±4.0 nmol/l, and TIMI 7 patients 23.0±7.1 nmol/l. Mean changes in serum neopterin were significantly higher for the uncoated stent group than for each of the other three groups (P<0.05). ConclusionsSerum neopterin concentrations have a high correlation with TIMI risk scores and may represent a marker useful in stratifying patients with acute coronary syndromes. Our results also suggest that the use of uncoated coronary stents results in macrophage activation not found with other treatment modalities.