Prophylaxis of hereditary angioedema attacks: A randomized trial of oral plasma kallikrein inhibition with avoralstat

Hereditary angioedema (HAE) is a rare disorder characterized by either deficient synthesis of C1 inhibitor (C1INH) (type I) or production of nonfunctional protein (type II),1Donaldson V.H. Evans R.R. A biochemical abnormality in herediatry angioneurotic edema: absence of serum inhibitor of C' 1-esterase.Am J Med. 1963; 35: 37-44Abstract Full Text PDF PubMed Scopus (679) Google Scholar with an estimated prevalence of ∼1 in 72,000.2Bygum A. Hereditary angio-oedema in Denmark: a nationwide survey.Br J Dermatol. 2009; 161: 1153-1158Crossref PubMed Scopus (201) Google Scholar The nonpitting, nonitching, subcutaneous or submucosal swelling attacks of HAE can be extremely debilitating, when involving the face, genitalia, extremities, or gastrointestinal tract, and life-threatening when involving the upper airways.3Bork K. Hardt J. Witzke G. Fatal laryngeal attacks and mortality in hereditary angioedema due to C1-INH deficiency.J Allergy Clin Immunol. 2012; 130: 692-697Abstract Full Text Full Text PDF PubMed Scopus (313) Google Scholar C1INH is the primary regulator of contact activation, both by inhibiting the conversion of prekallikrein to plasma kallikrein (PKK) by FXIIa, and by directly inhibiting PKK. PKK cleaves high molecular weight kininogen, releasing bradykinin, whose actions are responsible for the signs and symptoms of HAE.4Fields T. Ghebrehiwet B. Kaplan A.P. Kinin formation in hereditary angioedema plasma: evidence against kinin derivation from C2 and in support of “spontaneous” formation of bradykinin.J Allergy Clin Immunol. 1983; 72: 54-60Abstract Full Text PDF PubMed Scopus (170) Google Scholar, 5Nussberger J. Cugno M. Amstutz C. Cicardi M. Pellacani A. Agostoni A. Plasma bradykinin in angio-oedema.Lancet. 1998; 351: 1693-1697Abstract Full Text Full Text PDF PubMed Scopus (639) Google Scholar Avoralstat, an oral small molecule PKK inhibitor, is approximately 15-fold more potent than C1INH.6Babu Y.S. Wilson R. Zhang J. Cornpropst M. Collis P. Sheridan W. A simple, sensitive and selective fluorogenic assay to monitor plasma kallikrein inhibitory activity of BCX4161 in activated plasma.J Allergy Clin Immunol. 2014; 133 (Abstract 143): AB40Abstract Full Text Full Text PDF Google Scholar We report the findings of OPuS-1, the first randomized controlled trial of the prophylactic use of avoralstat in subjects with HAE. We used a randomized, cross-over design to allocate patients to 2 sequences consisting of 2 periods, each of 4 weeks' duration, with a 1-week between-period washout. Sequence A was avoralstat treatment in the first period (400 mg, 3 times per day) and matching placebo in the second period; sequence B followed the reverse order. We conducted the study in Germany and the United Kingdom from November 2013 to May 2014 (EudraCT no. 2013-002319-82, NCT01984788). Patients with HAE type I or II were included if aged between 18 and 65 years, and had an average of 1 or more attacks per week over at least 3 months in the last year. Patients taking tranexamic acid, chronic C1INH replacement therapy, or androgens for prophylaxis of HAE attacks were excluded from the study (see this article's Detailed listing of inclusion and exclusion criteria section in the Online Repository at www.jacionline.org). Clinical and laboratory evaluations were performed at baseline, at weeks 1, 2, and 4 of each treatment period, and at the final follow-up visit. Patients recorded the onset and details of HAE attacks using a paper diary. Attacks were adjudicated by an independent panel of 3 expert nonstudy physicians. The primary end point was the count of adjudicated HAE attacks during each 28-day period, expressed as a weekly rate of attacks. HAE-specific patient-reported outcomes, pharmacokinetics, and pharmacodynamics were also evaluated (see this article's Pharmacokinetic measurements section and Secondary attack analyses and patient-reported outcomes section in the Online Repository at www.jacionline.org). Safety was evaluated through assessments of clinical and laboratory adverse events (AEs) (see this article's Safety section in the Online Repository at www.jacionline.org). We determined a sample size of 24 to be sufficient for preliminary safety evaluation and estimating treatment effect (β ≤ 0.2; α ≤ 0.05). The difference in mean weekly attack rates on avoralstat versus placebo was analyzed using a mixed-effect model with adjustment for sequence, period, and treatment as fixed effects and subject within sequence as a random effect. All 24 randomized patients completed treatment, with mean adherence of 98% (range, 85% to 100%) (see this article's Patient disposition section in the Online Repository at www.jacionline.org). On average, patients were diagnosed with HAE for 27 years, with large variability in time from first symptoms to diagnosis (average, 5 years; range, −13 to 24) (Table I). The total number of adjudicated HAE attacks with avoralstat was 79, compared with 123 HAE attacks on placebo during 96 patient-weeks of treatment in each period. The adjudicated weekly attack rate was 0.82 (95% CI, 0.59-1.05) on avoralstat compared with 1.27 (95% CI, 1.06-1.49) on placebo; the adjusted difference was −0.45 attacks (95% CI, −0.23 to −0.68) (P < .001) (Fig 1). The weekly adjudicated attack rate fell in 21 patients while treated with avoralstat, compared with placebo; in 2, the attack rate increased; and in 1, it remained unchanged. Angioedema attacks were treated with C1INH or icatibant in 91% (72 of 79) of the instances during avoralstat treatment and 94% (116 of 123) during placebo treatment.Table IDemographic and clinical characteristics at baseline∗Plus-minus values are means ± SD.CharacteristicAll patients (N = 24)Sex: female, n (%)15 (63)Age (y)42 ± 11White, n (%)24 (100)Age at diagnosis (y)23 ± 11Duration of disease from first symptoms (y)32 ± 13Time from first symptoms to diagnosis (y) (range)5 (−13 to 24)History of facial swelling, n (%)23 (96)History of swelling of extremities, n (%)24 (100)History of genital swelling, n (%)21 (88)History of abdominal swelling, n (%)21 (88)History of substantial fatigue, n (%)20 (83)History of laryngeal attack, n (%)20 (83)History of laryngeal attack in the past year, n (%)13 (54)Median number (range) of laryngeal attacks in the past year, n = 132 (1-50)History of laparotomy because of an HAE attack, n (%)7 (29)Emergency room visits in the past year, mean (range)1 (0-10)Missed days of work/education in the past year8 ± 15Previous C1INH prophylaxis, n (%)3 (13)Previous androgen prophylaxis, n (%)11 (46)Previous tranexamic acid prophylaxis, n (%)4 (17)Other prophylaxis2 (8)∗ Plus-minus values are means ± SD. Open table in a new tab AEs were reported by all 24 patients: 17 patients (71%) experienced AEs during the avoralstat period and 20 (83%) during the placebo period (see this article's Safety section in the Online Repository at www.jacionline.org). No patient withdrew from the study because of an AE. One angioedema attack on placebo was classified as a serious AE, the only serious AE recorded during study treatment. This phase 2, cross-over, randomized, double-blind, placebo-controlled trial in patients with HAE and at least 1 attack per week demonstrated that 28 days of treatment with avoralstat was generally safe and well tolerated and significantly reduced HAE attacks. Patients recruited into this study represent the severe end of the spectrum of the disease, with higher placebo attack rates (1.27/week) compared with the recent C1INH prophylaxis trial (1.06/week).7Zuraw B.L. Busse P.J. White M. Jacobs J. Lumry W. Baker J. et al.Nanofiltered C1 inhibitor concentrate for treatment of hereditary angioedema.N Engl J Med. 2010; 363: 513-522Crossref PubMed Scopus (358) Google Scholar More than 50% of the patients suffered laryngeal attacks in the past year. The reduction in attack rates observed in this study is particularly relevant given the severe clinical course of HAE in this highly selected population. Avoralstat is the first oral prophylaxis drug with a mechanism of action on a specific target (PKK) to be tested in HAE. For several decades, attenuated androgens were the only oral prophylaxis drugs widely used in HAE despite their androgenic and anabolic effects.8Zuraw B.L. Banerji A. Bernstein J.A. Busse P.J. Christiansen S.C. et al.US Hereditary Angioedema Association Medical Advisory Board 2013 recommendations for the management of hereditary angioedema due to C1 inhibitor deficiency.J Allergy Clin Immunol Pract. 2013; 1: 458-467Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar Managing HAE with safe oral medicines is considered a critical unmet need.9Riedl M. Gower R.G. Chrvala C.A. Current medical management of hereditary angioedema: results from a large survey of US physicians.Ann Allergy Asthma Immunol. 2011; 106: 316-322Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar Given the encouraging results of this trial, studies of longer duration are indicated to understand the durability of benefit and long-term tolerability and safety profile of oral avoralstat. We thank the participating patients and staff at each of the study sites in the United Kingdom and Germany. We highly appreciated the valuable input of the members of the independent data monitoring committee, Drs Henriette Farkas and John Gnann. •Men and nonpregnant, nonlactating women aged 18 to 65 years having a body mass index of 19 to 36 kg/m2•A clinical diagnosis of HAE as documented at any time by a low C4 level and (1) a low C1INH antigenic level, or (2) a normal or increased C1INH antigenic level and a low C1INH functional level•Documentation of an average of 1 HAE attack per week over a period of at least 3 months demonstrated within the past year•Ability to provide written informed consent •Use within the 7 days before screening or planned use through the study of C1 inhibitor or tranexamic acid for prophylaxis of angioedema attacks•Use within the 30 days before screening or planned use through the study of anabolic steroids for prophylaxis of angioedema attacks•Concurrent use of anticoagulants, antiplatelet drugs, angiotensin-converting enzyme inhibitors, estrogen- or progestin-containing contraceptive, or nonsteroidal anti-inflammatory drugs•Prolonged activated partial thromboplastin time or prothrombin time at screening Plasma samples for pharmacokinetic and pharmacodynamic measurements were drawn on days 1, 7, 14, and 29 during both treatment periods. Analyses were performed for avoralstat concentration and PKK inhibition. PKK activity was assessed with an exploratory contact activation assay using a fluorogenic artificial substrate for kallikrein. In this assay, the contact pathway is activated by addition of ellagic acid; amidolytic activity is subsequently measured. The results of kallikrein activity were expressed as percent inhibition compared with the activity present in the predose plasma sample on day 1. Pharmacokinetic parameters were estimated by noncompartmental analysis (WinNonlin, Pharsight Corp, Princeton, NJ), using available data (N = 23) from blood draws over a 3-hour time frame on day 14. The percent ex vivo PKK inhibition in postdose samples was measured as reduction in enzyme activity from baseline (predose) samples. The exposure-response relationship between plasma concentrations of avoralstat and percent PKK inhibition were characterized using an Emax pharmacokinetic model with E = (Emax × Concentration)/(EC50 + Concentration) (Fig E1). Data on clinical outcomes were collected at baseline, at weeks 1, 2, and 4 of each treatment period, and at the final follow-up visit. Patients reported the onset and details of HAE attacks using a paper diary. All diary-reported attacks were adjudicated by an independent panel consisting of 3 expert nonstudy physicians. The primary end point was the number of adjudicated angioedema attacks during each 28-day period, expressed as a weekly rate of attacks. Patient-reported outcome measures included the Angioedema Activity Score (AAS),E1Weller K. Groffik A. Magerl M. Tohme N. Martus P. Metz M. et al.Development, validation, and initial results of the Angioedema Activity Score.Allergy. 2013; 68: 1185-1192PubMed Google Scholar recorded for each day during the entire study, and the Angioedema Quality of Life questionnaire (AE-QoL) score,E2Weller K. Groffik A. Magerl M. Tohme N. Martus P. Krause K. et al.Development and construct validation of the angioedema quality of life questionnaire.Allergy. 2012; 67: 1289-1298Crossref PubMed Scopus (149) Google Scholar which was assessed 3 times: at study baseline and at the end of each of the 2 treatment periods. The AAS summarizes characteristics of each swelling episode along the following dimensions: (1) level of discomfort, (2) performance of daily activities, (3) physical appearance, (4) overall severity, and (5) time. The AE-QoL measures quality of life in 4 dimensions (functioning, fatigue/mood, fears/shame, and nutrition). Both the AAS and the AE-QoL were scored according to the published scoring algorithms. The AAS sum of scores was calculated using a last observation carried forward (LOCF) approach for attacks that lasted over 1 day. A sensitivity analysis was performed without the LOCF approach. Cumulative AAS scores (AAS28) for all swelling episodes were compared between treatment periods. Differences were analyzed using a mixed effects model, as specified above; 95% CIs were calculated for the differences between avoralstat and placebo in changes from baseline. Changes from baseline in AE-QOL score were summarized by treatment group. Missing AE-QoL scores were not imputed. The cumulative AAS28 score was 64.5 (range, 0-220) for avoralstat and 97.1 (range, 24-216) for placebo, with an adjusted difference of 32.6 points (95% CI, 9.8-54.4; P = .007) comparing avoralstat to placebo (Table E1). The AAS28 score without LOCF was 21.7 (range, 3-56) for avoralstat and 28.8 (range, 5-59) for placebo, with an adjusted difference of 7.4 points (95% CI, 1.2-13.5; P = .022) comparing avoralstat to placebo. Patients experienced an improvement in all 4 dimensions of the AE-QoL with a change of −8.5 points in the total score (0 = best; 100 = worst) at the end of avoralstat treatment (Table E1) compared with virtually no improvement (−0.6 points) during placebo treatment and an adjusted difference of 7.9 (P = .004). Safety was evaluated through assessments of AEs (coded with version 16.0 of the Medical Dictionary for Regulatory Activities), serious AEs, laboratory analyses (hematology, coagulation, clinical chemistry, and urinalysis), vital signs, electrocardiograms, and physical examinations. The AEs occurring in 2 or more subjects and with a higher proportion during the avoralstat treatment periods versus placebo periods were splenomegaly (n = 3 [13%] vs n = 0 [0%]); contusion, cold sweats, and vertigo (n = 2 each [8%] vs n = 0 [0%]); and dyspepsia (n = 2 [8%] vs n = 1 [4%]) (Table E2). In 2 of the 3 patients reported with splenomegaly, spleen size was found to be normal on ultrasound. The third patient was 197 cm tall, had no laboratory abnormalities, and the enlarged spleen persisted through 3 months poststudy follow-up without symptoms. Flatulence (total n = 10 subjects, 42%) and diarrhea, described as soft stools (total n = 8 subjects, 33%), were reported with similar frequency in both treatment periods for active drug and placebo. No patient withdrew from the study because of an adverse event. One patient experienced an angioedema attack during the placebo treatment period, which was classified as a serious AE, the only serious AE recorded during study treatment. Of 28 patients who were screened for the study, 26 were randomized (1 patient did not meet the age eligibility criteria and 1 withdrew consent before randomization) (Fig E2). Two patients discontinued after randomization but before first dose of study drug (1 patient withdrew consent and the other was considered by the investigator to be unable to meet the visit schedule requirements). Twenty-four patients initiated treatment (first patient in: November 7, 2013) and all 24 completed the study (last patient out: May 13, 2014), with 98% adherence (range, 85% to 100%).Fig E2CONSORT diagram.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Table E1Summary of attack rates and patient-reported outcomes∗Plus-minus values are means ± SD.Attack rates per patient-weekAvoralstat (N = 24)Placebo (N = 24)(1) Adjudicated attacks (primary end point) per patient-week Overall (range)0.82 ± 0.55 (0-2.0)1.27 ± 0.50 (0.5-2.3) Period 10.75 ± 0.501.31 ± 0.61 Period 20.90 ± 0.611.24 ± 0.38Overall difference in attack rate (95% CI)†LSMeans procedure with fixed effect P value (sequence effect and period effect not significant).−0.45 (−0.68 to −0.23) P < .001(2) Patient-reported attacks per patient-week Overall (range)0.92 ± 0.66 (0-2.2)1.43 ± 0.60 (0.5-2.5) Period 1 (range)0.91 ± 0.681.48 ± 0.69 Period 2 (range)0.94 ± 0.671.38 ± 0.52Overall difference in attack rate (95% CI)†LSMeans procedure with fixed effect P value (sequence effect and period effect not significant).−0.50 (−0.80 to −0.20) P = .002(3) Adjudicated and treated attacks per patient-week Overall (range)0.75 ± 0.56 (0-2.0)1.20 ± 0.54 (0-2.3) Period 10.66 ± 0.471.23 ± 0.62 Period 20.83 ± 0.641.17 ± 0.48Overall difference in attack rate (95% CI)†LSMeans procedure with fixed effect P value (sequence effect and period effect not significant).−0.45 (−0.69 to −0.21) P < .001(4) AAS‡Based on LOCF. AAS28 score64.5 (52.1)97.1 (50.4) Adjusted difference from placebo (95% CI)†LSMeans procedure with fixed effect P value (sequence effect and period effect not significant).−32.6 (−9.8 to −55.4) P = .007(5) Angioedema quality-of-life (AE-QoL) score AE-QoL score for period37.245.0 Change in AE-QoL score from baseline−8.5 ± 13.4−0.6 ± 8.8 Adjusted difference in AE-QoL score change from baseline between avoralstat and placebo (95% CI)†LSMeans procedure with fixed effect P value (sequence effect and period effect not significant).−7.9 (−2.8 to −13.0) P = .004∗ Plus-minus values are means ± SD.† LSMeans procedure with fixed effect P value (sequence effect and period effect not significant).‡ Based on LOCF. Open table in a new tab Table E2AEs during active treatment and control periodsAEsAvoralstat periods (N = 24)Placebo periods (N = 24)Total periods (N = 24)Any, n (%)17 (71)20 (83)24 (100)Serious AE, n (%)∗Serious AE was defined as an event that was fatal or life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, caused persistent or substantial disability or incapacity, caused congenital anomaly or birth defect, or was considered by the investigator to be medically important.01 (4)1 (4)Death000Leading to discontinuation000Grade 3 or 4, n (%)†There were 3 grade 3 events during both the treatment and placebo periods, 2 of which (pruritus and thirst) occurred in the same subject and were considered drug-related. One patient experienced 2 serious AEs: an HAE attack during the screening period before randomization and a second (treatment-emergent) attack 12 days after the first dose of placebo during period 1. The patient experienced an abdominal attack of less than 24-hour duration that was treated with icatibant, but required hospitalization. Study drug was interrupted temporarily and 5 doses were missed.3 (13)3 (13)5 (21)Common AEs, n (%) Splenomegaly3 (13)03 (13) Gas4 (17)6 (25)10 (42) Soft stool3 (13)5 (21)8 (33) Dyspepsia2 (8)1 (4)3 (13) Nausea03 (13)3 (13) Nasopharyngitis4 (17)7 (29)10 (42) Contusion2 (8)02 (8) Musculoskeletal pain02 (8)2 (8) Headache4 (17)4 (17)7 (29) Vertigo2 (8)02 (8) Lethargy1 (4)1 (4)2 (8) Oropharyngeal pain02 (8)2 (8) Cold sweat2 (8)02 (8)∗ Serious AE was defined as an event that was fatal or life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, caused persistent or substantial disability or incapacity, caused congenital anomaly or birth defect, or was considered by the investigator to be medically important.† There were 3 grade 3 events during both the treatment and placebo periods, 2 of which (pruritus and thirst) occurred in the same subject and were considered drug-related. One patient experienced 2 serious AEs: an HAE attack during the screening period before randomization and a second (treatment-emergent) attack 12 days after the first dose of placebo during period 1. The patient experienced an abdominal attack of less than 24-hour duration that was treated with icatibant, but required hospitalization. Study drug was interrupted temporarily and 5 doses were missed. Open table in a new tab