Aygören-Pürsün, Emel; Bygum, Anette; Grivcheva-Panovska, Vesna; Magerl, Markus; Graff, Jochen; Steiner, Urs C.; Fain, Olivier; Huissoon, Aarnoud; Kinaciyan, Tamar; Farkas, Henriette; Lleonart, Ramon; Longhurst, Hilary J.; Rae, William; Triggiani, Massimo; Aberer, Werner; Cancian, Mauro; Zanichelli, Andrea; Smith, William B.; Baeza, Maria L.; Du-Thanh, Aurelie; Gompels, Mark; Gonzalez-Quevedo, Teresa; Greve, Jens; Guilarte, Mar; Katelaris, Constance; Dobo, Sylvia; Cornpropst, Melanie; Clemons, Desiree; Fang, Lei; Collis, Phil; Sheridan, William; Maurer, Marcus; Cicardi, Marco

BACKGROUND Hereditary angioedema is a life-threatening illness caused by mutations in the gene encoding C1 inhibitor (also called C1 esterase inhibitor) that lead to over-activation of the kallikrein-bradykinin cascade. BCX7353 is a potent oral small-molecule inhibitor of plasma kallikrein with a pharmacokinetic and pharmacodynamic profile that may help prevent angioedema attacks. METHODS In this international, three-part, dose-ranging, placebo-controlled trial, we evaluated four doses of BCX7353 (62.5 mg, 125 mg, 250 mg, and 350 mg once daily) for the prevention of angioedema attacks over a 28-day period. Patients with type I or II hereditary angioedema with a history of at least two angioedema attacks per month were randomly assigned to BCX7353 or placebo. The primary efficacy end point was the number of confirmed angioedema attacks. Key secondary end points included angioedema attacks according to anatomical location and quality of life. RESULTS A total of 77 patients underwent randomization, 75 received BCX7353 or placebo, and 72 completed the trial. The rate of confirmed angioedema attacks was significantly lower among patients who received BCX7353 at daily doses of 125 mg or more than among those who received placebo, with a 73.8% difference at 125 mg (P<0.001). Significant benefits with respect to quality-of-life scores were observed in the 125-mg and 250-mg dose groups (P<0.05). Gastrointestinal adverse events, predominantly of grade 1, were the most commonly reported adverse events, particularly in the two highest BCX7353 dose groups. CONCLUSIONS Once-daily oral administration of BCX7353 at a dose of 125 mg or more resulted in a significantly lower rate of attacks of hereditary angioedema than placebo. Mild gastrointestinal symptoms were the principal side effect.

Glycoprotein VI (GPVI) is the major platelet receptor for collagen-mediated platelet adhesion and activation. SAR264565 is an anti-GPVI-Fab, binds to GPVI with high affinity, and blocks GPVI function in human platelets in vitro.

The 10th C1-inhibitor deficiency workshop will be held between 18 and 21 May 2017 in Budapest (2017.haenetworkshop.hu),among the picturesque surroundings of Margaret Island.As indicated by the name of this event, most of the interest focused on angioedema due to C1-inhibitor deficiency in 1999, when it was first organized.The name is unchanged, but the range of angioedemas has expanded since to include all known varieties of hereditary and acquired angioedemas with a bradykinin-mediated pathomechanism.Looking back to the agenda of this biennial conference, many questions remained unanswered and new issues have arisen despite the enormous scientific progress made.On this occasion, 318 participants have registered from 42 countriesthis is the greatest attendance in the history of the Workshop since the start of the series.Eighty-six presentations have been submitted for this 4-day long scientific forum.The scientific program sounds interesting-it comprises novel achievements by leading scientific teams in basic research into bradykinin-mediated angioedema, the new findings of diagnostics and genetics, promising therapeutic solutions awaiting introduction, and the experience accumulated with the latest therapeutic procedures.Several presentations discuss the efforts related to improving the patients' quality of life.This time, we have invited five prominent experts-namely, Alvin Schmaier (Cleveland, OH, USA), Marco Cicardi (Milan, Italy), Avner Reshef (Tel-Hashomer, Israel), Dumitru Moldovan (Tirgu-Mures, Romania) and Attila Mócsai (Budapest, Hungary).Alvin Schmaier will show us that our knowledge about the underlying mechanisms of bradykinin-mediated angioedemas is still limited-this may be remedied by extending our interest to other forms of angioedema with different pathophysiological backgrounds.Marco Cicardi will expose the similarities and the differences between bradykinin-mediated edema formation, and the idiopathic systemic capillary leak syndrome.Avner Reshef will explore a similar issue in his presentation titled 'Angioedema-Histamine or Bradykinin?' .The lecture on neutrophil granulocytes by Attila Mócsai will take us closer to understanding the pathomechanism of angioedema.The agenda also contains the traditional roundtable session, an opportunity to develop consensus and international guidelines-this year, genetics will be in the limelight.In this session, the keynote lectures will be read by Margarita-Lopez Trascasa (Madrid, Spain) on the extended diagnostic approach integrating serological and genetic methodology; by Anastasios Germenis (Larissa, Greece) on the latest techniques for studying the SERPING1 gene; and by Nancy Brown (Nashville, TN, USA) on the pharmacogenetics of angiotensin-converting enzyme inhibitor-associated angioedema.Notwithstanding the remarkable progress made in South-America and in the former Soviet-bloc countries of Europe, state-of-the-art diagnostic and therapeutic modalities are still not available in many regions of the World.Dumitru Moldovan will review the stages along the way to making these accessible, and the experience accumulated in the effort to achieve high levels of patient care.The conference will be attended both by researchers and by clinicians-medical professionals and nurses, by the representatives of patient organizations, and by pharmaceutical industry experts involved in drug development, in order to assist the efforts of each other through joint thinking.Within the framework of this fruitful cooperation, the pharmaceutical companies also lent financial support to the conference-in addition to their scientific contribution.The travel grants, make it possible for an increasing number of professionals involved in the research or the management of patients with angioedema to attend the Workshop.The generous support by our Sponsors enabled us again to present the "For HAE Patients" award, as well as the "Grant for Young Investigators".The major donors to this event are CSL Behring and Shire.Pharming Group NV, Swedish Orphan Biovitrum, BioCryst Phamaceuticals, KininX SAS also contributed the sponsorship of the Workshop.On occasion of this tenth, jubilee event, the "For HAE Patients" award goes to Bruce Zuraw (San Diego, USA), who will present his lecture 'Let the Treatment Fit the Disease' on the festive session of the scientific section on Day 1.His achievements in bettering the management of patients will be recalled by Antony Castaldo, the chair of the International Patient Organization for C1 Inhibitor Deficiencies.The concluding event of the conference will be the awarding of the 'Grant for Young Investigators' to the top four young presenters.The support referred to above made it possible to publish the submitted abstracts of the Workshop in the journal Allergy, Asthma, and Clinical Immunology, in order to make them available to an even broader range of professionals interested in this subject.

BACKGROUND:Considerable interest exists in identifying calcineurin inhibitor (CNI)-free and thus, less-toxic immunosuppressive regimens, with mycophenolic acid (MPA)-based treatments being a suitable approach. Because pharmacokinetic analyses of MPA treatments in stable CNI-free renal transplant recipients are lacking, the authors aimed at comparing the steady-state pharmacokinetic characteristics of MPA in patients on stable treatment with mycophenolate mofetil (MMF) or enteric-coated mycophenolate sodium (EC-MPS) plus prednisone (≤5 mg/d). METHODS:In the prospective, nonrandomized, open-label study, patients with stable transplant function since ≥6 months received their routine single dose of either MMF (n = 12) or EC-MPS (n = 11). The MPA plasma concentration was recorded over 12 hours. Parameters assessed were predose MPA concentration (C0), postdose minimum and maximum concentration (Cmin and Cmax), time to maximum concentration (Tmax), and area under the concentration-time curve (AUC) for the 12-hours of exposure (AUC0-12). RESULTS:Baseline characteristics were comparable between both the groups. Consistent with enteric coating, the mean Tmax was significantly longer after the intake of EC-MPS compared with MMF (2.2 versus 0.8 hours; P = 0.0002). The exposure measures Cmin, Cmax, and AUC0-12 were not significantly different despite the higher mean MPA equivalent dose in patients receiving MMF compared with those receiving EC-MPS (85% versus 64% of the recommended single dose, respectively). Exposures as reflected by the median AUC0-12 values were 50.7 and 58.7 mg·h·L with MMF and EC-MPS, respectively (P = 0.340). All patients achieved a target AUC of >30 mg·h·L, and 61% had an AUC of >50 mg·h·L. CONCLUSIONS:The study provides first results on the steady-state pharmacokinetics of the 2 MPA drugs in CNI-free immunosuppressant regimens. Pharmacokinetic parameters measured in this study under real-life conditions were comparable in patients receiving MMF or EC-MPS.

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

BCX4161 is an oral kallikrein inhibitor under development for prevention of angioedema attacks in HAE. BCX4161 significantly reduced the HAE attack rate versus placebo in the OPuS-1 study. The effect of BCX4161 on disease activity and quality of life was assessed in OPuS-1 using the disease-specific Angioedema Activity Score (AAS), the Angioedema Quality of Life Questionnaire (AE-QoL) as well as the assessment of attack characteristics. Twenty-four subjects with HAE and frequent angioedema attacks received 4 weeks of treatment with BCX4161 400 mg TID and placebo in a randomized sequence in OPuS-1, a double-blind, placebo-controlled, 2-period crossover study. Subjects recorded attack details and an AAS for each attack, and completed the 17-item, 4-domain AE-QoL at baseline and at the end of each treatment period. Four-week activity scores (AAS28) and AE-QoL total and domain scores were calculated and the results from each treatment were compared using a mixed-effects model. Overall disease activity assessed by the AAS28 was markedly reduced with BCX4161 versus placebo (total score 21.4 vs 28.8, p=0.022). Quality of life was improved during BCX4161, with a mean AE-QoL score difference of 7.9 points versus placebo (p=0.004). An improvement in the functioning domain was seen with BCX4161 (-18.9 vs -5.5, p=0.016); trends in other domains were observed. Fewer subjects reported stomach/gut (58% vs 87%, p=0.049) and hand attacks (25% vs 71%, p=0.003) during BCX4161 versus placebo treatment. Four weeks of BCX4161 treatment in HAE subjects with frequent attacks reduced disease burden with improved quality of life and decreased disease activity.

Abstract Background: Stem cell mobilization (SCM) with G-CSF is efficient but - although overall safe - inconvenient because of the five-day injection regime and certain contraindications. Side effects, sometimes severe, are frequent. These disadvantages fuel the quest for alternative mobilizing agents. Mobilization with the CXCR4-inhibitor plerixafor is rapid, albeit insufficiently efficacious on its own. POL6326, a potent 2nd generation macrocycle CXCR4 antagonist, has demonstrated rapid mobilization kinetics and efficacy in mice. We herein report the results of a Phase IIa dose escalation trial where SCM in response to POL6326 was compared with G-CSF in healthy volunteer stem cell donors. Methods: In this Phase IIa open label trial, healthy volunteer stem cell donors with average mobilization (121±7 CD34+ cells/μL, MW±SEM)after a five-day course of G-CSF, and a wash-out period of at least 6 weeks, received POL6326 at 500-2500 µg/kg as a single 2-hour i.v. infusion. Safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) were assessed in 3-10 subjects/dose group. Subgroups received two doses of POL6326, 1000 and 2500 µg/kg or 1500 and 2500 µg/kg, at least 2 weeks apart (paired intra-individual analysis). For PK and PD blood samples were collected before (0) and at 2, 3, 4, 6, 8 and 24 hrs after infusion start. Complete blood count, CD34+, CFU-C count and PK were assessed at all time points. At 0, 4, 8 and 24 hrs extensive phenotyping of mobilized mature and immature leukocyte subsets was performed. Eight to 14 days after treatment volunteers underwent extensive clinical and laboratory follow-up. Results: POL6326 was very well tolerated. Several volunteers experienced a mild urticarial or itchy macular rash which responded well to H1/H2 blockade. Rating of tolerability/adverse events by volunteers (questionnaire) compared favourably with G-CSF administration. Exposure (Cmax, AUC) was dose-linear. At all doses tested POL6326 mobilized CD34+ progenitor cells and colony-forming cells (CFU-C, Figure 1) exceeding reported peak mobilization with plerixafor in donors at all except the lowest dose levels. In this dataset mobilization after doses of 2000 or 2500 µg/kg did not appear meaningfully stronger than after 1500 µg/kg. The SCM response for CD34+ cells to doses ≥1500 µg/kg was 36.9±2.4/µL (mean±SEM), or 1/3 that of G-CSF (y=0.324x). Good SCM with G-CSF was predictive of good SCM with POL6326 (r=0.63). One/5.7 POL6326-mobilized CD34+ cells was clonogenic (G-CSF: 1 CFU-C/3.4 CD34+ cells) possibly indicating a more immature phenotype of CD34+ cells mobilized by POL6326. POL6326 caused mixed leucocytosis with peak values in the mid-20K/µL. B-lymphocytosis was more and neutrophilia and monocytosis were less pronounced after POL6326 than G-CSF. Compared to G-CSF the subset of plasmocytoid dendritic cell progenitors (pDC) was enriched to a distinct population within the CD34+ cells following SCM with POL6326 as previously described for plerixafor. At the 24 h time point, blood values were well on their way towards normal, and at follow-up all laboratory values had normalized. Summary/Conclusions: The novel CXCR4-antagonist POL6326 is safe, well tolerated, and provides efficient mobilization of HSPCs. Based on the number of mobilized CD34+ cells at higher doses in this study, we conclude that a standard dose of 4x10E6 CD34+ cells/kg can be extracted with a single apheresis for most recipients unless their body weight significantly exceeds the donor weight. However, exploration of alternative dosing regimens may provide even higher mobilization responses. POL6326 can be an effective mobilizing agent for allogeneic donors, including subjects with contra-indications to G-CSF. Figure 1. Mobilization of CD34+ cells (left) and CFU-C (right) over time is shown (mean±SEM for each dose level of POL6326). Figure 1. Mobilization of CD34+ cells (left) and CFU-C (right) over time is shown (mean±SEM for each dose level of POL6326). Figure 2. Figure 2. Disclosures Escot: Polyphor Ltd.: Employment. Douglas:Polyphor Ltd.: Employment. Romagnoli:Polyphor Ltd.: Employment. Chevalier:Polyphor Ltd.: Employment. Dembowsky:Polyphor Ltd.: Consultancy. Hooftman:Polyphor Ltd.: Employment. Bonig:Polyphor Ltd.: Research Funding.

BCX4161 is an oral kallikrein inhibitor in development as a prophylactic agent in HAE. BCX4161 significantly reduced the mean HAE attack rate versus placebo in the OPuS-1 study. We evaluated the relationships between clinical efficacy, plasma BCX4161 concentrations, pharmacodynamic markers of activity and safety in OPuS-1 subjects. OPuS-1 was a double-blind, placebo-controlled, randomized 2-period crossover study conducted in 24 HAE subjects who received 28 days of treatment with BCX4161 400 mg TID and placebo. Subjects recorded HAE attack incidence daily. Pharmacokinetic and pharmacodynamic samples were drawn at trough (Ctrough) and a PK profile (0.5, 1, 2 and 3 hours post-dose) was assessed on Day 14. PT and aPTT samples were drawn throughout the study. Plasma kallikrein inhibitory levels were highly correlated with Ctrough (r= 0.73, p = 0.002). Ctrough was significantly correlated with the percent difference in HAE attack rate (Pearson correlation coefficient -0.42, p = 0.04), with an IC50 of approximately 34 ng/mL. The BCX4161 EC80 for kallikrein inhibition was 51 ng/mL. Four of 6 subjects (67%) with Ctrough greater than 51 ng/mL had an attack reduction on BCX4161 of at least 0.5 attacks/week compared to 5 of 18 subjects (33%) with concentrations below 51 ng/mL. Cmax and AUC0-3did not correlate with efficacy. There were no effects of BCX4161 on aPTT or PT. Despite a small sample size of 24 subjects, there were relationships suggestive of a pharmacokinetic/pharmacodynamic/efficacy association, and adequate, maintained BCX4161 exposure correlated with degree of benefit. BCX4161 did not affect coagulation parameters.

Novel oral anticoagulants are approved in several indications: rivaroxaban, apixaban, and dabigatran for the prevention of venous thromboembolism after elective hip or knee replacement surgery, and edoxaban for hip or knee replacement surgery and hip fracture surgery (in Japan only); rivaroxaban for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent DVT and PE; and rivaroxaban, apixaban, and dabigatran for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation. These agents overcome some limitations of traditional anticoagulants, are suggested to have no requirement for routine coagulation monitoring, and are administered orally. Rivaroxaban, apixaban, and dabigatran have different pharmacological characteristics, and guidance is needed on optimum doses and dosing intervals and the effects of renal or hepatic impairment, age, food, and other drugs. Dabigatran has stricter prescribing advice than rivaroxaban or apixaban for patients with moderate-to-severe renal impairment. All three drugs have restrictions on use in patients with hepatic impairment. Apixaban requires twice-daily dosing in all indications, whereas rivaroxaban and dabigatran are dosed once- or twice-daily depending on indication. Although head-to-head comparisons are lacking, the novel oral anticoagulants may show favorable cost–benefit relations compared with traditional vitamin K antagonists or no therapy.

The direct factor Xa (FXa) inhibitors rivaroxaban, apixaban and edoxaban, and the thrombin inhibitor dabigatran etexilate (dabigatran) have gained approval for use in several indications, most notably for the prevention and treatment of venous thromboembolism (VTE) and for the prevention of stroke in patients with atrial fibrillation. Hepatic impairment can affect the disposition of these anticoagulants considerably not only because of the hepatic metabolism of the direct FXa inhibitors but also because moderate to severely impaired hepatic function will affect coagulation. This review describes the key pharmacological properties of novel oral anticoagulants with special attention to patients with impaired hepatic function. In subjects with moderately impaired liver function (i.e. Child-Pugh classification B), the area under the plasma concentration–time curve (AUC) of rivaroxaban (10 mg single dose) is increased by 2.27-fold, which is paralleled by an increase in FXa inhibition. The AUC of apixaban (5 mg single dose) is increased by 1.09-fold, whereas the AUC of edoxaban (15 mg single dose) is decreased by 4.8 % and the AUC of dabigatran (150 mg single dose) is decreased by 5.6 %. Specific labelling restrictions for rivaroxaban, apixaban and dabigatran regarding impaired hepatic function are based on both the Child-Pugh classification and liver-related exclusion criteria applied in pivotal clinical trials. Rivaroxaban is contraindicated in patients with hepatic disease associated with coagulopathy and clinically relevant bleeding risk, including cirrhotic patients classified as Child-Pugh B and C. Apixaban can be used with caution in patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment or in patients with alanine aminotransferase and aspartate aminotransferase levels >2× upper limit of normal (ULN). Apixaban is not recommended in patients with severe hepatic impairment and is contraindicated in those with hepatic disease associated with coagulopathy and clinically relevant bleeding risk. Dabigatran is not recommended in patients with elevated liver enzymes (>2× ULN). Dabigatran is contraindicated in patients with hepatic impairment or liver disease expected to have any impact on survival. Currently, edoxaban is not available in the US or European markets. However, the Japanese label did not restrict use in hepatic dysfunction but advises care in patients with severe hepatic impairment.

Hereditary angioedema (HAE) is a rare disorder caused by functional C1-esterase inhibitor (C1-INH) deficiency and characterized by recurrent episodes of swelling. Initial symptoms usually occur during the first decade of life. There is uncertainty, however, as to whether disease severity is correlated with the age at first clinical manifestation. The relationship between age at first clinical manifestation of HAE and frequency of recurrences was retrospectively evaluated for 69 patients (group 1: early onset of symptoms at an age of 0-6 years [n=47], group 2: later onset of symptoms at an age of >6-18 years [n=22]). The course of the disease was defined based on the number of attacks per month (severe: ≥4 attacks/month, moderate: <1-4 attacks/month, mild: <1 attack/month). Attacks were treated with human pasteurized C1-INH. Overall, patients with an early onset of symptoms tended to be more likely to suffer from a severe course of the disease. In 6 patients (8.7%), who suffered from the most severe courses of HAE, the first clinical manifestation was at an age of <3 years. Treatment with human pasteurized C1-INH concentrate was efficacious and safe irrespective of disease severity. The severity of the course of HAE seems to be associated with the age at first clinical manifestation. The threat of developing a severe course with early onset of symptoms underlines the importance of early diagnosis in families with a history of HAE to allow for an optimal management of the disease.

OBJECTIVEUnder immunosupression with sirolimus (rapamycin) procoagulant effects and platelet activation have been controversially discussed.METHODSWe evaluated patients of a prospectly designed substudy as part of a randomized trial investigating the effect of a switch from non-mTOR-based immunosuppression to sirolimus in renal transplant recipients. Our substudy consisted of 7 patients who switched therapy from azathioprine to sirolimus (conversion group) and 8 patients who remained on azathioprine (controls) before (V1) and after (V2) 3 months of treatment. In all patients we assessed flowcytometric markers of platelet activation (PAC-1), platelet degranulation (CD62P), formation of platelet leukocyte-aggregates (PLA), monocyte activation (CD11b), endogenous thrombin potential (ETP) and platelet aggregation.RESULTSBoth groups were similar in terms of baseline demographics and had stable transplant function for at least 6 months. CD62P increased significantly in the control group (p < 0.03). PLA were significantly reduced in the sirolimus conversion group at V2 (p < 0.02), whereas no effect was seen in the controls. Expression of PAC-1, CD11b, ETP-peak, ETP-time to peak, ETP-AUC and platelet aggregation showed no significant changes in both groups compared to V2.CONCLUSIONFrom clinical data, performing in depth platelet function testing, we found no evidence for increased platelet activation parameters in RTR who switched therapy from azathioprine to sirolimus.

Gossmann, J.; Graff, J.; Dragutinovic, I.; Brandhorst, G.; Scheuermann, E.; Oellerich, M. Author Information

Aim Addictive behavior is importantly mediated by mesolimbic dopaminergic signaling. Here, we comprehensively analyzed the DRD2 gene locus, and in addition, the ANKK1 rs1800497C>T single nucleotide polymorphism (SNP), formerly known as ‘dopamine D2 receptor Taq1A C>T polymorphism', for associations with the risk of opiate addiction and the methadone dosage requirements. Methods Allelic frequencies of DRD2/ANKK1 polymorphisms were compared between 85 methadone-substituted Caucasian patients and a random sample of 99 healthy Caucasian controls. Within patients, the average and maximum daily methadone dose during the first year of treatment and the time when that maximum dose was reached were analyzed for an association with DRD2/ANKK1 genetics. Results Compared with the control group, drug users carried more frequently the minor allele of DRD2 SNP rs1076560G>T SNP (P=0.022, odds ratio 2.343) or the ATCT haplotype of DRD2 rs1799978A>G, rs1076560G>T, rs6277C>T, ANKK1 rs1800497C>T (P=0.048, odds ratio 2.23), with similar tendencies for ANKK1 rs1800497C>T (P=0.056, odds ratio 2.12) and the TCCTCTT haplotype of DRD2 rs12364283T>C, rs1799732C del, rs4648317C>T, rs1076560G>T, rs6275C>T, rs6277C>T, and ANKK1 rs1800497C>T (P=0.059, odds ratio 2.31). The average and maximum daily methadone doses were significantly associated with the DRD2 rs6275C>T SNP (P=0.016 and 0.005 for average and maximum dose, respectively). Carriers of the variant rs6275T allele needed higher methadone doses than noncarriers. In addition, this variant was associated with a longer time to reach the maximum methadone dose (P=0.025). Conclusion On the basis of an analysis spanning the whole gene locus, from the DRD2 promoter to the ANKK1 rs1800497C>T polymorphism, DRD2 genetic polymorphisms modulate both the risk of opiate addiction, leading to the necessity of methadone substitution therapy, and the course of this therapy in terms of dosage requirements.

OBJECTIVES:In the past, bleeding events have been described for patients with haemophilia taking HIV-1 protease inhibitors. Recently, the FDA published a warning concerning intracranial haemorrhage in patients taking the HIV-1 protease inhibitor tipranavir co-administered with ritonavir.METHODS:We investigated (i) platelet aggregation in vivo in HIV-1-infected adult patients (n = 5) immediately before and 2 and 4 h after dosing of tipranavir/ritonavir 500/200 mg. To further characterize the effects, we then evaluated (ii) platelet aggregation and (iii) thromboxane B2 (TxB2) formation (ELISA) with increasing tipranavir concentrations (TPV(conc)) in vitro of up to 100,000 ng/mL. Platelet aggregation was stimulated either with 2 microM ADP (ADP) or 10 mg/L collagen (COL). TPV(conc) were measured with validated EPI-LC-MS/MS. Intraindividual comparisons of values at time points and TPV(conc), respectively, were carried out with repeated samples ANOVA.RESULTS:Platelet aggregation (mean, maximal light transmission A(max)) was significantly decreased in patients 4 h post-dose in collagen- (from 79.8% to 57.1%; P < 0.001) and in ADP-stimulated (from 58.5% to 54.0%; not significant) samples at a median (range) TPV(conc) of 62 500 ng/mL (22,990-67,500). These results could be reproduced in vitro at TPV(conc) 50,000 ng/mL (A(max)ADP/A(max)COL = 20.7/36.9%; P = 0.003/<0.001) and 100 000 ng/mL (A(max)ADP/A(max)COL = 14.5/17.1%; P < 0.001/<0.001). Median (range) TxB2 concentrations were reduced (P = 0.07) from 327 ng/mL (187-500) at baseline to 265 ng/mL (152-428) at 5000 ng/mL and were significantly reduced (P < 0.001) to 187 ng/mL (81-362) at a TPV(conc) of 50,000 ng/mL, respectively.CONCLUSIONS:Five HIV-1-infected patients on tipranavir-containing highly active antiretroviral therapy presented marked decreases in platelet aggregation. In vitro these effects were reproduced and decreased TxB2 formation was also demonstrated. Inhibition of platelet aggregation while receiving tipranavir treatment might contribute to increased risk of bleeding.