Jonathan Edelman

Intravenous augmentation treatment and lung density in severe α1 antitrypsin deficiency (RAPID): a randomised, double-blind, placebo-controlled trial.

BACKGROUNDnThe efficacy of α1 proteinase inhibitor (A1PI) augmentation treatment for α1 antitrypsin deficiency has not been substantiated by a randomised, placebo-controlled trial. CT-measured lung density is a more sensitive measure of disease progression in α1 antitrypsin deficiency emphysema than spirometry is, so we aimed to assess the efficacy of augmentation treatment with this measure.nnnMETHODSnThe RAPID study was a multicentre, double-blind, randomised, parallel-group, placebo-controlled trial of A1PI treatment in patients with α1 antitrypsin deficiency. We recruited eligible non-smokers (aged 18-65 years) in 28 international study centres in 13 countries if they had severe α1 antitrypsin deficiency (serum concentration <11 μM) with a forced expiratory volume in 1 s of 35-70% (predicted). We excluded patients if they had undergone, or were on the waiting list to undergo, lung transplantation, lobectomy, or lung volume-reduction surgery, or had selective IgA deficiency. We randomly assigned patients (1:1; done by Accovion) using a computerised pseudorandom number generator (block size of four) with centre stratification to receive A1PI intravenously 60 mg/kg per week or placebo for 24 months. All patients and study investigators (including those assessing outcomes) were unaware of treatment allocation throughout the study. Primary endpoints were CT lung density at total lung capacity (TLC) and functional residual capacity (FRC) combined, and the two separately, at 0, 3, 12, 21, and 24 months, analysed by modified intention to treat (patients needed at least one evaluable lung density measurement). This study is registered with ClinicalTrials.gov, number NCT00261833. A 2-year open-label extension study was also completed (NCT00670007).nnnFINDINGSnBetween March 1, 2006, and Nov 3, 2010, we randomly allocated 93 (52%) patients A1PI and 87 (48%) placebo, analysing 92 in the A1PI group and 85 in the placebo group. The annual rate of lung density loss at TLC and FRC combined did not differ between groups (A1PI -1·50 g/L per year [SE 0·22]; placebo -2·12 g/L per year [0·24]; difference 0·62 g/L per year [95% CI -0·02 to 1·26], p=0·06). However, the annual rate of lung density loss at TLC alone was significantly less in patients in the A1PI group (-1·45 g/L per year [SE 0·23]) than in the placebo group (-2·19 g/L per year [0·25]; difference 0·74 g/L per year [95% CI 0·06-1·42], p=0·03), but was not at FRC alone (A1PI -1·54 g/L per year [0·24]; placebo -2·02 g/L per year [0·26]; difference 0·48 g/L per year [-0·22 to 1·18], p=0·18). Treatment-emergent adverse events were similar between groups, with 1298 occurring in 92 (99%) patients in the A1PI group and 1068 occuring in 86 (99%) in the placebo group. 71 severe treatment-emergent adverse events occurred in 25 (27%) patients in the A1PI group and 58 occurred in 27 (31%) in the placebo group. One treatment-emergent adverse event leading to withdrawal from the study occurred in one patient (1%) in the A1PI group and ten occurred in four (5%) in the placebo group. One death occurred in the A1PI group (respiratory failure) and three occurred in the placebo group (sepsis, pneumonia, and metastatic breast cancer).nnnINTERPRETATIONnMeasurement of lung density with CT at TLC alone provides evidence that purified A1PI augmentation slows progression of emphysema, a finding that could not be substantiated by lung density measurement at FRC alone or by the two measurements combined. These findings should prompt consideration of augmentation treatment to preserve lung parenchyma in individuals with emphysema secondary to severe α1 antitrypsin deficiency.nnnFUNDINGnCSL Behring.

Prevention of hereditary angioedema attacks with a subcutaneous C1 inhibitor

BACKGROUND Hereditary angioedema is a disabling, potentially fatal condition caused by deficiency (type I) or dysfunction (type II) of the C1 inhibitor protein. In a phase 2 trial, the use of CSL830, a nanofiltered C1 inhibitor preparation that is suitable for subcutaneous injection, resulted in functional levels of C1 inhibitor activity that would be expected to provide effective prophylaxis of attacks. METHODS We conducted an international, prospective, multicenter, randomized, double‐blind, placebo‐controlled, dose‐ranging, phase 3 trial to evaluate the efficacy and safety of self‐administered subcutaneous CSL830 in patients with type I or type II hereditary angioedema who had had four or more attacks in a consecutive 2‐month period within 3 months before screening. We randomly assigned the patients to one of four treatment sequences in a crossover design, each involving two 16‐week treatment periods: either 40 IU or 60 IU of CSL830 per kilogram of body weight twice weekly followed by placebo, or vice versa. The primary efficacy end point was the number of attacks of angioedema. Secondary efficacy end points were the proportion of patients who had a response (≥50% reduction in the number of attacks with CSL830 as compared with placebo) and the number of times that rescue medication was used. RESULTS Of the 90 patients who underwent randomization, 79 completed the trial. Both doses of CSL830, as compared with placebo, reduced the rate of attacks of hereditary angioedema (mean difference with 40 IU, –2.42 attacks per month; 95% confidence interval [CI], –3.38 to –1.46; and mean difference with 60 IU, –3.51 attacks per month; 95% CI, –4.21 to –2.81; P<0.001 for both comparisons). Response rates were 76% (95% CI, 62 to 87) in the 40‐IU group and 90% (95% CI, 77 to 96) in the 60‐IU group. The need for rescue medication was reduced from 5.55 uses per month in the placebo group to 1.13 uses per month in the 40‐IU group and from 3.89 uses in the placebo group to 0.32 uses per month in the 60‐IU group. Adverse events (most commonly mild and transient local site reactions) occurred in similar proportions of patients who received CSL830 and those who received placebo. CONCLUSIONS In patients with hereditary angioedema, the prophylactic use of a subcutaneous C1 inhibitor twice weekly significantly reduced the frequency of acute attacks. (Funded by CSL Behring; COMPACT EudraCT number, 2013‐000916‐10, and ClinicalTrials.gov number, NCT01912456.)

Long-term efficacy and safety of α1 proteinase inhibitor treatment for emphysema caused by severe α1 antitrypsin deficiency: an open-label extension trial (RAPID-OLE).

BACKGROUNDnPurified α1 proteinase inhibitor (A1PI) slowed emphysema progression in patients with severe α1 antitrypsin deficiency in a randomised controlled trial (RAPID-RCT), which was followed by an open-label extension trial (RAPID-OLE). The aim was to investigate the prolonged treatment effect of A1PI on the progression of emphysema as assessed by the loss of lung density in relation to RAPID-RCT.nnnMETHODSnPatients who had received either A1PI treatment (Zemaira or Respreeza; early-start group) or placebo (delayed-start group) in the RAPID-RCT trial were included in this 2-year open-label extension trial (RAPID-OLE). Patients from 22 hospitals in 11 countries outside of the USA received 60 mg/kg per week A1PI. The primary endpoint was annual rate of adjusted 15th percentile lung density loss measured using CT in the intention-to-treat population with a mixed-effects regression model. This trial is registered with ClinicalTrials.gov, number NCT00670007.nnnFINDINGSnBetween March 1, 2006, and Oct 13, 2010, 140 patients from RAPID-RCT entered RAPID-OLE: 76 from the early-start group and 64 from the delayed-start group. Between day 1 and month 24 (RAPID-RCT), the rate of lung density loss in RAPID-OLE patients was lower in the early-start group (-1·51 g/L per year [SE 0·25] at total lung capacity [TLC]; -1·55 g/L per year [0·24] at TLC plus functional residual capacity [FRC]; and -1·60 g/L per year [0·26] at FRC) than in the delayed-start group (-2·26 g/L per year [0·27] at TLC; -2·16 g/L per year [0·26] at TLC plus FRC, and -2·05 g/L per year [0·28] at FRC). Between months 24 and 48, the rate of lung density loss was reduced in delayed-start patients (from -2·26 g/L per year to -1·26 g/L per year), but no significant difference was seen in the rate in early-start patients during this time period (-1·51 g/L per year to -1·63 g/L per year), thus in early-start patients the efficacy was sustained to month 48.nnnINTERPRETATIONnRAPID-OLE supports the continued efficacy of A1PI in slowing disease progression during 4 years of treatment. Lost lung density was never recovered, highlighting the importance of early intervention with A1PI treatment.nnnFUNDINGnCSL Behring.

Phase II study results of a replacement therapy for hereditary angioedema with subcutaneous C1‐inhibitor concentrate

Hereditary angioedema (HAE) due to C1 inhibitor deficiency manifests as recurrent swelling attacks that can be disabling and sometimes fatal. Long‐term prophylaxis with twice‐weekly intravenous injections of plasma‐derived C1‐inhibitor (pdC1‐INH) has been established as an effective treatment. Subcutaneous (SC) administration of pdC1‐INH has not been studied in patients with HAE.

Safety and Usage of C1-Inhibitor in Hereditary Angioedema: Berinert Registry Data

BACKGROUNDnThe plasma-derived, highly purified, nanofiltered C1-inhibitor concentrate (Berinert; pnfC1-INH) is approved in the United States for treating hereditary angioedema (HAE) attacks and in many European countries for attack treatment and short-term prophylaxis.nnnOBJECTIVEnThe objective of this study was to describe safety and usage patterns of pnfC1-INH.nnnMETHODSnA multicenter, observational, registry was conducted between 2010 and 2014 at 30 United States and 7 European sites to obtain both prospective (occurring after enrollment) and retrospective (occurring before enrollment) safety and usage data on subjects receiving pnfC1-INH for any reason.nnnRESULTSnOf 343 enrolled patients, 318 received 1 or more doses of pnfC1-INH for HAE attacks (11,848 infusions) or for prophylaxis (3142 infusions), comprising the safety population. Median dosages per infusion were 10.8 IU/kg (attack treatment) and 16.6 IU/kg (prophylaxis). Approximately 95% of infusions were administered outside of a health care setting. No adverse events (AEs) were reported in retrospective data. Among prospective data (nxa0= 296 subjects; 9148 infusions), 252 AEs were reported in 85 (28.7%) subjects (rate of 0.03 events/infusion); 9 events were considered related to pnfC1-INH. Two thromboembolic events were reported in subjects with thrombotic risk factors. No patient was noted to have undergone viral testing for suspected blood-borne infection during registry participation.nnnCONCLUSIONSnThe findings from this large, international patient registry documented widespread implementation of pnfC1-INH self-administration outside of a health care setting consistent with current HAE guidelines. These real-world data revealed pnfC1-INH usage for a variety of reasons in patientsxa0with HAE and showed a high level of safety regardlessxa0ofxa0administration setting or reason for use.

Safety of C1-Esterase Inhibitor in Acute and Prophylactic Therapy of Hereditary Angioedema: Findings from the Ongoing International Berinert Patient Registry

BACKGROUNDnThe plasma-derived, pasteurized C1-inhibitor (C1-INH) concentrate, Berinert has a 4-decade history of use in hereditary angioedema (HAE), with a substantial literature base that demonstrates safety and efficacy. Thromboembolic events have rarely been reported with C1-INH products, typically with off-label use or at supratherapeutic doses.nnnOBJECTIVESnActive surveillance of safety and clinical usage patterns of pasteurized C1-inhibitor concentrate and the more recent pasteurized, nanofiltered C1-INH, with a particular interest in thromboembolic events.nnnMETHODSnA registry was initiated in April 2010 at 27 US and 4 EU sites to obtain both prospective and retrospective safety and usage data on subjects who were administered C1-INH (Berinert).nnnRESULTSnAs of May 10, 2013, data were available for 135 subjects and 3196 infusions. By subject, 67.4% were using C1-INH as on-demand therapy and 23.0% as both on-demand therapy and prophylactic administration. Approximately half of the infusions (49.5%) were administered for prophylaxis and >90% were given by the patient or a caregiver in the home setting. A total of 299 adverse events were reported, for an overall rate of 0.09 events per infusion with only 6 considered related to C1-INH. Two thromboembolic events were reported, both in patients with prothrombotic risk factors.nnnCONCLUSIONnThis large pool of real-world clinical usage data in HAE further supports the extensive safety profile of 2 Berinert formulations when used on demand and/or for prophylaxis in both home and health care settings. No evidence was found to suggest that Berinert is an independent, causative risk factor for thromboembolic events.

Pharmacokinetic Modeling and Simulation of Biweekly Subcutaneous Immunoglobulin Dosing in Primary Immunodeficiency

Abstract Replacement therapy with immunoglobulin G (IgG) given as intravenous or subcutaneous (SC) infusions is the standard treatment for patients with primary immunodeficiency. Due to the life-long need for replacement, increased flexibility in the administration and dosage regimens would improve patients quality of life. A population pharmacokinetic model that can predict plasma IgG concentrations for various routes, dosage regimens, and patient groups is a valuable tool to improve patient therapy. Such a model was developed based on IgG concentrations from 151 unique adult and pediatric patients who participated in 4 clinical trials of intravenous and SC IgG replacement therapy. Simulations predicted that the same total IgG dose, delivered SC, either in 1 biweekly dose (once every 2 weeks), or in 2 weekly doses, results in IgG peak and trough concentrations that remain within ± 10% of each other throughout the 14-day period. The developed population pharmacokinetic model predicted that biweekly SC Hizentra dosing offers a viable alternative to weekly SC therapy, allowing more flexible and optimized dosage regimens for patients with primary immunodeficiency.

The Effect of Alpha-1 Proteinase Inhibitor on Biomarkers of Elastin Degradation in Alpha-1 Antitrypsin Deficiency: An Analysis of the RAPID/RAPID Extension Trials

The RAPID (NCT00261833; N=180) and RAPID Extension (NCT00670007; N=140) trials demonstrated significantly reduced lung density decline in patients with alpha-1 antitrypsin deficiency (AATD) receiving alpha-1 proteinase inhibitor (A1PI) versus placebo. Desmosine and isodesmosine (DES/IDES) are unique crosslinkers of mature elastin fibers and are utilized as measures of elastin degradation. The aim of this post-hoc study was to determine the effect of A1PI therapy on DES/IDES levels in patients from RAPID/RAPID Extension. Plasma levels of DES/IDES were measured using high-performance liquid chromatography and tandem mass spectrometry. Correlation between changes in DES/IDES levels and computed tomography (CT) lung density decline was assessed. Analysis showed that DES/IDES levels were significantly reduced versus baseline in patients receiving A1PI at all time points, from month 3 through month 48. A significant increase from baseline in DES/IDES was observed with placebo at month 24 (n=54; 0.016; p=0.018). DES/IDES change from baseline was significantly different with A1PI versus placebo at months 3 (-0.021; 95% confidence interval [CI] -0.037, 0.004; p=0.026), 12 (-0.040; 95% CI -0.055, 0.025; p<0.001), and 24 (-0.052; 95% CI -0.070, 0.034; p<0.001). Placebo patients started A1PI therapy at month 24 and showed significant reductions in plasma DES/IDES at months 36 (p<0.001) and 48 (p<0.001). Reduced elastin degradation was associated with slower lung density decline (p=0.005), correlating a chemical index of therapy with an anatomical index by CT. In conclusion, A1PI therapy reduced elastin degradation, including pulmonary elastin, in patients with AATD. These data support using DES/IDES levels as biomarkers to monitor emphysema progression and treatment response.

Efficacy and Safety of an Intravenous C1-Inhibitor Concentrate for Long-Term Prophylaxis in Hereditary angioedema

Background The plasma-derived, pasteurized, nanofiltered C1-inhibitor concentrate (pnfC1-INH) is approved in the United States as an intravenous (IV) on-demand treatment for hereditary angioedema (HAE) attacks, and, in Europe, as on demand and short-term prophylaxis. Objective This analysis evaluated Berinert Patient Registry data regarding IV pnfC1-INH used as long-term prophylaxis (LTP). Methods The international registry (2010–2014) collected prospective and retrospective usage, dosing, and safety data on individuals who used pnfC1-INH for any reason. Results The registry included data on 47 subjects (80.9% female subjects; mean age, 44.8 years), which reflected 4082 infusions categorized as LTP and a total of 430.2 months of LTP administration. The median absolute dose of pnfC1-INH given for LTP was 1000 IU (range, 500–3000 IU), with a median time interval between infusion and a subsequent pnfC1-INH–treated attack of 72.0 hours (range, 0.0–166.4 hours). Fifteen subjects (31.9%) had no pnfC1-INH–treated HAE attacks within 7 days after pnfC1-INH infusion for LTP; 32 subjects (68.1%) experienced 246 attacks, with rates of 0.06 attacks per infusion and 0.57 attacks per month. A total of 81 adverse events were reported in 16 subjects (34.0%) (0.02 events per infusion; 0.19 events per month); only 3 adverse events were considered related to pnfC1-INH (noncardiac chest pain, postinfusion headache, deep vein thrombosis in a subject with an IV port). Conclusion In this international registry, IV pnf-C1-INH given as LTP for HAE was safe and efficacious, with a low rate of attacks that required pnfC1-INH treatment, particularly within the first several days after LTP administration.

Enhancing Patient Flexibility of Subcutaneous Immunoglobulin G Dosing: Pharmacokinetic Outcomes of Various Maintenance and Loading Regimens in the Treatment of Primary Immunodeficiency

IntroductionStandard treatment for patients with primary immunodeficiency (PID) is monthly intravenous immunoglobulin (IVIG), or weekly/biweekly subcutaneous immunoglobulin (SCIG) infusion. We used population pharmacokinetic modeling to predict immunoglobulin G (IgG) exposure following a broad range of SCIG dosing regimens for initiation and maintenance therapy in patients with PID.MethodsSimulations of SCIG dosing were performed to predict IgG concentration–time profiles and exposure metrics [steady-state area under the IgG concentration–time curve (AUC), IgG peak concentration (Cmax), and IgG trough concentration (Cmin) ratios] for various infusion regimens.ResultsThe equivalent of a weekly SCIG maintenance dose administered one, two, three, five, or seven times per week, or biweekly produced overlapping steady-state concentration–time profiles and similar AUC, Cmax, and Cmin values [95% confidence interval (CI) for ratios was 0.98–1.03, 0.95–1.09, and 0.92–1.08, respectively]. Administration every 3 or 4xa0weeks resulted in higher peaks and lower troughs; the 95% CI of the AUC, Cmax, and Cmin ratios was 0.97–1.04, 1.07–1.26, and 0.86–0.95, respectively. IgG levelsxa0>7xa0g/L were reached within 1xa0week using a loading dose regimen in which the weekly maintenance dose was administered five times in the first week of treatment. In patients with very low endogenous IgG levels, administering 1.5 times the weekly maintenance dose five times in the first week of treatment resulted in a similar response.ConclusionsThe same total weekly SCIG dose can be administered at different intervals, from daily to biweekly, with minimal impact on serum IgG levels. Several SCIG loading regimens rapidly achieve adequate serum IgG levels in treatment-naïve patients.