Subcutaneous engineered factor VIIa marzeptacog alfa (activated) in hemophilia with inhibitors: Phase 2 trial of pharmacokinetics, pharmacodynamics, efficacy, and safety
2021; Elsevier BV; Volume: 5; Issue: 6 Linguagem: Inglês
10.1002/rth2.12576
ISSN2475-0379
AutoresJohnny Mahlangu, Howard Levy, Marina Kosinova, Heghine Khachatryan, Bartosz Korczowski, Levani Makhaldiani, Genadi Iosava, Martin Lee, Frank Del Greco,
Tópico(s)Blood Coagulation and Thrombosis Mechanisms
ResumoResearch and Practice in Thrombosis and HaemostasisVolume 5, Issue 6 e12576 ORIGINAL ARTICLEOpen Access Subcutaneous engineered factor VIIa marzeptacog alfa (activated) in hemophilia with inhibitors: Phase 2 trial of pharmacokinetics, pharmacodynamics, efficacy, and safety Johnny Mahlangu MB BCh, MMed, FCPath(HAEM), BSc(Lab Med), Johnny Mahlangu MB BCh, MMed, FCPath(HAEM), BSc(Lab Med) @johnnynmahlangu Haemophilia Comprehensive Care Center, Charlotte Maxeke Johannesburg Academic Hospital, University of the Witwatersrand and NHLS, Johannesburg, South AfricaSearch for more papers by this authorHoward Levy MD, PhD, MMM, Corresponding Author Howard Levy MD, PhD, MMM hlevy@catbio.com @catalystbio Catalyst Biosciences, South San Francisco, CA, USA Correspondence Howard Levy, Catalyst Biosciences, 611 Gateway Boulevard, Suite 710, South San Francisco, CA 94080, USA. Email: hlevy@catbio.comSearch for more papers by this authorMarina V. Kosinova MD, Marina V. Kosinova MD Hematology, Kemerovo Regional Clinical Hospital, Kemerovo, RussiaSearch for more papers by this authorHeghine Khachatryan MD, PhD, Heghine Khachatryan MD, PhD R.H. Yeolyan Hemophilia and Thrombophilia Center, Yerevan, Republic of ArmeniaSearch for more papers by this authorBartosz Korczowski MD, PhD, Bartosz Korczowski MD, PhD Institute of Medical Sciences, College of Medical Sciences of the University of Rzeszow, University of Rzeszow, Rzeszow, PolandSearch for more papers by this authorLevani Makhaldiani MD, PhD, Levani Makhaldiani MD, PhD K. Eristavi National Center of Experimental and Clinical Surgery, Tbilisi, GeorgiaSearch for more papers by this authorGenadi Iosava MD, Genadi Iosava MD Institute of Hematology and Transfusiology, Tbilisi, GeorgiaSearch for more papers by this authorMartin Lee PhD, Martin Lee PhD Fielding School of Public Health, University of California Los Angeles, Los Angeles, CA, USASearch for more papers by this authorFrank Del Greco BA, MBA, Frank Del Greco BA, MBA Catalyst Biosciences, South San Francisco, CA, USASearch for more papers by this author Johnny Mahlangu MB BCh, MMed, FCPath(HAEM), BSc(Lab Med), Johnny Mahlangu MB BCh, MMed, FCPath(HAEM), BSc(Lab Med) @johnnynmahlangu Haemophilia Comprehensive Care Center, Charlotte Maxeke Johannesburg Academic Hospital, University of the Witwatersrand and NHLS, Johannesburg, South AfricaSearch for more papers by this authorHoward Levy MD, PhD, MMM, Corresponding Author Howard Levy MD, PhD, MMM hlevy@catbio.com @catalystbio Catalyst Biosciences, South San Francisco, CA, USA Correspondence Howard Levy, Catalyst Biosciences, 611 Gateway Boulevard, Suite 710, South San Francisco, CA 94080, USA. Email: hlevy@catbio.comSearch for more papers by this authorMarina V. Kosinova MD, Marina V. Kosinova MD Hematology, Kemerovo Regional Clinical Hospital, Kemerovo, RussiaSearch for more papers by this authorHeghine Khachatryan MD, PhD, Heghine Khachatryan MD, PhD R.H. Yeolyan Hemophilia and Thrombophilia Center, Yerevan, Republic of ArmeniaSearch for more papers by this authorBartosz Korczowski MD, PhD, Bartosz Korczowski MD, PhD Institute of Medical Sciences, College of Medical Sciences of the University of Rzeszow, University of Rzeszow, Rzeszow, PolandSearch for more papers by this authorLevani Makhaldiani MD, PhD, Levani Makhaldiani MD, PhD K. Eristavi National Center of Experimental and Clinical Surgery, Tbilisi, GeorgiaSearch for more papers by this authorGenadi Iosava MD, Genadi Iosava MD Institute of Hematology and Transfusiology, Tbilisi, GeorgiaSearch for more papers by this authorMartin Lee PhD, Martin Lee PhD Fielding School of Public Health, University of California Los Angeles, Los Angeles, CA, USASearch for more papers by this authorFrank Del Greco BA, MBA, Frank Del Greco BA, MBA Catalyst Biosciences, South San Francisco, CA, USASearch for more papers by this author First published: 17 August 2021 https://doi.org/10.1002/rth2.12576 Handling Editor: Pantep Angchaisuksiri. AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Abstract Background Marzeptacog alfa (activated) (MarzAA), a novel recombinant activated human factor VII (FVIIa) variant, was developed to provide increased procoagulant activity, subcutaneous (SC) administration, and longer duration of action in people with hemophilia. Objectives To investigate if daily SC administration of MarzAA in subjects with inhibitors can provide effective prophylaxis. Methods This multicenter, open-label phase 2 trial (NCT03407651) enrolled men with severe congenital hemophilia with an inhibitor. All subjects had a baseline annualized bleeding rate (ABR) of ≥12 events/year. Subjects received a single 18 μg/kg intravenous dose of MarzAA to measure 24-hour pharmacokinetics (PK) and pharmacodynamics (PD), single 30 μg/kg SC dose to measure 48-hour PK/PD, then daily SC 30 μg/kg MarzAA for 50 days. If spontaneous bleeding occurred, the dose was sequentially escalated to 60, 90, or 120 μg/kg, with 50 days at the final effective dose without spontaneous bleeding to proceed to a 30-day follow-up. The primary end point was reduction in ABR. Secondary end points were safety, tolerability, and antidrug antibody (ADA) formation. Results In the 11 subjects, the mean ABR significantly reduced from 19.8 to 1.6, and the mean proportion of days with bleeding significantly reduced from 12.3% to 0.8%. Of a total of 517 SC doses, six injection site reactions in two subjects were reported. No ADAs were detected. One fatal unrelated serious adverse event occurred: intracerebral hemorrhage due to untreated hypertension. Conclusions The data demonstrated that MarzAA was highly efficacious for prophylactic treatment in patients with inhibitors by significantly decreasing bleed frequency and duration of bleeding episodes. Essentials Marzeptacog alfa (activated; MarzAA) is a novel variant of activated human factor VII. MarzAA efficacy, safety, pharmacokinetics, and pharmacodynamics were evaluated in people with hemophilia with an inhibitor. MarzAA greatly reduced annualized bleeding rates and average proportion of days with bleeding. This data supports additional clinical trials for people with hemophilia with inhibitors. 1 INTRODUCTION Hemophilia A and B are X-linked, recessive, hereditary bleeding disorders caused by a deficiency of coagulation factor VIII (FVIII) or factor IX (FIX), respectively.1 Treatment of hemophilia A or B typically involves factor replacement therapy by intravenous (IV) injection of FVIII or FIX, respectively, to treat episodic bleeding or provide prophylaxis against bleeding episodes.1-3 Neutralizing antibodies (inhibitors) to the injected FVIII or FIX can be a complication of factor replacement therapy.4-7 Inhibitors can occur at high or low titers (quantitated in Bethesda Units), can neutralize the activity of the replacement therapy, and thus render treatment of bleeding episodes unsuccessful, resulting in potentially catastrophic clinical consequences for the patient, including an increased morbidity and mortality risk.1, 4 Prophylaxis treatment options have considerably improved for people with hemophilia A with inhibitors with the use of subcutaneous (SC) emicizumab (Hemlibra, Genentech, South San Francisco, CA, USA), a bispecific antibody that is an activated factor VIII mimetic.8 Unfortunately, not all people with hemophilia are appropriate candidates for emicizumab prophylaxis. People who develop anti-drug antibodies (ADAs) to emicizumab, those who have inadequate bleeding prevention, those with adverse effects precluding use, or those who have hemophilia B with inhibitors, require treatment with other agents, namely wild-type recombinant FVIIa (wt-rFVIIa) or activated prothrombin complex concentrates (aPCCs). 9-14 Due to the short half-life, prophylaxis with wt-rFVIIa or aPCCs require frequent IV dosing.9, 12, 13 Intravenous dosing often requires a medical professional or family member to perform the venipuncture, making home IV prophylaxis cumbersome.3, 15 Treatment of people who have inhibitors with wt-rFVIIa or aPCCs have limitations with regard to efficacy, safety, and convenience.16-18 Subcutaneous administration presents a major advantage over IV administration because it reduces the treatment burden, improves quality of life (QoL), and reduces health care costs.19, 20 Marzeptacog alfa (activated) (MarzAA), a novel rFVIIa variant, was developed using a structure-based rational protein design approach intended to enhance the biological properties of wt-rFVIIa via four amino acid substitutions. Two substitutions in the heavy-chain protease domain (Q286R and M298Q) increase catalytic activity for factor X activation in both a tissue factor–dependent and tissue factor–independent manner.21 The two other substitutions are in the light chain (T128N and P129A) to yield an additional N-linked glycosylation site to provide an extended duration of effect.21-24 These qualities of increased potency and resistance to protease destruction allow low-volume SC injection of MarzAA for bleeding prophylaxis (Figure 1). FIGURE 1Open in figure viewerPowerPoint Marzeptacog alfa (activated) has four amino acid substitutions: Q286R, M298Q, T128N, and P129A. FX, factor X Herein, we describe the phase 2 trial in people with hemophilia with inhibitors receiving MarzAA prophylaxis. 2 MATERIALS AND METHODS This open-label, multicenter, dose-escalation trial, was designed to investigate the pharmacokinetics (PK), bioavailability, pharmacodynamics (PD), efficacy, and safety of a daily SC injection of MarzAA for bleeding prophylaxis in adult subjects with hemophilia A or B with an inhibitor. The trial was registered at ClinicalTrials.gov (Registration Number: NCT03407651). This trial was conducted in accordance with the US Code of Federal Regulations, International Conference on Harmonisation Guidelines on Good Clinical Practices, and national and local laws and regulations. The trial protocol and all amendments were reviewed and approved by the institutional review board or independent ethics committees at each participating trial site. All subjects gave written informed consent before participation in the trial. Emicizumab was not approved in any participating country at the time this trial was conducted. 2.1 Study population Men aged ≥18 years with a confirmed diagnosis of severe congenital hemophilia with an inhibitor and a history of frequent spontaneous bleeding episodes (historical annualized bleeding rate [ABR] ≥12, as per the subject’s bleeding and treatment records), were eligible for enrollment. Individuals with a known hypersensitivity to the trial product or related products, known positive antibody to FVII or FVIIa detected by the central laboratory, and concomitant therapy with immunomodulating drugs were excluded. A complete list of inclusion and exclusion criteria can be found in Table S1. At screening, subjects received training and a diary to enter all investigational drug administration, injection site assessments, bleeding episodes, bleeding treatment, adverse events (AE) and patient-reported outcome (PRO) scales. During Part 1b, subjects received SC injection training. 2.2 Study design The trial included the following three parts, which occurred consecutively (Figure 2): FIGURE 2Open in figure viewerPowerPoint Phase 2, multicenter, open-label trial design. IV, intravenous; MarzAA: marzeptacog alfa (activated); SC, subcutaneous Part 1a (24 hours) measured PK, PD, and safety parameters after IV administration of a single 18 μg/kg dose of MarzAA. Assessments were done before dosing and after dosing at 5 and 30 minutes and at 1, 3, 6, 9, 12, and 24 hours. Part 1b (48 h) measured PK, PD, and safety parameters after SC administration of a single 30 μg/kg dose of MarzAA. Assessments were performed before dosing and repeated at 3, 5, 7, 9, 12, 24, 30, and 48 hours after dosing. Part 2 aimed to (i) find the optimal dose of MarzAA for each subject (ie, dose that prevented spontaneous bleeding); and (ii) determine the peak and trough MarzAA concentrations, PD, and safety of daily SC administration of MarzAA for each subject for an extended duration, reflecting the intended SC prophylactic use of MarzAA in subjects with hemophilia. At day 1 of daily SC dosing, subjects began their daily self-administered dosing regimen (at approximately the same time each day), starting with a SC dose of 30 μg/kg MarzAA for 50 consecutive days. At each dose, subjects recorded the day and time of the SC injections in their diary. If a spontaneous bleeding episode occurred before the fifth daily dose, subjects continued at the current dosing level. If a spontaneous bleeding episode occurred after the fifth daily dose, the MarzAA dose was escalated to the next dose level. Three dose escalations of 60, 90, and 120 μg/kg (maximum dose) were allowed. The dosing regimen in this trial was selected on the basis of previous preclinical and clinical studies. At each dose escalation level, safety, MarzAA concentration, and PD were monitored to ensure that dose escalation to a higher dose level was appropriate. If a subject required a dose escalation, they continued treatment with that dose for an additional 50 days to complete the trial. Subjects were allowed to use their current bypass regimen for any spontaneous or traumatic bleed that occurred while on the study drug. Subjects were required to contact the clinical investigative team immediately to report the event and have a treatment dose authorized. Follow-up plans for that event were made, including whether to arrange for a blood specimen to be drawn (if feasible) before further administration of either study drug or the bypassing agent used for treatment. The decision of whether to continue daily study drug administration was determined by the clinical trial team after discussion with the sponsor. This information was also recorded in the subject’s diary. Daily SC MarzAA injections could be interrupted if there was a need for a surgical procedure, an event requiring extended hospitalization (>48 hours), a thrombotic event, clinical evidence of inhibitor formation, or laboratory results suggesting an antibody may be developing. 2.3 Investigation product MarzAA was provided as a powder for injection, at a 4.62 mg/vial dosage strength, supplied in a 5-mL vial. 2.4 Outcome measures The primary objective was to evaluate the efficacy and safety of MarzAA for bleeding prophylaxis in adult subjects with hemophilia with an inhibitor, by (i) evaluating ABR (spontaneous and total) during Part 2 when on the final MarzAA dose level versus recorded ABR; and (ii) evaluating spontaneous bleeding, which required escalation to a higher dose level. A spontaneous bleeding episode was defined as one that was precipitated by normal activities of daily living. The secondary objectives were to (i) determine the PK and PD of SC administration of MarzAA in subjects with hemophilia with inhibitors and compare IV versus SC administration of MarzAA with regards to PK, PD, and safety parameters; (ii) find the optimal dose of MarzAA for each subject, that is, the dose that prevented spontaneous bleeding, and to determine the peak and trough concentrations, PD, and safety of daily SC administration of MarzAA at the optimal dose for each subject for an extended duration; (iii) determine the occurrence of and categorize breakthrough bleeds requiring escalation to a higher dose level as follows: (a) number of bleeds that were life threatening, (b) number of bleeds that required hospitalization and/or blood transfusion, (c) number of muscle bleeds, and (d) median time (and interquartile range) to resolution of bleeds. A breakthrough bleed was defined as any spontaneous or traumatic bleed. Exploratory objectives were to (i) identify potential biomarkers and determine the effect of SC administration of MarzAA on the QoL of subjects with hemophilia with inhibitors; (ii) identify biomarker(s) such as antigen levels, activity levels, or global thrombosis assay evaluation that could be used to predict or correlate with a subject’s lack of spontaneous bleeding; (iii) identify biomarker(s) such as D-dimer, or prothrombin fragment 1+2 (F1+2), or a functional assay of the FVIIa activity that would identify or predict clinical thrombogenicity of daily SC administration of MarzAA when use of rescue medication was required, and (iv) record PRO measurements using the European QoL-5 Dimensions (EQ-5D), Visual Analogue Scale (VAS), Haemophilia A Quality of Life Questionnaire (Haem-A-QoL), and Haemophilia Activities List (HAL). 2.5 Laboratory analysis MarzAA antigen and coagulation parameters were measured at day 1 (before dosing and 7 hours after dosing), day 3 (before dosing and postdose hour 7), day 5 (before dosing and postdose hour 7), and day 7 (before dosing and postdose hour 7). Fibrinogen was tested using HemosIL Fibrinogen-C; D-Dimer with HemosIL D-Dimer HS; thrombin-antithrombin (TAT) with Siemens Enzygnost TAT kit and F1+2 with Seimens Enzygnost F1+2 kit (Siemens Healthcare Diagnostics Products GmbH, Marburg, Germany). The MarzAA activity assays were performed using STACLOT VIIa-rTF kits manufactured by Diagnostica Stago (Parsippany, NJ, USA) on the Stago ST4/Start4 coagulation analyzer, and the test procedure was adapted from the STACLOT kit instructions. If spontaneous bleeding occurred after the fifth daily dose, MarzAA antigen levels were measured within 6 hours of the spontaneous bleed (if feasible). Specimens for coagulation and immunogenicity testing were also drawn. If it was determined to escalate to the next dose level because of spontaneous bleeding, a before dose and postdose 7-hour specimen was drawn for PK, coagulation, and thrombogenicity markers on day 7 after the escalation to estimate the new trough and peak concentrations and PD. MarzAA antigen and coagulation parameters were then measured before and after dosing at days 14, 21, and 28, and before dosing on day 50 after escalation. Specimens for ELISA-based immunogenicity testing (antibody to MarzAA, neutralizing activity, cross reactivity with wt-rFVIIa) were drawn at screening, Part 1a before dose, Part 1b before dose, and during Part 2 before dose on days 1, 7, 14, 21, 28, and 42, and then every 2 weeks until the end-of-trial visit at 30 days after the last dose. Immunogenicity assessments followed Food and Drug Administration guidance25 and included assay for any occurrence of antibody formation resulting in a decreased endogenous level of FVII or FVIIa, occurrence of antibody response to MarzAA, and the number and percentage of antibody formation resulting in a decreased endogenous level of FVII or FVIIa. Coagulation assays, thrombogenicity markers, and immunogenicity marker evaluations were performed at a central laboratory. 2.6 PK and PD analysis Standard PK parameters included terminal phase elimination half-life (t1/2), total plasma clearance, volume of distribution at steady state, area under the FVIIa activity time curve (AUC) from time zero to a definite time t and AUC from time zero to infinity, mean residence time (MRT), and bioavailability of the SC administration. The PK sampling schedule was specific to each part and dose administration. Pharmacokinetic analysis was performed using a noncompartmental analysis in professional PK software Phoenix WinNonLin version 6.4 or higher (Certara, Princeton, NJ, USA). A semiparametric model described by Lee et al26, 27 was used to calculate the t1/2. A noncompartmental model using the trapezoidal rule was used to compute the various AUCs and the parameters derived from them. Descriptive statistics were reported for each parameter including PK. Tables, listings, and figures were produced using SAS statistical package version 9.3 or higher (SAS Institute, Cary, NC, USA). Pharmacodynamic assessments including coagulation assays (activated partial thromboplastin time [aPTT], prothrombin time [PT], thrombin generation time, and fibrinogen); and thrombogenicity biomarkers (D-dimer, F1+2, and TAT complexes), were derived by noncompartmental analysis using intravascular or extravascular trapezoidal log-linear rule using Phoenix WinNonLin or SAS software packages. 2.7 Statistical analysis The null hypothesis (H0) was that the ABR (for MarzAA) equaled 12 versus the alternative hypothesis (H1) ABR (for MarzAA) <12. With a total of 12 subjects, if the true ABR for MarzAA is ≤6, with a one-tailed 2.5% significance level, there was near 100% power to demonstrate this using a one-sample Poisson test of the H0. Even if only six subjects were available for the analysis, the power would be in excess of 99%. Thus, a sample of 12 subjects was chosen and expected to provide sufficient power for the primary end point analysis in this trial. If a subject did not complete the trial as defined in the protocol, that is, before receipt of the study drug for 50 days at the same dose level (maximum, 120 μg/kg), a replacement subject could be enrolled. Missing data were not imputed in this trial. All analyses were based on available data. Baseline is defined as the last assessment before the first administration of study drug in Part 1a. This baseline was used for both Part 1a and Part 1b and was used in all efficacy and safety analyses. The analysis of the primary end point (ABR) of the final dose used to treat a subject was based on the evaluation of the ABR of MarzAA compared to a rate seen with prior 6-month episodic therapy. The latter was assumed to be 12 (or one bleed per month) as the null hypothesis. The comparison of the actual ABR for MarzAA, either pooled across all doses used or evaluated at the highest dose for an individual, was compared to this null hypothesized value using the one-sample test for a Poisson rate (using an exact calculation of the P value based on the program StatXact 11, Cytel, Inc., 2015). Because this was a one-tailed test (the alternative hypothesis: ABR for MarzAA will be 90% reduction in all bleeding, and seven of nine subjects had no bleeding (spontaneous or traumatic) at the final dose level (Figure 4). The mean ABR significantly reduced from 19.8 to 1.6 (95% confidence interval [CI], 15.2-21.1; P = .009), while the mean proportion of days with bleeding significantly declined from 12.3% to 0.8% (95% CI, 7.5%-15.6%; P = .009). The median pretreatment bleeding interval was 19.5 days (range, 13.9-25.0 days) and was prolonged to a median of 50 days (range, 5-50 days) while receiving MarzAA. No subjects required a blood transfusion. None of the enrolled subjects had been on a prophylactic treatment. In Part 2, the injection volume ranged from 0.6 to 1.3 mL for the 30 μg/kg SC dose, and for the 2 subjects who required 60 μg/kg the volumes were 1.7 and 1.75 mL, respectively; all doses were given as a single injection. FIGURE 4Open in figure viewerPowerPoint Marzeptacog alfa (activated) demonstrated statistically significant reduction in all bleeding. (A) Overall; (B) ABR; (C) PDB. ABR, annualized bleeding rate; PDB, proportion of days with bleeding 3.3 PK and PD PK parameters of SC versus IV MarzAA are summarized in Table 2. Of note, levels of MarzAA at the time taken to reach the maximum or peak drug concentration (tmax) for SC administration (SC tmax=7 hours) were comparable to the declining levels of MarzAA at 12 hours after IV infusion (SC = 18.1 ng/mL, IV = 16.0 ng/mL). The mean SC bioavailability was 27% (95% CI, 16%-37%). The t1/2β was prolonged when MarzAA was administered via SC administration compared with IV (SC t1/2β=17.0 hours, IV t1/2β=3.65 hours); the MRT for MarzAA was also prolonged when administered SC compared with IV dosing (SC MRT=25.8 hours, IV MRT=4.05 hours). These data document a more prolonged effect when MarzAA is administered SC. TABLE 2. Summary of pharmacokinetic antigen parameters for IV and SC administration of marzeptacog alfa (activated) PK parameter IV SC Mean SEM CI Mean SEM CI t1/2α (h) 1.47 0.29 1.08-2.12 NP NP NP t1/2β(h) 3.65 0.23 3.23-4.13 17.0 3.1 10.9-23.0 MRT (h) 4.05 0.39 3.30-4.80 25.8 4.5 17.0-34.6 Cmax (ng/mL) 375 54 257-467 24.0 4.5 15.7-32.8 tmax (h) 0.5 0.4 0-0.9 7.0 0.8 5.4-8.6 AUC0-t (h • ng/mL) 1076 97 866, 1252 473 132 188-688 AUC0-inf (h • ng/mL) 1102 101 902-1295 609 190 186-891 Bioavailability (%) NP NP NP 27 6 16-37 Trough (ng/mL) during 30 μg/kg dosing NP NP NP 6.3 1.15 3.69-8.02 Peak (ng/m
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