ALBERT

Beschreibung: Crovalimab (RO7112689) is a novel anti-human C5 antibody engineered with Sequential Monoclonal Antibody Recycling Technology (SMART Ig)(Fukuzawa et al., Sci Rep. (2017) 7(1):1080), resulting in significant half-life extension and enabling infrequent SC dosing using small volumes (1mL - 4mL) in C5 mediated diseases. We aimed at characterizing the exposure-response relationship of crovalimab used to define the minimum concentration of crovalimab achieving complete terminal inhibition. To establish pharmacokinetics (PK), pharmacodynamics (PD), safety, efficacy, and optimal dose of crovalimab, we conducted a four-part adaptive clinical trial (Figure 1): Part 1: 15 healthy subjects were enrolled. 3 received 75 mg RO7112689 IV, 3 received 125 mg RO7112689 IV, 3 received 100 mg RO7112689 SC, and 6 received placeboPart 2: 10 treatment-naïve PNH patients were enrolled in Part 2 to receive increasing IV doses of 375mg, 500mg, and 1000mg on days 1, 8 and 22, respectively, followed by weekly doses of 170mg SC starting on day 36Part 3: 19 eculizumab pre-treated PNH patients were enrolled in Part 3 to receive 1000mg IV before randomization into 3 different arms: Arm A: 680mg SC Q4W (N=7)Arm B: 340mg SC Q2W (N=6)Arm C: 170mg SC QW (N=6) SC dosing was initiated on day 8 after the IV dose in all the dosing groups. Part 4: 5 eculizumab pre-treated PNH patients and 5 treatment-naïve PNH patients are planned to be enrolled to receive IV dose of 1000mg on Day 1 followed by SC dose of 340mg on Day 2, Day 8, Day 15, Day 22 followed by SC dose of 680mg given Q4W from Day 29 Crovalimab concentrations and free C5 were measured using a validated ELISA. A population PK model was developed using all the available data to describe the crovalimab concentration-time profiles. Crovalimab PD was assessed by evaluating the extent and duration of terminal complement inhibition, quantified using a validated, functional ex vivo liposome immunoassay (LIA) (http://www.wakodiagnostics.com/r_ch50.html). Relationships between crovalimab PK and PD were analyzed using graphical analysis. The PK was best described by a two-compartment open model with first-order elimination and absorption. To describe the PK in eculizumab pre-treated patients, elimination of crovalimab was modeled as a combination of the first-order elimination used for naïve patients and a faster clearance which decreases exponentially over time. Body weight was introduced using allometry on the clearance and volume of the distribution. After SC administration, bioavailability is estimated at 100% and terminal half-life around 30 days. In all PNH patients, complete complement inhibition (defined as LIA

Beschreibung: Crovalimab (RO7112689) is a novel anti-human C5 antibody engineered with Sequential Monoclonal Antibody Recycling Technology (SMART Ig)(Fukuzawa et al., Sci Rep. (2017) 7(1):1080), resulting in significant half-life extension and enabling infrequent SC dosing using small volumes (1mL - 4mL) in C5 mediated diseases. To establish pharmacokinetics (PK), pharmacodynamics (PD), safety, efficacy, and optimal dose of crovalimab, we conducted a four-part adaptive clinical trial (Figure 1) in healthy volunteers (Part 1), treatment naïve PNH patients (Part 2, Part 4) and in eculizumab pre-treated patients (Part 3, Part 4). The conventional PK metrics to determine optimal target inhibition is drug concentration, however this has some limitations when considering an abundant fluctuating soluble target such as C5. Therefore, we proposed to characterize C5 inhibition by quantifying the level of crovalimab free paratopes (i.e. the concentration of free crovalimab antigen-binding sites not bound to C5) and to illustrate how it can be used to estimate the available binding capacity reserve of crovalimab. Total crovalimab concentration, free C5 and total C5 protein levels (measuring free C5, C5 bound to one crovalimab Fab arm, or two C5s bound to the two crovalimab Fab arms) were measured using validated assays. In assuming steady state conditions at every measurement time for the binding of crovalimab with C5 (due to the rapid binding of C5 with crovalimab), a mathematical model based on law mass action principle was used to describe the equilibrium between free C5, free crovalimab and crovalimab bound to one or two C5 molecules. Available crovalimab free paratope was estimated from the model in using total C5 and total crovalimab concentrations collected in the COMPOSER trial. Paratope level was expressed in C5-binding ability concentration equivalent (i.e. how much additional C5 could be bound). Relationships between total concentration time course, free C5 and available free epitopes were evaluated using graphical analysis. To complement these analyses and using the mathematical model, a sensitivity analysis was performed to identify key antibody properties driving the level of available free crovalimab paratopes. In COMPOSER Part 2, the longitudinal time course of crovalimab free paratope concentration (Figure 2) shows that 170mg SC weekly provided a median reserve of free paratopes that allows binding around 120µg/mL of additional C5 corresponding approximatively to two times the baseline C5 levels observed in Part 2 (i.e. 129µg/mL). Therefore, if the level of C5 in the circulation doubled from baseline, e.g. during infection, there would be a sufficient binding capacity to block the activity of these new C5 molecules at least for 75% of the patients (Figure 2). In COMPOSER Part 3, the observed median reserve of free paratopes was lower during the first 60 days after crovalimab initiation (Figure 2). This is driven by the remaining presence of eculizumab and the binding of both crovalimab and eculizumab to C5. Eculizumab and crovalimab bind different C5 epitopes and switching patients from eculizumab to crovalimab induces formation of drug target drug complexes (DTDC). DTDCs clearance was estimated to be ten times faster than crovalimab-C5 complexes clearance resulting in a drop of free paratope level during the first 60 days. Washout from eculizumab is not feasible in PNH patients. To increase the availability of crovalimab free paratopes after switching, crovalimab dose and regimen was optimized and is currently tested in COMPOSER Part 4 (Figure 1).The sensitivity analysis demonstrated that the main driver of free paratopes availability were the recycling efficiency of free crovalimab after endocytosis and the clearance of crovalimab while the affinity of crovalimab to C5 had little effect. Free paratope concentration enables characterization of available binding reserve of crovalimab. The capacity to adequately control C5 increase due to the SMART-Ig engineering is expected to result in a better control of breakthrough hemolysis in PNH patients compared with an antibody without this technology. For soluble targets, this approach provides more stringent criteria than antibody concentration as it defines the capacity of the drug to bind free target at any time. Therefore, this metric should prove helpful in guiding dose selection for monoclonal antibodies binding a soluble target. Disclosures Sostelly: F. Hoffmann-La Roche: Employment. Soubret:F. Hoffmann-La Roche: Employment, Equity Ownership. Bucher:F. Hoffmann-La Roche: Employment. Buatois:F. Hoffmann-La Roche: Employment. Charoin:F. Hoffmann-La Roche: Employment. Jordan:Roche Diagnostics GmbH: Employment; F. Hoffmann-La Roche: Equity Ownership. Klughammer:F. Hoffmann-La Roche Ag: Employment, Equity Ownership. Dieckmann:F. Hoffmann-La Roche: Employment. Fukuzawa:Chugai Pharmaceutical Co., Ltd.: Employment. Gotanda:Chugai Pharmaceutical Co., Ltd.: Employment. Shinomiya:Chugai Pharmaceutical Co., Ltd.: Employment, Patents & Royalties: (WO2018143266) A PHARMACEUTICAL COMPOSITION FOR USE IN THE TREATMENT OR PREVENTION OF A C5-RELATED DISEASE AND A METHOD FOR TREATING OR PREVENTING A C5-RELATED DISEASE. Yoon:Kyowa Hako Kirin: Research Funding; Amgen: Consultancy, Honoraria; Genentech, Inc.: Research Funding; Novartis: Consultancy, Honoraria; Janssen: Consultancy; Yuhan Pharma: Research Funding; MSD: Consultancy. Panse:Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Blueprint Medicines: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; MSD: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees; Chugai: Membership on an entity's Board of Directors or advisory committees. Nishimura:Chugai: Consultancy, Membership on an entity's Board of Directors or advisory committees; Alexion: Honoraria, Research Funding. Röth:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Alexion: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bioverativ: Consultancy, Honoraria; Apellis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Nagy:Roche: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees. Peffault de Latour:Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Amgen: Research Funding; Alexion: Consultancy, Honoraria, Research Funding.

Beschreibung: Background Inhibition of complement C5 is the current standard of care for paroxysmal nocturnal hemoglobinuria (PNH). C5 inhibition reduces transfusion requirements and improves anemia and quality of life by ameliorating intravascular hemolysis. However, current therapies require lifelong intravenous infusions at regular intervals, and breakthrough hemolysis may occur due to inadequate C5 inhibition. Crovalimab is a novel anti-human C5 antibody characterized by pH-dependent target binding, enhanced recycling by the neonatal Fc receptor, and high bioavailability, allowing for small-volume (2 × 2 mL) subcutaneous administration every 4 weeks. Part 3 of the Phase I/II COMPOSER study (Sostelly et al. Blood. 2019; Röth et al. Blood. 2020) demonstrated that in patients switched from eculizumab, enhanced crovalimab clearance occurred during the switching phase due to the formation of drug-target-drug complexes, with a risk of temporary loss of complete complement inhibition. Part 4 of COMPOSER tested a dosing regimen optimized to maintain complete complement inhibition in C5 inhibitor-naive patients and those switched from eculizumab to crovalimab. Objectives To evaluate the safety, pharmacokinetic (PK), and pharmacodynamic (PD) effects of an optimized crovalimab regimen. Study Design and Methods Crovalimab is being evaluated in the ongoing Phase I/II COMPOSER study (NCT03157635). Parts 1, 2, and 3 of COMPOSER assessed the PK and safety of crovalimab in healthy volunteers, C5 inhibitor-naive patients, and patients switched from eculizumab, respectively. In Part 4, patients received an intravenous loading series of crovalimab 1000 mg on day 1 followed by 340 mg subcutaneous on days 2, 8, 15, and 22. Maintenance dosing of 680 mg subcutaneous every 4 weeks was started on day 29 (week 5). Plasma concentrations of crovalimab, lactate dehydrogenase (LDH), and free and total C5, as well as complement activity were determined at follow-up visits. The primary endpoints were PK and PD effects of the dosing strategy. Patients were followed up for safety and efficacy, including transfusion avoidance, breakthrough hemolysis events, and hemoglobin stabilization. Results Data for 15 patients (8 naive, 7 switched) treated with the optimized crovalimab dosing strategy in Part 4 are presented here. The data cutoff was January 29, 2020. The PK profiles showed that crovalimab exposure was maintained above the target concentration (100 µg/mL) for complete complement inhibition in all patients, naive and switched. Complete complement inhibition, as measured by liposome immunoassay 〈 10 U/mL, was achieved immediately following the initial dose and maintained throughout the study treatment period. Consistent with these results, crovalimab-free C5 levels declined rapidly following the initial dose and remained low throughout the follow-up period. As expected based on the target-disposal properties of crovalimab, limited total C5 accumulation was observed in naive patients and a decline was seen in switched patients. Median LDH rapidly declined to ≤ 1.5-fold the upper limit of normal (ULN) in naive patients, remained ≤ 1.5-fold the ULN in switched patients, and remained below this level throughout the observation period in both patient groups (Figure). Crovalimab was well tolerated, and no serious treatment-related adverse events were observed. Conclusions These data showed that the optimized dosing strategy for crovalimab in PNH did not raise any safety concerns and suggest that the strategy results in sustained complete complement inhibition in patients naive to complement inhibitor therapy and those switched from eculizumab. These data support the continued development of crovalimab. Disclosures Peffault De Latour: Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Apellis: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Sica:F. Hoffmann-La Roche Ltd: Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland., Research Funding. Ramos:F. Hoffmann-La Roche Ltd: Other: All authors received editorial support for this abstract, provided by Scott Battle, PhD, of Health Interactions and funded by F. Hoffmann-La Roche.; Genentech, Inc: Current Employment, Other: Fellowship support. Hernández-Sánchez:F. Hoffmann-La Roche Ltd: Current Employment, Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland.. Kim:Alexion Pharmaceuticals Inc.: Honoraria, Research Funding. Kiialainen:F. Hoffmann-La Roche Ltd: Current Employment, Other: All authors received editorial support for this abstract, provided by Scott Battle, PhD, of Health Interactions and funded by F. Hoffmann-La Roche.. Yoon:F. Hoffmann-La Roche: Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland., Research Funding; Janssen: Consultancy; Novartis: Consultancy, Honoraria; YuhanPharma: Research Funding; Amgen: Consultancy, Honoraria; Kyowahako Kirin: Research Funding. Sreckovic:F. Hoffmann-La Roche Ltd: Current Employment, Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland.. Soubret:F. Hoffmann-La Roche Ltd: Current Employment, Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland.. Ninomiya:F. Hoffmann-La Roche Ltd: Other: All authors received editorial support for this abstract, provided by Scott Battle, PhD, of Health Interactions and funded by F. Hoffmann-La Roche., Research Funding; Alexion: Honoraria; Chugai: Membership on an entity's Board of Directors or advisory committees. Sostelly:F. Hoffmann-La Roche Ltd: Current Employment, Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland.. Panse:F. Hoffmann-La Roche Ltd: Consultancy, Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Grunenthal: Consultancy, Membership on an entity's Board of Directors or advisory committees; Apellis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees; Alexion: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Blueprint Medicines: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Chugai: Speakers Bureau; Pfizer: Speakers Bureau; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees. Buatois:F. Hoffmann-La Roche Ltd: Current Employment, Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland.. Schrezenmeier:Alexion Pharmaceuticals Inc.: Honoraria, Research Funding. Paz-Priel:Genentech, Inc: Current Employment; F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company, Other: All authors received editorial support for this abstract, provided by Scott Battle, PhD, of Health Interactions and funded by F. Hoffmann-La Roche.. Nishimura:F. Hoffmann-La Roche Ltd: Consultancy, Other: All authors received editorial support for this abstract, provided by Scott Battle, PhD, of Health Interactions and funded by F. Hoffmann-La Roche.; Alexion: Honoraria, Research Funding; Chugai: Consultancy. Röth:Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; Biocryst: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Apellis: Consultancy, Honoraria. OffLabel Disclosure: Yes. Crovalimab is an anti-C5 monoclonal antibody being evaluated as a therapy for paroxysmal nocturnal hemoglobinuria

Beschreibung: Introduction Paroxysmal nocturnal hemoglobinuria (PNH) is a hematopoietic stem cell disorder characterized by intravascular hemolytic anemia and hemoglobinuria. Lactate dehydrogenase (LDH) is a cytoplasmic enzyme that is abundant in red blood cells. Serum LDH level is used as a biomarker for intravascular hemolysis to monitor response to PNH treatment. Crovalimab is a novel antihuman C5 antibody engineered with Sequential Monoclonal Antibody Recycling Technology (SMART-Ig; Fukuzawa et al, Sci Rep. 2017) that is being evaluated as a therapy for PNH in the 4-part, dose-optimization Phase I/II COMPOSER trial (NCT03157635; Röth et al, Blood. 2020), which includes healthy volunteers and patients with PNH who received or did not receive prior C5 inhibition therapy with eculizumab. In this study, COMPOSER data were used to obtain a dose-concentration effect relationship between crovalimab and LDH through development of a pharmacokinetic (PK)-LDH model. Objectives To describe the LDH time course in patients with PNH and to confirm the adequate LDH-lowering effect of the optimized dose and regimen of crovalimab. Study Design and Methods At the clinical data cutoff date of September 4, 2019, data from 15 treatment-naive patients with PNH were used to develop the population PK-LDH model. Observations collected in patients switching treatment from eculizumab to crovalimab (n = 26) were not used to build the PK-LDH model but were used as an external validation tool to evaluate the predictive performance of the model at steady state. A sequential approach was followed (Zhang et al, J Pharmacokinet Pharmacodynam. 2003;30:387-404; Zhang et al, J Pharmacokinet Pharmacodynam. 2003;30:405-416): the individual PK parameters of crovalimab were derived from a population PK model by an empirical Bayesian analysis, and subsequently, the PK-LDH response relationship was modeled with an indirect response model in which LDH synthesis was inhibited by crovalimab concentrations. The predictive performance of the population PK-LDH model was evaluated using a prediction-corrected visual predictive check (pcVPC). The population PK-LDH analysis and all simulations were performed using NONMEM 7.4.0 software. All data sets were analyzed using SAS 9.4. Results For a typical patient, the maximal LDH-lowering effect was estimated to be 80% and the concentration of crovalimab leading to 90% of maximal reduction of LDH synthesis was estimated to be 34.9 μg/mL (90% CI, 15.9-67.5 μg/mL). The half-life for LDH was estimated to be 3 days and steady state for the LDH-lowering effect was predicted to be reached 15 days after first drug intake. The pcVPC in treatment-naive patients showed that the PK-LDH model had good predictive qualities (Figure 1). An external pcVPC was performed in patients who had switched from eculizumab to crovalimab with good predictive qualities, supporting the use of the model for simulation. Using the optimized crovalimab dose and regimen from Part 4, model-based simulations of the LDH time course showed that 〉 95% of patients were predicted to have LDH levels of ≤ 1.5 × upper limit of normal (ULN) (Figure 2). A sensitivity analysis, to assess the impact of uncertainty around the estimated concentration of crovalimab leading to 90% of maximal reduction of LDH synthesis, found a moderate impact on the predicted LDH-lowering effect of crovalimab, with a small decrease in the percentage of patients predicted to reach an LDH level of 〈 1.5 × ULN. Conclusions Simulations show a rapid and sustained decrease in LDH levels to 〈 1.5 × ULN in over 95% of treatment-naive patients with PNH who receive the optimized dose and regimen of crovalimab. The confirmation of the LDH-lowering effect of crovalimab supports further clinical study of the optimized regimen, which is being evaluated in the Phase III studies COMMODORE 1 (NCT04432584) and COMMODORE 2 (NCT04434092). Disclosures Buatois: F. Hoffmann-La Roche Ltd: Current Employment, Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland.. Sostelly:F. Hoffmann-La Roche Ltd: Current Employment, Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland.. Soubret:F. Hoffmann-La Roche Ltd: Current Employment, Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland.. Jaminion:F. Hoffmann-La Roche Ltd: Current Employment, Other: All authors received support for third party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland.. Cosson:F. Hoffmann-La Roche Ltd: Current Employment, Other: All authors received support for third party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland.. OffLabel Disclosure: Crovalimab is an anti-C5 monoclonal antibody being evaluated as a therapy for paroxysmal nocturnal hemoglobinuria

Beschreibung: Introduction Crovalimab is a novel anti-complement component 5 (C5) monoclonal antibody engineered with the Sequential Monoclonal Antibody Recycling Technology (SMART-Ig; Fukuzawa et al, Sci Rep. 2017) to extend half-life and enable infrequent, subcutaneous (SC) self-administration in C5-mediated diseases. Crovalimab is being investigated as a therapy for paroxysmal nocturnal hemoglobinuria (PNH), a disease for which C5 inhibition is the standard of care. The Phase I/II COMPOSER trial (NCT03157635; Röth, et al. Blood. 2020) is a global, open-label, multicenter study of crovalimab consisting of 4 sequential parts. Parts 1, 2, and 3 assessed the pharmacokinetics (PK) and safety of crovalimab in healthy volunteers, C5 inhibitor-naive patients, and patients switched from eculizumab, respectively. Part 4 assessed an optimized crovalimab dose and regimen in naive and switched patients with PNH. Because eculizumab and crovalimab bind to different C5 epitopes, drug-target-drug complexes (DTDCs) consisting of eculizumab, C5, and crovalimab motifs can temporarily form in the circulation of patients who switch treatments. DTDCs can form in a range of sizes, from single crovalimab-C5-eculizumab motif to larger complexes with multiple motifs. Larger DTDCs are a concern because they take longer to clear and may be more likely to induce type III hypersensitivity reactions. Objectives Describe the impact of DTDC formation on the safety, PK, and pharmacodynamics of crovalimab in patients with PNH who switched from eculizumab to crovalimab and to describe the effect of crovalimab dose on DTDC size distribution and kinetics. Study Design and Methods Using data from COMPOSER Parts 1-3, a biochemical mathematical model was developed to investigate the kinetics of the formation and dissociation of DTDCs under the assumption that larger complexes are formed by the reversible binding of smaller complexes. The model was calibrated using concentration-time profiles of total C5, total crovalimab, and the concentration of eculizumab at the time of crovalimab initiation. DTDC size distributions were measured using size-exclusion chromatography coupled to enzyme-linked immunosorbent assay. Using model-based simulations, an optimized crovalimab dosing strategy was identified to reduce the formation of large DTDCs while maintaining serum concentration of crovalimab above the target level of ≈ 100 μg/mL. The optimized dose and regimen were a loading series of 1000 mg intravenously on day 1 and 340 mg SC on days 2, 8, 15, and 22, followed by maintenance dosing of 680 mg SC every 4 weeks starting on day 29. The loading dose series increased the total crovalimab dose received during the first month of treatment to reduce the formation of larger DTDCs, in line with the lattice theory of complex formation. This optimized dosing strategy was investigated in Part 4 patients who switched from eculizumab. Results In COMPOSER, 19 patients with PNH were enrolled in Part 3 and switched from eculizumab to crovalimab. DTDCs were observed in all patients from Part 3 (Figure; larger DTDCs are found in fractions 1-4 and smaller crovalimab-containing complexes, such as single motifs and single crovalimab molecules, are found in fractions 5 and 6). Two Part 3 patients experienced clinical manifestations compatible with type III hypersensitivity reactions that were ascribed to DTDCs. The DTDC size distribution in Part 4 patients, who received the optimized dosing strategy, evolved differently than in Part 3 patients, consistent with model predictions. In the switched patients from Part 4, large DTDC levels started to decrease on day 8 and continued to decrease, in contrast to Part 3, in which they started to decrease on day 15. On day 22, the mean percentage of the largest DTDCs was reduced by 56% in patients in Part 4 relative to patients in Part 3. Part 4 patients achieved and maintained serum crovalimab concentrations above ≈ 100 µg/mL throughout follow-up. Despite DTDCs being observed in all Part 4 patients who switched from eculizumab, no adverse events suggestive of a type III hypersensitivity reaction occurred. Conclusions The optimized crovalimab regimen resulted in lower concentrations of large DTDCs than in patients who received the Part 3 regimen and reduced the persistence of DTDCs in patients who switched treatment. This regimen is now being evaluated in the Phase III COMMODORE 1 (NCT04432584) and COMMODORE 2 (NCT04434092) studies. Figure Disclosures Nishimura: F. Hoffmann-La Roche Ltd: Consultancy, Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland.; Alexion: Honoraria, Research Funding; Chugai: Consultancy. Soubret:F. Hoffmann-La Roche Ltd: Current Employment, Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland.. Buatois:F. Hoffmann-La Roche Ltd: Current Employment, Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland.. Charoin:F. Hoffmann-La Roche Ltd: Current Employment, Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland.. Sreckovic:F. Hoffmann-La Roche Ltd: Current Employment, Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland.. Bucher:F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company, Ended employment in the past 24 months, Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland.; ANAVEON AG: Current Employment. Hernández-Sánchez:F. Hoffmann-La Roche Ltd: Current Employment, Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland.. Jordan:F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company, Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland.. Ramos:F. Hoffmann-La Roche Ltd: Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland.; Genentech, Inc: Current Employment, Other: Received fellowship support from Genentech, Inc.. Arase:Osaka University: Current Employment; Chugai: Consultancy; Alexion: Research Funding; F. Hoffmann-La Roche. Ltd.: Consultancy, Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland.. Hotta:F. Hoffmann-La Roche Ltd: Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland.. Isaka:Osaka University: Current Employment; Chugai: Research Funding, Speakers Bureau; F. Hoffmann-La Roche Ltd: Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland.. Ito:F. Hoffmann-La Roche Ltd: Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland.. Kanakura:F. Hoffmann-La Roche Ltd: Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland.; Chugai Pharmaceutical: Consultancy. Kim:Alexion Pharmaceuticals Inc.: Honoraria, Research Funding. Kinoshita:Alexion: Honoraria; F. Hoffmann-La Roche Ltd: Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland.. Morii:F. Hoffmann-La Roche Ltd: Honoraria, Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland., Research Funding; Chugai: Honoraria, Research Funding. Panse:Apellis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Blueprint Medicines: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Chugai: Speakers Bureau; Grunenthal: Consultancy, Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Speakers Bureau; Alexion: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Peffault De Latour:Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Apellis: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Research Funding. Röth:Apellis: Consultancy, Honoraria; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Research Funding; Biocryst: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria. Schrezenmeier:Alexion Pharmaceuticals Inc.: Honoraria, Research Funding. Sica:F. Hoffmann-La Roche Ltd: Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland., Research Funding. Takamori:Alexion: Research Funding; F. Hoffmann-La Roche Ltd: Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland.. Ueda:Chugai: Research Funding; Novartis: Honoraria; Alexion: Consultancy, Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland.; Sanofi: Consultancy, Honoraria. Yoon:Kyowahako Kirin: Research Funding; Novartis: Consultancy, Honoraria; Janssen: Consultancy; F. Hoffmann-La Roche: Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland., Research Funding; YuhanPharma: Research Funding; Amgen: Consultancy, Honoraria. Paz-Priel:Genentech, Inc: Current Employment; F. Hoffmann-La Roche Ltd: Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland.. Sostelly:F. Hoffmann-La Roche Ltd: Current Employment, Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland..