Sutimlimab in patients with cold agglutinin disease: results of the randomized placebo-controlled phase 3 CADENZA trial.

Sutimlimab, a first-in-class humanized immunoglobulin G4 (IgG4) monoclonal antibody that selectively inhibits the classical complement pathway at C1s, rapidly halted hemolysis in the single-arm CARDINAL study in recently transfused patients with cold agglutinin disease (CAD). CADENZA was a 26-week randomized, placebo-controlled phase 3 study to assess safety and efficacy of sutimlimab in patients with CAD without recent (within 6 months prior to enrollment) transfusion history. Forty-two patients with screening hemoglobin ≤10 g/dL, elevated bilirubin, and ≥1 CAD symptom received sutimlimab (n = 22) or placebo (n = 20) on days 0 and 7 and then biweekly. Composite primary endpoint criteria (hemoglobin increase ≥1.5 g/dL at treatment assessment timepoint [mean of weeks 23, 25, 26], avoidance of transfusion, and study-prohibited CAD therapy [weeks 5-26]) were met by 16 patients (73%) on sutimlimab, and 3 patients (15%) on placebo (odds ratio, 15.9 [95% confidence interval, 2.9, 88.0; P < .001]). Sutimlimab, but not placebo, significantly increased mean hemoglobin and FACIT-Fatigue scores at treatment assessment timepoint. Sutimlimab normalized mean bilirubin by week 1. Improvements correlated with near-complete inhibition of the classical complement pathway (2.3% mean activity at week 1) and C4 normalization. Twenty-one (96%) sutimlimab patients and 20 (100%) placebo patients experienced ≥1 treatment-emergent adverse event. Headache, hypertension, rhinitis, Raynaud phenomenon, and acrocyanosis were more frequent with sutimlimab vs placebo, with a difference of ≥3 patients between groups. Three sutimlimab patients discontinued owing to adverse events; no placebo patients discontinued. These data demonstrate that sutimlimab has potential to be an important advancement in the treatment of CAD. This trial was registered at www.clinicaltrials.gov as #NCT03347422.

Simultaneous Hydrogenation of an Insulated Diarylacetylene Dimer Incorporated as Axle Molecules in a Cyclodextrin-Based [c2]Daisy Chain Rotaxane.

The [c2]daisy chain rotaxane is an attractive interlocked molecule for the development of functional materials because of its unique mechanical properties that respond to various external stimuli, resulting in extension and contraction motions along the molecular axis. The synthesis of several 'impossible' [2]rotaxanes that do not exhibit obvious binding motifs between their axle and wheel moieties has been achieved through further chemical modification of their axle moieties within pre-prepared [2]rotaxanes. However, no 'impossible' [c2]daisy chain rotaxane has been synthesized using similar strategies until now. In this study, we investigated the hydrogenation of diarylacetylene moieties within a permethylated α-cyclodextrin (PM α-CD)-based [c2]daisy chain rotaxane using Pd/C or Pd/CaCO3 under hydrogen. A new [c2]daisy chain rotaxane featuring two diarylethane moieties was successfully synthesized through the simultaneous full hydrogenation of the insulated diarylacetylene moieties under optimized conditions. The new rotaxane is classified as an 'impossible' [c2]daisy chain rotaxane due to the lack of obvious binding motifs between diarylethane and the PM α-CD. This work demonstrates for the first time that the insulated axle moieties of [c2]daisy chain rotaxanes can undergo novel chemical modifications using a synthetic strategy employing transition-metal-catalyzed hydrogenation, which can potentially advance the development of nanoarchitectures with functional interlocked molecules.

Enhanced Orientation of Liquid Crystals Inside Micropores of Metal-Organic Frameworks Having Thermoresponsivity.

With the aim of controlling the orientation of liquid crystals (LCs) toward realizing external stimuli-responsive materials with tunable functionalities, we synthesized a composite of LCs and metal-organic frameworks (MOFs) by filling LCs into the pores of MOFs (LC@MOFs) for the first time. The included LCs interact with the MOFs through coordination bonds between the cyano groups of the LCs and the metal ions of the MOFs, enabling the orientation of the LC molecules inside the pores of the MOFs and the realization of birefringence of LC@MOFs. The three-dimensional nanometer interstice frameworks maintained the LC orientation even at temperatures much higher than the isotropic phase transition temperature of bulk LCs. Furthermore, the orientational state changed upon heating or cooling, inducing temperature-dependent birefringence. This study provides a new approach to the development of stimuli-responsive optical materials and stimuli-responsive MOFs.

Phase 2 study of ibrutinib plus venetoclax in Japanese patients with relapsed/refractory mantle cell lymphoma.

BACKGROUND: Despite high response rates to initial therapy, most patients with mantle cell lymphoma (MCL) experience relapsed or refractory (R/R) disease. Here, we report the efficacy, safety, and pharmacokinetics of the Phase 2, single-arm M20-075 study (NCT04477486) of ibrutinib and venetoclax combination therapy in Japanese patients with R/R MCL. METHODS: Patients received 560 mg ibrutinib and 400 mg venetoclax (after a 5-week ramp-up from 20 mg) once daily for up to 104 weeks. Primary endpoint was complete response (CR) rate by independent review committee (IRC). Secondary endpoints included overall response rate (ORR), duration of response (DOR), undetectable minimal residual disease (uMRD) rate, progression-free survival (PFS), overall survival (OS), safety including dose-limiting toxicity (DLT) assessment in the first six patients, and pharmacokinetic parameters. Full analysis set (FAS) comprised all treated patients. Per protocol set (PPS) excluded treated patients with non-evaluable disease at baseline by IRC. RESULTS: Thirteen patients were treated (FAS n = 13; PPS, n = 12). Median age was 71 years, patients had a median of two prior treatments. After a median follow-up of 9.6 months, IRC-assessed CR rate and ORR were both 83% (PPS). All six MRD-evaluable patients had uMRD. Median DOR, PFS, and OS were unreached. The most common Grade ≥ 3 treatment-emergent adverse event (TEAE) was neutropenia (23%); 1 patient discontinued due to squamous cell carcinoma of the lung. No DLTs, tumor lysis syndrome, or deaths related to TEAEs were observed. CONCLUSION: Ibrutinib plus venetoclax exhibited high response rates and a well-tolerated safety profile in Japanese patients with R/R MCL.

Nanostructured Polymer-Dispersed Liquid Crystals Using a Ferroelectric Smectic A Liquid Crystal.

Nanostructured polymer-dispersed liquid crystals (nano-PDLCs) are transparent and optically isotropic materials in which submicron-sized liquid crystal (LC) domains are dispersed within a polymer matrix. Nano-PDLCs can induce birefringence by applying an electric field (E-field) based on the reorientation of the LC molecules. If nano-PDLCs are utilized as light-scattering-less birefringence memory materials, it is necessary to suppress the relaxation of the LC molecule orientation after the removal of the E-field. We focused on the ferroelectric smectic A (SmA) phase to suppress the relaxation of LC molecules, owing to its layered structure and high viscosity. Although nano-PDLCs require a strong E-field to reorient their LC molecules because of the anchoring effect at the LC/polymer interface, the required field strength can be reduced using a ferroelectric smectic A (SmAF) LC with a large dielectric constant. In this study, we fabricated a nano-PDLC by shining an ultraviolet light on a mixture comprised an SmAF LC, photocurable monomers, and a photo-initiator. The electro-birefringence effect was evaluated using polarizing optical microscopy. After the removal of the E-field, an enhanced memory effect was observed in the sample using SmAF LC compared with nematic LC-based nano-PDLCs.

Fludarabine plus reduced-intensity busulfan versus fludarabine plus myeloablative busulfan in patients with non-Hodgkin lymphoma undergoing allogeneic hematopoietic cell transplantation.

Allogeneic hematopoietic cell transplantation (HCT) offers a possible cure for patients with relapsed and refractory non-Hodgkin lymphoma (NHL) through potentially beneficial graft versus lymphoma effects. However, allogeneic HCT is associated with high nonrelapse mortality (NRM). Fludarabine with reduced-intensity busulfan (Flu/Bu2) and myeloablative busulfan (Flu/Bu4) are commonly used in conditioning regimens for allogeneic HCT; however, data on their use in patients with NHL is limited. We investigated the effect of busulfan dose on outcomes by comparing Flu/Bu2 and Flu/Bu4 in patients with NHL who underwent allogeneic HCT. Our study included 415 adult patients with NHL who received Flu/Bu2 (315 patients) or Flu/Bu4 (100 patients) between January 2008 and December 2019. All patients were enrolled in the Transplant Registry Unified Management Program 2 of the Japanese Data Center for Hematopoietic Cell Transplantation. The primary endpoint was the 5-year overall survival (OS). To minimize potential confounding factors that may influence outcomes, we performed propensity score matching. The 5-year OS was 50.6% (95% confidence interval (CI), 39.4%-60.8%) and 32.2% (95% CI, 22.4-42.4%) in the Flu/Bu2 and Flu/Bu4 groups, respectively (p = 0.006). The hazard ratio comparing the two groups was 2.13 (95% CI, 1.30-3.50; p = 0.003). Both groups had a similar 5-year cumulative incidence of relapse (38.2% vs 41.3%; p = 0.581), and the Flu/Bu4 group had a higher cumulative incidence of 5-year NRM (15.7% vs 31.9%; p = 0.043). In this study, Flu/Bu4 was associated with worse OS compared with Flu/Bu2 because of high NRM in patients with NHL.

Sutimlimab provides clinically meaningful improvements in patient-reported outcomes in patients with cold agglutinin disease: Results from the randomised, placebo-controlled, Phase 3 CADENZA study.

Cold agglutinin disease (CAD) is a rare chronic autoimmune haemolytic anaemia, driven mainly by classical complement pathway activation, leading to profound fatigue and poor quality of life. In the Phase 3 CADENZA trial, sutimlimab-a C1s complement inhibitor-rapidly halted haemolysis, increased haemoglobin levels and improved fatigue versus placebo in patients with CAD without a recent history of transfusion. Patient-reported outcomes (PROs) included Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue), 12-Item Short Form Health Survey (SF-12), EuroQol visual analogue scale (EQ-VAS), Patient Global Impression of Change (PGIC) and Patient Global Impression of (fatigue) Severity (PGIS). Sutimlimab resulted in significant rapid and meaningful improvements versus placebo in PROs. From Week 1, the FACIT-Fatigue mean score increased >5 points above baseline (considered a clinically important change [CIC]). Least-squares (LS) mean change in FACIT-Fatigue score from baseline to treatment assessment timepoint was 10.8 vs. 1.9 points (sutimlimab vs. placebo; p < 0.001). Improvements in physical (PCS) and mental (MCS) component scores of the SF-12 were also considered CICs (LS mean changes from baseline to Week 26: PCS 5.54 vs. 1.57 [p = 0.064]; MCS 5.65 vs. -0.48 [p = 0.065]). These findings demonstrate that in addition to improving haematologic parameters, sutimlimab treatment demonstrates significant patient-reported benefits. Study registered at www.clinicaltrials.gov: NCT03347422.

Intermediate-dose cyclophosphamide and bortezomib for PBSC mobilization in multiple myeloma.

Although the incorporation of bortezomib into induction regimens has improved response rates in patients with multiple myeloma (MM), the role of bortezomib in the peripheral blood stem cell (PBSC) mobilization remains unclear. We assessed the PBSC mobilization efficacy, safety, and disease response of intermediate-dose cyclophosphamide and bortezomib in the PBSC mobilization. Twenty-one patients with newly diagnosed MM were enrolled in a phase II, non-randomized study that used bortezomib (1.3 mg/m2/day on days 1, 4, 8, and 11) and intermediate-dose cyclophosphamide (2 g/m2/day on days 2, 3) (Bor-ID-CY). The data from 15 patients who received intermediate-dose cyclophosphamide (ID-CY) were used as a historical control group. The total CD34 + cell yield of Bor-ID-CY and ID-CY groups were not significantly different (median 6.3 ×106/kg vs. 6.5 ×106/kg, p = 0.26). All three patients with mobilization failure of two groups had t(11;14). Six patients in Bor-ID-CY group were upgraded from a status that was less than a very good partial response (VGPR) at the time of PBSC mobilization to a VGPR or better after PBSC mobilization (p = 0.014). Four patients in Bor-ID-CY group developed sepsis. The time to engraftment was similar in the two groups. The addition of bortezomib to ID-CY did not impact the stem cell yield or quality.

Efficacy and safety of Wilms' tumor 1 helper peptide OCV-501 in elderly patients with acute myeloid leukemia: a multicenter, randomized, double-blind, placebo-controlled phase 2 trial.

PURPOSE: Complete remission (CR) of acute myeloid leukemia (AML) in elderly patients has a short duration, and there is no suitable post-remission therapy. We explored the role of the Wilms' tumor 1 helper peptide OCV-501 to prevent recurrence after remission. METHODS: This placebo-controlled phase 2 study was designed to evaluate accurately the efficacy and immunogenicity of OCV-501 in elderly AML patients. Elderly AML patients who achieved first CR were randomly allocated to receive either OCV-501 (N = 69) or placebo (N = 65) once a week for eight weeks and then every two weeks until week 104. The primary endpoint was disease-free survival (DFS). RESULTS: Nineteen (27.5%) patients in the OCV-501 group and 23 (35.4%) patients in the placebo group completed the study without relapse. The median DFS in the OCV-501 and placebo groups was 12.1 and 8.4 months, respectively (p = 0.7671, hazard ratio [95% confidence interval]: 0.933 [0.590, 1.477]). The major drug adverse reactions were injection-site reactions. Although treatment with OCV-501 did not prolong DFS for elderly AML patients, post hoc analysis found that immune responders to OCV-501 whose specific IgG was > 10,000 ng/mL (N = 16) and whose WT1-specific interferon-γ response was > 10 pg/mL (N = 26) had significantly longer overall survival compared with placebo. CONCLUSIONS: The placebo-controlled design of this study and quantitative immunological monitoring provides new insight into the relationship between peptide-induced immune responses and survival, suggesting future perspectives for cancer immunotherapy.

Gene rearrangements of MLL and RUNX1 sporadically occur in normal CD34+ cells under cytokine stimulation.

Gene rearrangements of MLL/KMT2A or RUNX1 are the major cause of therapy-related leukemia. Moreover, MLL rearrangements are the major cause of infant leukemia, and RUNX1 rearrangements are frequently detected in cord blood. These genes are sensitive to topoisomerase II inhibitors, and various genes have been identified as potential fusion partners. However, fetal exposure to these inhibitors is rare. Therefore, we postulated that even a proliferation signal itself might induce gene rearrangements in hematopoietic stem cells. To test this hypothesis, we detected gene rearrangements in etoposide-treated or non-treated CD34+ cells cultured with cytokines using inverse PCR. In the etoposide-treated cells, variable-sized rearrangement bands were detected in the RUNX1 and MLL genes at 3 hours of culture, which decreased after 7 days. However, more rearrangement bands were detected in the non-treated cells at 7 days of culture. Such gene rearrangements were also detected in peripheral blood stem cells mobilized by cytokines for transplantation. However, none of these rearranged genes encoded the leukemogenic oncogene, and the cells with rearrangements did not expand. These findings suggest that MLL and RUNX1 rearrangements, which occur with very low frequency in normal hematopoietic progenitor cells, may be induced under cytokine stimulation. Most of the cells with gene rearrangements are likely eliminated, except for leukemia-associated gene rearrangements, resulting in the low prevalence of leukemia development.

The Transcription Factors PU.1 and IRF4 Determine Dendritic Cell-Specific Expression of RALDH2.

RALDH2 expressed in dendritic cells (DCs) plays a critical role in the development of regulatory T cells in mesenteric lymph nodes. Despite the importance of RALDH2 in intestinal immunity, little is known about the mechanism of DC-specific expression of RALDH2. In the current study, we focused on the hematopoietic cell-specific transcription factors PU.1 and IRF4 as the determinants of Aldh1a2 gene expression. The mRNA level of Aldh1a2, and subsequently the enzyme activity, were decreased by knockdown of PU.1 and IRF4 in bone marrow-derived DCs (BMDCs) of BALB/c mice. Chromatin immunoprecipitation assays showed that PU.1 and IRF4 bound to the Aldh1a2 gene ∼2 kb upstream from the transcription start site in BMDCs. A reporter assay and an EMSA revealed that the Aldh1a2 promoter was synergistically transactivated by a heterodimer composed with PU.1 and IRF4 via the EICE motif at -1961/-1952 of the gene. The effect of small interfering RNAs for Spi1 and Irf4 and specific binding of PU.1 and IRF4 on the Aldh1a2 gene were also observed in DCs freshly isolated from spleen and mesenteric lymph nodes, respectively. GM-CSF stimulation upregulated the Aldh1a2 transcription in Flt3 ligand-generated BMDCs, in which the IRF4 expression and the PU.1 recruitment to the Aldh1a2 promoter were enhanced. We conclude that PU.1 and IRF4 are transactivators of the Aldh1a2 gene in vitro and ex vivo.

Microcapsule-Based Signal Amplification Method for Biomolecules.

The direct signal amplification of target molecules could be an effective means of increasing the sensitivity and reducing the size of biosensors. The purpose of this study was to propose a novel signal amplification method suitable for the detection of biomolecules using microcapsules that can quickly respond to concentration variation. This microcapsule-based amplification method consists of two elements-microcapsules and a well-array. The microcapsules consist of (i) an inner shell fabricated through layer-by-layer assembly, (ii) a lipid bilayer, and (iii) loaded target molecules. In this method, the inner surface of the well-array was modified using TiO2 as a photocatalyst. The diameter and thickness of the fabricated micro-capsules for biomarker loading were shown to be 2.7 µm and 78 nm, respectively. An ultraviolet (UV) irradiation time of 5 min was needed when the change in optical density reached 90% saturation of the optical density change. Dye molecules were incorporated into the microcapsules and were subsequently released, and the concentration of the released solution changed in proportion with the encapsulated dye concentration. This demonstrates the proof of concept for this novel signal amplification method based on microcapsules.

[Mild hemophilia A diagnosed in an adult patient on the occasion of post-operative bleeding following a second knee surgery].

A 48-year-old male underwent an osteosynthesis surgery for right patellar fracture without bleeding episodes around the surgery. After 7 months, he presented with a bleeding episode after a nail extraction surgery from his knee joint. He was diagnosed with mild hemophilia A after his second surgery. The patient's clinical course suggested that he had mild hemophilia A, although he had a past surgical history without any bleeding episodes. Early diagnosis is important in patients with mild hemophilia A because bleeding episodes complicated with surgery can be prevented by the administration of prophylactic replacement therapy.

Motion analysis of operating a balance exercise assist robot system during forward and backward movements.

[Purpose] Stand-and-ride personal mobility devices controlled by movements of the user's center of gravity are used for balance training. We aimed to describe the physical activity required to operate this type of mobility device. [Participants and Methods] Eleven healthy males performed the following tasks: 1) moving their center of gravity forward or backward while standing on the floor (control task) and, 2) moving the mobility device forward or backward by moving their center of gravity (experimental task). [Results] We observed that the displacement of the center of gravity and the center of pressure, as well as angular displacements of the hips and knee joints, and maximum muscle activities of the biceps femoris, the medial head of the gastrocnemius and peroneus longus muscles were lesser during the experimental than during the control task. The distance moved by the device was significantly greater than the displacement of the user's center of gravity during the experimental task. [Conclusion] We observed that moving the device forward or backward required lesser physical activity than that required to shift the user's center of gravity forward or backward while standing on the floor. Additionally, we observed that even a small displacement of the user's center of gravity produced a large displacement of the device. We concluded that during balance training, the greater and more easily perceived movement of the mobility device would provide helpful feedback to the user.

Kinematic, kinetic, and electromyographic characteristics during quiet standing on a balance exercise assist robot.

[Purpose] The balance exercise assist robot is a training device based on a personal transport assistance robot ridden in the standing position. The personal transport assistance robot uses an inverted pendulum control system and moves in response to movements of the user's center of gravity. The purpose of this study was to describe the characteristics of postural control during the action of stopping the personal transport assistance robot. [Participants and Methods] Eleven healthy male participants were required to maintain a standing position for 30 s; each task was performed 10 times. The measurement conditions were as follows: (1) on the floor; (2) on the robot, touching the handlebars; and (3) on the robot, not touching the handlebars. [Results] During the robotic tasks, the total locus lengths of the center of gravity and total joint momentums of the hip, knee, and ankle joints were larger, and the amount of displacement of the center of pressure was smaller than that during the floor task. Posture control on the robot was performed actively by mechanical interaction of the ankle, knee, and hip joints within a small base of support. [Conclusion] The balance exercise assist robot can be useful for postural control exercises because maintaining a standing position on the personal transport assistance robot required active postural control.

Disposable collection kit for rapid and reliable collection of saliva.

OBJECTIVES: To describe and evaluate disposable saliva collection kit for rapid, reliable, and reproducible collection of saliva samples. METHODS: The saliva collection kit comprised of a saliva absorbent swab and an extractor unit was used to retrieve whole saliva samples from 10 subjects. The accuracy and precision of the extracted volumes (3, 10, and 30 µl) were compared to similar volumes drawn from control samples obtained by passive drool. Additionally, the impact of kit collection method on subsequent immunoassay results was verified by assessing salivary cortisol levels in the samples and comparing them to controls. RESULTS: The recovered volumes for the whole saliva samples were 3.85 ± 0.28, 10.79 ± 0.95, and 31.18 ± 1.72 µl, respectively (CV = 8.76%) and 2.91 ± 0.19, 9.75 ± 0.43, and 29.64 ± 0.91 µl, respectively, (CV = 6.36%) for the controls. There was a close correspondence between the salivary cortisol levels from the saliva samples obtained by the collection kit and the controls (R(2) > 0.96). CONCLUSIONS: The disposable saliva collection kit allows accurate and repeatable collection of fixed amounts of whole saliva and does not interfere with subsequent measurements of salivary cortisol. The simple collection process, lack of elaborate specimen recovery steps, and the short turnaround time (<3 min) should render the kit attractive to test subjects and researchers alike.

Risk Factors for COVID-19 Cluster Infection in Hospitalized Patients.

Introduction In Japan, in the seventh wave of coronavirus disease 2019 (COVID-19) from July 2022 to September 2022, followed by the eighth wave of COVID-19 from November 2022 to January 2023, nosocomial clusters became more frequent in many healthcare facilities. If a cluster occurs in a hospital, the restrictions on general healthcare and the impact on hospital management, as well as the impact on community healthcare, are enormous. We analyzed the risk factors for COVID-19 cluster infection in hospitalized patients. Methods We retrospectively collected cases of COVID-19 infection among hospitalized patients in the seventh and eighth waves. The occurrence of a COVID-19 patient in a hospitalized patient was defined as one event. Results A total of 40 events were observed in the seventh and eighth waves. There were 17 events that developed into clusters. The following factors showed a significant association with cluster infection in a univariate analysis: "seventh wave," "originated from healthcare worker," and "initial examination according to contact list." The multivariate analysis revealed that "originated from healthcare worker" was independently associated with cluster infection. Conclusion Preventing the development of COVID-19 clusters is very important for nosocomial infection control. Our study suggests that COVID-19 infection in a healthcare worker is a risk factor for the development of a cluster. When healthcare workers are infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), it is often due to household transmission. Measures against household transmissions are important to prevent infection among healthcare workers.

Long-term safety profile of sutimlimab in adult Japanese patients with cold agglutinin disease.

Sutimlimab, a complement inhibitor, has recently been approved in Japan for treating cold agglutinin disease (CAD). We report the safety and efficacy of sutimlimab in Japanese patients with CAD who completed a global phase 3 clinical trial (CARDINAL/CADENZA: 26-week treatment with 1-2 years of open-label extension [OLE] periods) and subsequently participated in the Japanese OLE study. Patients with a recent history of blood transfusion (CARDINAL, n = 3) and those without (CADENZA, n = 4) were analyzed (71.4% female; median [range] baseline age: 70 [46-83] years). For CARDINAL/CADENZA, the treatment duration (median [range]) was 140.9 (104.9-157.3) weeks, and the cessation period was 70 (61-133) weeks. For the Japanese OLE study, the treatment duration was 47.1 (15.1-49.1) weeks. Three (42.9%) patients experienced treatment-related and treatment-emergent adverse events (TEAEs): injection site erythema, cystitis bacterial, viral infection, and blood pressure increased during CARDINAL/CADENZA. One (14.3%) patient experienced one treatment-related TEAE (urinary tract infection) during the Japanese OLE study. One patient died of renal failure, considered unrelated to sutimlimab, that was exacerbated by hepatorenal syndrome due to liver cirrhosis and bacterial peritonitis, in addition to CKD. Hemoglobin and bilirubin levels improved during treatment but deteriorated after withdrawal and recovered on retreatment. Sutimlimab was well tolerated over a median of 3.8 years, with no new safety concerns identified during retreatment.

Sustained improvements in patient-reported outcomes after long-term sutimlimab in patients with cold agglutinin disease: results from the CADENZA study open-label extension.

Background: Cold agglutinin disease (CAD) is a rare subtype of autoimmune haemolytic anaemia characterised by classical complement pathway-mediated haemolysis, fatigue, and poor quality of life (QoL). Sutimlimab, a C1s inhibitor, rapidly halted haemolysis, and improved patient-reported outcomes (PROs) in patients with CAD in two phase 3 trials (CARDINAL and CADENZA). Here we report PROs from the CADENZA open-label extension (Part B). Methods: The first patient was enrolled in CADENZA (NCT03347422) in March 2018 (Part A) and the last patient completed the study in December 2021 (Part B). All patients who completed the 26-week Part A were eligible to receive biweekly doses of sutimlimab in Part B for up to 1 year after the last patient completed Part A. PROs were assessed throughout Part B, until the last on-treatment visit with available assessment (LV), and after a 9-week washout. Findings: In total, 32/39 patients completed Part B; median Part B treatment duration: 99 weeks. Patients switching from placebo to sutimlimab in Part B experienced rapid improvement in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score and other PROs. Sustained, clinically important improvements in FACIT-Fatigue were observed throughout Part B in patients who switched to sutimlimab and those continuing sutimlimab treatment (combined-group mean [SE] change from baseline at LV: 8.8 [2.1]). Similarly, the combined-group mean [SE] change for 12-Item Short Form Health Survey physical (4.9 [1.7]) and mental (4.0 [1.8]) component scores exceeded clinically important changes from baseline at LV. EuroQol visual analogue scale showed consistent and sustained increases from baseline with sutimlimab treatment. Following a 9-week washout, all PROs approached baseline values. Interpretation: Continued inhibition of the classical complement pathway with sutimlimab results in meaningful long-term improvements in PROs (fatigue and QoL) in patients with CAD. Funding: Sanofi.