Serious Treatment-emergent Adverse Events Research Articles

Gemcitabine and nab-paclitaxel combined with afatinib in metastatic pancreatic cancer – Results of a phase 1b clinical trial

PurposeThe combination of gemcitabine/nab-paclitaxel is an established standard treatment in the first-line treatment of metastatic ductal adenocarcinoma of the pancreas (mPDAC). Afatinib, an oral second-generation pan ErbB family tyrosine kinase inhibitor, has shown promising pre-clinical signs in the treatment of pancreatic cancer. The aim of this phase 1b trial was to determine the maximum tolerated dose (MTD) of afatinib in combination with gemcitabine/nab-paclitaxel in patients with mPDAC. MethodsTreatment naïve patients (≥18 years) with histologically proven mPDAC and good performance status (ECOG 0/1) were enrolled to receive gemcitabine/nab-paclitaxel in combination with afatinib. Treatment was continued until disease progression, or unacceptable toxicity. The primary endpoint MTD was determined using a 3 + 3 design. Treatment started at dose level 0 with intravenous gemcitabine/nab-paclitaxel 1000 mg/m2 / 125 mg/m2 (day 1, 8, 15 of a 28-day cycle) + oral afatinib 30 mg daily. At dose level + 1 afatinib was increased to 40 mg. Secondary endpoints included safety parameters and exploratory endpoints evaluated treatment efficacy. ResultsTwelve patients were included in this trial, and 11 patients were treated and analysed in the safety and full analysis set (FAS). At dose level 0 the first three patients did not experience a dose-limiting toxicity (DLT). At dose leve (DL) + 1 two patients experienced a DLT. Accordingly, enrolment continued at DL 0 with three more patients, of which one experienced DLT (skin rash ≥ CTCAE grade 3). Seven patients (63.6%) experienced at least one treatment-emergent serious adverse event (TESAE), with four patients (36.4%) experiencing TESAEs grade 3–5 related to the study medication. In the FAS, the objective response rate (ORR) was 36.4%, median progression-free survival (PFS) was 3.5 months and median overall survival in nine evaluable patients was 7.5 months. ConclusionsIn this phase 1b clinical trial, the MTD of gemcitabine/nab-paclitaxel (1000 mg/m2 / 125 mg/m2) and afatinib (30 mg) was established. In a cohort of 11 patients, the combination showed an acceptable safety profile.

Efficacy and Safety of Risankizumab in Patients with Psoriatic Arthritis: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Currently, the cause of psoriatic arthritis (PsA) is unknown, and the effectiveness of current drug treatments is unsatisfactory. In March 2019, the US Food and Drug Administration (FDA) approved risankizumab, a humanized immunoglobulinG1 (IgG1) monoclonal antibody targeting the p19 subunit of interleukin (IL)-23, for the treatment of PsA in adults. This study aimed to conduct a meta-analysis of double-blind, randomized, placebo-controlled trials to evaluate the effectiveness and safety of risankizumab in moderate-to-severe PsA. We conducted a thorough search of relevant databases from the establishment of the databases to October 1, 2023. We conducted a meta-analysis using Stata 12.0 and utilized I2 and Egger tests to assess heterogeneity and publication bias among the studies. Bias assessment was performed using the risk bias map and bias risk summary diagram generated by Revman5.4 software. The review protocols were registered on PROSPERO (CRD42023451894) and adhered to the preferred reporting item of system evaluation (PRISMA) guideline. Six randomized controlled trials (RCTs) involving 5038 patients with PsA treated with either risankizumab or placebo were included in the analysis. At 24weeks, the risankizumab group demonstrated a significantly higher American College of Rheumatology-20 (ACR20) response rate compared to the placebo group (RR1.760, 95%CI 1.568-1.977, P < 0.001). Additionally, the risankizumab group showed a significantly higher Minimal Disease Activity (MDA) response rate compared to the placebo group (RR1.827, 95%CI 1.048-3.184, P < 0.05). The risankizumab group also exhibited improvement in Short Form 36 Questionnaire (SF-36) score (SMD 0.51, 95%CI 0.33-0.69, P < 0.001), with significantly lower Health Assessment Questionnaire Disability Index (HAQ-DI) score (SMD - 0.27, 95%CI - 0.37 to - 0.17, P < 0.001) and higher Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) score (SMD 0.27, 95%CI 0.20-0.35, P < 0.001) compared to the placebo group. Moreover, the risankizumab group had a significantly lower Psoriasis Area and Severity Index (PASI) score (SMD - 6.12, 95%CI - 10.02 to 2.23, P < 0.001). A study by Mease et al. indicated that patients receiving risankizumab generally demonstrated numerical improvements in the Leeds Enthesitis Index (LEI), although the small sample size limits the evidence. Further research is necessary to provide evidence-based guidelines. There were no significant differences in the incidence of serious adverse events (SAE) and serious treatment-emergent adverse events (STEAE) between the risankizumab and placebo groups (RR0.76, 95%CI 0.45-1.28, P = 0.31; RR0.99, 95%CI 0.49-1.99, P = 0.97, respectively), and the overall incidence of adverse events (AE) was not comparable (RR1.10, 95%CI 0.63-1.94, P = 0.73). Risankizumab showed superior efficacy across multiple outcome measures compared to placebo, with no significant increase in adverse events. Our findings endorse risankizumab as an excellent treatment option for PsA, offering valuable insights for clinicians and patients when choosing appropriate therapeutic interventions. Retrospectively registered (CRD42023451894, 16 August 2023).

Comparative Safety of Long-Acting Injectable Antipsychotics: A Systematic Review and Network Meta-Analysis.

To find the safety of long-acting injectable antipsychotics (LAIs) compared to each other, and/or placebo in the treatment of schizophrenia (SCZ) and/or schizoaffective disorder (SZA). We performed a systematic review and a network meta-analysis of randomized controlled trials (RCTs) comparing the safety of LAIs versus other LAIs or placebo in adults diagnosed with SCZ or SZA. The primary outcomes were treatment emergent adverse events (TEAEs), serious treatment emergent adverse events (STEAEs), and deaths. The secondary outcomes included treatment discontinuations due to adverse events and all-cause discontinuations. Seventeen RCTs were included (n=7,908). There were no significant differences between LAIs and placebo in the risk of presenting TEAEs. LAIs had a significant lower risk of presenting STEAEs except for aripiprazole. No significant differences in deaths were found. LAIs showed a significant protective effect against all-cause discontinuation, except for haloperidol. Only aripiprazole had a significantly lower risk of treatment discontinuation due to adverse events. We found no significant differences in the risk of presenting TEAEs between LAIs and placebo. The majority of LAIs had a significantly lower risk of presenting STEAEs than placebo. Development of international guidelines for the report of safety outcomes related to antipsychotics especially for LAIs in clinical trials could minimize report and interpretation biases and improve the accuracy of posterior meta-analysis.

Long-term safety of brazikumab in the open-label period of a randomized phase 2a study of patients with Crohn’s disease

BackgroundShort-term efficacy and safety of brazikumab (MEDI2070), a human monoclonal antibody and anti-p19 subunit inhibitor of interleukin-23, was demonstrated in a phase 2a trial in patients with moderate-to-severe active Crohn’s disease (CD). We report brazikumab long-term safety and tolerability from the open-label period of this phase 2a study.MethodsPatients who completed the 12-week, double-blind induction period were eligible for inclusion in an open-label period where all patients received subcutaneous brazikumab (210 mg) every 4 weeks for 100 weeks. Patients had moderate-to-severe active CD and had failed or were intolerant to ≥ 1 anti-tumour necrosis factor alpha (TNFα) agent. Safety assessments included treatment-emergent adverse events (TEAEs); further assessments were pharmacokinetics and immunogenicity.ResultsOf the 104 patients who entered the open-label period, 57 (54.8%) continued to the end of the open-label period and 47 (45.2%) discontinued brazikumab. The most common reasons for discontinuation were lack of response (14.4%), patient decision (12.5%), and TEAEs (11.5%). In total, 44 (84.6%) in the group switching from placebo to brazikumab (placebo/brazikumab) and 43 (82.7%) in the group continuing brazikumab (brazikumab/brazikumab) experienced 1 or more TEAEs. Most TEAEs were mild-to-moderate in severity. Common TEAEs included nasopharyngitis and headache. Numbers of treatment-emergent serious adverse events (TESAEs) were similar between groups. Infections occurred in 40.4% of patients in the placebo/brazikumab group and 50% in the brazikumab/brazikumab group. There were 5 TESAEs of infection, none of which were opportunistic. No major adverse cardiac events, malignancies, or deaths were reported.ConclusionsBrazikumab was well tolerated with an acceptable safety profile over a 100-week period in patients with moderate-to-severe active CD who failed or were intolerant to 1 or more anti-TNFα agents.Trial registrationNCT01714726; registered October 26, 2012.

Combined Safety Data for Sutimlimab in Cold Agglutinin Disease: A Post-Hoc Analysis of the Phase 3 Cardinal and Cadenza Studies

Background: Cold agglutinin disease (CAD) is a rare, chronic, autoimmune hemolytic anemia mediated by the classical complement pathway (CP).Sutimlimab is a first-in-class, humanized, monoclonal antibody that selectively inhibits C1s of the C1 complex, preventing CP activation and CP-mediated hemolysis. CARDINAL (NCT03347396) was an open-label, single-arm, Phase 3 study of sutimlimab in patients with CAD and recent history of transfusion; CADENZA (NCT03347422) was a randomized, double-blind, placebo-controlled, Phase 3 study of sutimlimab in patients with CAD and no recent history of transfusion. Both studies had a 26-week treatment period (Part A) followed by a long-term extension (Part B), reporting data up to 2 years after the last patient finished Part A of CARDINAL and up to 1 year after the last patient finished Part A of CADENZA. With long-term treatment in both studies, sutimlimab demonstrated sustained efficacy with improvements in hemolysis and anemia, sustained clinically meaningful improvements in quality of life, and it had a favorable safety profile. Aims: To report combined safety data from Part A and B of the Phase 3 CARDINAL and CADENZA studies in sutimlimab-treated patients with CAD. Methods: In CARDINAL Part A, patients received sutimlimab on Days 0 &amp; 7, then biweekly until the end of Part B. In CADENZA Part A, patients received sutimlimab or placebo on Days 0 &amp; 7, then biweekly; in Part B, patients continued to receive biweekly sutimlimab or switched from placebo to receive sutimlimab on Days 0 &amp; 7, then biweekly. Data fromall enrolled patients who received at least 1 dose of sutimlimab in CARDINAL (N=24) and CADENZA (N=42), including a post-treatment follow-up 9 weeks after the last dose, were combined into the Safety Analysis Set. Endpoints for this analysis included the incidence of treatment-emergent adverse events (TEAEs), treatment-emergent serious adverse events (TESAEs), and adverse events of special interest (AESIs). AESIs were selected based on a list of important identified risks and important potential risks for sutimlimab. Results: The Safety Analysis Set included 66 patients. At baseline, the median age was 69.5 years (range 46-88) and the majority (72.7%) were female, with a median duration since CAD diagnosis of 5.7 years (range 0-33). The median patient follow-up was 129.1 weeks (range 5-175). Sixty-four (97.0%) patients experienced ≥1 TEAE ( Table 1). Eighty-six TEAEs assessed as related to sutimlimab by the investigator occurred in 30 (45.5%) patients. Fifty-three TESAEs were reported in 22 (33.3%) patients. Three (4.6%) patients each experienced one TESAE assessed as related or possibly related to sutimlimab by the investigator (related vitreous hemorrhage, related viral infection, and possibly related severe cerebral venous thrombosis). Seven patients discontinued sutimlimab treatment and/or the studies due to ≥1 TEAE, 4 in CARDINAL and 3 in CADENZA. Four patients died during the studies: 1 in CADENZA with a TESAE of lung squamous cell carcinoma and sutimlimab was withdrawn due to this TESAE prior to the patient's death; 3 in CARDINAL, 1 patient died after premature discontinuation of sutimlimab due to AEs (fatal infection of Klebsiella pneumoniae, acrocyanosis), 1 patient died due to a newly diagnosed hepatic cancer in the first month of the study, and 1 patient died due to exacerbation of CAD during the 9-week washout period approximately 1.5 months after the last dose of sutimlimab. No deaths were assessed as related to sutimlimab by the investigator. Treatment-emergent AESIs (selected based on a list of important identified risks and important potential risks for sutimlimab) are presented in Table 1. Fourteen TEAEs of serious infection were reported in 9 patients (13.6%; one assessed as related to sutimlimab by the investigator), 31 TEAEs of hypertension were reported in 17 patients (25.8%), 28 TEAEs of acrocyanosis and/or Raynaud's phenomenon were reported in 13 patients (19.7%), and 4 TEAEs of thromboembolic events were reported in 4 patients (6.1%). No TEAEs of serious hypersensitivity reaction and/or anaphylaxis, meningococcal infection or development of systemic lupus erythematosus were reported. Conclusion: The combined safety analysis of the Phase 3 CARDINAL and CADENZA studies (Part A and B) demonstrated that sutimlimab was generally well tolerated, with the type and frequency of TEAE consistent with an older and medically complex population.

Tolerability, Incidence of Second Primary Skin Malignancies and Diarrhea in Patients with Relapsed Refractory Multiple Myeloma Treated with Isatuximab: A Systematic Review and Meta-Analysis of Phase III Randomized Controlled Trials

Introduction Multiple myeloma, which accounts for 1% of all cancers, is a hematologic cancer in which clonal plasma-cell proliferation leads to complications and death. Isatuximab is a human, CD38-targeting, IgG1 monoclonal antibody with direct antitumor effects, and an immunomodulatory component, resulting in apoptosis of myeloma cells. Over the recent years, it has shown that the addition of isatuximab to proteasome inhibitors and immunomodulatory drugs has improved outcomes in patients with relapsed or refractory multiple myeloma (RRMM). However, there are considerable safety concerns. The purpose of our study is to determine the risks of second primary skin malignancy, diarrhea, treatment emergent serious adverse events (SAE) and treatment discontinuation due to treatment emergent adverse events (TEAE) in patients with RRMM treated with isatuximab. Methods We systematically conducted a comprehensive literature search using MEDLINE, EMBASE databases and meeting abstracts from inception through June 30 th, 2023. Phase III RCTs utilizing isatuximab in patients with relapsed or refractory multiple myeloma that mention second primary skin malignancy, diarrhea, treatment emergent serious adverse events and treatment discontinuation were incorporated in the analysis. Mantel-Haenszel (MH) method was used to calculate the estimated pooled risk ratio (RR), with 95% confidence interval (CI). Heterogeneity was assessed with Cochran's Q- statistic. Random effects model was applied. Results A total of 600 patients with RRMM from 2 phase III RCTs (ICARIA-MM and IKEMA were eligible. ICARIA-MM and IKEMA compared isatuximab (I) + pomalidomide (P) + dexamethasone (d) vs Pd, and isatuximab (I) + Carfilzomib (K) + dexamethasone (d) vs Kd respectively. The randomization ratios were 1:1 in ICARIA-MM, and 3:2 in IKEMA studies. The I 2 statistic for heterogeneity was 0, suggesting homogeneity among RCT. Second primary skin malignancy was reported in 16 of patients (4.9%) treated with isatuximab based combination treatment compared to 7 (2.6%) but RR was not statistically significant at 1.79 (95% CI: 0.74 - 4.31; P = 0.19). More events of any-grade diarrhea were noted in study arm (36.2%) compared to 26.9% in control arm with RR of 1.31 (95% CI: 1.03 - 1.67; P=0.03) but RR for high-grade diarrhea was not statistically significant at 1.26 (95% CI: 0.42 - 3.82; P = 0.68). TD due to TEAE was noted in 40 patients (12.2%) in study group vs 43 (15.9%) in control group with RR of 0.76 (95% CI: 0.51 -1.13; P = 0.17). Treatment emergent SAEs were reported in 71.4% vs 60.1 % in control group (RR, 1.19; 95% CI: 1.06-1.34; P = 0.004). Conclusions Our meta-analysis showed that there was no significant difference in the treatment discontinuation due to adverse events in patients with RRMM treated with isatuximab combination regimen, compared to control arm although rate of treatment emergent SAEs and any-grade diarrhea were slightly higher in the isatuximab-treated arm than the control arm. Furthermore, differences in the risks of second primary skin malignancy and high-grade diarrhea were found to be statistically not significant between study and control arms. Further studies and longer follow up are required to determine the actual relationship of second primary skin malignancies. In addition, close observation and supportive care is essential to improve treatment-emergent SAEs.

Efficacy and Tolerability of Luspatercept in Patients with Lower Risk Myelodysplastic Syndrome and Anemia: A Systematic Review and Meta-Analysis of Phase III Randomized Controlled Trials

Introduction: Erythropoietin Stimulating Agents (ESAs) are the standard-of-care treatment for most patients with lower risk myelodysplastic syndrome (MDS) and anaemia. However, there has been unmet need for those who failed ESAs other than regular blood transfusion. Luspatercept is a recombinant fusion protein which binds TGF beta ligands resulting in reduction of erythroid maturation through reduction of SMAD2 and SMAD3 signaling. In recent years, studies have shown that luspatercept has significantly improved efficacy in patients with lower risk MDS who failed ESAs with some notable adverse events. The purpose of our meta-analysis is to determine efficacy by observing the rate of transfusion independence for 12 weeks or longer and haematological improvement in erythroid (HIE), and tolerability by rate of treatment emergent serious adverse events (SAE), treatment discontinuation (TD) and treatment interruption (TI) or dose reduction and treatment related mortality in patients with lower risk MDS treated with luspatercept. Methods: We systematically conducted a comprehensive literature search using MEDLINE, EMBASE databases and meeting abstracts from inception through June 30 th, 2023. Phase III RCTs utilizing luspatercept in patients with lower risk MDS that mention efficacy i.e. transfusion independence 12 weeks or longer and HIE and tolerability i.e. rate of treatment discontinuation and interruption, dose reduction, treatment emergent serious adverse events, treatment related mortality were incorporated in the analysis. Mantel-Haenszel (MH) method was used to calculate the estimated pooled risk ratio (RR) with 95% confidence interval (CI). Heterogeneity was assessed with Cochran's Q- statistic. Fixed effects model was applied. Results: 2 phase III RCTs (MEDALIST and COMMANDS) including total 583 patients were eligible in our meta-analysis. MEDALIST trial compared luspatercept vs placebo and COMMANDS trial compared luspatercept vs erythropoietin stimulating agent. The randomization ratios were 2:1 in MEDALIST and 1:1 in COMMANDS trials. Transfusion independence for 12 weeks or longer was noted in 141 (47%) in study arm vs 77 (33.5%) in control arm at RR of 1.67 (95% CI: 1.35 -2.06; P &amp;lt;0.00001). 190 (63.3%) patients in study arm achieved HIE response compared to 88 (38.3%) in control arm at RR of 1.85 (95% CI: 1.53 -2.24; P&amp;lt;0.00001). TD due to TEAE was reported in 21 (6.3%) of luspatercept group vs 10 (4%) in control group with RR of 1.38 (95% CI: 0.67 -2.84; P = 0.39). The incidence for TI or dose reduction due to TEAE was similar between the two groups at 18% with RR of 1.23 (95% CI: 0.88 -1.72; P = 0.22). Treatment emergent SAEs were observed in 116 (35%) in the luspatercept group vs 83 (32.9%) in control group (RR, 1.09; 95% CI: 0.87-1.38; P=0.45). Treatment related mortality was noted in 13 (3.9%) of patients in the study group compared to 16 (6.3%) in the control group with RR of 0.65 (95% CI: 0.31 -1.33; P = 0.24). Conclusions: According to our meta-analysis, luspatercept significantly improved transfusion independent rate and HIE response in patients with lower risk MDS and anaemia compared to control arm. Furthermore, there was no statistically significant difference in the treatment emergent SAEs, treatment discontinuation, treatment interruption or dose reduction and treatment related mortality between the two groups.

Tolerability in Transplant-Ineligible Patients with Newly Diagnosed Acute Myeloid Leukemia Treated with Venetoclax Based Combination Therapy: A Systematic Review and Meta-Analysis of Phase III Randomized Controlled Trials

Introduction Therapeutic challenge remains in older patients with acute myeloid leukemia (AML) with significant comorbidities who are not fit for induction chemotherapy and haemopoietic stem cell transplantation. Leukemic cells depend on BCL-2 protein (anti-apoptotic protein) for their survival. Venetoclax is a selective small-molecule BCL-2 inhibitor which binds to BCL-2 resulting in apoptosis of leukemic cells. In recent years, venetoclax has been approved in combination with azacitidine or low dose cytarabine in transplant-ineligible patients with newly diagnosed AML (ND AML). However, there are notable toxicities. The purpose of our meta-analysis is to determine tolerability, rates of treatment emergent serious adverse events (SAE), treatment discontinuation (TD) and treatment interruption (TI), dose reduction and 30-day mortality in transplant-ineligible patients with ND AML treated with venetoclax based combination therapy. Methods We systematically conducted a comprehensive literature search using MEDLINE, EMBASE databases and meeting abstracts from inception through June 30 th, 2023. Phase III RCTs utilizing venetoclax in transplant-ineligible patients with ND AML that mention tolerability, rate of treatment discontinuation and interruption, dose reduction, treatment emergent serious adverse events, 30-day mortality were incorporated in the analysis. Mantel-Haenszel (MH) method was used to calculate the estimated pooled risk ratio (RR) with 95% confidence interval (CI). Heterogeneity was assessed with Cochran's Q- statistic. Fixed effects model was applied. Results A total of 637 transplant-ineligible patients with ND AML from 2 phase III RCTs (VIALE-A and VIALE-V) were eligible. VIALE-A and VIALE-V compared azacitidine + venetoclax vs azacitidine + placebo, and venetoclax + low dose cytarabine vs placebo + low dose cytarabine respectively. The randomization ratio was 2:1 in both studies.TD due to treatment emergent adverse events (TEAE) was noted in 104 (24.5%) of venetoclax group vs 45 (21.2%) in control group with RR of 1.15 (95% CI: 0.85 -1.57; P = 0.37).TI due to TEAE was higher in the venetoclax group (68.9%) compared to control group (55.6%) with RR of 1.24 (95% CI: 1.08 -1.42; P = 0.002). 21 (4.9%) of patients in venetoclax group and 10 (4.7%) in the control group required dose reduction of treatment due to TEAE, RR 1.03 (95% CI: 0.50 -2.16; P = 0.93).Treatment emergent SAEs were reported in 77.4% in the venetoclax group vs 60% in control group (RR, 1.30; 95% CI: 1.15-1.46; P &amp;lt;0.0001). 30-day mortality was reported in 39 (9.1%) of patients in the venetoclax group and 20 (9.4%) in the control group with RR of 0.96 (95% CI: 0.58 -1.60; P = 0.89). Conclusions Our meta-analysis showed that there was no significant difference in the rate of treatment discontinuation and dose reduction due to adverse events in transplant-ineligible patients with ND AML treated with venetoclax combination regimens, compared to control arm although rates of treatment emergent SAEs and treatment interruption were considerably higher in the venetoclax-treated arm. However, the 30-day mortality rate was similar between the two groups. Longer follow up and timely supportive care are required to improve treatment emergent SAEs and treatment interruption.

Efficacy and Safety of Subcutaneous Ravulizumab in Patients with Paroxysmal Nocturnal Hemoglobinuria Who Received Prior Intravenous Eculizumab: 2-Year Follow-up

Background : Subcutaneous (SUBQ) ravulizumab, administered weekly via an on-body delivery system, showed pharmacokinetic (PK) non-inferiority to intravenous (IV) ravulizumab over 71 days in adult patients with paroxysmal nocturnal hemoglobinuria (PNH) who were clinically stable on prior IV eculizumab treatment (NCT03748823). This analysis reports results through 2 years of SUBQ ravulizumab treatment during the extension period of a phase 3 randomized trial. The reporting period started at day 15 for patients who continued SUBQ ravulizumab during the extension period (SUBQ/SUBQ) and day 71 for patients who switched from IV ravulizumab to SUBQ ravulizumab (IV/SUBQ). Objectives: To evaluate the PK, pharmacodynamics (PD), efficacy, and safety of SUBQ ravulizumab through 2 years (day 743) of treatment in adult patients with PNH previously treated with IV eculizumab. Methods: Patients (≥ 18 years) who received IV eculizumab (once every 2 weeks) for at least 3 months prior to study entry with clinically stable PNH (lactate dehydrogenase [LDH] levels ≤ 1.5 × upper limit of normal [246 U/L]) were enrolled in the study, which consisted of a screening period (day −1 to day −30), a 10-week randomized treatment period, and an extension period of up to 172 weeks. During the randomized treatment period, patients were assigned (2:1) to receive either SUBQ ravulizumab (weekly) or IV ravulizumab (once every 8 weeks); all patients received SUBQ ravulizumab during the extension period. PK/PD endpoints through 2 years of treatment included serum ravulizumab and free C5 concentrations. Efficacy endpoints included change in LDH from baseline, incidence of breakthrough intravascular hemolysis (BTH), maintenance of transfusion avoidance, and maintenance of stabilized hemoglobin (avoidance of a ≥ 2 g/dL decrease in hemoglobin in the absence of transfusion). Fatigue was assessed using the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue subscale questionnaire. Safety outcomes, including adverse events (AEs), serious AEs (SAEs), and adverse device effects (ADEs), were also assessed up to the 2-year data cut-off. Results: In total, 128 patients received SUBQ ravulizumab (SUBQ/SUBQ: n = 84; IV/SUBQ: n = 44; mean [range] duration of SUBQ treatment: 839.4 [37 - 1108] days). During 2 years of SUBQ treatment, serum ravulizumab concentrations were maintained ≥ 175 μg/mL and serum free C5 concentrations &amp;lt; 0.5 μg/mL, the previously defined thresholds for achieving and sustaining complete terminal complement inhibition ( Figure). Efficacy endpoints remained consistent over time. Mean (standard deviation [SD]) percentage change in LDH from baseline to day 743 was +2.3% (21.6%; n = 108). BTH events were infrequent: 5/128 patients (3.9%). Transfusion avoidance was maintained in 74.2% of patients (n = 95/128) and 69.1% (n = 85/123) achieved stabilized hemoglobin. Mean (SD) change in FACIT-Fatigue subscale score from baseline to day 743 was +1.3 (9.09; n = 68). The most common AEs (excluding ADEs related to device product issues) during SUBQ treatment were COVID-19 (25.0%), headache (18.8%), and pyrexia (18.0%). Treatment-emergent SAEs were experienced by 29.7% of patients. No treatment-emergent anti-drug antibodies were observed. ADEs not related to a medical device issue were reported by 25.0% of patients. The most frequently reported ADEs unrelated to a medical device issue were injection site reaction (4.7%), medical device site erythema (4.7%), and injection site erythema (3.1%). Among 30,221 devices used in the study, full volume per device was delivered by 98.6% of devices. Complaints were reported in 1.6% of devices used: 0.1% had a confirmed technical defect, 0.8% had a use error, and 0.7% had other/unknown defects. Conclusions: The efficacy of ravulizumab was maintained following the switch from IV to SUBQ ravulizumab and no new safety signals were identified through 2 years of treatment in patients with PNH. SUBQ ravulizumab demonstrated a favorable benefit-risk profile and the types and incidences of AEs were comparable with those reported for IV eculizumab and IV ravulizumab in previous studies, except for local site reactions. The SUBQ method of administration provides an additional treatment choice for patients with PNH receiving ravulizumab treatment.

Pooled Safety Analysis of IncobotulinumtoxinA in the Treatment of Neurological Disorders in Adults (P12-11.007)

<h3>Objective:</h3> To examine the pooled incidence of treatment-emergent adverse events (TEAEs) and immunogenicity by indication in sponsored incobotulinumtoxinA (INCO) clinical trials in adults. <h3>Background:</h3> The safety and efficacy of INCO in adult neurological disorders has been investigated in multiple prospective clinical trials, including several not yet published. A comprehensive assessment combining available data would provide additional insights into INCO safety. <h3>Design/Methods:</h3> TEAEs were identified in the integrated clinical database of Merz-sponsored placebo (PBO)-controlled studies in adults with cervical dystonia (CD), blepharospasm, upper limb (UL) and lower limb (LL) spasticity, sialorrhea and essential tremor of the UL. Overall incidences of TEAEs and the categories of serious TEAEs (SAEs), TEAEs leading to discontinuation, fatal TEAEs, TEAEs of special interest (AESIs; indicating possible toxin spread) and treatment-related (TR) events were determined for INCO and PBO after a single injection cycle and for INCO after multiple cycles; the most frequent TEAEs, TR-TEAEs and TR-AESIs after a single cycle of INCO were summarized. Neutralizing antibody (NAb) testing was performed in most studies. <h3>Results:</h3> After a single cycle, the incidences of overall TEAEs were similar between INCO and PBO in all indications, although between-indication differences were observed. Most TEAEs were mild to moderate in intensity, and only one subject experienced a TR-SAE. Few TEAEs led to discontinuation of INCO; there were no fatal TEAEs in subjects receiving INCO. In general, repeated cycles did not increase the incidences of any TEAE category. TR-TEAEs affecting ≥1% of patients were uncommon in patients with spasticity. TR-AESIs across all indications were most commonly muscular weakness and dry mouth. Few subjects developed NAb; the vast majority of those positive at the end of the study were also positive at baseline. <h3>Conclusions:</h3> Results of this pooled analysis support and extend the favorable safety and tolerability profile of INCO for the treatment of adult neurological disorders. <b>Disclosure:</b> Dr. Comella has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Acorda Therapeutics. Dr. Comella has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Lundbeck LTD. Dr. Comella has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Allergan Inc. Dr. Comella has received personal compensation in the range of $0-$499 for serving as a Consultant for Merz. Dr. Comella has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Acadia. Dr. Comella has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Neurocrine. Dr. Comella has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Revance. Dr. Comella has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Sunovion. Dr. Comella has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Aeon. Dr. Comella has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Jazz . Dr. Comella has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Ipsen. Dr. Comella has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Jazz Pharmaceutical. Dr. Comella has received publishing royalties from a publication relating to health care. Dr. Comella has received publishing royalties from a publication relating to health care. Michael Hast has received personal compensation for serving as an employee of Merz. Angelika Hanschmann has received personal compensation for serving as an employee of Merz Pharmaceuticals GmbH.

Real-world use of defibrotide for veno-occlusive disease/sinusoidal obstruction syndrome: the DEFIFrance Registry Study

Veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially life-threatening complication of haematopoietic cell transplantation (HCT) conditioning. The DEFIFrance post-marketing registry study evaluated effectiveness and safety in patients who received defibrotide. It collected retrospective/prospective patient data from 53 French HCT centres from July 2014 to March 2020. Primary endpoints were survival and complete response (CR; total serum bilirubin <2 mg/dL, multiorgan failure resolution) at Day 100 post-HCT among patients with severe/very severe VOD/SOS. A secondary endpoint was evaluation of treatment-emergent serious adverse events (TESAEs) of interest. Of 798 patients analysed, 251 and 81 received defibrotide treatment for severe/very severe VOD/SOS and mild/moderate VOD/SOS post-HCT, respectively; 381 received defibrotide for VOD/SOS prophylaxis. In patients with severe/very severe VOD/SOS post-HCT, Kaplan–Meier–estimated CR at Day 100 was 74% (95% confidence interval [CI]: 66%, 81%). At Day 100, 137/251 (55%) were alive and in CR. Kaplan–Meier–estimated Day 100 post-HCT survival was 61% (95% CI: 55%, 67%) in patients with severe/very severe VOD/SOS. TESAEs of interest occurred in 29% of these patients; VOD/SOS-related mortality at 12 months was 15%. DEFIFrance represents the largest collection of real-world data on post-registration defibrotide use, supporting the real-world utility of defibrotide for patients with severe/very severe VOD/SOS post-HCT.

Terminal Complement Inhibition and Control of Hemolysis in Paroxysmal Nocturnal Hemoglobinuria Following Switching from High-Dose Eculizumab to Ravulizumab: An Interim Analysis

Background: Intravenous (IV) complement component 5 (C5) inhibitors, eculizumab and ravulizumab, are the current standards of care in patients with paroxysmal nocturnal hemoglobinuria (PNH), a rare chronic blood disorder characterized by terminal complement activation, intravascular hemolysis (IVH), thrombotic events and organ damage. Ravulizumab is a second-generation analog of eculizumab with substitutions of four amino acids in the chemical backbone. This design enables ravulizumab to provide the same clinical benefit as eculizumab in patients with PNH at a longer dosing interval (every 8 weeks [q8w] vs every 2 weeks [q2w]). Approximately 10-15% of patients with PNH who receive the approved, fixed eculizumab dose (900 mg q2w) experience insufficient inhibition of IVH, as characterized by breakthrough hemolysis (BTH) towards the end of the dosing interval. In such patients, increasing the eculizumab dose (to > 900 mg q2w) can be effective. However, currently there are no recommendations or clinical trial data regarding the impact of switching these patients to ravulizumab. Aim: To assess the safety of switching from high-dose eculizumab to approved, weight-based ravulizumab dosing in patients with PNH. Methods: Study 401 (NCT04320602) is an ongoing, phase 4, single-arm, multicenter trial designed to investigate the impact of switching treatment from fixed, high-dose IV eculizumab (1200 mg q2w) to weight-based IV ravulizumab q8w in adult (≥ 18 years of age; N = 18) patients with PNH. Prior to (≥ 3 months) screening, patients receive high-dose IV eculizumab (1200 mg q2w); patients continue to receive this throughout the 3-month screening period before switching to weight-based IV ravulizumab. Patients receive loading and maintenance ravulizumab doses, as per the approved prescribing information (Alexion, AstraZeneca Rare Disease. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/761108s000lbl.pdf). The primary endpoint is the proportion of patients who experience serum free C5-associated BTH (defined as ≥ 1 new or worsening symptom or sign of IVH [fatigue, hemoglobinuria, abdominal pain, dyspnea, anemia, major adverse vascular events, dysphagia or erectile dysfunction] with lactate dehydrogenase [LDH] levels ≥ 2 × upper limit of normal [ULN] and free C5 concentrations ≥ 0.5 μg/mL). Other endpoints include change in free C5 concentrations and LDH levels over time, and the proportion of patients with treatment-emergent adverse events (TEAEs) and treatment-emergent serious adverse events (TESAEs). This interim analysis describes data up to day 183 of follow-up. Results: Data for 10/18 enrolled patients (55.6%) were available. Baseline demographics and clinical characteristics are described in Table 1. From baseline to day 183, no instances of free C5-associated BTH were reported and free C5 concentrations remained below 0.5 μg/mL for all patients at all study timepoints (Figure 1). Similarly, from baseline to day 183, LDH levels remained ≤ 1.5 × ULN in all patients. Up to day 183, 7/10 patients (70.0%) reported TEAEs that were mild (n = 3, 30.0%) or moderate (n = 4, 40.0%) in severity. There were no instances of meningococcal infection, TESAEs and none of the documented TEAEs led to death or study withdrawal. BTH was reported in one patient (local laboratory-reported LDH level = 492.0 U/L; local normal range: 120.0-246.0 U/L), this was deemed to be vaccine-related as both coronavirus disease 2019 and influenza vaccinations were administered the day prior to the event. However, no elevated free C5 level was detected in the earliest available sample (0.11 μg/mL, collected four days after the event) and the patient continued ravulizumab treatment. Conclusions: Results of this interim analysis showed that, based on a small sample of patients with PNH (N = 10), switching treatment from high-dose IV eculizumab (1200 mg q2w) to standard, weight-based IV ravulizumab q8w was well tolerated, with minimal changes in laboratory measures associated with PNH symptoms. Up to day 183, no free C5-associated BTH was reported and the safety profile of ravulizumab was considered comparable to previously published studies, with no instances of meningococcal infection or TESAEs reported. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Final Clinical Outcomes from a Phase 2 Trial of Posoleucel, an Off-the-Shelf, Multivirus-Specific T-Cell Therapy, for the Prevention of Clinically Significant Viral Infections Post-HCT

Background: Allogeneic hematopoietic cell transplant (allo-HCT) recipients are highly susceptible to reactivation of double-stranded DNA viruses. Approximately 70% of high-risk allo-HCT recipients develop clinically significant infections (CSI, defined as viremia + treatment or end organ disease). We present results from a phase 2 trial evaluating the safety and efficacy of posoleucel, a partially HLA-matched, off-the-shelf, multivirus-specific T cell investigational product, for preventing CSIs due to adenovirus (AdV), BK virus (BKV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), human herpesvirus 6 (HHV-6), or JC virus (JCV). Methods: This open-label trial enrolled high-risk allo-HCT recipients, including those with grafts from haploidentical, umbilical cord blood, mismatched unrelated donors, and matched unrelated donors with lymphocytes <180/mm3 as well as recipients who underwent T cell depletion. To be eligible, patients had to be engrafted and within 15-49 days of allo-HCT. Those with grade ≥3 GVHD and those requiring steroids (>0.5 mg/kg/day prednisone equivalent) at enrollment were ineligible. Patients received up to 7 infusions of posoleucel once every 14 days and were tested weekly for viremia using quantitative PCR assays. The primary endpoint was the number of CSIs due to AdV, BKV, CMV, EBV, HHV-6, or JCV by week 14. IFN-γ ELISpot analysis was performed for each targeted virus on serial peripheral blood samples to assess functional T cell immune reconstitution and determine the frequency of circulating virus-specific T cells detected over time. To evaluate the persistence and potential contribution of posoleucel to antiviral immune reconstitution, T-cell receptor (TCR) β immunosequencing was performed at selected timepoints. TCR sequences unique to posoleucel were identified computationally and used to track in vivo persistence in serial samples. Results: Twenty-six patients were dosed. Posoleucel dosing began a median of 42 days after allo-HCT. Twenty (77%) patients had viral DNA detected in blood (reactivation) from one or more viruses, 13 (50%) had 2 or more viral reactivations, and 7 (27%) had 3 or more viral reactivations in the 14 weeks after the initiation of posoleucel dosing (Figure). However, by week 14, only 3 patients (12%) had CSIs (2 CMV viremia requiring treatment and 1 EBV-post-transplant lymphoproliferative disorder). No patient had a CSI with more than 1 virus. Nine patients (35%) experienced adverse events that were possibly or probably related to treatment. Eight patients (31%) had serious adverse events (SAEs), 2 of which were judged to be possibly related to treatment (skin and pulmonary GVHD) and 1 probably related to treatment (allergic reaction). Overall, 8 patients (31%) had acute GVHD Grade II-IV. One patient (4%) discontinued posoleucel due to a treatment-emergent SAE of chronic pulmonary GVHD. No patient experienced cytokine release syndrome. TCR sequencing data (N=12) indicated that posoleucel was detectable in vivo during the dosing phase of the study and for up to 12 weeks after the last infusion, with polyclonal VSTs detected in all 12 patients. Six of the 7 patients with available ELISpot data demonstrated IFN-γ-producing virus-specific T cell responses coincident with viral replication. The confirmed persistence of posoleucel and expansion of IFN-γ-producing virus-specific T cells directed against reactivating viruses, suggests a contribution of posoleucel to functional immune reconstitution. Conclusion: Results from this open-label phase 2 trial show that high-risk allo-HCT patients who received posoleucel had lower than expected rates of clinically significant viral infections from the 6 targeted viruses despite the observed and expected low-level viral reactivations throughout the study. Repeat dosing of posoleucel was generally safe and well tolerated. Posoleucel VSTs were detected in vivo for up to 26 weeks, and reconstituting T cells demonstrated functional specificity for multiple viruses. A placebo-controlled global phase 3 trial evaluating the safety and tolerability of posoleucel for the prevention of clinically significant AdV, BKV, CMV, EBV, HHV-6, and JCV infections is ongoing (NCT05305040). Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

RAAV immunogenicity, toxicity, and durability in 255 clinical trials: A meta-analysis.

Recombinant Adeno-associated virus (rAAV) is one of the main delivery vectors for gene therapy. To assess immunogenicity, toxicity, and features of AAV gene therapy in clinical settings, a meta-analysis of 255 clinical trials was performed. A total of 7,289 patients are planned to be dosed. AAV2 was the most dominantly used serotype (29.8%, n=72), and 8.3% (n=20) of trials used engineered capsids. 38.7% (n=91) of trials employed neutralizing antibody assays for patient enrollment, while 15.3% (n=36) used ELISA-based total antibody assays. However, there was high variability in the eligibility criteria with cut-off tiers ranging from 1:1 to 1:1,600. To address potential immunogenicity, 46.3% (n=118) of trials applied immunosuppressants (prophylactic or reactive), while 32.7% (n=18) of CNS and 37.5% (n=24) of ocular-directed trials employed immunosuppressants, possibly due to the immune-privileged status of CNS and retina. There were a total of 11 patient deaths across 8 trials, and 18 out of 30 clinical holds were due to toxicity findings in clinical studies. 30.6% (n=78) of trials had treatment-emergent serious adverse events (TESAEs), with hepatotoxicity and thrombotic microangiopathy (systemic delivery) and neurotoxicity (CNS delivery) being the most prominent. Additionally, the durability of gene therapy may be impacted by two distinct decline mechanisms: 1) rapid decline presumably due to immune responses; or 2) gradual decline due to vector dilution. The durability varied significantly depending on disease indication, dose, serotypes, and patient individuals. Most CNS (90.0%) and muscle trials (73.3%) achieved durable transgene expression, while only 43.6% of ocular trials had sustained clinical outcomes. The rAAV production system can affect rAAV quality and thus immunogenicity and toxicity. Out of 186 trials that have disclosed production system information, 63.0% (n=126) of trials used the transient transfection of the HEK293/HEK293T system, while 18.0% (n=36) applied the baculovirus/Sf9 (rBac/Sf9) system. There were no significant differences in TESAEs and durability between AAV generated by rBac/Sf9 and HEK293/HEK293T systems. In summary, rAAV immunogenicity and toxicity poses significant challenges for clinical development of rAAV gene therapies, and it warrants collaborative efforts to standardize monitoring/measurement methods, design novel strategies to overcome immune responses, and openly share relevant information.

THE DEFIFRANCE REGISTRY STUDY: EFFECTIVENESS AND SAFETY OF DEFIBROTIDE IN PATIENTS WITH VENO-OCCLUSIVE DISEASE/SINUSOIDAL OBSTRUCTION SYNDROME FOLLOWING CHEMOTHERAPY

Veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially life-threatening complication of haematopoietic cell transplantation (HCT) that can also occur after high-dose chemotherapy. Defibrotide is approved in Brazil and the US for treatment of VOD/SOS with renal or pulmonary dysfunction post-HCT in adult and paediatric patients (pts), and in the EU for treatment of severe hepatic VOD/SOS post-HCT in pts aged >1 month. This analysis presents outcomes in pts who received defibrotide treatment for VOD/SOS post-chemotherapy from the DEFIFrance registry study. This post-marketing registry study collected retrospective and prospective real-world data on pts receiving defibrotide at 53 HCT centres in France. VOD/SOS diagnosis was per the investigator's typical clinical practice. Disease severity was categorised using adult EBMT severity criteria in adults; paediatric pts (<18 years) were retrospectively/prospectively categorised using paediatric EBMT severity criteria. Survival and complete response (CR; total serum bilirubin < 2 mg/dL and multiorgan failure [MOF] resolution per investigator's assessment) rates by Day 100 post-VOD/SOS diagnosis were calculated. Treatment-emergent serious adverse events (TESAEs) of interest were haemorrhage, coagulopathy, injection-site reactions, infections, and thromboembolic events, irrespective of relationship to treatment. Overall, 46 pts (19 [41%] paediatric and 27 [59%] adults) received defibrotide for VOD/SOS post-chemotherapy. Median age was 5.8 years (range: 2, 17) in paediatric pts and 56.6 years (range: 18, 72) in adults. Paediatric pts were more likely than adults to have a primary diagnosis of ALL (paediatric: 53%; adult: 22%) or neuroblastoma/solid tumour (32%; 0%), while AML (11%; 63%) was more common in adults. Paediatric pts were less likely to have prior exposure to gemtuzumab ozogamicin and inotuzumab ozogamicin (11% and 0%, respectively) than adults (41% and 15%). VOD/SOS was severe/very severe in all paediatric pts and 22 (81%) adults. MOF was present in 5 (26%) paediatric pts and 10 (37%) adults, including renal failure (paediatric: 60%; adult: 70%), respiratory failure (100%; 80%), and cerebral failure (20%; 70%). By Day 100 post-VOD/SOS diagnosis, the Kaplan-Meier (KM)–estimated survival rate was 74% in paediatric pts and 37% in adults, and the CR rate was 68% in paediatric pts and 37% in adults. Of 5 paediatric pts who died within 100 days of VOD/SOS diagnosis, all 5 had very severe VOD/SOS (4 with MOF). Of 17 adults who had died by Day 100, 10 had very severe VOD/SOS (9 with MOF). By Day 100, 2 paediatric pts and 6 adults had died due to relapse/progressive disease and there were no VOD/SOS-related deaths. TESAEs of interest occurred in 15% of pts with VOD/SOS post-chemotherapy (paediatric: 11%; adult: 19%), including infection and haemorrhage (each 9% in the overall group). In this real-world DEFIFrance study, the majority of pts who received defibrotide for VOD/SOS post-chemotherapy had severe/very severe VOD/SOS and a notable proportion had MOF, indicating advanced disease in this pt population. These data indicate that VOD/SOS is a concern outside the HCT setting and suggest a need for continuous vigilance for signs and symptoms of VOD/SOS among those monitoring pts after chemotherapy, to facilitate earlier diagnosis.

Hypoxia-inducible factor prolyl hydroxylase inhibitors for anaemia in maintenance dialysis: a meta-analysis.

Anaemia is a common complication of end-stage renal disease (ESRD) that relies on dialysis. Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHI) is a new class of small-molecule oral drugs for the treatment of anaemia in chronic kidney disease. They demonstrate several advantages over traditional exogenous erythropoietin (EPO). We conducted a meta-analysis of studies that compared the efficacy of HIF-PHI in erythropoiesis and iron metabolism, and its safety with EPO in maintenance dialysis patients. A sensitive search strategy in the PubMed, EMBASE and Cochrane databases identified all citations for randomised controlled trials (RCTs) comparing HIF-PHI agents with EPO/placebo through December 2021. Fourteen RCTs were identified, which included 2738 patients. No statistical difference was found in haemoglobin increase (p = 0.37) between HIF-PHI treatment and EPO using the random-effects model. HIF-PHI administration upregulated transferrin (MD 36.12, 95% CI 27.04-45.20) and soluble transferrin receptors (sTfR) (MD 1.28, 95% CI 0.44-2.13), but did not statistically reduce hepcidin level (p = 0.37). Total and LDL-cholestrol levels were suppressed by HIF-PHI (MD - 0.99, 95% CI - 1.34 to - 0.63) (MD - 0.99, 95% CI - 1.34 to - 0.64), while triglyceride (TG) was not different between HIF-PHI and EPO (p = 0.74). The total incident rates of treatment-emergent adverse events (TEAE) (p = 0.20) from HIF-PHI treatment were not different from those of erythropoietin, while the treatment-emergent serious adverse events (TSAE) (p = 0.02) were higher in the HIF-PHI group than those in the EPO controls with the fixed-effect model. HIF-PHI could effectively upregulate and maintain haemoglobin levels in patients with anaemia receiving maintenance dialysis. Furthermore, HIF-PHI could elevate iron metabolism activity and utility without inducing treatment-associated serious adverse events. Robust data from larger RCTs with longer treatment duration and follow-up are needed.

†Efficacy and Safety of Inclisiran in Patients with Polyvascular Disease: Pooled Post hoc Analysis of the phase 3 ORION-9, ORION-10, and ORION-11 Randomized Controlled Trials

<h3>Lead Author's Financial Disclosures</h3> Wolfgang Koenig, MD has received consulting fees and lecture fees from AstraZeneca, Novartis and Amgen; consulting fees from Pfizer, the Medicines Company, DalCor Pharmaceuticals, Genentech, Esperion, OMEICOS, Novo Nordisk, LIB Therapeutics, Kowa, Corvidia Therapeutics and Daiichi Sankyo; lecture fees from Berlin- Chemie, Bristol-Myers Squibb and Sanofi; and grant support and provision of reagents from Singulex, Abbott, Roche Diagnostics and Dr. Beckmann Pharma. <h3>Study Funding</h3> Novartis Pharma AG, Basel, Switzerland. <h3>Background/Synopsis</h3> Approximately 25% of patients with atherosclerotic cardiovascular disease (ASCVD) have polyvascular disease (PVD) involving 2 or more coronary, cerebrovascular, and peripheral artery beds. PVD is an independent predictor of major adverse cardiovascular events (MACE) and death. Agents that inhibit proprotein convertase subtilisin/kexin type 9 (PCSK9) reduce low-density lipoprotein cholesterol (LDL-C) concentrations and MACE incidence in patients with PVD. Inclisiran is a small interfering RNA agent targeting PCSK9 messenger RNA that is well tolerated and provides effective and sustained LDL-C reductions. <h3>Objective/Purpose</h3> To describe the effect of inclisiran vs placebo in patients with and without PVD. <h3>Methods</h3> This was a post hoc analysis of patients with heterozygous familial hypercholesterolemia or ASCVD or its risk equivalents randomized 1:1 to 300mg inclisiran sodium (equivalent to 284mg inclisiran) or placebo at baseline, Day 90, and 6 monthly thereafter in ORION-9 (NCT03397121), ORION-10 (NCT03399370), and ORION-11 (NCT03400800). Evaluations included LDL-C percentage change from baseline to Day 510 and corresponding time-averaged change from Day 90 to Day 540, with both evaluated by PVD presence or absence, and safety over 540 days. <h3>Results</h3> Baseline characteristics for 470 patients (13.6%) with PVD and 2984 (86.4%) without PVD were generally balanced between treatment arms in both groups, with higher cardiovascular risk factors and lower LDL-C concentrations in patients with PVD (Table 1). Mean (95% CI) placebo-corrected LDL-C percentage changes from baseline to Day 510 with inclisiran were −48.9% (−55.6 to −42.2) in patients with PVD and −51.5% (−53.9 to −49.1) in those without (Table 2). Treatment-emergent adverse events (TEAEs) and treatment-emergent serious adverse events (TESAEs) were similar between treatment arms irrespective of PVD status, although reported TESAEs trended higher with PVD in both treatment arms (Table 2). Clinically relevant injection site TEAEs were more frequent with inclisiran vs placebo in both groups; all were mild or moderate. Few patients had clinically relevant laboratory measurements (Table 2). <h3>Conclusions</h3> Twice-yearly dosing with inclisiran (after the initial and 3-month doses) provided effective and sustained LDL-C lowering in patients with ASCVD irrespective of their PVD status, with a safety profile similar to that of placebo except for a modest increase in mainly mild TEAEs at the injection site. Notably, TESAEs were reported more frequently in patients with PVD, which was likely due to their more advanced disease. Since patients with PVD are at high risk of cardiovascular events, intensive LDL-C lowering may be beneficial to reduce this risk.

P813: EFFICACY, TREATMENT ADMINISTRATION SATISFACTION AND SAFETY OF SUBCUTANEOUS RAVULIZUMAB THROUGH 1 YEAR IN PATIENTS WITH PAROXYSMAL NOCTURNAL HEMOGLOBINURIA WHO RECEIVED PRIOR INTRAVENOUS ECULIZUMAB

Background: The efficacy of ravulizumab (intravenous [IV] formulation; administered every 8 weeks) for the treatment of patients with paroxysmal nocturnal hemoglobinuria (PNH) has been demonstrated in several randomized trials (NCT02946463, NCT03056040, NCT03406507). In study 303 (NCT03748823), subcutaneous (SC) ravulizumab, administered weekly via an on-body delivery system, showed pharmacokinetic non-inferiority to IV ravulizumab in adult patients with PNH who were clinically stable on prior IV eculizumab treatment. Here, we report results from the first 1 year of SC treatment, starting at day 15 for patients who continued SC ravulizumab during the extension period (SC/SC) and day 71 for patients who switched from IV ravulizumab to SC ravulizumab (IV/SC). Aims: To evaluate the efficacy, treatment administration satisfaction and safety of SC ravulizumab through the first 1 year (day 351) of treatment in adult patients with PNH previously treated with eculizumab. Methods: Patients (≥ 18 years) with clinically stable PNH (lactate dehydrogenase [LDH] levels ≤ 1.5 × upper limit of normal [246 U/L]) and ≥ 3 months prior eculizumab treatment were enrolled in the study, which consisted of a screening period (day -1 to day -30), a 10-week randomized treatment period and an extension period of up to 172 weeks. During the randomized treatment period, patients were assigned (2:1 ratio) to receive either SC ravulizumab or IV ravulizumab; all patients received SC ravulizumab during the extension period. Efficacy endpoints included: change in LDH from baseline; incidence of breakthrough hemolysis; transfusion avoidance; and stabilized hemoglobin (avoidance of a ≥ 2 g/dL decrease in hemoglobin in the absence of transfusion). Treatment administration satisfaction was assessed via the Treatment Administration Satisfaction Questionnaire (TASQ), which has been validated in a PNH population. Safety, including adverse events (AEs), serious AEs (SAEs) and adverse device effects (ADEs), were also assessed up to the 1-year data cut-off. Results: In total, 128 patients received SC ravulizumab (SC/SC: n = 84; IV/SC: n = 44; mean [range] duration of SC treatment: 486.4 [37–709] days). Efficacy endpoints (SC/SC and IV/SC) remained stable over time through 1 year of SC ravulizumab treatment. Mean (standard deviation [SD]) percentage change in LDH from baseline to SC day 351 was 0.9% (20.5%). Breakthrough hemolysis events were infrequent: 5/128 patients (3.9%); no event was considered free C5-related. Transfusion avoidance was maintained in 83.6% of patients during SC treatment, and 79.7% achieved stabilized hemoglobin. Improvement in total TASQ score with SC ravulizumab (compared with baseline IV eculizumab) was apparent at the first post-SC treatment assessment (SC day 29) and maintained until data cut-off (Figure). The most common AEs (reported by ≥ 10% of patients, excluding ADEs related to device product issues) during SC treatment were headache (14.1%, all grade ≤ 2), COVID-19 (14.1%, one death) and pyrexia (10.9%); injection site reaction (4.7%) was the most common non-device related ADE. Treatment-emergent SAEs were experienced by 21.1% of patients through to data cut-off. Although many patients had ≥ 1 device issue ADE, full SC dose administration was achieved in 99.9% of attempts. ADE incidence decreased over time. Image:Summary/Conclusion: The SC method of administration provides an additional treatment option for patients with PNH receiving ravulizumab therapy. Patients may be switched from IV eculizumab or IV ravulizumab to SC ravulizumab without loss of efficacy.

P1355: VENO-OCCLUSIVE DISEASE/SINUSOIDAL OBSTRUCTION SYNDROME (VOD/SOS) AFTER AUTOLOGOUS HEMATOPOIETIC CELL TRANSPLANTATION (HCT): OUTCOMES OF DEFIBROTIDE-TREATED ADULT PATIENTS FROM THE DEFIFRANCE STUDY

Background: Hepatic VOD/SOS is a potentially fatal complication of HCT conditioning. Although allogeneic HCT (allo-HCT) and autologous HCT (auto-HCT) conditioning regimens often contain the same drugs, their protocols differ. VOD/SOS is more common after allo-HCT, but it also occurs after auto-HCT. Defibrotide is approved for the treatment of severe VOD/SOS post-HCT in patients aged >1 month in the European Union and for VOD/SOS with renal or pulmonary dysfunction post-HCT in the United States. The DEFIFrance study collected real-world data on the effectiveness and safety of defibrotide from HCT centers in France. Aims: This post-hoc analysis presents patient characteristics and effectiveness and safety outcomes in adult patients who received defibrotide treatment for VOD/SOS after auto-HCT. Methods: This post-marketing registry study collected retrospective and prospective real-world data on patients receiving defibrotide at 53 HCT centers in France. Diagnosis of VOD/SOS was at the investigator’s discretion using standard criteria, per typical clinical practice. Disease severity was categorized using adult EBMT severity criteria in patients aged ≥18 years. The primary endpoints were Kaplan-Meier (KM)–estimated Day 100 post-HCT survival and complete response (CR; total serum bilirubin <2 mg/dL and multiorgan failure resolution per investigators’ assessment) in patients with severe/very severe VOD/SOS. A secondary endpoint was the evaluation of treatment-emergent serious adverse events (SAEs) of interest: hemorrhage, coagulopathy, immunogenicity, injection-site reaction, septicemia, infection, and thromboembolic event, irrespective of relationship to treatment. Results: Of 249 adult patients in the post-HCT population treated with defibrotide, 22 (9%) underwent auto-HCT. Median age of this subgroup was 53.7 (range: 22, 66) years. The most common primary disease was lymphoma/chronic lymphocytic leukemia (n = 18 [82%]), and 1 (5%) patient each had either ALL, AML, neuroblastoma/solid tumor, or myeloma. The majority of patients with available data (20/21 [95%]) received intensive, myeloablative conditioning. The median time from auto-HCT to VOD/SOS diagnosis was 14.0 (range: 0, 185) days. At diagnosis, 17 (77%) patients had ascites, 16 (73%) had refractory thrombocytopenia, and 10 (45%) had anicteric VOD/SOS. Seven (32%) patients had mild/moderate VOD/SOS, 9 (41%) had severe, and 4 (18%) had very severe. The median duration of defibrotide treatment was 15.0 (range: 3, 55) days. By Day 100 post-HCT, the KM–estimated survival rate was 73% (95% CI: 49%, 87%). The CR rate at Day 100 was 55% (95% CI: 32%, 76%). Treatment-emergent SAEs of interest occurred in 4 (18%) patients, specifically: catheter site hemorrhage, gastrointestinal hemorrhage, coagulopathy, and hypotension, each occurring in 1 patient. Summary/Conclusion: VOD/SOS can develop after auto-HCT and can be severe. Defibrotide treatment has previously demonstrated efficacy among patients with VOD/SOS after auto-HCT. The DEFIFrance study represents the largest collection of real-world data on post-registration use of defibrotide. The effectiveness and safety observed in this post-hoc analysis support the real-world use of defibrotide in adult patients who develop VOD/SOS after auto-HCT.

DS-7300 (B7-H3 DXd-ADC) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC): A subgroup analysis of a phase 1/2 multicenter study.

87 Background: DS-7300 is an antibody drug conjugate with an exatecan derivative payload that targets B7-H3, which is overexpressed in various cancers. Initial findings from an ongoing phase 1/2 dose escalation study for advanced solid tumors, and dose-expansion studies in esophageal squamous cell carcinoma and mCRPC (NCT04145622) showed that DS-7300 was generally well tolerated with early signs of clinical activity (ESMO 2021, abstract 513O). Here, we present preliminary results from the mCRPC pt subset. Methods: This study consisted of 2 parts: dose- escalation (part 1) and expansion (part 2). Part 1 assessed the safety and tolerability of DS-7300 with doses ranging from 0.8 to 16 mg/kg. A dose of 12 mg/kg was selected for part 2. Part 2 assessed safety and prospective efficacy of DS-7300 in the selected tumor types, including mCRPC. DS-7300 was administered intravenously every 3 weeks in parts 1 and 2. Results: At data cutoff (August 8, 2021), 29 pts with mCRPC from the US and Japan were enrolled in parts 1 (n = 24) and 2 (n = 5). Pts enrolled in this study were heavily pretreated, with a median of 6.0 (range, 2-10) and 5.0 (range, 3-10) prior lines of therapy in parts 1 and 2, respectively. Baseline B7-H3 expression was highly prevalent in the study population. Enrolled pts were 44 to 82 years of age (median, 68.0 years) and had an ECOG performance status ≤1. Treatment-emergent adverse events (TEAEs) occurred in 29 pts (100.0%) in parts 1 and 2, with 7 pts (21.4%) with TEAEs leading to dose interruption, 2 pts (6.9%) with TEAEs leading to dose reduction, and no pts with TEAEs associated with drug discontinuation. The most common (≥20%) all-grade (Gr) TEAEs were nausea (65.5%), infusion-related reactions (IRRs; 34.5%), fatigue (34.5%), chills (31.0%), vomiting (31.0%), anemia (27.6%), diarrhea (27.6%), and dehydration (20.7%). Gr ≥3 TEAEs occurred in 10 pts (34.5%); the most common was anemia (17.2%). There were no Gr ≥3 treatment-related serious TEAEs (SAEs) reported. All IRR cases were Gr 1/2 and manageable with supportive care. No ILD/pneumonitis cases were reported. RECIST responses were observed in pts treated with DS-7300 between 6.4- and 16.0-mg/kg doses, including 6 partial responses (4 confirmed) and 15 stable diseases. The median duration of treatment was 13.9 weeks (range, 3-40 weeks) in part 1 and 6.0 weeks (range, 3-9.14 weeks) in part 2. At data cutoff, 8 pts (66.7%) in the 12.0-mg/kg group in part 1 and 4 pts (80.0%) in part 2 were ongoing treatment. Moreover, preliminary data indicate improvements in prostate-specific antigen (PSA) and bone metastases. Conclusions: DS-7300 was well tolerated with an acceptable safety profile in pts with mCRPC. The preliminary safety and efficacy data are encouraging and warrant further investigation. Clinical trial information: NCT04145622.