Clinical Safety Data Research Articles

Integrating PARP Inhibitors in mCRPC Therapy: Current Strategies and Emerging Trends.

Metastatic castrate-resistant prostate cancer (mCRPC) is associated with poor prognosis. DNA damage response (DDR) genes are commonly altered in mCRPC rendering them as promising therapeutic targets. Poly (ADP ribose) polymerase inhibitors (PARPi) demonstrated antitumor activity in mCRPC patients with DDR gene mutations through synthetic lethality. Multiple clinical trials with PARPi monotherapy exhibited encouraging clinical outcomes in selected patients with mCRPC. More recently, three Phase III randomized clinical trials (RCTs) combining PARPi with androgen receptor signaling inhibitors (ARSIs) demonstrated improved antitumor activity compared to ARSI monotherapy in mCRPC patients as the first-line therapy. Clinical benefit was more pronounced in patients harboring DDR alterations, specificallyBRCA1/2. Interestingly, antitumor activity was also observed irrespective of DDR gene mutations, highlighting BRCAness phenotype with androgen receptor blockade resulting in synergistic activity between ARSIs and PARPi. In this review, we discuss the clinical efficacy and safety data of the combination of PARPi plus ARSI in all Phase 3 randomized controlled trials (RCTs), emphasizing strategies for patient selection and highlighting emerging trends based on clinical trial data.

Safety and efficacy of colchicine in crystal-induced arthritis flare in 54 patients with severe chronic kidney disease

IntroductionColchicine, commonly used in gout flare, is contraindicated in severe chronic kidney disease (CKD) (estimated glomerular filtration rate <30 mL/min). However, in this context, there are few alternatives, and colchicine...

Risankizumab: Mechanism of action, clinical and translational science.

Risankizumab is a high-affinity neutralizing anti-interleukin (IL)-23 monoclonal antibody marketed in over 40 countries across the globe to treat several inflammatory diseases, such as plaque psoriasis (PsO), psoriatic arthritis (PsA), and Crohn's disease (CD). This paper reviews the regulatory approval, mechanism of action, pharmacokinetics (PKs)/pharmacodynamics, immunogenicity, and clinical efficacy and safety data for risankizumab, focusing on the three main approved indications. Risankizumab binds to the p19 subunit of IL-23 and inhibits IL-23 from interacting with the IL-23 receptor and subsequent signaling. Biomarker data obtained following treatment with risankizumab in multiple indications provided supportive evidence for downstream blockade of IL-23 signaling associated with disease pathology. The PKs of risankizumab is linear and time-independent, consistent with typical IgG1 monoclonal antibodies, across all evaluated indications. Risankizumab exhibited positive exposure-response relationships for efficacy with no apparent exposure-dependent worsening in safety. Immunogenicity to risankizumab had no major clinical consequences for either efficacy or safety. Efficacy and safety of risankizumab have been established in PsO, PsA, and CD in the pivotal clinical trials where superior benefit/risk profiles were demonstrated compared to placebo and/or active comparators. Moreover, safety evaluations in open-label extension studies following long-term treatment with risankizumab showed stable and favorable safety profiles consistent with shorter-term studies. These data formed the foundation for risankizumab's marketing approvals to treat multiple inflammatory diseases across the globe.

Cost-effectiveness analysis of 11 pharmacotherapies for recurrent glioblastoma in the USA and China.

Several studies have systematically assessed the efficacy and safety of progressive or recurrent glioblastoma multiforme (GBM). However, the discernible limitations of efficacy and the elevated costs of interventions instigate an investigation into the cost-effectiveness of these treatments. This study aimed to evaluate cost-effectivenesses of 11 pharmacotherapeutic interventions for recurrent GBM from the perspective of healthcare payers in the United States (US) and China. A model-based pharmacoeconomic evaluation. A partitioned survival model was employed to evaluate the cost-effectiveness of 11 distinct drug-based treatments. The clinical efficacy and safety data were obtained from a network meta-analysis, while the medical expenditure and health utility were primarily derived from published literature. One-way sensitivity analyses, scenario analyses, and probabilistic sensitivity analyses (PSA) were performed to scrutinize the impact of potential uncertainties to ensure the robustness of the model. The primary endpoint was the incremental cost-effectiveness ratio. Among the therapeutic interventions evaluated, lomustine emerged as the cheapest option, with costs amounting to $78,998 in the United States and $30,231 in China, respectively. Regorafenib displayed the highest quality-adjusted life years at 0.475 in the United States and 0.465 in China. The one-way sensitivity analyses underscored that drug price was a key factor influencing cost-effectiveness. Both scenario and PSA consistently demonstrated that, considering the willingness-to-pay thresholds, lomustine was a cost-effective treatment with probability of more than 94%. In comparison to the alternative antitumor agents, lomustine was likely to be a cost-effective option for relapsed GBM patients from the perspective of healthcare payers in both the United States and China.

HTA236 A Systematic Review of Clinical Efficacy and Safety Data in Penta-Refractory Multiple Myeloma: Findings Indicate the Challenges for HTA Submission

HTA236 A Systematic Review of Clinical Efficacy and Safety Data in Penta-Refractory Multiple Myeloma: Findings Indicate the Challenges for HTA Submission

Phase 1/2 Multicenter, Open-Label Study of CTX-712 in Patients with Relapsed/Refractory Acute Myeloid Leukemia and Higher Risk Myelodysplastic Syndromes

Background and Significance Dysregulation of alternative splicing, caused by abnormal expression or mutation of splicing factors, has been identified as an important contributor to the genesis and progression of cancer, and suggested as a novel target for anticancer treatment. CDC2-like kinases (CLK) represent a family of dual-specificity tyrosine and serine-threonine kinases that are involved in the regulation of splicing by phosphorylation of serine/arginine-rich splicing factors (SRSFs) which play a central role in exon recognition. CTX-712 is an orally available, potent, selective, and a first-in-class pan-CLK inhibitor (CLK 1-4), that inhibits phosphorylation of SRSFs resulting in significant antitumor activity in vitro and multiple xenograft models in vivo. CTX-712 formulated in capsules is currently being evaluated in an ongoing first-in-man study in Japan, evaluating tolerability and early efficacy in patients with solid tumors or hematologic malignancies (JapicCTI-184188). Preliminary data from the Japanese study were presented during ASCO 2022 and ASH 2022, and showed an acceptable safety profile (doses up to 175 mg (MTD 140 mg) twice a week in 28-day cycles, observed DLTs included dehydration, decreased platelets, hypokalemia, and pneumonia) with early signs of clinical antitumor activity (2 partial responses / 26 treated solid tumor patients, 5 complete remissions and complete remission with incomplete hematologic recovery/ 8 treated patients with AML or MDS), warranting further clinical investigations.. (J Clin Oncol (2022) 40(16_suppl):3080. Blood (2022) 140(Supplement 1):6211-2.). This abstract details a second study with CTX-712 that has just been initiated. Study Design and Methods A new film-coated tablet formulation will be evaluated in this phase 1/2 multicenter, open-label study of CTX-712 in patients with (mutated or wild type spliceosomes genes) relapsed/refractory AML, higher risk MDS (IPSS-R intermediate, high, or very high), or high marrow blast (≥5 %) MDS/MPN (including CMML). The phase 1 part of the study will be conducted at 4 US sites, and all sites are currently open for enrolment. The study allows patients with performance status 0, 1, or 2, adequate organ function, and up to four prior lines of therapy. Due to potential risk of interactions (in vitro studies suggest CYP3A4 as main metabolic pathway for CTX-712), concomitant use of strong CYP3A4 inhibitors is prohibited. Use of azole antifungals that are not strong CYP3A4 inhibitors (e.g., isavuconazole) is permitted. The phase 1 part of the study consists of dose-escalation (sequential standard 3 + 3 design), where cohorts of 3 (or 6) patients will receive ascending doses of CTX-712 once weekly in a 28-day cycle with continuous monitoring of emerging clinical PK, PD, safety, and efficacy data, to determine the recommended phase 2 dose (RP2D) based on the suggestion by the Safety Review Committee (SRC). The protocol defines five different dose levels (20-140 mg, once weekly) but also authorizes the SRC to suggest up to two interim dose levels or alternate schedules (e.g., dosing two times a week) if supported by emerging data. The suggested RP2D will be used in a confirmatory phase 1 expansion cohort where an additional 10 patients (total n = 16; 8 patients with AML and 8 patients with MDS) will be treated to gain further confidence in the selected dose level. The phase 2 part of the study will commence after the RP2D has been identified and confirmed and aims at evaluating therapeutic activity in R/R AML (Cohort 2a) or R/R HR-MDS (Cohort 2b), in addition to confirmation of the safety profile. Clinical trial registry number: NCT05732103

Patient-Reported Outcomes from the MCL Cohort of the Phase 1, Seamless Design TRANSCEND NHL 001 Study of Lisocabtagene Maraleucel in Patients with R/R B-Cell NHL

Background: MCL is an aggressive form of NHL. Despite high initial response rates to currently available frontline therapies for newly diagnosed MCL, patients will inevitably experience relapse. Survival outcomes are poor for patients with R/R MCL. Lisocabtagene maraleucel (liso-cel) is an autologous, CD19-directed, 4-1BB CAR T cell product administered at equal target doses of CD8 + and CD4 + CAR + T cells. In the primary analysis of the MCL cohort from the phase 1, seamless design TRANSCEND NHL 001 study (NCT02631044), liso-cel treatment resulted in a rapid, high ORR and high rate of durable CR with low incidences of grade ≥ 3 cytokine release syndrome, neurological events, and infections in heavily pretreated patients with high-risk, aggressive R/R MCL (Wang M, et al. Hematol Oncol 2023). Here, we present patient-reported outcomes (PRO) results from the MCL cohort of TRANSCEND NHL 001. Methods: Patients had R/R MCL after ≥ 2 lines of prior therapy, including a Bruton tyrosine kinase inhibitor, alkylating agent, and CD20-targeted agent. After leukapheresis and lymphodepleting chemotherapy (LDC), patients received liso-cel. Patients completed the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-30 items (EORTC QLQ-C30) and EQ-5D-5L utility index ≤ 7 days before LDC; before infusion on the day of liso-cel infusion (Day 1; baseline); then on Days 29, 60, 90, 180, 270, 365, 545, and 730 posttreatment; and at disease progression/relapse. Based on clinical relevance to MCL, the prespecified primary domains of interest were EORTC QLQ-C30 global health status/quality of life (QOL), physical functioning, fatigue, and pain. PRO analyses were conducted in all MCL patients treated with liso-cel who had an evaluable measure at baseline and at ≥ 1 postbaseline visit. The least squares (LS) mean change from baseline was estimated from a linear mixed-effects model for repeated measures at each time point above. Published minimally important difference thresholds (Cocks K, et al. Eur J Cancer 2012; Pickard AS, et al. Health Qual Life Outcomes 2007) were used to interpret whether LS mean changes from baseline were clinically meaningful. Proportions of patients with clinically meaningful change were calculated using published responder definitions of 5-30 points for EORTC QLQ-C30 domains (Cocks K, et al. Qual Life Res 2023), 0.08 for EQ-5D-5L utility index (Hernández-Alava M, et al. Pharmacoeconomics 2023), and 7 for EQ-5D-5L visual analog scale (EQ-VAS) (Pickard AS, et al. Health Qual Life Outcomes 2007). Results: Of 88 patients who received liso-cel, 66 were included in the PRO analyses (median age, 68.5 years [range, 36-86]; 76% male; 89% White; 94% not Hispanic or Latino). Baseline and clinical characteristics were comparable with those of the total liso-cel-treated population, including baseline ECOG PS scores and best response to any prior therapy. Baseline PRO scores for most primary domains were comparable with scores from a US general population norm; other domains fluctuated. Questionnaire completion rates ranged from 55% to 76% from Day 29 to Day 365 postinfusion. Overall LS mean changes from baseline showed significant and meaningful improvements for all primary domains except for pain, as well as for most other PRO domains. Although not showing meaningful improvement, pain scores remained largely unchanged through last assessment (Table 1). Across visits, most patients (60%-100%) experienced meaningful improvement or no meaningful change for all domains (primary domains shown in Table 2). More than 50% of patients achieved meaningful improvement in global health status/QOL, fatigue, social functioning, and EQ-VAS across visits after Day 29. In analyses evaluating the subset of patients in the MCL cohort with secondary CNS lymphoma (n = 5), improvements from baseline exceeded those of the non-secondary CNS population. Conclusions: Patients with R/R MCL who were treated with liso-cel in the MCL cohort of TRANSCEND NHL 001 showed meaningful improvements across relevant aspects of health-related QOL, including symptoms and functioning. Clinically meaningful improvements were observed for all primary domains except for pain, and for many of the other PRO domains. These findings complement the clinical efficacy and safety data from the primary analysis of the MCL cohort of TRANSCEND NHL 001, further supporting the benefit of liso-cel in patients with R/R MCL.

Safety profile of herbal medicines submitted for marketing authorization in Tanzania: a cross-sectional retrospective study

BackgroundThe popular use of herbal medicines necessitates national regulatory authorities to have efficient mechanisms for the control of these products including marketing authorization (MA) and safety follow-up. Herbal medicines like conventional medicines require assessment of efficacy, safety and quality information before MA can be granted. However, the complete proof of safety is mainly based on the history of the long-term traditional use. Herbal medicines can cause adverse reactions due to various factors and thus require clinical trials to ensure their safety. Herbal medicines treatment practices involve combinations of different plants to achieve the desired effect while multiple herbal components have been known to cause herbal–herbal toxicity and interactions due to variety of complex active ingredients in plants. Compliance with regulatory requirements on herbal medicines has been shown to be difficult for manufacturers since different countries have different regulatory requirements with wide variations which results in the MA of very few herbal medicines. Limited studies on dossiers of marketing authorization of herbal medicines have been performed in other countries, with no studies in African regulatory system settings. The aim of this study is to determine the type of safety documentation that is submitted on herbal medicines application dossiers to support MA in Tanzania.MethodsA cross-sectional retrospective study of herbal medicines dossiers submitted at the Tanzania Medicines and Medical Devices Authority from 2009 to 2020 was conducted.ResultsAs many as 75% of the herbal products applications were combination products made by more than one herbal substance or plant. Out of 84 dossiers subjected to analysis the majority did not provide evidence of preclinical (55%) and clinical safety data (68%). Evidence of safety data in humans was mostly from the literature (70%) and not manufacturers’ clinical studies. Quality parameters with safety implications were not included in 48% and 23% of the active herbal substance and finished product specifications, respectively.ConclusionAnalysis of the herbal medicine dossiers submitted showed major deficiencies of safety data to support MA. Manufactures need to provide evidence to support the safety of their products for evidence-based regulatory decisions and to avoid multiple reviews of the applications.

Cost-effectiveness of adding serplulimab to first-line chemotherapy for extensive-stage small-cell lung cancer in China

ABSTRACT Objective The aim of the current study was to evaluate the cost-effectiveness of serplulimab plus chemotherapy compared chemotherapy alone as first-line strategy for patients with ES-SCLC in China. Methods A decision-analytic model that based on the Chinese health-care system perspective was conducted to evaluate the economic benefits for the two competing first-line treatment. The clinical survival and safety data were obtained from the ASTRUM-005 trial, cost and utility values were gathered from the local charges and previously published study. Both cost and utility values were discounted at an annual rate of 5%. Sensitivity analyses and subgroup analyses were performed to examine the robustness of the model results. Results Serplulimab plus chemotherapy could bring additional 0.25 QALYs with the marginal cost of $37,569.32, resulting in an ICER of $147,908.74 per additional QALY gained. Sensitivity analyses confirmed that model results were robust. Subgroup analyses revealed that adding serplulimab to first-line chemotherapy were unlikely to be the cost-effective option for all subgroup patients. Conclusions Serplulimab plus chemotherapy was unlikely to be the cost-effective first-line strategy compared with chemotherapy alone for patients with ES-SCLC in China. Reduced the price of serplulimab could increase its cost-effective.

Cost-utility analysis of Palbociclib + letrozole and ribociclib + letrozole versus Letrozole monotherapy in the first-line treatment of metastatic breast cancer in Iran using partitioned survival model

BackgroundPalbociclib and Ribociclib are cyclin-dependent kinase 4/6 oral molecular inhibitors that have the potential to improve overall survival (OS), progression-free survival (PFS), and quality of life in patients with metastatic breast cancer (MBC). The objective of this study was to analyze the cost-utility of Palbociclib and Ribociclib in comparison with Letrozole monotherapy as the first-line treatment for hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2–) MBC patients in Iran.MethodsA Cost-Utility Analysis (CUA) was conducted using a partitioned survival model (PSM) from the perspective of the Iranian healthcare system. The comparative strategies considered were Palbociclib + Letrozole, Ribociclib + Letrozole, and Letrozole monotherapy. The model was structured with a 1-month cycle length and a 15-year time horizon. Clinical safety, efficacy, and survival data in terms of PFS and OS for Palbociclib + Letrozole and Ribociclib + Letrozole were obtained from the latest updates of the PALOMA-1, 2, and MONALEESA-2 studies, respectively. Direct medical costs, including drug costs, visits, hospitalization, CT scans, bone x-rays, monitoring and laboratory testing, as well as medication side effects, were considered. Uncertainty evaluations were performed through deterministic sensitivity analysis and probabilistic sensitivity analysis. Excel 2016 and TreeAge 2020 were used for all stages of the evaluation.ResultsThe base case results indicated that, despite its lower effectiveness, Letrozole monotherapy was the most cost-effective strategy, while Palbociclib + Letrozole and Ribociclib + Letrozole were not cost-effective. The incremental cost-effectiveness ratios (ICERs) for Palbociclib + Letrozole and Ribociclib + Letrozole compared to Letrozole monotherapy were estimated at $137,302 and $120,478 per quality-adjusted life-year (QALY), respectively, which exceeded the target threshold of $4565. Deterministic sensitivity analysis demonstrated that the CUA results were not sensitive to changes in the values of uncertain variables. Probabilistic sensitivity analysis also indicated that Palbociclib + Letrozole and Ribociclib + Letrozole had no chance of being cost-effective based on changes in various parameters and simulations.ConclusionsPalbociclib and Ribociclib showed significant efficacy in combination with Letrozole, as evidenced by improvements in PFS. However, in the first-line treatment of MBC in Iran, these strategies were not cost-effective compared to Letrozole monotherapy.

AsCas12a Gene Editing of HBG1/2 Promoters with EDIT-301 Results in Rapid and Sustained Normalization of Hemoglobin and Increased Fetal Hemoglobin in Patients with Severe Sickle Cell Disease and Transfusion-Dependent Beta-Thalassemia

Background: Sickle cell disease (SCD) and transfusion-dependent β-thalassemia (TDT) are hereditary blood disorders caused by mutations in the β-globin gene. Clinical evidence has demonstrated that increased fetal hemoglobin (HbF, α2γ2) can reduce or eliminate SCD and TDT complications. EDIT-301, an investigational gene-edited autologous hematopoietic stem cell medicine, has a unique genomic modification that mimics naturally occurring mutations of hereditary persistence of fetal hemoglobin in the γ-globin gene ( HBG1/2) promoters. These mutations reactivate γ-globin expression and increase HbF production. EDIT-301 is manufactured with a highly efficient and specific, proprietary gene editing nuclease, AsCas12a. In preclinical studies, edited CD34 + cells from patients with SCD or TDT increased HbF production in red blood cells (RBCs) sufficient for a therapeutic effect, including reduced sickling (SCD) and improved erythropoiesis (TDT). Aim: RUBY (NCT04853576) and EdiThal (NCT05444894) are Phase I/II, multicenter, open-label, single-arm studies evaluating the safety, efficacy, and tolerability of EDIT-301 in patients with severe SCD and TDT, respectively. As of June 28, 2023, 7 SCD patients and 2 TDT patients have received EDIT-301 treatment. Preliminary clinical efficacy and safety data are reported. Methods: Patients aged 18-50 years with severe SCD (defined as ≥2 severe vaso-occlusive events [VOEs] per year in the 2 years prior to informed consent [IC]) and patients aged 18-35 years with TDT (defined as at least 100 mL/kg/year or 10 U/year of packed RBC transfusions in the 2 years prior to IC) were eligible to enroll in RUBY and EdiThal, respectively. Autologous CD34 + hematopoietic stem and progenitor cells collected by apheresis after plerixafor (RUBY) or plerixafor + filgrastim (EdiThal) mobilization were edited at the HBG1/2 promoters with AsCas12a. After myeloablative conditioning with busulfan, patients received a single infusion of EDIT-301 (a minimum of 3 × 10 6 CD34 + cells/kg), and were monitored for engraftment, total hemoglobin (Hb), HbF, mean HbF concentration/F-cell (MCH-F/F-cell), percentage of F-cells, markers of hemolysis, transfusion requirement, VOEs (SCD only), and adverse events (AEs) for 24 months. Results: Based on a data cut of June 28, 2023, Patients 1-4 with SCD were 12-, 9-, 4-, and 4-months post-EDIT-301 infusion, respectively. Patients 5-7 with SCD were &amp;lt;1-month post-EDIT-301 infusion. Patients 1-2 with TDT were 3- and &amp;lt;1-months post-EDIT-301 infusion, respectively. Neutrophil and platelet engraftment were achieved after a mean (range) of 25 (23-29) and 27 (19-37) days in Patients 1-4 with SCD and on Day 23 and 26 in Patient 1 with TDT, respectively. There were no VOEs in SCD patients post-EDIT-301 infusion, compared with a mean (range) of 4.2 (3.0-5.5) VOEs/year in the 2 years before enrollment (n=6). Following EDIT-301 infusion, Hb levels rapidly increased to 14.2 (12.4-15.7) g/dL by Month 4 (n=4), reaching the normal physiological range, from a mean (range) of 10.5 (8.5-11.9) g/dL at baseline (n=5). By Month 4, the mean (range) HbF concentration was 6.8 (5.7-7.6) g/dL and HbF was &amp;gt;40% (n=4); Patients 3 and 4 had &amp;gt;50% HbF. Percentage of F-cells and MCH-F/F-cell also increased. Key markers of hemolysis improved or normalized in all patients with SCD. Patient 1 with TDT had a HbF concentration of 7.2 g/dL by Month 3, stopped receiving RBC transfusions 20 days after EDIT-301 infusion, and remained transfusion free through the 3-month period. Patient 2 with TDT also showed early improvements. The safety profile of EDIT-301 in both SCD and TDT was consistent with myeloablative conditioning with busulfan. No serious AEs were reported after EDIT-301 infusion. Conclusion: These data demonstrated successful engraftment, a rapid and sustained normalization of Hb as early as 4 months after infusion, an increase in HbF and percentage of F-cells, resolution of VOEs (SCD) and transfusion independence (TDT). In addition, there were improvements in key markers of hemolysis (SCD) and a favorable safety profile in EDIT-301-treated patients. EDIT-301 treatment showed promising results for the first clinical use of AsCas12a in both SCD and TDT patients after gene editing of the γ-globin gene ( HBG1/2) promoters. These findings support further investigation of EDIT-301 in the RUBY and EdiThal trials. Updated data with additional outcomes will be presented.

Identification of Optimal Dosing Regimen for Subcutaneous Epcoritamab in Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma

Background: Epcoritamab SC, a CD3xCD20 bispecific antibody developed using the DuoBody ® platform, engages T cells to target CD20-expressing B cells. Epcoritamab was granted approval by the US FDA in May 2023 for the treatment of adults with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL), not otherwise specified, including DLBCL arising from indolent lymphoma, and high-grade B-cell lymphoma after ≥2 lines of systemic therapy. The recommended dosing regimen for epcoritamab is presented in the Table. Methods: A wide range of epcoritamab doses was explored in patients with R/R B-cell non-Hodgkin lymphoma, including priming doses (0.004-0.16 mg), intermediate doses (0.25-1.6 mg), and full doses (0.0128-60 mg). To identify the optimal dosing regimen for epcoritamab, comprehensive analyses of clinical safety, efficacy, pharmacokinetic (PK), and pharmacodynamic (PD) data (including PK/PD modeling and exposure-efficacy and exposure-safety analyses) were conducted using data from patients with R/R large B-cell lymphoma (LBCL) in the phase 1/2 EPCORE™ NHL-1 (NCT03625037) and EPCORE NHL-3 (NCT04542824) trials with a clinical data cutoff of Jan 31, 2022. Logistic regression analyses were performed to investigate the relationship between epcoritamab exposure and efficacy and safety across the entire range of studied doses. Results: Treatment with the approved dosing regimen led to a high overall response rate (ORR; 63%) and complete response (CR) rate (39%) and durable responses in this highly refractory patient population (median duration of response, 12.0 mo [95% CI, 6.6-not reached]; Thieblemont et al, JCO 2023). Overall, the safety profile of epcoritamab with the recommended dosing regimen is manageable. Higher exposure was associated with higher ORR ( P&amp;lt;0.0005 for the EPCORE NHL-1 LBCL population; n=192, 116 [60%] with response) and CR rate ( P&amp;lt;0.0005 for the EPCORE NHL-1 LBCL population; n=192, 74 [39%] with CR). Additionally, higher exposure improved progression-free survival ( P&amp;lt;0.0005 for the EPCORE NHL-1 LBCL population; lower 50%, n=97; upper 50%, n=98) and overall survival ( P=0.003 for the EPCORE NHL-1 LBCL population; lower 50%, n=97; upper 50%, n=98). The duration of response data exhibited a similar numerical trend ( P=0.278 for the EPCORE NHL-1 LBCL population; lower 50%, n=58; upper 50%, n=58). The pooled analysis of EPCORE NHL-1 and EPCORE NHL-3 LBCL populations showed similar trends. Importantly, a potential plateau of efficacy was observed at 48 mg or above. Furthermore, the majority of initial responses (94%) were achieved within the first 3 cycles (QW dosing interval), with a median time to response of 1.4 mo and a median time to CR of 2.7 mo in the expansion portion of EPCORE NHL-1 (Thieblemont et al, JCO 2023). Most responders maintained or improved their responses during the subsequent Q2W and Q4W dosing schedules, independent of exposure (C trough) during these periods. The step-up doses (0.16/0.8 mg) were clinically active and helped mitigate the risk of CRS at the subsequent therapeutic full (48-mg) doses. Complete B-cell depletion was observed as early as following the first priming dose. Very few first CRS events occurred after the second full dose or subsequent doses in patients who had not previously experienced CRS. The exposure-safety analysis did not identify any safety concerns with the approved dosing regimen. The rate of AEs, including grade ≥3 treatment-emergent AEs (TEAEs), serious TEAEs, grade ≥3 neutropenia, grade ≥3 infections, TEAEs leading to dose delay, TEAEs leading to treatment discontinuation, any-grade CRS, grade ≥2 CRS, CRS requiring tocilizumab, ICANS, and clinical tumor lysis syndrome, did not increase with increasing epcoritamab exposure. Conclusions: Our analyses informed the optimal dosing regimen for epcoritamab. Clinically active step-up doses (0.16/0.8 mg) demonstrated antitumor activity and mitigated the risk of CRS at subsequent therapeutic full doses. The recommended full dose (48 mg) provided deep and durable responses and a manageable safety profile in patients with LBCL. Lower full doses resulted in compromised efficacy without improvement of the benefit-risk profile, whereas increasing the full dose is not expected to lead to significantly higher efficacy. The recommended dosing intervals for epcoritamab treatment not only induced rapid responses but also maintained or improved responses during treatment.

Aloe Vera: A Potential Herb for Periodontitis Management

Background:: The Aloe Vera plant has been used in India for several decades for the treatment of periodontal disease. The plant has been considered to have antimicrobial and antiinflammatory properties, but it is still used for the treatment of periodontitis inflammation. Objective:: The study's goal was to assess the function of Aloe vera in the treatment of periodontitis. The article summarized numerous clinical research studies, clinical trials reports, patent reports, and safety data in addition to the mechanism of action to provide an overview of Aloe Vera’s usefulness in the treatment of periodontitis. Methods:: The information for their review articles was acquired by using Google Scholar and PubMed as search engines, as well as a number of publishers, including Springer Nature, Bentham Science, Taylor &amp; Francis, and Elsevier. ClinicalTrials.gov.in was referred to study the clinical trials data, and Google Patents was used as a search engine for collecting patent reports. Results:: Aloe Vera is useful for Periodontitis prevention and treatment due to its antiinflammatory, antibacterial, and antioxidant features. Aloe Vera can be used as an alternative to treat periodontitis and its related physiological effects such as gingivitis and mucositis, and various pre-clinical and clinical studies have been summarized that have demonstrated that using Aloe Vera significantly improved the mentioned parameters. Conclusion:: Aloe Vera is an herb that may be used to treat periodontitis and its associated negative effects. However, more preclinical and clinical research, might contribute to raising awareness and managing periodontitis.

Secukinumab in the treatment of hidradenitis suppurativa.

The IL-17 pathways are involved in the pathophysiology of many inflammatory skin conditions, including hidradenitis suppurativa. Secukinumab, an IL-17A inhibitor, has been used for years in inflammatory skin disorders such as psoriasis. To date, the only USFDA-approved medication for hidradenitis suppurativa is adalimumab, a TNF-αinhibitor. Recently, secukinumab has demonstrated promising results in the treatment of hidradenitis suppurativa in the phase III SUNSHINE and SUNRISE clinical trials. This article reviews the mechanism of action of secukinumab and summarizes the available clinical efficacy and safety data regarding secukinumab in the management of hidradenitis suppurativa.

Tenecteplase, 0.4 mg/kg, in Moderate and Severe Acute Ischemic Stroke: A Pooled Analysis of NOR-TEST and NOR-TEST 2A.

Background The optimal dose of tenecteplase in acute ischemic stroke remains to be defined. We present a pooled analysis of the 2 NOR-TESTs (Norwegian Tenecteplase Stroke Trials) exploring the efficacy and safety of tenecteplase, 0.4 mg/kg. Methods and Results We retrospectively reviewed 2 PROBE (Prospective Randomized Open, Blinded End-point) trials, NOR-TEST and NOR-TEST 2A. Patients were randomized to either tenecteplase, 0.4 mg/kg, or alteplase, 0.9 mg/kg. The primary end point was favorable functional outcome at 3 months (modified Rankin Scale score, 0-1) or return to baseline if prestroke modified Rankin Scale score was 2. Secondary end points included favorable functional and clinical outcome and safety data. The pooled analysis includes patients with National Institutes of Health Stroke Scale score ≥6 from both trials and an additional post hoc analysis of patients with National Institutes of Health Stroke Scale score ≤5 from NOR-TEST. The per-protocol analysis contains 483 patients, of whom 235 were assigned to tenecteplase and 248 were assigned to alteplase. In per-protocol analysis, functional outcome was better in the alteplase arm with cutoff modified Rankin Scale score of 2 (odds ratio [OR], 0.52 [95% CI, 0.33-0.80]; P=0.003) and expressed by ordinal shift analysis (OR, 1.64 [95% CI, 1.17-2.28]; P=0.004). Mortality at 3 months was higher in the tenecteplase arm (OR, 2.48 [95% CI, 1.20-5.10]; P=0.01). Mortality and intracranial hemorrhage rates were higher in the severe stroke group randomized to tenecteplase, whereas these rates were similar for alteplase and tenecteplase in moderate and mild stroke. Conclusions Tenecteplase, 0.4 mg/kg, is unsafe in moderate and severe stroke, and the risk of death and intracranial hemorrhage probably increases with stroke severity. A lower tenecteplase dose should be tested in future trials. Registration URL: https://www.clinicaltrials.gov; Unique identifiers: NCT01949948, NCT03854500.

Real-World Use, Safety, and Patient Experience of 20% Subcutaneous Immunoglobulin for Primary Immunodeficiency Diseases.

The CORE study aimed to provide a detailed understanding of real-world immune globulin subcutaneous (human) 20% solution (Ig20Gly) utilization in patients with primary immunodeficiency diseases (PIDs) in Germany and Switzerland. Patients with PIDs receiving a stable dose of any subcutaneous immunoglobulin for≥3months before enrollment were eligible for this multicenter (n=5), phase 4, non-interventional, prospective, longitudinal cohort study. Besides baseline demographics and clinical characteristics, Ig20Gly utilization and safety data, and patient-reported outcomes (Life Quality Index/Treatment Satisfaction Questionnaire for Medication) were collected at baseline, 6 and 12months. Statistical analysis was descriptive. Overall, 36 patients provided data at baseline [69.4% female; mean age: 41.6 years (7-78years)]. Totals of 23 and 26patients attended 6- and 12-month visits, respectively; 16 attended all three visits. One patient withdrew consent before 6-month follow-up. Median maximum infusion rates of Ig20Gly at baseline, 6 months,and 12months were 26.7, 24.5, and 40.0mL/h, respectively (10-60mL/h). Infusion and dosing parameters remained consistent across time points: patients used a median of two infusion sites, primarily the abdomen, and all patients used an infusion pump; all but one infused at home and most self-administered Ig20Gly (80.8-83.3%) at once-weekly intervals (69.2-73.9%). During follow-up, 10 adverse events were reported: none were rated serious, while 2 were considered probably related to Ig20Gly. Total patient-reported outcome scores remained high throughout the study. The CORE study provides real-world evidence of the flexibility, feasibility, safety, and tolerability of Ig20Gly infusions, at mostly weekly intervals, over 1year in patients with PIDs. German Clinical Trials Register, DRKS00014562. Registered April 9, 2018, https://drks.de/search/en/trial/DRKS00014562.

Prospective assessment of inter-rater reliability of a neonatal adverse event severity scale.

Introduction: To ensure the quality of clinical trial safety data, universal data standards are required. In 2019 the International Neonatal Consortium (INC) published a neonatal adverse event severity scale (NAESS) to standardize the reporting of adverse event (AE) severity. In this study the reliability of AE severity grading with INC NAESS was prospectively assessed in a real-world setting. Methods: Severity of AEs was assessed by two independent observers at each of four centers across the world. In each center two series of 30 neonatal adverse events were assessed by both observers: in a first phase with a generic (Common Terminology Criteria for Adverse Events, CTCAE) severity scale not specific to neonates, and in a second phase with INC NAESS (after a structured training). Intraclass correlation coefficients (ICC) were calculated to express inter-rater agreement in both phases, and bootstrap sampling was used to compare them. Results: 120 AEs were included in each of both phases. The ICC with the use of INC NAESS in phase 2 was 0.69. This represents a significant but modest improvement in comparison to the initial ICC of 0.66 in phase 1 (confidence interval of ratio of ICC in phase 2 to phase 1 = 1.005-1.146; excludes 1). The ICC was higher for those AEs for which a diagnosis specific AE severity table was available in INC NAESS (ICC 0.80). Discussion: Good inter-rater reliability of the INC NAESS was demonstrated in four neonatal intensive care units (NICUs) across the globe. The ICC is comparable to what is reported for scales with similar purposes in different populations. There is a modest, but significant, improvement in inter-rater agreement in comparison to the naïve phase without INC NAESS. The better performance when reviewers use AE-specific NAESS tables highlights the need to expand the number of AEs that are covered by specific criteria in the current version of INC NAESS.

Clinical Efficacy and Safety of AdV-tk Gene Therapy for Patients with Cervical Squamous Intraepithelial Lesion: A Prospective Study.

Cervical cancer is the fourth most common type of cancer for women in 2020, and many more women have cervical pre-cancerous lesion-squamous intraepithelial lesion (SIL). Early treatment of cervical SIL to reverse or delay its progression is an important approach to reduce the incidence of cervical cancer. The efficacy and safety of adenovirus-based vectors expressing the thymidine kinase gene (AdV-tk) in the treatment of multiple types of cancers shows promise for its use in gynecology. We aim to provide relevant clinical efficacy and safety data after introducing AdV-tk for the treatment of cervical SIL for the first time through this prospective study. We conducted a maximum of 6-sessions to administer AdV-tk gene therapy to 23 patients (mean age: 35 years old) with cervical low-/high-grade SIL (LSIL/HSIL) who were enrolled from August 2015 to April 2018 and analyzed the clinical characteristics and follow-up outcomes (mean follow-up period: 7.3 months). The present study consisted of 17 patients (73.9%) with cervical HSIL and six patients with LSIL confirmed by colposcopy-directed biopsy. We observed an overall histological remission and regression rate of 87.0% (20/23, 95% confidence interval [95%CI]: 73.2-100%, P<0.001) after AdV-tk gene therapy. Eight patients (34.8%) were detected with human papillomavirus (HPV) 16/18 subtypes and 13 patients were found to be positive with at least one of the other 13 high-risk HPV (HR-HPV) subtypes, while two patients did not have any of the 15 HR-HPV subtypes. The overall clearance rate of HR-HPV was 76.2% (16/21, 95%CI: 58.0-94.4%, P=0.016) after AdV-tk gene therapy. For safety evaluation, no severe complications were reported in any of the 23 patients. The most commonly reported symptom was fever in 52.2% (12/23) of patients and all symptoms were fully resolved after symptomatic treatment. Our data indicates that AdV-tk gene therapy has high efficacy and safety in the treatment of cervical SIL among gynecological patients. Our findings provide clinical evidence on the potential promotion and application of AdV-tk in the treatment of cervical SIL, and potentially for cervical cancer, among gynecological patients.

Real-world dostarlimab use in advanced/recurrent endometrial cancer in France

In October 2020, the French Health Authority granted early access outside of the clinical trial setting for dostarlimab, a programmed death-1 inhibitor. Dostarlimab was approved by the European Medicines Agency (in April 2021) as monotherapy for patients with post-platinum mismatch repair deficient/microsatellite instability-high advanced/recurrent endometrial cancer, based on the results of the GARNET trial (NCT02715284). This was a real-world descriptive analysis of patients granted cohort temporary authorization of use to receive dostarlimab between November 2020 and June 2021. Physicians could complete follow-up forms at each treatment cycle to provide clinical information, safety, and efficacy data. Safety and disease progression data were also captured through pharmacovigilance reports. Of 95 temporary authorization of use requests made by 80 oncologists in 59 French hospitals, 87 patients were eligible, and 80 received≥1 dose of dostarlimab. Based on treatment response assessments received (n=43), the mean (standard deviation) time from treatment initiation to response evaluation was 11 (6) weeks. The disease control rate (complete plus partial responses plus stable disease rates) was 56% (n=24/43), and the overall response rate was 35% (n=15/43); both consistent with those reported in the GARNET trial. No new safety signals were reported. The enrolment of 80 patients in an 8-month period highlights the need for access to novel treatment regimens in France for these patients post-platinum. Prospective randomized studies are ongoing to assess the efficacy and safety of dostarlimab and other checkpoint inhibitors as first-line treatment in patients with endometrial cancer.

Cost-effectiveness of Trastuzumab Deruxtecan for HER2-low Advanced Breast Cancer in the United States

Trastuzumab deruxtecan has been shown to be effective for advanced breast cancer with low levels of human epidermal growth factor receptor 2. To optimize the allocation of limited health care resources, this study evaluated the cost-effectiveness of trastuzumab deruxtecan from the US payer perspective. A partitioned survival model was developed to project the disease course of advanced breast cancer. Clinical efficacy, treatment utilization, safety, and cost data were gathered from the DESTINY-Breast04 (Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer) trial and the Centers for Medicare & Medicaid Services. Transition probabilities were obtained from the reported survival probabilities per DESTINY-Breast04 group. The incremental cost-effectiveness ratio (ICER), the incremental monetary benefit, and the incremental net health benefit were measured. One-way sensitivity analysis, probabilistic sensitivity analysis, and subgroup analysis were performed to explore the uncertainty of the model. Trastuzumab deruxtecan had an ICER of $307,751 per quality-adjusted life-year (QALY) gained, with an incremental net health benefit of -0.317 QALY and an incremental monetary benefit of -$63,313 compared with the physician's choice of alternative chemotherapy agents. Subgroup analysis indicated that trastuzumab deruxtecan had an ICER of $383,776 per QALY gained for the hormone receptor-positive subgroup and an ICER of $194,424 per QALY for the hormone receptor-negative subgroup. One-way sensitivity analysis showed that the cost of trastuzumab deruxtecan had the most impact on model outcomes. The cost-effectiveness acceptability curve projected that the probability of trastuzumab deruxtecan being cost-effective was 5% in the overall population, 2% in the hormone receptor-positive subgroup, and 56% in the hormone receptor-negative subgroup at the willingness-to-pay threshold of $200,000 per QALY. Trastuzumab deruxtecan may be a cost-effective option for hormone receptor-negative patients with advanced breast cancer with low levels of human epidermal growth factor receptor 2.