Severe Treatment-emergent Adverse Events Research Articles

Brexpiprazole for the treatment of agitation associated with dementia due to Alzheimer's disease: A 12-week, active-treatment, extension trial.

A 12-week randomized controlled trial demonstrated that brexpiprazole is efficacious for treating agitation in patients with dementia due to Alzheimer's disease. To assess the long-term safety and tolerability of brexpiprazole for the treatment of agitation associated with dementia due to Alzheimer's disease. This 12-week, active-treatment (oral brexpiprazole 2 or 3 mg/day) extension trial ran from October 2018-September 2022 at 66 sites in Europe/US. Patients with agitation in dementia due to Alzheimer's disease in a care facility/community-based setting who completed the randomized trial were eligible (N = 259 enrolled/analyzed for safety; 88.4% completed). Stable Alzheimer's disease medications were permitted. The primary safety endpoint was the frequency and severity of treatment-emergent adverse events (TEAEs). Change in Cohen-Mansfield Agitation Inventory (CMAI) total score was an exploratory efficacy endpoint. Mean (SD) age was 74.3 (7.6) years, 145 patients (56.0%) were female, and 248 (95.8%) were White. TEAEs were reported by 67 patients (25.9%), most commonly headache (3.5%) and fall (2.3%). Most TEAEs were mild or moderate in severity; 5 patients (1.9%) reported a severe TEAE, including 3 severe falls attributed to tripping, misjudging sitting, or dehydration. Twelve patients (4.6%) discontinued due to TEAEs. No patients died. Mean CMAI total score improved by 9.1 points over 12 weeks. Considering the randomized and extension trials together, brexpiprazole 2 or 3 mg was generally well tolerated for up to 24 weeks in elderly patients with agitation associated with dementia due to Alzheimer's disease. Patients showed continued improvement in agitation. NCT03594123 (registration date: July 11, 2018).

Oral LPCN 1148 improves sarcopenia and hepatic encephalopathy in male patients with cirrhosis: A randomized, placebo-controlled phase 2 trial.

Sarcopenia is highly prevalent in patients with liver cirrhosis and is associated with adverse clinical outcomes including hepatic encephalopathy (HE). Androgen receptor agonists, ARAs, can address these conditions through multimodal mechanisms of action, however their safety and efficacy in patients with cirrhosis have not been well established. In this multicenter, double-blind, phase 2 trial, men with sarcopenia and cirrhosis awaiting liver transplant were randomized 1:1 to receive either oral ARA LPCN 1148 or placebo for 24 weeks (NCT04874350). The primary endpoint was the change from baseline to 24 weeks in skeletal muscle index measured by computed tomography scan of the L3 region (L3-SMI), analyzed with a prespecified modified intent-to-treat population. The secondary endpoint was the number of overt HE events. 29 participants (mean age=59y, MELD=17) received at least one dose of LPCN 1148 (n=15) or placebo (n=14). Baseline characteristics were similar between groups. Primary endpoint analysis demonstrated an increase in L3-SMI in the LPCN 1148 group (n=15) compared to placebo (n=10), with a mean group difference of 4.4cm2/m2 (95% CI, 1.3-7.4cm2/m2, p=0.007). Participants in LPCN 1148 experienced fewer episodes of overt HE (CTCAE grade ≥2; p=0.02) than placebo. The number and severity of treatment-emergent adverse events were similar between arms. LPCN 1148 treatment improved sarcopenia and reduced the number of overt HE episodes in men with cirrhosis and sarcopenia awaiting liver transplant. These findings support additional research on the efficacy of LPCN 1148 in treating sarcopenia and preventing HE recurrence.

Safety and efficacy of pegcetacoplan treatment for cold agglutinin disease and warm antibody autoimmune hemolytic anemia

Cold agglutinin disease (CAD) and warm antibody autoimmune hemolytic anemia (wAIHA) are rare autoimmune hemolytic anemias characterized by red blood cell destruction, largely attributable to complement activation resulting in intravascular and extravascular hemolysis. Pegcetacoplan is a subcutaneously administered C3-targeted therapy, which may be suitable for treating CAD and wAIHA. In this open-label phase 2 study, analyses were conducted in two cohorts, one for patients with CAD and the other wAIHA. In each cohort, patients were randomly assigned to receive 270 or 360 mg/day pegcetacoplan for up to 48 weeks. Safety endpoints included the incidence and severity of treatment-emergent adverse events (TEAEs) and adverse events of special interest (AESI). Efficacy endpoints included change from baseline in hemoglobin (Hb), lactate dehydrogenase, absolute reticulocyte count, haptoglobin, indirect bilirubin, and Functional Assessment of Chronic Illness Therapy (FACIT)-fatigue scale. Thirteen (100%) and 10 out of 11 (91%) patients with CAD and wAIHA respectively experienced at least 1 TEAE. Ten patients had at least 1 serious adverse event; none were considered related to pegcetacoplan. The only treatment-related AESIs were injection site reactions. Pegcetacoplan increased Hb levels, reduced hemolysis, and increased FACIT-fatigue scale scores in the first weeks; at week 48 the median (interquartile range) change from baseline Hb for the CAD and wAIHA total groups was 2.4 (0.90 to 3.00) and 1.7 g/dL (-1.40 to 2.90), respectively, and improvements in hemolysis and FACIT-fatigue scale scores were maintained. This study demonstrated that pegcetacoplan is generally well tolerated and suggests it can be effective in patients with CAD and wAIHA. Registered at www.clinicaltrials.gov (NCT03226678).

Retrospective analysis of survival and safety of bevacizumab biosimilar and original drug combination chemotherapy in non-small cell lung cancer.

The advent of bevacizumab has considerably transformed the therapeutic landscape for non-small cell lung cancer (NSCLC) patients devoid of specific genetic mutations. A pivotal milestone has been reached with the recent approval of a bevacizumab biosimilar, following rigorous phase III clinical investigations, poised to augment NSCLC therapeutic strategies. This retrospective analysis encompasses a large-scale study conducted between January 2021 and December 2023, involving 1058 NSCLC patients (metastatic or locally advanced stages). The research design entailed a comparative assessment of the safety and efficacy profiles of combined therapies using the original bevacizumab and its biosimilar, adhering to RECIST v1.1 criteria. Adverse event grading was standardized using the National Cancer Institute's CTCAE v5.0. Notably, the biosimilar demonstrated an objective response rate (ORR) of 29.79% in 606 patients, closely paralleling the 27.41% ORR observed in 452 patients receiving the original drug, with insignificant risk differences (-0.03) and a risk ratio of 0.987, affirming equivalence. Progression-free survival (PFS) was influenced by radiation status, treatment lines, and regimen combinations, while dosage intensity and genetic factors had negligible impacts. The incidence of treatment-emergent adverse events (TEAEs) was slightly higher in the biosimilar group (75.11%) versus the original drug group (72.78%), with grade 3 or more severe TEAEs occurring in 23.6% and 18.5% of patients, respectively (Detailed criteria for the definition and assessment of TEAEs have been added to the Methods section, including the use of the National Cancer Institute's CTCAE v5.0 for grading). The study affirms that bevacizumab biosimilars offer equivalent therapeutic efficacy and a similar safety profile to the originator product in the management of locally advanced or metastatic NSCLC. The tolerability of the toxicity profile, coupled with the absence of unforeseen adverse reactions, underscores the viability of biosimilar bevacizumab as a valuable addition to NSCLC treatment regimens. These findings also imply potential benefits for a broader patient population beyond clinical trial confines through the adoption of biosimilar beta-adrenergic blocking agents.

MDMA-assisted psychotherapy for the treatment of PTSD: A systematic review and meta-analysis of randomized controlled trials (RCTs).

Post-traumatic stress disorder (PTSD) is a mental health disorder resulting from exposure to traumatic events, manifesting in various debilitating symptoms. Despite available treatments, many individuals experience inadequate response or significant side effects. Previous reviews suggest promising outcomes with MDMA-assisted psychotherapy (MDMA-AT), but limitations prompt the need for a comprehensive evaluation. We searched various online databases and registries such as MEDLINE (via PubMed), Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov to retrieve RCTs that fit our inclusion criteria. We performed meta-analyses using Review Manager by applying a random-effects model. Dichotomous and continuous outcomes were pooled as risk ratios (RR) and standard mean difference (SMD), respectively. Nine studies with a total of 297 participants with PTSD were included in our meta-analysis. The control group consisted of inactive doses of MDMA (25-40 mg) or placebo. Our meta-analysis showed that MDMA-AT led to a significant reduction in the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) severity scores as compared to the control group (SMD -1.10, 95% CI: -1.62 to -0.59). More patients in the MDMA-AT group exhibited significant response (RR 1.59, 95% CI: 1.22, 2.08) and remission (RR 2.32, 95% CI: 1.47 to 3.66) as compared to patients in the control group. There was no significant difference regarding the incidence of ≥1 treatment-emergent adverse events (TEAE), ≥1 severe TEAE, and suicidal ideation between the two groups. MDMA-AT demonstrates significant efficacy in improving PTSD symptoms, enhancing both response and remission rates in individuals with chronic, treatment-resistant PTSD, while maintaining a favorable safety profile.

A phase 2 multicenter trial of ruxolitinib to treat bronchiolitis obliterans syndrome after allogeneic HCT

AbstractBronchiolitis obliterans syndrome (BOS) occurring after allogeneic hematopoietic cell transplantation (HCT) is a high-risk manifestation of chronic graft-versus-host disease. In this prospective, multicenter phase 2 trial, adult participants with BOS were treated with ruxolitinib 10 mg twice daily, continuously in 28-day cycles for up to 12 cycles. Participants enrolled into newly diagnosed (<6 months since BOS diagnosis, cohort A) or established (≥6 months since BOS diagnosis, cohort B) disease cohorts. The primary objective was to evaluate the early treatment effect of ruxolitinib, assessed by the change in forced expiratory volume in 1 second (FEV1) at 3 months compared with enrollment. The primary end point differed according to cohort (cohort A, improvement, defined as ≥10% increase in FEV1; cohort B, stabilization, defined as an absence of ≥10% decrease in FEV1). Between 2019 and 2022, 49 participants meeting the criteria for BOS were enrolled and treated (cohort A, n = 36; cohort B, n = 13). The primary end point was achieved by 27.8% of participants with new BOS and 92.3% of participants with established BOS. According to the 2014 National Institutes of Health Consensus Criteria, the best lung-specific overall response rate on ruxoltinib for the 49 participants was 34.7% (16.3% complete response and 18.4% partial response), with most responses occurring in mild or moderate disease. Noninfectious severe (grade ≥3) treatment-emergent adverse events were infrequent. Nine severe infectious events occurred and were largely respiratory in nature. These results support the use of ruxolitinib in the management of BOS after allogeneic HCT. This trial was registered at www.ClinicalTrials.gov as #NCT03674047.

Effect of apremilast on hand and whole-body MRI assessments of inflammation in patients with psoriatic arthritis (MOSAIC): a phase 4, multicentre, single-arm, open-label study.

The Psoriatic Arthritis Magnetic Resonance Imaging Scoring System (PsAMRIS) and MRI Whole-Body Scoring System for Inflammation in Peripheral Joints and Entheses in Inflammatory Arthritis (MRI-WIPE) have not been used together to assess treatment of psoriatic arthritis in a clinical trial. We aimed to assess the effect of apremilast treatment on inflammation, with outcomes measured by PsAMRIS and MRI-WIPE. MOSAIC was a phase 4, multicentre, single-arm, open-label study conducted at 29 sites across ten countries (Belgium, Canada, Denmark, Germany, Italy, Russia, Spain, Switzerland, the UK, and the USA). Adults aged 18 years or older with a documented diagnosis of psoriatic arthritis for a duration of 3 months to 5 years self-enrolled and were included if they met the classification criteria for active psoriatic arthritis at screening. Patients were required to have at least three swollen and three tender joints with hand involvement and at least one active enthesitis site according to the Spondyloarthritis Research Consortium of Canada enthesitis index or the Leeds enthesitis index. Patients were excluded if they had previous treatment with a biological disease-modifying antirheumatic drug or previous treatment with more than two conventional synthetic disease-modifying antirheumatic drugs. After a 5-day titration period, patients received apremilast 30 mg orally twice per day. Concomitant stable methotrexate up to 25 mg per week was permitted. The primary endpoint was change from baseline to week 24 in a composite inflammation score of bone marrow oedema, synovitis, and tenosynovitis in the hand as assessed by PsAMRIS. The full analysis set and safety population included all enrolled patients who received at least one dose of apremilast. This completed study is registered with ClinicalTrials.gov (NCT03783026). Between Feb 6, 2019, and May 11, 2022, 123 patients were enrolled in the MOSAIC study. Of these 123 patients, 122 (99%) were treated with apremilast and included in the full analysis set and safety population. 67 (55%) of 122 patients were female, 55 (45%) were male, and 116 (95%) were White. 80 (66%) of 122 patients completed 48 weeks of treatment. The least squares mean change from baseline to week 24 in the composite inflammation score of bone marrow oedema, synovitis, and tenosynovitis as assessed by PsAMRIS was -2·32 (95% CI -4·73 to 0·09). 95 (78%) of 122 patients had at least one treatment-emergent adverse event. Six (5%) patients had a severe treatment-emergent adverse event and six (5%) patients had a serious treatment-emergent adverse event. No serious treatment-emergent adverse events were considered to be related to apremilast. Apremilast improved inflammation in joints and entheses on assessment of MRI measures in the hand and the whole body. Our findings encourage the use of MRI, including whole-body MRI, as an objective outcome measure in trials in patients with psoriatic arthritis. Amgen.

Usefulness of Mirogabalin in Central Neuropathic Pain After Stroke: Post Hoc Analysis of a Phase3 Study by Stroke Type and Location.

Central post-stroke pain (CPSP) is a common type of central neuropathic pain (CNeP) that can occur following the onset of stroke. The oral gabapentinoid mirogabalin besylate (mirogabalin) is a selective α2δ ligand that is effective for the treatment of CNeP, including CPSP. However, it is unknown whether the analgesic effect of mirogabalin on CPSP varies in patients with different background factors. This was a post hoc subgroup analysis of a multinational, open-label, long-term phase3 study of mirogabalin for the treatment of CNeP conducted between March 2019 and December 2020. Data from patients with CPSP were stratified by type of stroke (ischemic or hemorrhagic), stroke location (thalamus, putamen, brainstem, or other), presence/absence of motor weakness, median time since stroke (≥ 59 or < 59months), and median duration of CPSP (≥ 55.5 or < 55.5months). Efficacy was assessed with the short-form McGill Pain Questionnaire (SF-MPQ), and treatment-emergent adverse events (TEAEs) and adverse drug reactions (ADRs) were recorded. This subanalysis included all 94 patients with CPSP from the phase3 study; all were Japanese, and the mean age was 65.3years. The least squares mean change [95% confidence interval] in SF-MPQ visual analog scale (VAS) score from baseline at week52 (last observation carried forward) was - 17.0 [- 22.1, - 11.9] mm. Among the subgroups, least squares mean changes in SF-MPQ VAS scores were not different. Most TEAEs were mild or moderate; severe TEAEs occurred in six patients (6.4%). Somnolence (25.5%), peripheral edema (13.8%), dizziness (11.7%), and weight gain (6.4%) were the most common ADRs, and the types and frequencies of ADRs were similar among subgroups. Mirogabalin was generally effective and well tolerated in patients with CPSP, regardless of background factors such as stroke type or location, presence/absence of motor weakness, time since stroke, and duration of CPSP. Trial registration number NCT03901352.

Abstract C162: Prespecified interim analysis of the DARolutamide ObservationaL (DAROL) study in Black/African American patients with nonmetastatic castration-resistant prostate cancer (nmCRPC)

Abstract Introduction: Black/African American (B/AA) men are disproportionately affected by prostate cancer, having higher incidence and mortality rates compared with other ethnic/racial populations. Darolutamide (DARO) is a structurally distinct and highly potent androgen receptor inhibitor with low blood–brain barrier penetration and limited potential for drug–drug interactions. In ARAMIS (NCT02200614; phase 3), DARO significantly improved metastasis- free survival (MFS) by ∼2 years and reduced the risk of death by 31% vs placebo in patients with nmCRPC, with favorable tolerability. The DAROL study (NCT04122976) is assessing the real- world safety and effectiveness of DARO in patients with nmCRPC. Here we report a subgroup analysis of B/AA patients from the prespecified third interim analysis (IA3). Methods: DAROL is an ongoing, global, open-label, single-arm, non-interventional study in patients aged ≥18 years with nmCRPC for whom the decision to be treated with DARO was decided pre-enrollment. The primary endpoint is safety, including incidence and severity of treatment-emergent adverse events (TEAEs). Secondary endpoints include MFS, overall survival (OS), prostate-specific antigen (PSA) progression, and PSA response. IA3 was conducted when 550 patients completed ≥6 months of treatment (data cut-off July 17, 2023). Results: Of 550 patients, 199 (36%)/191 (35%)/152 (28%)/8 (2%) were from Europe/North America/Asia Pacific/Latin America, respectively. All 23 B/AA patients were from North America and represented 12% of this cohort. At baseline, PSA levels (median 4.2 ng/mL vs 4.0 ng/mL) and PSA doubling time (median 5.9 months vs 5.3 months) were similar in the B/AA and overall DAROL population, whereas B/AA patients were generally younger than the overall population (median 74 [range 49–94] vs 79 [range 29–98] years, respectively) with proportionately fewer patients aged ≥75 yrs (12 [52%] vs 387 [70%]), fewer B/AA patients (33%) had a Gleason score ≥8 vs the overall population (53%), and proportionally more B/AA patients (94%) had ECOG PS 0 vs the overall population (64%). Consistent with the DAROL IA3 overall population, DARO showed a favorable safety profile in the B/AA subgroup, and TEAEs were mostly grade 1/2. In the DAROL IA3 overall population, the proportion of patients who achieved a 90% reduction in PSA from baseline was 54%, while MFS and OS rates at 2 years were 78% and 88%, respectively. Effectiveness and safety outcomes for the B/AA subgroup will be presented. Conclusion: Findings from the DAROL IA3 B/AA subgroup were similar to the overall population and consistent with the favorable efficacy and safety profile of DARO observed in the ARAMIS B/AA subgroup and overall population. Citation Format: Evan Y. Yu, Christopher Pieczonka, Hiroyoshi Suzuki, Alberto Briganti, Murilo Luz, Declan Murphy, Patrick Adorjan, Mercedeh Ghadessi, Frank Verholen, Andrew J. Armstrong. Prespecified interim analysis of the DARolutamide ObservationaL (DAROL) study in Black/African American patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C162.

Efficacy and safety of therapeutic alpha-1-microglobulin RMC-035 in reducing kidney injury after cardiac surgery: a multicentre, randomised, double-blind, parallel group, phase 2a trial

Cardiac surgery invariably triggers acute kidney stress causing adverse renal outcomes. The AKITA study evaluated the efficacy and safety of RMC-035, a novel analogue of alpha-1-microglobulin, for reducing cardiac surgery-associated kidney injury. In this randomised double-blind placebo-controlled phase 2a study, we randomly assigned (1:1) adult hospitalised patients undergoing open-chest cardiac surgery at high risk for acute kidney injury (AKI) at 21 sites in North America and Europe to receive either RMC-035 (1.3 or 0.65mg/kg) or placebo (1:1) for 2 days (5 intravenous infusions), stratified by region and renal function. Eligible patients had at least one pre-defined AKI risk factor. Patients with severe renal impairment (estimated glomerular filtration rate [eGFR] <30mL/min/1.73m2) were excluded. The co-primary efficacy and safety endpoints were AKI (Kidney Disease: Improving Global Outcomes definition) within 72h after surgery and nature, frequency, and severity of treatment-emergent adverse events (TEAEs). Secondary endpoints included eGFR and Major Adverse Kidney Events (MAKE) up to Day 90. Randomised patients who had received at least one dose of study drug were analysed for primary and safety analyses. Participants, investigators and sponsor were masked to treatment allocation. This study is registered at ClinicalTrials.gov (NCT05126303) and EudraCT (2021-004040-19). Patient enrolment was stopped at interim analysis due to futility. Between March 31, 2022 and July 12, 2023, 177 patients (RMC-035: 89, placebo: 88) were randomised and treated. AKI rate for RMC-035 vs placebo was 50.6% (n=45) and 39.8% (n=35) (relative risk [RR]: 1.30, 90% confidence interval [90% CI]: 0.99, 1.71; p=0.12). A short-lived creatinine increase was observed with the higher RMC-035 dose. Treatment with RMC-035 was associated with improved secondary renal outcomes at Day 90: placebo-adjusted eGFR change from baseline 4.3mL/min/1.73m2, 90% CI 0.51-8.12, p=0.06; and MAKE 6.7% (n=6) vs 15.9% (n=14); RR: 0.41, 90% CI: 0.19, 0.88, p=0.05. The most frequently reported TEAEs for RMC-035 were chills (30.3%), nausea (21.3%), anaemia (20.2%); and atrial fibrillation (29.5%), anaemia (20.5%), hypervolemia (14.8%) for placebo. The majority of TEAEs in both treatment groups were mild or moderate in severity. In the RMC-035 group, 26 (29.2%) patients experienced at least one severe or life-threatening TEAE and in the placebo group 16 (18.2%) patients. There were 4 deaths per treatment arm (one treatment-related, in placebo group). In this proof-of-concept study, RMC-035 did not reduce AKI 72h after cardiac surgery. Evaluations may have been confounded by a drug-induced transient creatinine increase in a subgroup of patients. RMC-035 was associated with improved secondary renal outcomes. These results merit further investigation and should be interpreted with caution, as the study was not powered for these outcomes. Guard Therapeutics.

Safety and efficacy of fruquintinib-based therapy in patients with advanced or metastatic sarcoma.

The purpose of this study was to evaluate the efficacy and safety of fruquintinib-based therapy as a salvage therapy for patients with advanced or metastatic sarcoma, including soft tissue sarcoma (STS) and bone sarcoma. Patients with advanced or metastatic sarcoma were divided into two groups. One group received fruquintinib monotherapy, while the other received fruquintinib combined therapy. Safety and efficacy of fruquintinib-based therapy were recorded and reviewed retrospectively, including progression-free survival (PFS), overall response rate (ORR), and adverse events (AEs). Between August 2021 and December 2022, 38 sarcoma patients were retrospectively included. A total of 14 patients received fruquintinib alone (including 6 STS and 8 bone sarcoma), while 24 were treated with fruquintinib combined therapy (including 2 STS and 22 bone sarcoma). The median follow-up was 10.2 months (95% CI, 6.4-11.5). For the entire population, the median PFS was 8.0 months (95% CI, 5.5-13.0). The ORR was 13.1%, while the disease control rate (DCR) was 86.8%. The univariate analysis showed that radiotherapy history (HR, 4.56; 95% CI, 1.70-12.24; p = 0.003), bone sarcoma (HR, 0.34; 95% CI, 0.14-0.87; p = 0.024), and treatment method of fruquintinib (HR, 0.36; 95% CI, 0.15-0.85; p = 0.021) were significantly associated with PFS. The multivariate analysis showed that patients without radiotherapy history were associated with a better PFS (HR, 3.71; 95% CI: 1.31-10.55; p = 0.014) than patients with radiotherapy history. Patients in combination group reported pneumothorax (8.3%), leukopenia (33.3%), thrombocytopenia (12.5%), diarrhea (4.2%), and anemia (4.2%) as the most frequent grade 3 or higher treatment-emergent AEs (TEAEs), while there was no severe TEAEs occurred in the monotherapy group. Fruquintinib-based therapy displayed an optimal tumor control and an acceptable safety profile in patients with advanced or metastatic sarcoma.

Phase 1b/2a Study Assessing the Safety and Efficacy of Felzartamab in Anti-Phospholipase A2 Receptor Autoantibody–Positive Primary Membranous Nephropathy

IntroductionPrimary membranous nephropathy (PMN) is most often caused by autoantibodies to phospholipase A2 receptor (PLA2R). M-PLACE (NCT04145440) is an open-label, phase 1b/2a study that assessed the safety and efficacy of the fully human anti-CD38 monoclonal antibody felzartamab in high-risk anti-PLA2R+ PMN. MethodsPatients with PMN that was newly diagnosed or relapsed (Cohort 1 [C1]; n=18) or refractory to immunosuppressive therapy (Cohort 2 [C2]; n=13) received nine infusions of felzartamab 16 mg/kg in the 24-week treatment period, followed by a 28-week follow-up. The primary endpoint was the incidence and severity of treatment-emergent adverse events (TEAEs). ResultsThirty-one patients were enrolled and received felzartamab. Twenty-seven (87.1%) patients had TEAEs, including infusion-related reactions (29.0%), hypogammaglobulinemia (25.8%), peripheral edema (19.4%), and nausea (16.1%). Five (16.1%) patients had serious TEAEs that all resolved. Immunologic response (anti-PLA2R titer reduction ≥50%) was achieved by 20/26 (76.9%) efficacy-evaluable patients (C1, 13/15 [86.7%]; C2, 7/11 [63.6%]). Anti-PLA2R titer reductions were rapid (week 1 response, 44.0%; response 7 months after last felzartamab dose [end of study, EOS], 53.8%). Partial proteinuria remission (UPCR reduction ≥50%, UPCR <3.0 g/g, and stable eGFR) was achieved by 9/26 (34.6%) patients (C1, 7/15 [46.7%]; C2, 2/11 [18.2%]) before or at EOS (median follow-up, 366 days). Serum albumin increased from baseline to EOS in 20/26 (76.9%) patients (C1, 12/15 [80.0%]; C2, 8/11 [72.7%]). ConclusionIn this population with high-risk anti-PLA2R+ PMN, felzartamab was tolerated and resulted in rapid partial and complete immunologic responses and partial improvements in proteinuria and serum albumin in some patients.

DUET-01: A first-in-human, phase 1/2 study of BOXR1030 in patients with advanced glypican-3-positive solid tumors.

TPS2681 Background: Glypican-3 (GPC3) is a membrane-bound heparin sulfate proteoglycan involved in cell proliferation that is overexpressed in several tumor types. BOXR1030 is an autologous T-cell therapy that co-expresses a chimeric antigen receptor (CAR) targeting GPC3 on tumor cells and glutamic-oxaloacetic transaminase 2 (GOT2), a mitochondrial enzyme that plays an important role in maintaining mitochondrial function and improving T-cell functionality in the solid tumor microenvironment. In non-clinical studies, BOXR1030 showed GPC3-specific cytotoxicity, proliferation and cytokine release only in the presence of GPC3+ cells. Methods: DUET-01 (NCT05120271) is an open-label, dose escalation and expansion clinical trial to determine a safe dose of BOXR1030 in patients with advanced GPC3-positive solid tumors. Dose escalation will be guided by the occurrence of dose-limiting toxicities (DLTs) within 28 days of dosing. The Bayesian logistic regression model will be used on the accumulated DLT data to estimate the maximum tolerated dose (MTD). The Dose Escalation Committee will select the recommended phase 2 dose (RP2D) to be used in the expansion phase cohort(s) (10-20 subjects each) based on data accumulated in the dose escalation cohorts. Eligible subjects will undergo leukapheresis to obtain T cells for BOXR1030 manufacturing and will receive 3 days of lymphodepleting chemotherapy with fludarabine and cyclophosphamide within 5 days prior to BOXR1030 administration. The starting dose is 0.3 × 106 BOXR1030 T cells/kg body weight. Antitumor activity will be assessed every 6 weeks after cell infusion per Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1 and RECIST for immune-based therapeutics (iRECIST). Six months after BOXR1030 administration, subjects will enter long-term follow-up for up to 15 years. Long-term follow-up assessments will focus on long-term safety and disease status. Main inclusion criteria are histologically confirmed advanced unresectable or metastatic hepatocellular carcinoma, squamous cell carcinoma of the lung, myxoid/round cell liposarcoma, or Merkel cell carcinoma; GPC3 overexpression by immunohistochemistry assay confirmed centrally on tumor specimen taken within 6 months prior to signing consent and after the initiation of the subject’s most recent systemic anticancer therapy; body weight of ≥ 50 kg (≥ 65 kg for dose level 1); and life expectancy &gt; 16 weeks. The primary endpoints are the incidence of DLTs; determination of the MTD and RP2D; the type, frequency and severity of treatment-emergent adverse events; clinically significant abnormal safety laboratory findings and vital signs. Key secondary endpoints include efficacy parameters such as objective response rate, BOXR1030 T-cell expansion and persistence, and levels of inflammatory markers and cytokines. The first patient was treated with BOXR1030 in December 2022. Clinical trial information: NCT05120271 .

Phase 3 trial evaluating efficacy and safety of odronextamab plus CHOP vs rituximab plus CHOP in previously untreated diffuse large B-cell lymphoma (DLBCL; OLYMPIA-3).

TPS7086 Background: Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) remains a standard of care first-line (1L) treatment for patients (pts) with DLBCL. However, poor outcomes persist for certain DLBCL pt subgroups, including those with high-risk features: activated B-cell-like (ABC) cell of origin (5-yr progression-free survival [PFS]/overall survival [OS] 48%/56%), MYC and BCL2 rearrangements (median OS 15 months), or International Prognostic Index [IPI] score 4–5 (5-yr PFS/OS 46%/54%). Improving outcomes through effective 1L treatment continues to be important, highlighted by the dismal prognosis in pts who are primary refractory (2-yr OS 24%) or who relapse early after 1L treatment (4-yr OS 30%). Odronextamab, a CD20×CD3 bispecific antibody, showed encouraging efficacy (objective response rate 52%; complete response [CR] rate 31%; 47% maintained CR at 2 years) and generally manageable safety as a monotherapy in pts with heavily pretreated relapsed/refractory DLBCL, including in pts who were anti-CD20 antibody refractory (Ph 2 ELM-2 study; Ayyappan, et al. ASH 2023). These data provide the rationale to evaluate the efficacy and safety of odronextamab plus CHOP (O-CHOP) vs R-CHOP in pts with previously untreated DLBCL. Methods: OLYMPIA-3 (NCT06091865) is a Ph 3, randomized, open-label, multicenter study of O-CHOP vs R-CHOP in pts with previously untreated DLBCL and intermediate- or high-risk features. The study consists of Part 1A (dose escalation), Part 1B (dose optimization), and Part 2 (randomized controlled). Part 1A will assess the safety of O-CHOP. In Part 1B, pts will be randomized 1:1 to one of two O-CHOP regimens, selected based on Part 1A results. In Part 2, pts will be randomized 1:1 to O-CHOP or R-CHOP, with odronextamab dosing dependent on Part 1 results, and R-CHOP given per standard practice. Intravenous odronextamab will be administered weekly from Cycle (C) 1 Day (D) 8 until C5D8, with step-up dosing during C1 and C2, then every 2 weeks until the end of C6. CHOP will be administered in six 21-day cycles, starting on C1D1. Key inclusion criteria: aged ≥18 years; untreated CD20+ DLBCL; ECOG PS ≤2; and IPI score ≥2. Pts with central nervous system lymphoma, Grade ≥3 peripheral neuropathy, or an active infection are excluded. The primary endpoints are the incidence of dose-limiting toxicities, and incidence and severity of treatment-emergent adverse events (Part 1), and PFS by independent central review (Part 2). Part 2 key secondary endpoints are event-free survival and CR rate (both by independent central review), as well as OS. Other secondary endpoints are minimal residual disease (by ctDNA) and patient-reported outcomes (EORTC QLQ-C30, FACT-LymS, PGIS, PGIC, and EQ-5D-5L). The trial is currently recruiting and is expected to enroll up to 64 pts in Part 1 and ~840 pts in Part 2 at ~200 global sites. Clinical trial information: NCT06091865 .

A phase 1/1b first-in-human (FIH) study of JZP898 as monotherapy and in combination with pembrolizumab in adult patients with advanced or metastatic solid tumors.

TPS3190 Background: JZP898 is a conditionally activated prodrug of interferon alpha (IFNα) that can preferentially deliver IFNα to the tumor microenvironment while potentially minimizing systemic IFNα therapy-associated toxicity. Antitumor activity of IFNα is well-established, but concerns regarding systemic toxicity restrict its use in clinical practice. JZP898, in combination with a checkpoint inhibitor such as pembrolizumab, may provide lasting and potent antitumor activity with minimal additive toxicity attributed to conventional or pegylated IFNα. This phase 1 FIH study will determine a maximum tolerated dose (MTD)/recommended dose (RD) and investigate safety, tolerability, pharmacokinetics (PK), immunogenicity, and preliminary antitumor activity of JZP898 monotherapy and JZP898 combined with pembrolizumab in adult patients with advanced or metastatic solid tumors. Methods: This phase 1, FIH, open-label, multicenter study (NCT06108050) is investigating JZP898 intravenous infusion in adult patients (≥18 years old) with histological or cytological diagnosis of advanced or metastatic solid tumors, European Cooperative Oncology Group performance status ≤1, and measurable disease per RECIST v1.1 criteria. The study consists of a dose finding phase (JZP898 as monotherapy and in combination with pembrolizumab; Part A) and a combination dose expansion phase (JZP898 in combination with pembrolizumab; Part B). In Part A (dose finding), the JZP898 MTD and/or monotherapy RD will be determined using Bayesian optimal interval (BOIN) design based on the incidence of dose-limiting toxicities (DLTs) and all available safety and PK data; the combination recommended phase 2 dose (RP2D) will be determined using BOIN criteria and all available safety, PK/PD, immunogenicity, and preliminary signal of antitumor activity data. Patients will be treated until disease progression, death, unacceptable toxicity, or withdrawal from the study. All patients will be followed for survival until 18 months after the last patient starts study intervention. Primary endpoints include: the incidence and nature of DLTs (Part A); investigator-assessed objective response rate (ORR) per RECIST v1.1 (Part B); the incidence and severity of treatment-emergent adverse events (TEAEs) and serious adverse events; changes in laboratory values or vital signs; and the incidence of dose modifications or discontinuations due to TEAEs. Secondary endpoints include: PK parameters; incidence of antidrug antibodies; investigator-assessed duration of response; progression-free survival; disease control rate; investigator-assessed ORR (Part A); and overall survival (Part B). The study is actively enrolling patients with a planned enrollment of up to 177 patients. Clinical trial information: NCT06108050 .

Pharmacokinetics, pharmacodynamics, and tolerability of an aqueous formulation of rusfertide (PTG-300), a hepcidin mimetic, in healthy volunteers: A double-blind first-in-human study.

Rusfertide is a potent peptide mimetic of hepcidin being investigated for the treatment of polycythemia vera. This randomized, placebo-controlled, double-blind study evaluated the safety, pharmacokinetics, and pharmacodynamics of single and repeated subcutaneous doses of an aqueous formulation of rusfertide in healthy adult males. Subjects received single doses of 1, 3, 10, 20, 40, or 80 mg rusfertide or placebo. A separate cohort of subjects received two doses of 40 mg rusfertide or placebo 1 week apart. Blood samples for pharmacokinetics and pharmacodynamics were collected, and adverse events, clinical laboratory tests, 12-lead electrocardiograms, and vital signs were monitored. Rusfertide was well tolerated. There were no serious or severe treatment-emergent adverse events, and no patterns of clinically important adverse events, or laboratory, vital sign, or electrocardiogram abnormalities. Mean maximum rusfertide plasma concentration (Cmax) and area under the concentration-time curve increased with dose, but less than dose proportionally. Median time to Cmax was 2-4.5 h for 40 and 80 mg rusfertide and 8-24 h for lower doses. Apparent clearance and half-life increased with dose. Single doses of rusfertide 1-80 mg were associated with dose-dependent decreases in serum iron and transferrin-iron saturation. Rusfertide was well tolerated and showed dose-dependent pharmacokinetics and pharmacodynamics.

Efficacy and safety of netupitant/palonosetron in preventing nausea and vomiting in diffuse large B cell lymphoma patients undergoing R–CHOP chemotherapy

Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin’s lymphoma, for which cyclophosphamide, doxorubicin, vincristine, and prednisone with rituximab(R–CHOP) is one of the standard regimens. Given that R–CHOP is highly emetogenic, chemotherapy-induced nausea and vomiting (CINV) prevention is clinically important. However, there is a paucity of studies focusing on these patients. This study aimed to ascertain the effectiveness of an oral fixed-dose combination of netupitant and palonosetron (NEPA) in preventing CINV in patients with DLBCL undergoing first-line R-CHOP chemotherapy. Seventy patients were enrolled in this single-center prospective non-comparative study conducted between November 2020 and May 2023 in South Korea. NEPA was administered 1 h prior to chemotherapy initiation on day 1. The primary endpoint of the study was the complete response rate (no emesis, and no rescue medication) during the acute, delayed, and overall phases, which were assessed over a period of 120 h post-chemotherapy. The complete response rates for NEPA were 90.0% [95% CI 80.5, 95.9] for the acute phase, 85.7% [95% CI 75.3, 92.9] for the delayed phase, and 84.3% [95% CI 73.6, 91.9] for the overall phase, with no-emesis rates (acute: 97.1% [95% CI 97.1, 99.7], delayed: 95.7% [95% CI 88.0, 99.1], overall: 92.9% [95% CI 84.1, 97.6]). NEPA was well tolerated with no severe treatment-emergent adverse events. NEPA exhibited substantial efficacy in mitigating CINV in DLBCL patients undergoing R–CHOP chemotherapy, demonstrating high CR and no-emesis rates, and favorable safety profiles.

Long-term safety and efficacy of Glycopyrronium tosylate in patients with primary axillary hyperhidrosis: a systematic review and meta-analysis

Background: Hyperhidrosis, a condition characterized by excessive sweating, affects ≈ 4.8% of the US population. (1) Glycopyrronium tosylate (GT) is a topical anticholinergic drug approved for primary axillary hyperhidrosis (PAH) treatment. (2) However, no meta-analysis exists on GT’s long-term safety and efficacy. Aim: To evaluate the long-term safety and efficacy of GT as a treatment for PAH. Methods: We systematically searched PubMed, Scopus, and ClinicalTrials.gov. Study selection, quality assessment, and data extraction followed the eligibility criteria. The primary endpoints were changes in the Dermatology Life Quality Index (DLQI), Hyperhidrosis Disease Severity Scale (HDSS), and Axillary Sweating Daily Diary (ASDD) or Axillary Sweating Daily Diary – Change (ASDD-C). Safety endpoints included mydriasis, dry mouth, urinary hesitation, and treatment-emergent adverse events (TEAEs). Statistical analysis was conducted using RevMan 5.1. Results: Our meta-analysis demonstrated that topical GT is clinically effective in treating PAH. GT significantly improves the quality of life of patients, as measured by the DLQI (MD = -2.81, 95% CI = [-4.04, -1.59],P = 0.001), HDSS (OR = 3.72, 95% CI = [2.92, 4.74], P = 0.001), and ASDD/ASDD-C (OR = 4.91, 95%CI = [3.75, 6.44], P = 0.001). Adverse effects such as mydriasis, dry mouth, and urinary hesitation were observed; however, no difference was found between GT and control groups in serious TEAEs, deaths, and severe TEAEs. Conclusion: Topical GT is effective with minimal side effects, providing a valuable option for patients unresponsive to or experiencing significant side effects from other treatments.

Long-term safety of fezolinetant in Chinese women with vasomotor symptoms associated with menopause: the phase 3 open-label MOONLIGHT 3 clinical trial.

We aimed to assess long-term safety and tolerability of fezolinetant, a nonhormonal neurokinin 3 receptor antagonist, among Chinese women with vasomotor symptoms associated with menopause participating in the MOONLIGHT 3 trial. In this phase 3 open-label study, women in menopause aged 40-65 years received fezolinetant 30 mg once daily for 52 weeks. The primary endpoint was frequency and severity of treatment-emergent adverse events (TEAEs), assessed at every visit through week 52 and one follow-up visit at week 55. Overall, 150 women were enrolled (mean age, 54 years) and 105 completed treatment. The frequency of TEAEs was 88.7%. Most TEAEs were mild (63.3%) or moderate (22.7%). The most common TEAE was upper respiratory tract infection (16.0%), followed by dizziness, headache, and protein urine present (10.7% each). There was no clinically relevant change (mean ± standard deviation) in endometrial thickness (baseline, 2.95 ± 1.11 mm; week 52, 2.94 ± 1.18 mm). Alanine aminotransferase and/or aspartate aminotransferase levels >3 times the upper limit of normal were reported in 1.4% of women; no Hy's Law cases occurred. Fezolinetant 30 mg once daily was generally safe and well tolerated over a 52-week period among women in China with vasomotor symptoms associated with menopause.ClinicalTrials.gov Identifier: NCT04451226.

Phase I DAVIO Trial: EYP-1901 Bioerodible, Sustained-Delivery Vorolanib Insert in Patients With Wet Age-Related Macular Degeneration

PurposeTo evaluate safety and tolerability of EYP-1901, an intravitreal insert containing vorolanib, a pan–vascular endothelial growth factor (VEGF) receptor inhibitor packaged in a bioerodible delivery technology (Durasert E™) for sustained delivery, in patients with wet age-related macular degeneration (wAMD) previously treated with anti-VEGF therapy. DesignPhase 1, multicenter, prospective, open-label, dose-escalation trial. ParticipantsPatients with wAMD and evidence of prior anti-VEGF therapy response. MethodsPatients received a single intravitreal injection of EYP-1901. Main Outcome MeasuresThe primary objective was to evaluate safety and tolerability of EYP-1901. Secondary objectives assessed biologic activity of EYP-1901 including best-corrected visual acuity (BCVA) and central subfield thickness (CST). Exploratory analyses included reduction in anti-VEGF treatment burden and supplemental injection-free rates. ResultsSeventeen patients enrolled in the 440 μg (3 patients), 1030 μg (1 patient), 2060 μg (8 patients), and 3090 μg (5 patients) dose cohorts. No dose-limiting toxicity, ocular serious adverse events (AEs), or systemic AEs related to EYP-1901 were observed. There was no evidence of ocular or systemic toxicity related to vorolanib or the delivery technology. Moderate ocular treatment-emergent AEs (TEAEs) included reduced visual acuity (2/17) and retinal exudates (3/17). One patient with reduced BCVA had 3 separate reductions of 17, 18, and 16 letters, and another had a single drop of 25 letters. One severe TEAE, neovascular AMD (i.e., worsening/progressive disease activity), was reported in 1 of 17 study eyes but deemed unrelated to treatment. Mean change from baseline (CFB) in BCVA was –3.7 letters and –5.4 letters at 6 and 12 months. Mean CFB in CST was +1.7 μm and +2.3 μm at 6 and 12 months. Reduction in treatment burden was 76% and 72% at 6 and 12 months. Of 16 study eyes, 13, 9, and 6 were injection-free up to 3, 6, and 12 months. ConclusionIn the DAVIO trial (ClinicalTrials.gov identifier, NCT04747197), EYP-1901 had a favorable safety profile and was well tolerated in previously treated eyes with wAMD. Measures of biologic activity remained relatively stable following a single EYP-1901 injection. These preliminary data support ongoing Phase 2 and planned Phase 3 trials to assess efficacy and safety.