Additional Endpoints Research Articles

Deucravacitinib in Japanese patients with plaque, generalized pustular, or erythrodermic psoriasis: Patient-reported outcomes in the POETYK PSO-4 study.

Deucravacitinib, an oral, selective, allosteric tyrosine kinase 2 inhibitor, is approved in Japan for adult patients with plaque, generalized pustular, or erythrodermic psoriasis. POETYK PSO-4 (NCT03924427), an open-label, single-arm, phase 3 trial, showed that deucravacitinib was effective and well tolerated in Japanese patients with plaque (n = 63), generalized pustular (n = 3), or erythrodermic (n = 8) psoriasis. Additional end points in POETYK PSO-4 included change measured by the patient-reported outcome measures Psoriasis Symptoms and Signs Diary and Dermatology Life Quality Index. Mean changes from baseline in score on each measure and the response rate for achieving Dermatology Life Quality Index scores of 0 or 1 were assessed in each patient group over 52 weeks. All assessments were reported as observed, without imputation, in the as-treated population. Each group reported week 16 score improvements from baseline for both patient-reported outcome measures that were maintained or numerically improved at week 52. At week 52, approximately two-thirds of patients in each group achieved a Dermatology Life Quality Index score of 0 or 1, indicating no impact of disease on quality of life. These results demonstrate improvements in psoriasis symptoms and signs and in quality of life with deucravacitinib treatment in Japanese patients with plaque, generalized pustular, or erythrodermic psoriasis. The small number of patients with generalized pustular or erythrodermic psoriasis limits the generalized interpretability of the findings in these groups.

Methodological insights from the EPISTOP trial to designing clinical trials in rare diseases-A secondary analysis of a randomized clinical trial.

In clinical research, the most appropriate way to assess the effect of an intervention is to conduct a randomized controlled trial (RCT). In the field of rare diseases, conducting an RCT is challenging, resulting in a low rate of clinical trials, with a high frequency of early termination and unpublished trials. The aim of the EPISTOP trial was to compare outcomes in infants with tuberous sclerosis (TSC) who received vigabatrin preventively before the seizures onset with those who received it conventionally after. The study was designed as a prospective, multicentre, randomized clinical trial. However, ethics committees at four centres did not approve this RCT design, resulting in an open-label trial (OLT) in these four centres and an RCT in the other six centres. In this paper, we re-analyse the data from the EPISTOP trial using methods to investigate the influence of allocation bias on the results of the EPISTOP trial. A bias-corrected analysis is used to support and strengthen the published results. We included a term representing the effect of selection bias as an influencing factor on the corresponding endpoint in the statistical model. Thus, the treatment effect estimates for the primary endpoint of time to first seizure and additional secondary endpoints are adjusted for the bias effect. The bias-corrected analyses for the primary endpoint show that the estimated hazard ratio and associated confidence intervals are in a very similar range (original analysis: HR 2.91, 95%-CI [1.11 to 7.67], p-value 0.0306; bias-corrected analysis: HR 2.89, 95%-CI [1.10 to 7.58], p-value 0.0316). This was also the case for the secondary endpoints. The statistical re-analysis of the raw trial data therefore supports the published results and confirms that there is no additional bias introduced by randomization, thereby increasing the value of the results. However, this highlights that this aspect needs to be considered in future trials, especially in rare diseases, to avoid additional biases in an already small sample size where it may be difficult to reach significance.

The Efficacy and Safety of Mirvetuximab Soravtansine in FRα-Positive, Third-Line and Later, Recurrent Platinum-Sensitive Ovarian Cancer: The Single-Arm Phase 2 PICCOLO Trial

Mirvetuximab soravtansine-gynx (MIRV) is a first-in-class, folate receptor alpha (FRα)-targeting antibody-drug conjugate with US Food and Drug Administration approval for FRα-positive platinum-resistant ovarian cancer. PICCOLO is a phase 2, global, open-label, single-arm trial of MIRV as third-line or greater (≥3L) treatment in patients with FRα-positive (≥75% of cells with ≥2+ staining intensity) recurrent platinum-sensitive ovarian cancer (PSOC). Participants received MIRV (6 mg/kg adjusted ideal body weight every 3 weeks) until progressive disease (PD), unacceptable toxicity, withdrawal of consent, or death. Primary endpoint was investigator-assessed objective response rate (ORR). Key secondary endpoint was investigator-assessed duration of response (DOR). Additional endpoints included investigator-assessed progression-free survival (PFS), overall survival (OS), and safety. Analyses of subgroups by disease characteristics (eg, platinum-free interval) and treatment history (eg, prior bevacizumab and poly [ADP-ribose] polymerase inhibitor [PARPi] treatment), were exploratory. Seventy-nine participants were enrolled and efficacy evaluable. The primary endpoint was met; ORR was 51.9% (95% CI, 40.4-63.3). Median DOR was 8.25 months (95% CI, 5.55-10.78) and median PFS was 6.93 months (95% CI, 5.85-9.59). OS was not mature at data cutoff. ORR was 45.8% (95% CI, 32.7-59.2) in participants with PD while on/within 30 days of prior PARPi (n=59) and 60.0% (95% CI, 14.7-94.7) in those without PD with prior PARPi (n=5). No new safety signals occurred; most common treatment-emergent adverse events (TEAEs) were gastrointestinal, neurosensory, and resolvable ocular events. TEAEs led to discontinuation in 13 participants (16%) and death in 2 participants (3%). MIRV as ≥3L treatment in heavily pretreated recurrent FRα-positive PSOC demonstrated notable efficacy and tolerable safety, including among those with prior PD on or within 30 days of PARPi. (Funding, ImmunoGen, Inc; NCT05041257).

Long-term efficacy and safety of secukinumab in patients with moderate-to-severe hidradenitis suppurativa: Week 104 results from the SUNSHINE and SUNRISE extension trial.

SUNSHINE and SUNRISE demonstrated sustained clinical efficacy of secukinumab in patients with moderate-to-severe hidradenitis suppurativa (HS) through 52 weeks. Patients completing the core trials could enter a 4-year extension trial. To evaluate the long-term efficacy, safety/tolerability, and maintenance of clinical response of secukinumab through Week 104 in the extension trial. Patients with a HS clinical response (HiSCR) at Week 52 of the core trials (extension trial baseline visit) entered a randomised withdrawal period. HiSCR responders receiving subcutaneous (s.c.) secukinumab 300 mg every 2/4 weeks (SECQ2W/SECQ4W) through Week 52 in the core trials were randomised 2:1 to continue secukinumab (SECQ2W-R-Q2W or SECQ4W-R-Q4W) or receive placebo (SECQ2W-R-PBO or SECQ4W-R-PBO) through Week 104. The primary endpoint was time to loss of response (LOR; newly-defined for this trial) through Week 104 in Week 52 HiSCR responders (SECQ2W-R-Q2W vs. SECQ2W-R-PBO and SECQ4W-R-Q4W vs. SECQ4W-R-PBO). Time to LOR was tested at 1.25% (one-sided) for each comparison (one-sided familywise alpha of 2.5%) through Week 104. If LOR was met, patients could remain in the trial on open-label secukinumab treatment. Additional endpoints included safety and HiSCR. Overall, 84.3% of patients completing the core trials entered the extension trial; 55.9% were Week 52 HiSCR responders. The primary endpoint was not met for either secukinumab dosing regimen. The estimated risk reduction for LOR was 13% (SECQ2W-R-Q2W vs. SECQ2W-R-PBO; one-sided P=0.250) and 30% (SECQ4W-R-Q4W vs. SECQ4W-R-PBO; one-sided P=0.044). The median time to LOR was numerically longer in secukinumab arms versus placebo (SECQ2W-R-Q2W [283 days; 95% CI: 176, -] vs. SECQ2W-R-PBO [239 days; 95% CI: 120, -]; SECQ4W-R-Q4W [365 days 95% CI: 225, -] vs. SECQ4W-R-PBO [171 days; 95% CI: 113, 337]). In Week 52 HiSCR responders reporting LOR, 43.8% (SECQ2W-R-Q2W), 57.5% (SECQ2W-R-PBO), 39.7% (SECQ4W-R-Q4W) and 34.1% (SECQ4W-R-PBO) were achieving HiSCR at the time of LOR. Overall, the safety of secukinumab was consistent with the core trials. The primary endpoint of this trial was not met. HiSCR was maintained in many patients at the time of LOR. The safety of secukinumab was consistent with the previously characterised safety profile in the core trials. Clinicaltrials.gov ID NCT04179175.

Tafasitamab Plus Lenalidomide and Rituximab for Relapsed or Refractory Follicular Lymphoma: Results from a Phase 3 Study (inMIND)

Background: Follicular lymphoma (FL) is characterized by episodes of remission and relapse, with patients (pts) requiring multiple lines of treatment (tx). While chemoimmunotherapy is often used frontline, it yields shorter response duration with successive lines of tx. In the relapsed/refractory (R/R) setting, immunotherapy approaches are preferred but there remains a need to improve durability. Lenalidomide (len) + rituximab (R) is approved after ≥1 prior line of tx and frequently used. Tafasitamab (tafa), a humanized CD19-targeting monoclonal antibody (mAb), induces direct cytotoxicity and enhances NK cell and macrophage immune-mediated mechanisms. Tafa has been previously approved in combination with len for R/R DLBCL based on the L-MIND study. inMIND (NCT04680052) is an international phase 3, double-blind, randomized, placebo (pbo)-controlled, multicenter trial evaluating efficacy and safety of adding tafa to len+R in pts with R/R FL or marginal zone lymphoma. The trial was powered to assess PFS in pts with FL only and the planned primary analysis is presented here.Methods: Pts ≥18 y with R/R CD19+ and CD20+ FL (grade 1-3A) and ECOG PS ≤2, requiring tx after ≥1 prior systemic therapy including an anti-CD20 mAb, were randomized 1:1 to receive tafa 12 mg/kg iv or pbo on days (D) 1, 8, 15, and 22 of cycles (C) 1-3 and D1 and D15 of C4-12 with standard dosing of len+R for up to twelve 28-day cycles. Primary endpoint was investigator-assessed PFS, planned for analysis after 174 events were observed. Additional endpoints included PET-CR rate (FDG-avid population), OS, PFS (by independent review committee [IRC]), ORR, DOR, safety, and TTNT.Results: 548 pts with FL were randomized: tafa, n=273; pbo, n=275. Baseline demographics were similar between arms: median age 64 y (range, 31-88); 55% male; 79% intermediate- or high-risk FLIPI; 83% high tumor burden per GELF criteria. Median number of prior lines of tx was 1 (range, 1-10), 45% had ≥2 prior lines, 32% had disease progression within 24 m (POD24), and 43% were refractory to prior anti-CD20 mAb. At data cutoff, pts in tafa and pbo arms had received a median of 12 and 11 cycles of tx, 19% and 15% were still on tx, 81% and 84% had discontinued tx, primarily due to tx completion (54% and 43%) or disease progression (11% and 31%), respectively. With median follow-up of 14.1 m, addition of tafa to len+R resulted in significantly lower risk of progression, relapse, or death vs pbo (median investigator-assessed PFS, 22.4 m vs 13.9 m; hazard ratio [HR] [95% CI], 0.43 [0.32, 0.58]; P<0.0001). Benefit was confirmed by IRC assessment (median PFS not reached [NR] with tafa vs 16.0 m with pbo; HR [95% CI], 0.41 [0.29, 0.56]; P<0.0001). PFS benefit with tafa was consistent in all prespecified subgroups analyzed including: pts with POD24, pts refractory to prior anti-CD20 mAb, pts receiving multiple prior lines of tx. PET-CR rate (49.4% vs 39.8%; P=0.029) and ORR (83.5% vs 72.4%; P=0.0014) were higher with tafa vs pbo. DOR was improved with tafa vs pbo (median 21.2 m vs 13.6 m; HR [95% CI], 0.47 [0.33, 0.68]; P<0.0001), as was TTNT (median NR vs 28.8 m; HR [95% CI], 0.45 [0.31, 0.64]; P<0.0001). Despite OS data being immature, there was a trend favoring tafa (HR [95% CI], 0.59 [0.31, 1.13]). A similar rate of tx-emergent adverse events (TEAEs) (99% vs 99%), grade (gr) 3 or 4 AEs (71% vs 69.5%), and serious AEs (36% vs 32%) were observed with tafa and pbo, respectively. Most common gr 3 or 4 AEs with tafa vs pbo were neutropenia (40% vs 38%), pneumonia (8% vs 5%), thrombocytopenia (6% vs 7%), decreased neutrophils (6% vs 7%), COVID-19 (6% vs 2%), and COVID-19 pneumonia (5% vs 1%). TEAEs leading to discontinuation were reported by 11% and 7% of pts in tafa and pbo arms. In total, 15 pts (5.5%) in the tafa arm and 23 (8.5%) in the pbo arm died during the study, including 5 (2%) vs 17 (6%) due to disease progression and 6 (2%) in each arm due to fatal AEs.Conclusions: Addition of tafa to len+R resulted in significant and clinically meaningful improvement in PFS, representing a 57% reduction in risk of progression, relapse, or death in pts with R/R FL. Although OS data are immature, a trend in favor of tafa was observed. The safety profile was manageable and consistent with expected toxicities. This study is the first to validate combining two mAbs (anti-CD19 with anti-CD20) in the tx of lymphoma. Tafa+len+R can be administered in community as well as academic settings and represents a potential new standard of care option for pts with R/R FL.

Pharmacokinetics, Efficacy, and Safety of Upadacitinib in Pediatric Patients with Polyarticular-Course Juvenile Idiopathic Arthritis: An Interim Analysis of an Open-label, Phase 1 Trial.

This work aimed to evaluate the pharmacokinetics, efficacy, and safety of upadacitinib, an oral selective JAK inhibitor, in pediatric patients with polyarticular-course juvenile idiopathic arthritis (pcJIA). In an open-label, phase 1 study (SELECT-YOUTH), enrolled patients, aged 2 to <18 years with pcJIA, received bodyweight-based upadacitinib doses using a twice-daily (BID) oral solution or once-daily (QD) extended-release tablet based on their body weight and ability to swallow tablets. The study included a 7-day pharmacokinetic assessment, followed by a long-term efficacy and safety evaluation for up to 156 weeks, including an additional long-term safety cohort. This interim analysis included available pharmacokinetic and safety data and efficacy data collected through Week 48. A total of 57 patients received upadacitinib. The median time to maximum upadacitinib concentration was approximately 3 hours and 1 hour for the tablet and oral solution regimens, respectively; the harmonic mean functional half-life was approximately 5 hours and 2 hours, respectively. Juvenile idiopathic arthritis (JIA) American College of Rheumatology (ACR)30/50/70/90/100 responses at Week 12 were 91.8/89.8/69.4/49.0/32.7%, respectively. Efficacy was generally maintained through Week 48, and improvement in additional efficacy endpoints was also observed. At a median exposure duration of 412 days, 52 of 57 patients reported adverse events, of these 6 experienced serious adverse events. Adverse events were predominately mild to moderate in severity and consistent with the known safety profile of upadacitinib. This interim analysis demonstrates that the bodyweight-based dosing regimen of upadacitinib was well tolerated and efficacious in pediatric patients with pcJIA.

CTIM-25. PHASE2B/3 STUDY OF NEOANTIGEN-SPECIFIC T CELL IMMUNOTHERAPY IN NEWLY DIAGNOSED O6 – METHYLGUANINE METHYLTRANSFERASE UNMETHYLATED (MGMT -) GLIOBLASTOMA

Abstract MGMT- glioblastoma (GBM) is the most common malignant primary brain tumor, yet outcomes have not improved in decades despite intensive investigations. TVI-AST-008 is a randomized clinical trial of a novel neoantigen-specific T cell immunotherapy regimen proven invariably curative in rodent models and clinically effective in trials of patients with relapsed/resistant GBM. TVAX neoantigen-specific T cell immunotherapy exploits the fact that cancer cells express neoantigens, and adoptive transfer can bypass the immunosuppressive milieu near the resection cavity. In this manner, TVAX effector T cells initiate apoptosis in any residual GBM. After pathologic confirmation, autologous GBM tumor tissue sent to the TVAX GMP manufacturing facility is irradiated and utilized for proprietary vaccine production. Patients are vaccinated with a series of two intradermal injections and the resulting cancer neoantigen-specific T cells are harvested by leukapheresis. These T cells are activated and proliferated ex vivo by TVAX manufacturing to generate effector T cells. These are re-infused following standard radio-chemotherapy, followed by low-dose interleukin-2 to further stimulate T cell proliferation. In the study, MGMT- GBM patients are randomly assigned to treatment or control arms. Patients in the treatment arm undergo vaccination, then standard concurrent IMRT-chemotherapy, followed by re-infusion of TVAX autologous effector T cells. Patients in the control arm undergo standard IMRT-chemotherapy followed by adjuvant chemotherapy with temozolomide. TVI-AST-008 is an ongoing, randomization-controlled study with Fast Track designation from the FDA. The primary end point is overall survival. Additional end points include progression free survival, safety and immune response. Patients are followed with physical exams and surveillance MRI for evidence of disease progression. The trial is targeted for 15 centers in the US.

Stent Retriever AssIsted Lysis Technique with Tirofiban: A Potential Bailout Alternative to Angioplasty and Stenting.

Angioplasty and stent placement have been described as a bailout technique in individuals with failed thrombectomy. We aimed to investigate Stent retriever AssIsted Lysis (SAIL) with tirofiban before angioplasty and stent placement. Patients from 2 comprehensive stroke centers were reviewed (2020-2023). We included patients with failed thrombectomy and/or underlying intracranial stenosis who received SAIL with tirofiban before the intended angioplasty and stent placement. SAIL consisted of deploying a stent retriever through the occluding lesion to create a bypass channel and infuse 10 mL of tirofiban for 10 minutes either intra-arterially or IV. The stent retriever was re-sheathed before retrieval. The primary end points were successful reperfusion (expanded TICI 2b-3) and symptomatic intracerebral hemorrhage. Additional end points included 90-day mRS 0-2 and mortality. After a median of 3 (interquartile range, 2-4) passes, 44 patients received the SAIL bridging protocol with tirofiban, and later they were considered potential candidates for angioplasty and stent placement bailout (43.2%, intra-arterial SAIL). Post-SAIL successful reperfusion was obtained in 79.5%. A notable residual stenosis (>50%) after successful SAIL was observed in 45.7%. No significant differences were detected according to post-SAIL: successful reperfusion (intra-arterial SAIL, 80.0% versus IV-SAIL, 78.9%; P = .932), significant stenosis (33.3% versus 55.0%; P = .203), early symptomatic re-occlusion (0% versus 8.0%; P = .207), or symptomatic intracerebral hemorrhage (5.3% versus 8.0%; P = .721). Rescue angioplasty and stent placement were finally performed in 15 (34.1%) patients (intra-arterial SAIL 21.0% versus IV-SAIL 44%; P = .112). At 90 days, mRS 0-2 (intra-arterial SAIL 50.0% versus IV-SAIL 43.5%; P = .086) and mortality (26.3% versus 12.0%; P = .223) were also similar. In patients with stroke in which angioplasty and stent placement are considered, SAIL with tirofiban, either intra-arterial or IV, seems to safely induce sustained recanalization, offering a potential alternative to definitive angioplasty and stent placement.

A Phase II study of avenciguat, a novel soluble guanylate cyclase activator, in patients with systemic sclerosis: Study design and rationale of the VITALISScE™ study.

Systemic sclerosis is a rare autoimmune connective tissue disease characterised by (1) microvasculopathy; (2) immune dysregulation; and (3) progressive fibrosis of the skin and internal organs. Soluble guanylate cyclase plays an important role in maintaining vascular and immunological homeostasis and preventing organ fibrosis. Pharmacological modulation of soluble guanylate cyclase with soluble guanylate cyclase stimulators has shown anti-inflammatory and antifibrotic effects in animal models of systemic sclerosis, with a trend towards clinical efficacy in a Phase II study (RISE-SSc). However, the efficacy of soluble guanylate cyclase stimulators may be reduced under conditions of hypoxia and oxidative stress. Soluble guanylate cyclase activators have the potential to overcome this limitation. This paper describes the study design of VITALISScE™, a Phase II clinical trial assessing the efficacy, safety and tolerability of avenciguat, a novel soluble guanylate cyclase activator in patients with active systemic sclerosis at risk of progression. The VITALISScE™ study (NCT05559580) is evaluating the action of avenciguat on all three aspects of systemic sclerosis pathophysiology. The primary endpoint is the rate of decline in forced vital capacity (mL) over 48 weeks. Secondary endpoints include absolute change from baseline at Week 48 in modified Rodnan skin score, Health Assessment Questionnaire Disability Index score and the proportion of responders based on the revised Composite Response Index in Systemic Sclerosis. Additional endpoints include a composite assessment of Raynaud's phenomenon, digital ulcer burden, functional outcomes and quality of life, safety, pharmacokinetics, and biomarkers associated with systemic sclerosis and the mechanism of action of avenciguat. VITALISScE™ is an ongoing, multicentre (180 sites; 38 countries), placebo-controlled, double-blind, parallel-group, Phase II clinical study. Recruitment is currently ongoing. The VITALISScE™ study is assessing the efficacy, safety and tolerability of avenciguat in patients with active systemic sclerosis at risk of progression. Results will inform further development of avenciguat. VITALISScE™; EU CT No. 2022-500332-11-00; Clinicaltrials.gov: NCT05559580 (https://www.clinicaltrials.gov/study/NCT05559580).

Rationale and Design of the DEFIANCE Study: A Randomized Controlled Trial of Mechanical Thrombectomy Versus Anticoagulation Alone for Iliofemoral Deep Vein Thrombosis

BackgroundDeep vein thrombosis (DVT) is a common medical condition that is associated with clinically significant sequelae, including postthrombotic syndrome (PTS). Anticoagulation alone remains the guideline-recommended treatment for many patients with iliofemoral DVT. Recent technological advances have led to an increase in the use of mechanical thrombectomy for DVT, but mechanical thrombectomy-based procedures have not yet been compared with standard-of-care anticoagulation therapy in randomized studies. MethodsThe DEFIANCE study (ClinicalTrials.gov: NCT05701917) is an international and actively enrolling randomized controlled trial (RCT) in lower extremity DVT assessing an interventional strategy that includes mechanical thrombectomy with the ClotTriever System (Inari Medical, Irvine, CA) versus anticoagulation alone. Approximately 300 patients with unilateral iliofemoral DVT and symptom duration ≤12 weeks will be randomized 1:1. Study conduct includes an independent core laboratory for duplex ultrasound assessment, an independent medical monitor for safety adjudication, and evaluation of PTS severity on the Villalta scale using best clinical practices. The primary endpoint is a composite outcome structured as a hierarchal win ratio of 1) the occurrence of treatment failure or therapy escalation as adjudicated by the medical monitor, with failure defined as amputation or gangrene of the target leg or venous thromboembolism-related mortality, and 2) the assessment of PTS severity at the 6-month follow-up visit. In addition to being a component of the primary endpoint, the severity of PTS at 6 months is also evaluated as a stand-alone secondary endpoint. An additional secondary endpoint is a composite of outcomes at the 10-day visit and is structured as a hierarchal win ratio of 1) vessel compressibility on duplex ultrasound, 2) patient-reported pain, and 3) improvement of edema. The safety endpoints are access site complications requiring endovascular or surgical repair and the occurrence through the 30-day visit of mortality, major bleeding, or new symptomatic pulmonary embolism. ConclusionsDEFIANCE will be the first RCT to evaluate a mechanical thrombectomy-based interventional approach versus anticoagulation therapy alone for DVT. The results will inform the treatment of patients with iliofemoral DVT and the prevention of PTS-associated morbidity. Trial RegistrationDEFIANCE: RCT of ClotTriever System Versus Anticoagulation In Deep Vein Thrombosis (DEFIANCE), ClinicalTrials.gov: NCT05701917, URL: https://clinicaltrials.gov/study/NCT05701917?cond=Deep%20Vein%20Thrombosis&term=defiance&rank=1

Setmelanotide in patients aged 2-5 years with rare MC4R pathway-associated obesity (VENTURE): a 1 year, open-label, multicenter, phase 3 trial.

Setmelanotide, a melanocortin-4 receptor (MC4R) agonist, has been shown to reduce hunger and weight in patients aged 6 years and older with proopiomelanocortin (POMC) deficiency (including biallelic variants in proprotein convertase subtilisin/kexin type 1 [PCSK1]), leptin receptor (LEPR) deficiency, or Bardet-Biedl syndrome (BBS). No approved therapies for patients younger than 6 years old currently exist. The phase 3, open-label VENTURE trial aimed to evaluate the efficacy and safety of setmelanotide in patients aged 2-5 years with POMC or LEPR deficiency or BBS. This phase 3, open-label, multicentre trial, conducted across six sites in the USA, the UK, Spain, and Australia, enrolled eligible patients aged 2-5 years who had hyperphagia and obesity due to biallelic POMC (including PCSK1) or LEPR variants or genetically confirmed BBS. Open-label subcutaneous setmelanotide was administered once daily for 52 weeks, starting at 0·5 mg with doses increasing every 2 weeks in 0·5 mg increments until reaching the maximum dose based on weight. The co-primary endpoints at week 52 were the percentage of patients reaching a 0·2-point decrease or greater in BMI Z score (a statistical measure used to assess BMI in paediatric patients considering a patient's BMI and comparing it to reference values for the same age and sex) and mean percent change in BMI. Additional endpoints measured safety, hunger, weight-related outcomes, and caregiver burden. The study is registered at ClinicalTrials.gov (NCT04966741) and is complete. Between March 8, 2022, and Sept 18, 2023, 13 patients were screened at the six sites, and 12 patients were enrolled in the study (seven with POMC or LEPR and five with BBS); one patient with BBS was excluded as their BMI was not at the 97th percentile or above. Of the 12 patients enrolled, most were male (seven [58%] vs five [42%] for female) and the mean age was 3·6 years (SD 0·9). 11 patients completed the trial. Ten (83%) of the 12 overall participants reached a 0·2-point reduction or more in BMI Z score per WHO methodology at week 52 (95% CI 58·7-99·8). The mean percent change in BMI from baseline at week 52 was -18% (SD 13) in the overall safety population. Mean percent change in BMI at week 52 was -26% (SD 11) in patients with POMC or LEPR deficiency and -10% (9) in patients with BBS. Mean reductions in secondary endpoints of BMI Z score (3·4 [2·5]) and percent of the BMI 95th percentile (32·5 [22·9]) were seen at Week 52. 91% of caregivers reported that patients were less hungry than at baseline. All adverse events were mild or moderate; skin hyperpigmentation, vomiting, nasopharyngitis, upper respiratory tract infection, and injection site reactions were most common. No serious adverse events or adverse events leading to study discontinuation or death were reported. To our knowledge this is the first trial of setmelanotide in patients younger than 6 years old. These results support the benefit of the drug as an early intervention to manage obesity in this population. Rhythm Pharmaceuticals.

Non-invasive imaging to guide percutaneous coronary revascularization in chronic total occlusion: a systematic review and meta-analysis

Abstract Background and aims Whether recanalization of coronary chronic total occlusions (CTO) leads to improved patient outcomes is uncertain. We set out to investigate the use of noninvasive imaging modalities to guide patient selection for percutaneous recanalization of coronary chronic total occlusions (CTO-PCI) and its association with outcomes. Methods Systematic review and meta-analysis of studies involving patients undergoing CTO-PCI to detail use of preprocedural non-invasive imaging, change in clinical endpoints and the occurrence of clinical events in these patient cohorts. PubMed and Embase, the Cochrane Database of Systematic Reviews, the PROSPERO database and the Clinical Trials Registry were searched for relevant randomized and observational studies up to May 2023. This study is registered with PROSPERO. The study primary endpoint was a composite of all-cause death and nonfatal myocardial infarction (MI), with a secondary composite endpoint of cardiovascular death, nonfatal MI and target vessel revascularization (TVR). Additional endpoints were individual components of the composite endpoints along with changes in angina burden, LV ejection fraction, ischemic burden, and infarct extent after PCI. Results Of 1264 publications retrieved, 31 studies (26 observational and 5 randomized) were finally included for a total of 7260 patients. Guidance to CTO-PCI varied greatly among included studies, with only a minority implementing routine preprocedural inducible ischemia and myocardial viability assessment. At a median of 3.1 years (range 1-5 years), the primary endpoint occurred at a rate of 3.1 events per 100 patient-years (95%CI: 2.4-3.7). When non-invasive imaging was used to guide CTO-PCI, patients with myocardial ischemia and/or viability, a reduced risk for the primary endpoint was observed (OR 0.3 95%CI 0.2-0.5) compared to CTO-PCI without evidence of myocardial ischemia and/or viability. CTO-PCI was associated with improvements in SAQ summary score, LVEF, reduction of ischemic burden, improvement in myocardial perfusion (all P-values &amp;lt; 0.01), with no change in the burden of myocardial scarring. At meta-regression analysis, a greater improvement in LVEF was observed in studies enrolling patients with lower average baseline LVEF (≤ 45%) (R2 = 63%, p &amp;lt; 0.0001). Conclusions CTO-PCI led to a significant improvement in symptom status (reduction of chest pain) and LV ejection fraction. CTO-PCI guided by the presence of ischemia and/or viability was associated with improved patient outcomes compared with CTO-PCI in the absence of ischemia and/viability, or in patients where non-invasive imaging testing was not performed. Future randomized clinical trials testing whether ischemia and viability-guided CTO-PCI improves clinical outcomes are lacking and warranted.PRISMA Flow diagramGraphical abstract

Treatment of Post-COVID-19 POTS by inhibiting FcRn: a phase 2 randomized, placebo controlled, double-blind, proof of concept study with efgartigimod

Abstract Background While the underlying pathophysiology is unknown, post–COVID-19 postural orthostatic tachycardia syndrome (POTS) may be related to immune dysfunction and autoimmunity precipitated by SARS-CoV-2 infection. Various autoantibodies, including those targeting G-protein coupled receptors (GPCRs), have been observed in patients with POTS. Binding of these autoantibodies to adrenergic receptors, which are prototypical GPCRs, has been hypothesized to modulate receptor activity, increase sympathetic tone, and cause tachycardia. Moreover, IgG anti-GPCR autoantibodies, acting as partial agonists, are thought to decrease the effect of peripheral vasomotor control, leading to an increased sympathetic response to upright posture that can result in postural tachycardia in the absence of hypotension. Purpose We hypothesize that a reduction in autoantibody levels by efgartigimod, a FcRn-antagonist, will ameliorate the underlying immune-mediated pathogenesis and lead to clinical improvements in patients who developed POTS following COVID-19 infection. We propose a phase II multicenter, randomized, placebo-controlled, double-blind, proof-of-mechanism study initiated to evaluate the safety and efficacy of efgartigimod in adults with post–COVID-19 POTS. Methods Adult patients diagnosed with new-onset of POTS following SARS-CoV-2 infection are eligible for participation in the study. Prior COVID-19 must be confirmed by documentation of historical PCR test, and POTS diagnosis must meet consensus criteria. Study subjects must have moderate to severe autonomic symptoms (COMPASS-31 score ≥ 35 points at screening). Approximately 42 patients will be randomly allocated (2:1) to receive weekly intravenous efgartigimod or placebo for 24 weeks. At the end of the treatment period, participants who complete the study may roll over into an open-label extension (OLE). The co-primary endpoints are change from baseline to week 24 in the COMPASS-31 and Malmo POTS Symptom Score as well as safety and tolerability outcomes. Key secondary endpoints include assessments of disease activity, fatigue, cognitive function, walking capacity and quantitative autonomic testing. Additional exploratory endpoints include intraepidermal small fiber densities (optional), sudomotor innervation (optional) and peripheral blood biomarkers to define histopathological and immune determinants associated with treatment response. Conclusions This phase II study of efgartigimod will evaluate the effect of FcRn inhibition on disease pathology and the potential for therapeutic benefit in patients with post–COVID-19 POTS.

Atrial fibrillation ablation with temperature-controlled very high-power short-duration, with conventional-power, or with combined modes in clinical practice: 12-month outcomes from SECURE

Abstract Background/Introduction QDM is a contact force-sensing catheter optimized for temperature-controlled radiofrequency ablation in very high-power short-duration (vHPSD; 90 W/4 s), conventional-power (CP; ≤50 W), or vHPSD/CP combined modes. Purpose Evaluate 12-month (M) safety and effectiveness of atrial fibrillation (AF) ablations performed with 3 different ablation modes using the QDM catheter, a frequently used single tip catheter in Europe. Methods SECURE is an observational, prospective, post-market study collecting data on procedures performed per standard-of-care with up to 12M follow-up, in 16 enrolling sites in 8 countries across Europe and Israel. Index pulmonary vein (PV) isolation procedures are reported here. The primary safety endpoint is the incidence of primary adverse events (PAEs); the primary effectiveness endpoint is PV isolation (entrance block) of targeted PVs. Additional endpoints include acute reconnections, incidence of char and steam pop, 12M recurrence, repeat ablation, and healthcare utilization (HCU). Ablation strategy, impedance drop, and catheter stability were analysed with a cloud-based data management and artificial intelligence-powered algorithm. Results Since Feb 2021, 291 patients (70% male, 61±11 yrs, CHA2DS2-VASc 1.9±1.5) completed 12M follow-up in 11 sites. Most patients (175 [60.1%]) were treated for paroxysmal (PAF), 85 (29.2%) for persistent (PsAF), and 31 (10.7%) for long-standing persistent (LsPsAF) AF, under general anaesthesia (44.0%) or sedation (55.7%). A combined workflow was used in 66.0% of ablations, while vHPSD-only and CP-only were used in 13.4% and 20.6% of cases, respectively. Four (1.4%) patients reported a PAE; all resolved, and none were catheter related. Acute effectiveness was achieved in all targeted veins; 5.0% of PVs had acute reconnections, with the most common being the left superior PV. No steam pops were reported; 2 counts of char were noted in PsAF ablations with combined modes. Freedom from documented recurrence were 95.8% for PAF, 88.1% for PsAF, and 73.5% for LsPsAF (Fig 1). Freedom from repeat ablation post-blanking and freedom from cardioversion were both 96.8%. Cardiovascular hospitalization and emergency room visits decreased by 65.3% and 76.5% from 12M pre- to 12M post-procedure, respectively. Application-level analyses showed larger impedance drop and greater catheter stability with vHPSD. In procedures using a combined workflow, vHPSD was used preferentially for most PV segments, except anteriorly on the left wide area circumferential ablation (Fig 2). Conclusions Real-world data demonstrates that AF ablation with the QDM catheter is safe and effective with a low PAE rate, high 12M effectiveness, and reduced HCU. Most procedures were done with combined modes, where vHPSD was used preferentially, except at left anterior thicker regions. Larger impedance drop and greater catheter stability were observed with vHPSD applications.

Case Studies on the use of Microsampling for Nonclinical Studies in Pharmaceutical Drug Discovery and Development.

The implementation of microsampling approaches for use in nonclinical discovery and development pharmaceutical studies can have a major impact on improving animal ethics through the use of fewer animals and less invasive procedures for the collection of toxicokinetic and pharmacokinetic samples. In addition, the approach offers the opportunity for obtaining improved quality of data for these studies. This can include the determination of additional timepoints and endpoints, and the ability to obtain exposure data from the same animals utilized to measure other study endpoints. This manuscript presents a number of cases where a variety of microsampling approaches have been successfully implemented by a number of organizations and serves as a guide for those considering the use of microsampling approaches as part of their drug discovery and development programs, as the adoption of these approaches are not yet universal.

Outcomes of Nonagenarian Patients in Vascular Surgery Service in a Tertiary Institution.

With the world population growing and aging, nonagenarians have become a distinct patient cohort with specific characteristics that render the prediction of outcomes essential. We aimed to investigate the specific characteristics of this patient's cohort in a tertiary vascular center. Retrospective analysis was conducted for all consecutive patients 90 years and above referred or treated in the Department of Vascular Surgery between January 2017 and December 2022 for vascular pathologies. The main endpoint was to analyze the type of vascular services required for nonagenarians. Additional endpoints involved evaluation of treatment outcomes during the study period based on medical records. The analysis was patient-based. A total of 148 nonagenarians were included in the study. In all, 71 (48%) of the patients underwent surgery, whereas 77 (52%) had conservative treatment. Most of the patients were referred for peripheral arterial (PAD; 56, 37.8%) and aortic-related (39, 26.4%) diseases. Other pathologies encountered involved acute limb ischemia (ALI; 25, 16.9%), carotid diseases (12, 8.1%), renal/dialysis-related consultations (8, 5.4%), and referrals from other departments (12, 5.4%). Urgent interventions were performed in 27% of the cases. Indications for surgery included PAD Rutherford Stages IV, V, and VI; symptomatic and ruptured aortic aneurysms; ALI Rutherford Stages I, IIa, and IIb; symptomatic and near total occlusion asymptomatic carotid disease; and dialysis-related procedures for patients with chronic renal failure on regular hemodialysis. Perioperative complications were experienced in 22 patients (14.9%), the 30-day reintervention rate was 7.4%, and 30-day mortality was 4.7%. The overall length of hospital stay for operated patients was a median of 8 nights. The proportion of nonagenarians in the population is growing and so is their referral to vascular surgery. Satisfactory short-term treatment outcomes can be achieved in this highly selected cohort of patients. Thirty-day mortality is higher in patients undergoing urgent procedures. Follow-up mortality was higher in the operated nonagenarians as compared with those who were treated conservatively. Careful patient selection and thorough preparation are crucial to enhance clinical outcomes. Further research on therapy outcomes of nonagenarians will enable physicians to make better evidence-based approaches to individual patients and should be encouraged. The study highlights the growing need to manage vascular diseases in nonagenarians, emphasizing that age alone should not exclude patients from surgical interventions. By demonstrating acceptable short-term outcomes with careful patient selection, this research challenges the traditional bias against operating on the elderly. Clinicians should refine risk assessment and treatment plans, particularly when balancing surgical and conservative options. Comorbidities, rather than age, are key determinants of patient suitability, encouraging more individualized, evidence-based approaches in this expanding demographic.

7519 Withdrawal of DCCR (Diazoxide Choline) Extended-Release Tablets Worsens Hyperphagia and Increases Weight and BMI in a 16-week Double-blind, Placebo-controlled, Randomized Withdrawal Period in Patients with Prader Willi Syndrome

Abstract Disclosure: E.F. Gevers: Advisory Board Member; Self; Pfizer, Inc., Soleno. Research Investigator; Self; Soleno Therapeutics, Inc.. Speaker; Self; Pfizer, Inc., Novo Nordisk, Soleno Therapeutics, Inc. J.L. Miller: Research Investigator; Self; Soleno Therapeutics, Inc. N.A. Bridges: Research Investigator; Self; Soleno Therapeutics, Inc. E.I. Felner: Research Investigator; Self; Soleno Therapeutics, Inc. P. Salehi: Research Investigator; Self; Soleno Therapeutics, Inc. D. Stevenson: Research Investigator; Self; Soleno Therapeutics, Inc. J. Yanovski: Research Investigator; Self; Soleno Therapeutics, Inc. L. Bird: Research Investigator; Self; Soleno Therapeutics, Inc. V. Kimonis: Research Investigator; Self; Soleno Therapeutics, Inc. A.H. Shoemaker: Research Investigator; Self; Soleno Therapeutics, Inc. K.S. Obrynba: Research Investigator; Self; Soleno Therapeutics, Inc. M. Lah: Research Investigator; Self; Soleno Therapeutics, Inc. E. Littlejohn: Research Investigator; Self; Soleno Therapeutics, Inc. N. Cowen: Employee; Self; Soleno Therapeutics, Inc.. Stock Owner; Self; Soleno Therapeutics, Inc. N. Cowen: Employee; Self; Soleno Therapeutics, Inc.. Stock Owner; Self; Soleno Therapeutics, Inc. K. Yen: Employee; Self; Soleno Therapeutics, Inc.. Stock Owner; Self; Soleno Therapeutics, Inc. S. Ballal: Employee; Self; Soleno Therapeutics, Inc.. Stock Owner; Self; Soleno Therapeutics, Inc. P. Hirano: Employee; Self; Soleno Therapeutics, Inc.. Stock Owner; Self; Soleno Therapeutics, Inc. M. Huang: Employee; Self; Soleno Therapeutics, Inc.. Stock Owner; Self; Soleno Therapeutics, Inc. A. Bhatnagar: Employee; Self; Soleno Therapeutics, Inc.. Stock Owner; Self; Soleno Therapeutics, Inc.. Background: Prader-Willi syndrome (PWS) is a rare genetic neurobehavioral-metabolic disease characterized by hyperphagia, endocrinopathies, weight gain, hypotonia, behavioral problems, and an increased risk of mortality and reduced life expectancy. There are currently no approved treatments for hyperphagia in PWS. Diazoxide choline extended-release (DCCR) is a novel, once daily oral therapy being developed for the treatment of PWS. Herein, we present results of the Randomized Withdrawal Period (RWP) of Clinical Study C602, a long-term treatment study of DCCR in people with PWS. Objectives and Methods: This was a 16-week multi-center, double-blind, placebo-controlled RWP that enrolled participants ≥4 years of age who were actively enrolled in the open label period of Clinical Study C602 and had received 2-4 years of DCCR treatment (target dose: ≥3.3 mg/kg; optimal range: 4.2-5.8 mg/kg) at the time of RWP entry. RWP-eligible participants were randomized 1:1 to continue DCCR or withdraw from DCCR and receive Placebo. The primary objective was to evaluate the effect of continued DCCR administration versus Placebo on hyperphagia based on the change in Hyperphagia Questionnaire for Clinical Trials (HQ-CT) Total Score from Baseline to Week 16. Additional endpoints included: the Clinical Global Impression of Severity (CGI-S) and Clinical Global Impression of Improvement (CGI-I) at Week 16; changes in body composition (weight, BMI, and BMI z-scores) at Week 16; and the safety profile of DCCR. Results: DCCR (n=38) and Placebo (n=39) groups were generally balanced for demographic and baseline characteristics. At Week 16, a statistically significant difference in change from baseline in HQ-CT Total Score was observed between DCCR and Placebo groups with HQ-CT Total Scores increasing markedly (indicating worsening hyperphagia) in the Placebo group compared to the DCCR group (LSMean difference [SE] -5.0 [1.57], p=0.002). CGI-S and CGI-I showed trends towards worsening in the Placebo group versus the DCCR group (p=0.079 and 0.092, respectively). The Placebo group also experienced significantly greater increases in weight, BMI, and BMI z-scores (p=0.035, 0.034, and 0.023, respectively) than the DCCR group. DCCR was well-tolerated, with no new or unexpected safety signals, and no serious adverse events or discontinuations due to adverse events in the DCCR group. Conclusions: In this 16-week RWP, the Placebo group experienced significant worsening in hyperphagia and increases in body weight, BMI, and BMI z-scores, along with worsening trends for the CGI-S and CGI-I, compared to the DCCR group. DCCR was well tolerated, with a safety profile that was consistent with prior experience. These data suggest treatment with DCCR may lead to clinical benefits in people with PWS by reducing hyperphagia and improving body composition. Presentation: 6/2/2024

Standardization and optimization of the hiPSC-based PluriLum assay for detection of embryonic and developmental toxicants.

New approach methodologies (NAMs) for predicting embryotoxicity and developmental toxicity are urgently needed for generating human relevant data, while reducing turnover time and costs, and alleviating ethical concerns related to the use of animal models. We have previously developed the PluriLum assay, a NKX2.5-reporter gene 3D model using human-induced pluripotent stem cells (hiPSCs) that are genetically modified to enable the assessment of adverse effects of chemicals on the early-stage embryo. Aiming at improving the predictive value of the PluriLum assay for future screening purposes, we sought to introduce standardization steps to the protocol, improving the overall robustness of the PluriLum assay, as well as a shortening of the assay protocol. First, we showed that the initial size of embryoid bodies (EBs) is crucial for a proper differentiation into cardiomyocytes and overall reproducibility of the assay. When the starting diameter of the EBs exceeds 500 µm, robust differentiation can be anticipated. In terms of reproducibility, exposure to the fungicide epoxiconazole at smaller initial diameters resulted in a larger variation of the derived data, compared to more reliable concentration-response curves obtained using spheroids with larger initialdiameters. We further investigated the ideal length of the differentiation protocol, resulting in a shortening of the PluriLum assay by 24 h to 7 days. Following exposure to the teratogens all-trans and 13-cis retinoic acid, both cardiomyocyte contraction and measurement of NKX2.5-derived luminescence were recorded with a similar or increased sensitivity after 6 days of differentiation when compared to the original 7 days. Finally, we have introduced an efficient step for enzymatic dissociation of the EBs at assay termination. This allows for an even splitting of the individual EBs and testing of additional endpoints other than the NKX2.5-luciferase reporter, which was demonstrated in this work by the simultaneous assessment of ATP levels. In conclusion, we have introduced standardizations and streamlined the PluriLum assay protocol to improve its suitability as a NAM for screening of a large number of chemicals for developmental toxicity testing.

S770 Efficacy and Safety of Linaclotide in Patients With Chronic Idiopathic Constipation: A Post Hoc Analysis of Phase 3 Clinical Study Data Assessing Primary and Additional Endpoints by Race and Ethnicity, and by Age

S770 Efficacy and Safety of Linaclotide in Patients With Chronic Idiopathic Constipation: A Post Hoc Analysis of Phase 3 Clinical Study Data Assessing Primary and Additional Endpoints by Race and Ethnicity, and by Age

Revefenacin Area Under the Curve Spirometry in Patients with Moderate to Very Severe COPD.

Several lung function endpoints are utilized in clinical trials of inhaled bronchodilators for chronic obstructive pulmonary disease (COPD). Trough forced expiratory volume in 1 second (FEV1) is a commonly reported endpoint in COPD trials and can be complemented by area under the FEV1 vs time curve (FEV1 AUC), which provides information on duration and consistency of bronchodilation over a dosing interval. Revefenacin, a once-daily bronchodilator, significantly improved lung function in patients with COPD when measured by trough FEV1 in two replicate Phase 3 trials. Here, we report an FEV1 AUC substudy using data from these trials. This post hoc analysis examined substudy data from 12-week replicate Phase 3 trials (NCT02459080/NCT02512510); patients with moderate to very severe COPD were randomized 1:1 to revefenacin 175μg or placebo once daily. The substudy patients had FEV1 AUC0-2h assessed on Day 1, and those who continued to Day 84 also underwent 24-hour serial spirometry postdose where FEV1 AUC0-2h, AUC0-12h, AUC12-24h, and AUC0-24h were evaluated. Fifty and 47 patients who received revefenacin and placebo underwent 24-hour serial spirometry; most baseline characteristics were aligned between groups. At Day 84 postdose, revefenacin demonstrated sustained improvements in bronchodilation over 24hours; differences in least squares mean vs placebo were 282, 220, 205, and 212 mL for FEV1 AUC0-2h, AUC0-12h, AUC12-24h, and AUC0-24h (all P <0.001), respectively. This substudy analysis supplements previous findings that revefenacin provides sustained bronchodilation over 24hours. Assessing additional complementary COPD clinical trial endpoints can help clinicians make treatment decisions.