Open-label Multicenter Study Research Articles

Inadequate Efficacy of Biologics for Treating Proximal Ileal Lesions in Crohn's Disease; a prospective multicenter study.

While biologic therapy has revolutionized the treatment of Crohn's disease (CD), surgery remains unavoidable in cases involving ileal complications. We aimed to evaluate the efficacy of biologics on proximal ileal lesions using balloon-assisted enteroscopy (BAE). This open-label multicenter prospective study was conducted at tertiary referral centers in Japan. We enrolled 253 patients with active ileal CD who were treated with biologics (infliximab/adalimumab/ustekinumab/vedolizumab). BAE was performed at week 0 and week 26, and endoscopic findings were centrally assessed. We evaluated the rate of endoscopic remission (defined as having a maximum mSES-CD <4) at week 26 and patient prognosis (CD-related hospitalization and surgery). At baseline, 74 (29.2%) patients had proximal ileal ulcerations without terminal ileal ulcerations. The second BAE showed that endoscopic remission was achieved in 91 (36.0%) patients. Of the patients with complete ulcer healing of the terminal ileum, 28.6% (22/77) had residual ulcers in the proximal ileum. The rate of endoscopic remission in the proximal ileum (50.9%) was relatively lower compared to the colon (63.4%) and terminal ileum (56.7%), a trend consistently observed across all treatment agents. After a median follow-up of 134 weeks, residual ulcerations in the proximal ileum were associated with a poorer prognosis (P=0.0126 for hospitalization and P=0.0014 for surgery). A substantial proportion of patients with CD exhibited ulcerations in the proximal ileum which correlated with a poorer prognosis. These lesions proved challenging to heal, regardless of the type of biologic used.

A prospective multicentre open label study of Magseed Pro marker and Sentimag Gen3 system to localise breast cancer and axillary lymph nodes: initial results

A prospective multicentre open label study of Magseed Pro marker and Sentimag Gen3 system to localise breast cancer and axillary lymph nodes: initial results

The ventilatory efficiency parameters outperform peak oxygen consumption in monitoring the therapy effects on the right ventricular load in patients with hypertrophic cardiomyopathy

Abstract Aim We sought the cardiopulmonary exercise testing (CPET) parameter that is the most reflective of right ventricular (RV) load and its coupling with pulmonary artery (PA) in patients diagnosed with hypertrophic cardiomyopathy (HCM) undergoing medical therapy. Methods CPET on recumbent bike was performed in adult patients with symptomatic non-obstructive HCM with NYHA class I–III, during phase II, randomised, open-label multicentre study, before and after diverse medical treatment for 16 weeks. Endpoints were the changes in: 1) peak oxygen consumption (peak VO2); 2) minute ventilation (VE)/carbon-dioxide (CO2) production slope during the whole CPET; 3) VE/VCO2 slope before anaerobic threshold (AT); 4) VE/VCO2 slope after AT; 5) VE/VCO2 nadir; 6) VE/VCO2 at AT; and 7) VE/VCO2 intercept. Standard ehocardiography at rest was performed concomitantly with CPET to assess tricuspid annular plane systolic excursion (TAPSE), pulmonary artery systolic pressure (PASP), severity of mitral regurgitation (MR) and TAPSE/PASP ratio as a measure of RV-PA coupling. Results Of 115 screened patients, 61 (mean age 52 years [SD 14], 43% women) met the study inclusion criteria and underwent CPET. On regression analysis, among all CPET end-point variables, the best independent predictor of the change in PASP, TAPSE and MR severity after 16 weeks of medical treatment was VE/VCO2 below AT (B=-0.28, -0.01,-0.11; SE=0.10, 0.05, 0.01; CI=-0.48 to -0.08, -0.22 to -0.01; -0.02 to 0.01; p=0.007, 0.035, 0.004, respectively), whereas the best predictor of TAPSE/PASP ratio was intercept of the VE/VCO2 curve (B=0.014, CI=0.01to 0.03, p=0.005). Conclusion The changes in VE/VCO2 slope below anaerobic threshold, and intercept of the VE/VCO2 curve outperform peak VO2 in the monitoring of therapy effects on the right heart load and RV-PV coupling in patients with hypertrophic cardiomyopathy.

The ventilatory efficiency parameters outperform peak oxygen consumption in monitoring the therapy effects in patients with hypertrophic cardiomyopathy

AimWe sought the cardiopulmonary exercise testing (CPET) parameter that most accurately reflected therapeutic efficacy in patients with hypertrophic cardiomyopathy (HCM). MethodsWell-being questionnaire, N-terminal brain natriuretic peptide measurements, echocardiography, and CPET were performed in patients with symptomatic non-obstructive HCM during phase II, randomized, open-label multicentre study, before and after 16 weeks of traditional or sacubitril/valsartan treatment. Patients were followed 36 months after the initial CPET. Primary endpoints were changes in: 1) peak oxygen consumption (VO2); 2) VO2 at anaerobic threshold (AT); 3) oxygen pulse; 4) minute ventilation (VE)/carbon-dioxide (CO2) production slope; 5) VE/VCO2 at AT (VE/VCO2_AT); 6) VE/VCO2 nadir; 7) VE/VCO2 intercept; and 8) partial end-tidal pressure of carbon-dioxide (PETCO2) change during CPET. ResultsOf 115 screened patients, 61 (52 ± 14 years, 43 % women) were included. Within subject therapy effects were detected only by the VE/VCO2 intercept and PETCO2 change, whereas the differences between medical regimens were detected by differences in VE/VCO2 nadir and VE/VCO2_AT changes after the treatment. The best predictors of the change in well-being were left ventricular outflow tract maximal gradient and VE/VCO2 intercept (B = 0.41,0.36; SE = 0.16,0.30; CI = 0.14–0.79, 0.15–1.14; p = 0.006,0.016, respectively). Adverse cardiac events were best predicted by the initial VE/VCO2 nadir. ConclusionVentilatory efficiency parameters outperform peak VO2 in gauging therapy effects in patients with HCM.

Multichannel tDCS with advanced targeting for major depressive disorder: a tele-supervised at-home pilot study.

Proof-of-principle human studies suggest that transcranial direct current stimulation (tDCS) over the dorsolateral prefrontal cortex (DLPFC) may improve depression severity. This open-label multicenter study tested remotely supervised multichannel tDCS delivered at home in patients (N=35) with major depressive disorder (MDD). The primary aim was to assess the feasibility and safety of our protocol. As an exploratory aim, we evaluated therapeutic efficacy: the primary efficacy measure was the median percent change from baseline to the end of the 4-week post-treatment follow-up period in the observer-rated Montgomery-Asberg Depression Mood Rating Scale (MADRS). Participants received 37 at-home stimulation sessions (30 minutes each) of specifically designed multichannel tDCS targeting the left DLPFC administered over eight weeks (4 weeks of daily treatments plus 4 weeks of taper), with a follow-up period of 4 weeks following the final stimulation session. The stimulation montage (electrode positions and currents) was optimized by employing computational models of the electric field generated by multichannel tDCS using available structural data from a similar population (group optimization). Conducted entirely remotely, the study employed the MADRS for assessment at baseline, at weeks 4 and 8 during treatment, and at 4-week follow-up visits. 34 patients (85.3% women) with a mean age of 59 years, a diagnosis of MDD according to DSM-5 criteria, and a MADRS score ≥20 at the time of study enrolment completed all study visits. At baseline, the mean time since MDD diagnosis was 24.0 (SD 19.1) months. Concerning compliance, 85% of the participants (n=29) completed the complete course of 37 stimulation sessions at home, while 97% completed at least 36 sessions. No detrimental effects were observed, including suicidal ideation and/or behavior. The study observed a median MADRS score reduction of 64.5% (48.6, 72.4) 4 weeks post-treatment (Hedge's g = -3.1). We observed a response rate (≥ 50% improvement in MADRS scores) of 72.7% (n=24) from baseline to the last visit 4 weeks post-treatment. Secondary measures reflected similar improvements. These results suggest that remotely supervised and supported multichannel home-based tDCS is safe and feasible, and antidepressant efficacy motivates further appropriately controlled clinical studies. https://clinicaltrials.gov/study/NCT05205915?tab=results, identifier NCT05205915.

Treatment of moderate-to-severe canine atopic dermatitis with modified-release mycophenolate (OKV-1001): A pilot open-label, single-arm multicentric clinical trial.

Mycophenolate is an immunomodulating agent successfully used for the treatment of moderate-to-severe atopic dermatitis (AD) in people. Mycophenolate is an effective steroid-sparing treatment option for use in dogs with inflammatory skin diseases. To evaluate whether once-daily modified-release mycophenolate (OKV-1001) is safe and effective for treating moderate-to-severe canine AD. Client-owned atopic dogs (n = 9) were enrolled. In an open-label multicentre pilot study, OKV-1001 (30 mg/kg every 24 h) was given orally for ≤84 days. Concomitant tapering doses of glucocorticoids were administered up to Day (D)28. Clinicians assessed Canine Atopic Dermatitis Extent and Severity Index, 4th iteration (CADESI-04) on D0, D14, D28, D56 and D84. Body weight and clinical pathological parameters were measured at baseline and at the end of the study. Treatment with OKV-1001 combined with glucocorticoids significantly reduced the severity of AD within two weeks in seven of nine (77.8%) dogs. The mean percentage change from baseline in the CADESI-04 score was 29% (p = 0.009) at D14 (n = 9), 39% (p = 0.008) at D28 (n = 9) and 49% (p = 0.03) at D56 (n = 7) at which point glucocorticoids had been withdrawn. In two dogs the improvement in CADESI-04 was 62% and 23% (respectively) on D84. No significant adverse events including clinical pathological findings were reported. Modified-release mycophenolate (OKV-1001) may represent a promising alternative treatment option for dogs with moderate-to-severe AD. The safety and efficacy profile of OKV-1001 will need to be established in larger, placebo-controlled clinical trials.

Sacubitril/valsartan for the treatment of non-obstructive hypertrophic cardiomyopathy: An open label randomized controlled trial (SILICOFCM).

Sacubitril/valsartan treatment reduces mortality and hospitalizations in heart failure with reduced ejection fraction but has limited application in hypertrophic cardiomyopathy (HCM). The aim of this study was to evaluate the effect of sacubitril/valsartan on peak oxygen consumption (VO2) in patients with non-obstructive HCM. This is a phase II, randomized, open-label multicentre study that enrolled adult patients with symptomatic non-obstructive HCM (New York Heart Association class I-III) who were randomly assigned (2:1) to receive sacubitril/valsartan (target dose 97/103 mg) or control for 16 weeks. The primary endpoint was a change in peak VO2. Secondary endpoints included echocardiographic measures of cardiac structure and function, natriuretic peptides and other cardiac biomarkers, and Minnesota Living with Heart Failure quality of life. Between May 2018 and October 2021, 354 patients were screened for eligibility, 115 patients (mean age 58 years, 37% female) met the study inclusion criteria and were randomly assigned to sacubitril/valsartan (n = 79) or control (n = 36). At 16 weeks, there was no significant change in peak VO2 from baseline in the sacubitril/valsartan (15.3 [4.3] vs. 15.9 [4.3] ml/kg/min, p = 0.13) or control group (p = 0.47). No clinically significant changes were found in blood pressure, cardiac structure and function, plasma biomarkers, or quality of life. In patients with HCM, a 16-week treatment with sacubitril/valsartan was well tolerated but had no effect on exercise capacity, cardiac structure, or function.

Efficacy of benralizumab in severe eosinophilic asthma: results of a real clinical practice prospective study BEST in Russia

The study of the efficacy of biological therapy in patients with severe bronchial asthma in real world settings is a relevant task since observational research programs allow answering questions that fall out of focus with a strict selection of patients in RCT. Multicenter studies are prioritized because they allow combining and systematizing additional previously undescribed data in a wider population.The aim of the BEST study (Real World Evidence of Benralizumab in Eosinophilic Severe AsThma in Russia) was to confirm the clinical effectiveness of benralizumab regarding change of disease control and quality of life (QoL) level associated with respiratory status in patients with eosinophilic phenotype of uncontrolled severe asthma in real clinical practice in Russia.Methods. An open-label non-randomised multicenter study was conducted involving 59 adult patients with severe eosinophilic asthma. Benralizumab was prescribed according to indications used in routine practice in addition to maintenance therapy. The duration of follow-up was 56 weeks. Disease control level was assessed using the Asthma Control Questionnaire-5 (ACQ-5), and QoL associated with respiratory status was assessed using the St. George’s Respiratory Questionnaire (SGRQ). Patients’ Global Impression of Change (PGIC) and Patients’ Global Impression of Severity (PGIS) were used for subjective assessments of the well-being of patients. The frequency of exacerbations, usage of systemic corticosteroids (SCS), and functional parameters were also evaluated.Results. The use of benralizumab led to a clinically significant improvement in ACQ-5 and SGRQ scores, a significant decrease in the frequency of exacerbations and a significant increase in pre- and post-bronchodilation FEV1 and FVC. There was an improvement in the well-being of patients according to the PGIC and PGIS scales. The SCS dose did not change. The therapeutic effect of benralizumab occurred quickly and persisted throughout the whole study, demonstrating the most significant changes in effectiveness values by the 56th week of treatment.Conclusion. The use of benralizumab in real clinical practice significantly improved the control of severe eosinophilic asthma and QoL of patients and was associated with a favorable safety profile.

Hand, foot, and mouth disease: could EPs® 7630 be a treatment option? A prospective randomized open-label multicenter clinical study.

Hand, foot and mouth disease (HFMD) is a viral contagious disease of children caused by human enteroviruses (EVs) and coxsackieviruses (CVs). There is no specific treatment option for HFMD. EPs® 7630's anti-infective and immunomodulatory properties have previously been demonstrated in several in vitro and in vivo studies; however, the use of this herbal medicine in children with HFMD has not previously been investigated. This prospective randomized multicenter clinical study included 208 children with HFMD. The diagnosis was made by pediatricians. The patients who were within the first 48 h of symptom onset (according to the first onset of fever and skin findings) were enrolled. The study participants were assigned into 2 groups as EPs® 7630 and control groups. All patients were followed up twice more, 48 h after the first admission and on the 5th-7th day. Another phone evaluation was conducted for those with continued complaints from the previous visit. The median age was 27 (12-112) months. The male-female ratio was 0.98. One hundred thirty one (63%) of 190 patients had no history of household contact. EPs® 7630 group included 94 and control group included 96 patients. A significant difference was found between the groups in terms of complaint scores at the visits made at the 48th h of the treatment and on days 5-7 (p < 0.001). The mean ± SD disease duration of EPs® 7630 users was significantly shorter 6.07 ± 0.70 days (95% CI: 5.92-6.21)] than the control group [8.58 ± 0.94 days (95% CI: 8.39-8.77)] (p < 0.001). Besides, the hospitalization rate among the EPs® 7630 users were significantly lower (p = 0.019). No side effects were observed, except for unpleasant taste, which was reported in 5 patients (EPs® 7630 group). Considering its efficacy and safety profile EPs® 7630 may represent a feasible herbal-based treatment option for children with HFMD. ClinicalTrials.gov, identifier (NCT06353477).

Efficacy and Safety of Ustekinumab for Chronic Pouchitis: A Prospective Open-label Multicenter Study

Seventeen percent of patients with ulcerative colitis that undergo proctocolectomy with pouch surgery will develop chronic pouchitis. We evaluated the efficacy of ustekinumab for these patients. We performed a prospective study of chronic pouchitis patients receiving ustekinumab intravenously at baseline (∼6mg/kg) and 90mg ustekinumab subcutaneously every 8 weeks thereafter. The modified pouchitis disease activity index (mPDAI) was assessed at baseline, week 16 and 48. The primary endpoint was the proportion of patients achieving steroid-free remission (mPDAI <5 and reduction by ≥2 points) at week 16. Secondary endpoints included the proportion of patients achieving remission at week 48, the proportion of patients achieving response (reduction of mPDAI by ≥2 points) at week 16 and 48, and change in mPDAI. We enrolled 22 patients (59% male, median age 42.2 years). Remission was achieved in 27.3% at week 16 and 36.4% at week 48. Response was achieved in 54.5% both at week 16 and 48. The median (IQR) mPDAI decreased from 8 (7-10) to 7 (4-9) at week 16 (p=0.007) and 4 (1.75-7.25) at week 48 (p<0.001). The clinical mPDAI subscore decreased from 3.5 (2-4) to 2 (1-3) at week 16 (p=0.009) and 1 (0-2.25) at week 48 (p=0.001). The endoscopic mPDAI subscore decreased from 5.5 (4-6) to 4 (3-6) at week 16 (p=0.032) and 3 (1.75-4.25) at week 48 (p=0.001). Ustekinumab was efficacious in half of the patients suffering from chronic pouchitis. Ustekinumab should therefore be positioned in the treatment algorithm of chronic pouchitis. (ClinicalTrials.gov Number NCT04089345).

Eculizumab in Adolescent Patients With Refractory Generalized Myasthenia Gravis: A Phase 3, Open-Label, Multicenter Study

BackgroundThis study evaluated the efficacy and safety of eculizumab, a terminal complement C5 inhibitor, in juvenile generalized myasthenia gravis (gMG). MethodsAdolescents aged 12 to 17 years with refractory anti-acetylcholine receptor (AChR) antibody-positive gMG received eculizumab (weekly induction [one to two doses of 600 mg or four doses of 900 mg] followed by maintenance doses [300 to 1200 mg] every two weeks for up to 26 weeks) in a phase 3, open-label multicenter study (NCT03759366). Change from baseline to week 26 in Quantitative Myasthenia Gravis (QMG) total score (primary end point) and secondary end points including Myasthenia Gravis-Activities of Daily Living (MG-ADL) total score, Myasthenia Gravis Composite score, Myasthenia Gravis Foundation of America postintervention status, EuroQol 5-Dimensions (Youth) and Neurological Quality-of-Life Pediatric Fatigue questionnaire scores, as well as pharmacokinetics, pharmacodynamics, and safety, were recorded. ResultsEleven adolescents (mean ± S.D. age 14.8 ± 1.8 years) were enrolled; 10 completed the primary evaluation period. Least-squares mean changes from baseline at week 26 were −5.8 (standard error [SE] 1.2; P = 0.0004) for QMG total score and −2.3 (SE 0.6; P = 0.0017) for MG-ADL total score. Overall, the primary and all secondary efficacy end point analyses met statistical significance from the first assessment and were sustained throughout. Complete terminal complement inhibition was sustained through 26 weeks in all patients. Treatment-emergent adverse events were all mild/moderate and predominantly unrelated to eculizumab. ConclusionsEculizumab was effective in reducing disease burden and was well tolerated in adolescents with refractory AChR antibody-positive gMG.

Abstract CT052: A phase IB study of mRNA-based active cancer vaccine, BI1361849, combined with durvalumab and tremelimumab immunotherapy in patients with non-small cell lung cancer (NSCLC)

Abstract Introduction. BI1361849 is an RNA-based cancer vaccine, encoding for 6 tumor-associated antigens, including MUC1, survivin, NY-ESO-1, 5T4, MAGE-C2 and MAGE-C1, to balance systemic antigen-specific immune response. This open-label multicenter 2-arm Phase IB study evaluated the safety and preliminary efficacy of the addition of BI1361849 to durvalumab with or without tremelimumab for NSCLC. Methods. Patients with metastatic NSCLC were enrolled in one of the two arms, Arm A: BI1361849 + durvalumab and Arm B: BI1361849 + durvalumab+ tremelimumab, to determine Recommended Combination Dose (RCD) for durvalumab according to a standard 3 + 3 design with a starting dose of 1500 mg and possible de-escalation to 750 mg, and a fixed total dose of BI1361849 at 960 μg and tremelimumab at 75 mg. Primary endpoints were safety and tolerability. Secondary endpoints were progression free survival (PFS), objective response rate (ORR), disease control rate (DCR), duration of response (DOR), and overall survival (OS), based on irRECIST and RECIST. Statistical analysis included descriptive statistics, Fisher exact test, and Kaplan-Meier method. Results. A total of 57 patients were treated with 23 patients in Arm A and 34 patients in Arm B for safety analysis. Among them, 36 patients received at least 75% of the scheduled doses of durvalumab and tremelimumab and at least 4 vaccine doses in the first 2 cycles to meet efficacy analysis requirement with 17 patients in Arm A and 19 patients in Arm B. The RCD was durvalumab at 1500 mg, BI 1361849 at 960 μg, and tremelimumab at 75 mg. Both arms had comparable treatment related adverse events (56-57%) with generally low grade and manageable within current guidelines. Both arms had a comparable rate of treatment discontinuation (22-24%). For efficacy analysis, patients in Arm A had 29% ORR and 71% DCR, median months of 10, 7.3 5.7, and not reached for DOR, irPFS, PFS, and OS, respectively. In contrast, Arm B yielded 11% ORR and 53% DCR, median months of 6, 2.5, 2.5 and 10 for DOR, irPFS, PFS, and OS, respectively. Conclusions. Overall, the doublet and triplet regimens were well tolerated. In comparison to recent published studies treated with durvalumab and/or tremelimumab, incorporation of BI1361849 to durvalumab yielded comparable or better treatment response, PFS, and OS than durvalumab alone or with chemotherapy. However, tremelimumab did not add clinical benefit. Citation Format: Dung-Tsa Chen, Joshua Sabari, Jonathan Thompson, Jiaxin Niu, Hirva Mamdani, Ram Thapa, Zachary Thompson, Thanmai Posina, Aileen Ryan, Ralph Venhaus, Toni Ricciardi, Kristen Ramirez, Tawee Tanvetyanon, Jhanelle Gray. A phase IB study of mRNA-based active cancer vaccine, BI1361849, combined with durvalumab and tremelimumab immunotherapy in patients with non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT052.

A phase I study of pevonedistat, azacitidine, and venetoclax in patients with relapsed/refractory acute myeloid leukemia.

Azacitidine/venetoclax is an active regimen in patients with newly diagnosed acute myeloid leukemia (AML). However, primary or secondary resistance to azacitidine/venetoclax is an area of unmet need and overexpression of MCL1 is suggested to be a potential resistance mechanism. Pevonedistat inhibits MCL1 through activation of NOXA, and pevonedistat/azacitidine has previously shown activity in AML. To assess the tolerability and efficacy of adding pevonedistat to azacitidine/ venetoclax in relapsed/refractory AML, we conducted a phase I, multicenter, open-label study in 16 adults with relapsed/ refractory AML. Patients were treated with azacitidine, venetoclax along with pevonedistat intravenously on days 1, 3 and 5 of each 28-day cycle at doses of 10, 15 or 20 mg/m2 in successive cohorts in the dose escalation phase. The impact of treatment on protein neddylation as well as expression of pro-apoptotic BCL2 family members was assessed. The recommended phase II dose of pevonedistat was 20 mg/m2. Grade 3 or higher adverse events included neutropenia (31%), thrombocytopenia (13%), febrile neutropenia (19%), anemia (19%), hypertension (19%) and sepsis (19%). The overall response rate was 46.7% for the whole cohort including complete remission in five of seven (71.4%) patients who had not previously been treated with the hypomethylating agent/venetoclax. No measurable residual disease was detected in 80.0% of the patients who achieved complete remission. The median time to best response was 50 (range, 23-77) days. Four patients were bridged to allogeneic stem cell transplantation. The combination of azacitidine, venetoclax and pevonedistat is safe and shows encouraging preliminary activity in patients with relapsed/refractory AML. (NCT04172844).

(193) Low Intensity Shockwave Therapy in Combination with Phosphodiesterase-5 Inhibitors is an Effective and Safe Treatment Option in Patients with Vasculogenic ED who are PDE5i Nonresponders: A Multicenter Single-Arm Clinical Trial

Abstract Introduction Low-intensity shockwave therapy (Li-ESWT) has been shown to be an effective and safe treatment for vasculogenic erectiledysfunction (ED) Objective We aim to evaluate the effectiveness and safety of LiESWT in treating patients affected from vasculogenic ED who did not respond to oral treatment with Phosphodiesterase 5 inhibitors (PDE5-i) Methods It is a multicentric open-label prospective study, in a cohort of patients non-responders to PDE-5i. Li-ESWT was performed in an outpatient setting by using the following schedule: 3000 shockwaves with an energy of 0.25 mJ/mm2 and a frequency of 4–6 Hz, twice a week for 3 weeks. International Index of Erectile Function, Erection Hardness Score and Sexual Quality of Life-Male questionnaires, and penile doppler ultrasound (PDU) are the outcome measurements. Results The Student t-test or Wilcoxon signed-rank test were applied to compare variables, with results considered statistically significant at p &amp;lt; 0.05. 106 (97.2%) completed treatment and performed follow-up visit after 4 weeks. At follow up visit, the mean IIEF-EF increased by 8.6 points (13.47 ± 4.61 vs 22.07 ± 5.27; p &amp;lt; 0.0001). A clinically significant improvement of IIEF-EF was achieved in 75 patients (70.7%). An EHS score ≥ 3, sufficient for a full intercourse, was reported by 72 patients (67.9%) at follow-up visit. 37 (34.9%) patients reported a full rigid penis (EHS = 4) after treatment. Li-ESWT treatment was also able to improve quality of life (SQOL-M: 45.56 ± 8.00 vs 55.31 ± 9.56; p &amp;lt; 0.0001). Li-ESWT significantly increased mean PSV (27.79 ± 5.50 vs 41.66 ± 8.59; p &amp;lt; 0.0001) and decreased mean EDV (5.66 ± 2.03 vs 1.93 ± 2.11; p &amp;lt; 0.0001) in PDU. Conclusions Combination of Li-ESWT and PDE5-i represents an effective and safe treatment for patients affected from ED who do not respond to first line oral therapy Disclosure No.

TARGET: A phase I/II open-label multicenter study to assess safety and efficacy of fexagratinib in patients with relapsed/refractory FGFR fusion-positive glioma

Abstract Background Oncogenic FGFR–TACC fusions are present in 3–5% of high-grade gliomas (HGGs). Fexagratinib (AZD4547) is an oral FGFR1–3 inhibitor with preclinical activity in FGFR–TACC+ gliomas. We tested its safety and efficacy in patients with recurrent FGFR–TACC + HGGs. Patients and Methods TARGET (NCT02824133) is a phase I/II open-label multicenter study that included adult patients with FGFR–TACC + HGGs relapsing after ≥1 line of standard chemoradiation. Patients received fexagratinib 80 mg bd on a continuous schedule until disease progression or unacceptable toxicity. The primary endpoint was the 6-month progression-free survival rate (PFS6). Results Twelve patients with recurrent IDH wildtype FGFR–TACC + HGGs (all FGFR3–TACC3+) were included in the efficacy cohort (male/female ratio = 1.4, median age = 61.5 years). Most patients (67%) were included at the first relapse. The PFS6 was 25% (95% confidence interval 5–57%), with a median PFS of 1.4 months. All patients without progression at 6 months (n = 3) were treated at first recurrence (versus 56% of those in progression) and remained progression-free for 14–23 months. The best response was RANO partial response in 1 patient (8%), stable disease in 5 (42%), and progressive disease in 6 (50%). Median survival was 17.5 months from inclusion. Grade 3 toxicities included lymphopenia, hyperglycaemia, stomatitis, nail changes, and alanine aminotransferase increase (n = 1 each). No grade 4–5 toxicities were seen. A 32-gene signature was associated with the benefit of FGFR inhibition in FGFR3–TACC3 + HGGs. Conclusions Fexagratinib exhibited acceptable toxicity but limited efficacy in recurrent FGFR3–TACC3 + HGGs. Patients treated at first recurrence appeared more likely to benefit, yet additional evidence is required.

Equitable Care for Severe Hemophilia_A: Distributional Cost-Effectiveness of Prophylactic Weekly Efanesoctocog Alfa Versus Standard-Care Factor VIII in Patients with Severe Hemophilia_A in the United States

Introduction: Prophylactic coagulation factor replacement is crucial to decrease bleeding episodes and improve quality-adjusted life expectancy (QALE) for patients with severe hemophilia A. Even with prophylactic treatment (i.e., at three to four times weekly) patients remain at risk of bleeding events and still develop chronic arthropathy across their lifetimes. The additional economic burden associated with lifelong prophylactic treatment is a major equity concern for patients with hemophilia A and their families. Efanesoctocog alfa is a recently developed extended half-life agent for hemophilia A prophylaxis and management, supporting the possibility of once-weekly prophylaxis. An open-label multicenter study (XTEND-1) showed that once-weekly dosing of efanesoctocog alfa improves the annualized bleeding rate (ABR) by 77% versus prophylaxis with standard-care factor VIII in patients with severe hemophilia A. We sought to evaluate, both for the first time, the conventional and distributional cost-effectiveness of prophylaxis with efanesoctocog alfa versus with standard-care factor VIII for patients with severe hemophilia A in the United States. Methods: For this independent analysis free of industry influence, we built a Markov model to examine the conventional cost-effectiveness of prophylaxis with efanesoctocog alfa versus standard-care factor VIII for patients with severe hemophilia A. Transition probabilities for ABRs and product utilization were informed by phase 3 study data and supplemented with FDA package insert information. Within ABRs, we accounted for treated bleeding severity and bleeding event types, inclusive of hemarthrosis, intracranial hemorrhage, in addition to assuming the prevalence of chronic arthropathy with SHL (i.e., due to silent bleed burden) is eliminated by efanesoctocog alfa. Costs for the base-case were sourced from the Centers for Medicare &amp; Medicaid Services with negotiated (i.e., lower) cost of efanesoctocog alfa supplied from the Veterans Affairs Federal Supply Schedule Service (VA-FSS). Age-, sex- and disease-specific background mortality were employed. Utilities for severe hemophilia A and disutilities for bleed events and hospitalizations were informed by extensive literature specific to severe hemophilia A. The primary outcome was the incremental cost-effectiveness ratio (ICER) in USD/QALY, at a willingness-to-pay threshold of $150,000/quality-adjusted life-year (QALY). The secondary outcome was a threshold analysis for the maximum efanesoctocog alfa price that renders efanesoctocog alfa prophylaxis cost-effective. To account for health inequities in the care of patients with hemophilia A we then conducted a distributional cost-effectiveness analysis (DCEA) to derive an equity weight threshold (i.e., inequality aversion parameter) for the decision of prophylaxis with efanesoctocog alfa versus with standard-care factor VIII. This threshold was then compared to prior estimates for commonly used equity weights in the United States (range 0.5-3.0). Results: In the base-case, prophylaxis with efanesoctocog alfa versus with standard-care factor VIII accrued 19.4 and 15.4 QALYs at mean costs of $17.3 and $9.7 million. The ICER for efanesoctocog alfa was $1,890,000/QALY (95% credible interval 1,190,000-3,330,000). Threshold analysis showed that prophylaxis with efanesoctocog alfa became cost-effective when the price of efanesoctocog alfa decreased by at least 59%. In deterministic sensitivity analysis, the model was most sensitive to the costs of efanesoctocog alfa and factor VIII. In probabilistic sensitivity analysis, standard-care factor VIII was favored over efanesoctocog alfa in 100% of 10,000 Monte Carlo simulations. The equity weight threshold for the treatment decision of prophylaxis with efanesoctocotog alfa versus with standard-care factor VIII was 7.4, higher than commonly used equity weights in the US. This implies a threshold that is higher than what has previously been used in the United States, per DCEA standards. Conclusion: As compared to standard-care factor VIII and at VA-FSS pricing, efanesoctocog alfa prophylaxis is conventionally cost-ineffective for patients with severe hemophilia A. Prophylaxis with efanesoctocog alfa does not meet commonly used distributive equity standards in the United States at this time.

Safety and Efficacy Results from the Phase I Study of a Novel Dual Covalent and Non-Covalent Next Generation Inhibitor of Bruton's Tyrosine Kinase LP-168 in Patients with Relapsed/Refractory Mantle Cell Lymphoma

Background: Relapsed/Refractory (R/R) mantle cell Lymphoma (MCL) has poor long-term survival compared with other B-cell malignancies. As a result, there is an urgent need for safe and effective treatments, particularly for patients who have progressed on covalent (c) Bruton tyrosine kinase inhibitors (BTKis) therapy. LP-168 is a highly selective, next-generation BTKi with a unique dual binding mode: covalent binding to wild-type BTK and reversible binding to mutated BTK. Pre-clinical data has demonstrated that LP-168 is highly potent in inhibiting C481 mutated BTK. Here, we report the safety and efficacy of LP-168 monotherapy in the R/R MCL patients as part of an ongoing phase 1 study (NCT04993690) in B-cell malignancies. Methods: This is a Phase 1 first-in-human multicenter open-label study of LP-168 enrolling Chinese patients with B cell Non-Hodgkin Lymphoma (NHL) who have progressed after at least 1 or 2 prior treatments. The study has two parts: Phase 1a: “3+3” dose escalation and Phase 1b: dose expansion in disease-specific cohorts (e.g. R/R MCL, R/R MZL, etc.). Results: Between 10 August 2021 and 31 May 2023, 33 R/R MCL patients who received at least one dose were enrolled and received LP-168 100mg (n=8), 150mg (n=24), and 200mg (n=1) QD, respectively. Baseline characteristics are summarized in Table 1. The median age was 58 (range, 32-79) years old; 27 (81.8%) were male. 15 (45.5%) subjects had intermediate to high risk disease per MCL International Prognostic Index (MIPI). Median lines of prior therapies were 2 (range, 1-11) with 24.2% refractory to the last prior treatment. All patients have received rituximab or a rituximab-containing regimen. 19 (57.6%) subjects have received at least a cBTKi or cBTKi-containing regimen. The most common treatment emergent adverse events (TEAEs) (occurring in ≥20% subjects) were platelet count decreased (30.3%), neutropenia and anemia (27.3% each) and COVID-19 (24.2%), most of which were Grade 1. Grade 3 or more TEAEs were seen in 9 (27.3%) subjects. Serious AE (SAE) (lung infection, oral cavity infection and lymphocytosis, all Grade 3) occurred in 3 (9.1%) subjects. Dose interruptions due to AE occurred in 7 patients (21.2%)，but no AE has led to dose adjustment, drug discontinuation or death. Of 31 efficacy evaluable subjects with median follow up of 5.5 months (range: 2.0-22.5), 24 (77.4%) achieved response including 12 (38.7%) complete metabolic response or complete response (CMR/CR). In addition, 5 (71.4%) out of 7 subjects with blastoid/ pleomorphic variant MCL achieved response (2 CMR/CR, 3 PMR/PR). More importantly, of 17 subjects who had prior cBTKi exposure, 12 (70.6%) responded to LP-168 and 6 (35.3%) achieved CMR. LP-168 also showed efficacy in 2 subjects who have received ≥ 2 cBTKi treatments. Another 2 subjects responded to LP-168 even after disease progression on a cBTKi and a BTK degrader. 5 subjects have achieved progression-free survival (PFS) more than 1 year and are still on treatment (Figure 1). Conclusion: In this Phase 1 trial, the novel BTK inhibitor LP-168 demonstrated a high CR rate and durable response in heavily pre-treated R/R MCL including blastoid/pleomorphic variant with favorable safety. Moreover, LP-168 could effectively overcome the acquired resistance to prior cBTKi. Based on the safety, PK and preliminary efficacy data from the Phase 1 study so far, we have determined the recommended phase 2 dose (RP2D) for MCL as 150 mg QD. A phase 2 trial of LP-168 in R/R MCL is currently ongoing (NCT05716087).

CTNI-33. TARGET TRIAL: A PHASE I/II OPEN-LABEL MULTICENTER STUDY TO ASSESS SAFETY, TOLERABILITY, AND CLINICAL EFFICACY OF AZD4547 IN PATIENTS WITH RELAPSED/REFRACTORY FGFR FUSION POSITIVE GLIOMA

Abstract BACKGROUND AZD4547 is a potent oral FGFR1-3 inhibitor. We tested its safety, tolerability, and efficacy in patients presenting relapsed/refractory (r/r) high-grade gliomas (HGGs) with FGFR fusion in a phase I/II open label multicenter study (NCT02824133). METHODS the study was based on a two-stage design and included adult patients with HGG expressing a FGFR-TACC gene fusion (as centrally confirmed by RT-PCR sequencing) relapsing after at least one line of standard chemoradiation. Patients received AZD4547 (AstraZeneca) at a dose of 80mg bd on a continuous schedule, until disease progression or inacceptable toxicity. The primary endpoint was the 6-months progression-free survival rate (PFS6). This research was conducted with support from AstraZeneca. RESULTS 12 patients with r/r isocitrate dehydrogenase wildtype HGGs positive for FGFR-TACC fusions (all FGFR3-TACC3) were included in the efficacy analysis cohort (male/female ratio = 1.4, median age = 61.5 years). Most patients (67%) were included at the first tumor relapse. The PFS6 was 25% (95% confidence interval [CI] 5-57%), with a median PFS of 1.4 months. All patients without progression at six months (n = 3) were at the first tumor recurrence (versus 56% of those in progression) and remained progression-free for 14-23 months. The best response was stable disease in six patients and progressive disease in six. Median OS was 17.5 months. Grade 3 toxicities included hematological, metabolic, nail changes, stomatitis, or other disorder (n = 1 each). No grade 4 toxicities were seen. CONCLUSION overall, tolerance was acceptable. The study did not meet the predetermined objective of PFS6 ≥ 35% and was stopped. A molecular characterization is ongoing to identify potential markers associated with prolonged stabilizations.

Sacubitril/valsartan for treatment of symptomatic non-obstructive hypertrophic cardiomyopathy: a randomised, controlled, phase II clinical trial (SILICOFCM)

Abstract Aim To evaluate the effect of sacubitril/valsartan on exercise capacity, cardiac structure, and function in patients with hypertrophic cardiomyopathy (HCM). Methods Phase II, randomised, open-label multicentre study enrolled adult patients with symptomatic non-obstructive HCM (NYHA class I–III) who were randomly assigned (2:1) to receive sacubitril/valsartan (target dose 97/103mg) or usual care for 16 weeks. Primary endpoint was a change in peak oxygen consumption (peak VO2). Secondary endpoints included echocardiography measures of cardiac structure and function, natriuretic peptides and other biomarkers, and Minnesota Living with Heart Failure quality of life (QoL). Results Between May 2018 and November 2021, 354 patients were screened for eligibility, 115 patients (mean age 58 years [SD 11], 37% women) met the study inclusion criteria and were randomly assigned to sacubitril/valsartan (N=79) or usual care (N=36). At 16 weeks, there was no significant change in peak VO2 from baseline in sacubitril/valsartan (15.3 [4.3] vs 15.9 [4.3] ml/kg/min, p=0.13), or usual care group (p=0.47). There was a significant reduction in ventilatory efficiency slope (30.1 [7] vs 28.4 [4.9], p=0.03), but not in the control group (p=0.09). No significant changes were found in systolic or diastolic function, cardiac structure, or plasma biomarkers. The QoL score decreased significantly in the sacubitril/valsartan by 6 points (p=0.005) but not in the usual care group (p=0.66). Conclusion In patients with hypertrophic cardiomyopathy, 16 weeks of treatment with sacubitril/valsartan was well tolerated and contributed to a significant improvement in ventilatory efficiency and quality of life but not in exercise capacity or cardiac function.

Serpin-PC in Persons with Severe Hemophilia (PwH): Updated Results from a Multicenter Multi-Part, First-in-Human Study

Introduction SerpinPC is an investigational serine protease inhibitor (SERPIN) engineered to specifically inhibit Activated Protein C (APC). The previously presented data from the completed parts of AP-0101 showed that administration of SerpinPC reduced bleeding in persons with severe hemophilia with no observations of unexplained chronic elevation in D-dimer. We will now present all results up to the end of Part 5 by which time we anticipate the median continuous exposure will be more than 3 years. Methods AP-0101 is an ongoing first-in-human open-label multicenter study utilizing an adaptive design to investigate the safety, tolerability, pharmacokinetics and efficacy of SerpinPC in subjects with severe hemophilia A and B. Part 1a was a Single Ascending Dose Study of SerpinPC in 15 healthy male volunteers and 12 males with severe hemophilia. Part 2 enrolled 23 males with severe hemophilia (19 hemophilia A and 4 hemophilia B), who were not on replacement factor prophylaxis, to receive SerpinPC at 0.3, 0.6 or 1.2 mg/kg, administered as a subcutaneous (SC) injection once every 4 weeks over a 24-week period (6 total doses). In Part 3, subjects who completed Part 2 received a flat dose of 60 mg of SerpinPC once every 4 weeks for 48 weeks. Part 4 was a further extension in which subjects who completed Part 3 received 1.2 mg/kg of SerpinPC once every 2 weeks for 24 weeks. Part 5 was a further extension in which subjects who completed Part 4 continued to receive 1.2 mg/kg of SerpinPC once every 2 weeks for 52 weeks. Results Annualized bleed rates, safety and tolerability for Part 5 will be available and a complete summary of all results to the end of Part 5 will be presented, including available pharmacokinetic and anti-drug antibody data.