Takeda (Switzerland)

BackgroundThrombotic thrombocytopenic purpura (TTP) is a life-threatening blood disorder resulting from ADAMTS13 deficiency, caused by mutations in the ADAMTS13 gene in congenital TTP (cTTP), and by neutralizing antibodies against ADAMTS13 in immune-mediated TTP (iTTP). This systematic review summarizes available economic evaluations, healthcare resource utilization (HCRU), cost, utility, and health-related quality of life (HRQoL) literature in TTP, with a focus on cTTP. Given the limited availability of cTTP-specific data, broader TTP evidence was also reviewed to infer potential implications for cTTP where appropriate.MethodsThree systematic literature searches were conducted in January 2024 in accordance with PRISMA guidelines, each tailored to identify studies reporting economic evaluations, HCRU/cost data, and utility/HRQoL data respectively. For the economic evaluation and utility/HRQoL reviews, inclusion criteria were broadened to include studies reporting data on iTTP and unspecified TTP from which findings for cTTP were inferred.ResultsIn total 431, 989, and 849 records were identified for the economic evaluation, HCRU/cost, and utility/HRQoL reviews, respectively. No economic evaluations were identified for treatments in cTTP populations. Eight economic studies (all in iTTP) were included. Overall, 5 studies found caplacizumab to be cost-effective, whereas 3 did not, highlighting variability across model assumptions and healthcare settings. Six HCRU/cost studies reported that cTTP was associated with frequent hospital interactions, missed work time, and high costs. Fourteen studies (1 in cTTP, 10 in iTTP, and 3 in unspecified TTP) were included in the utility/HRQoL review and showed that TTP is associated with reduced utility scores and lower HRQoL, irrespective of TTP subtype.ConclusionThese findings underscore the meaningful patient burden observed across the TTP spectrum and highlight the need for further research to evaluate the cost-effectiveness of emerging therapies in cTTP. However, the predominance of iTTP data reflects ongoing challenges in evidence generation for rare TTP subtypes such as cTTP.

ABSTRACTMucopolysaccharidosis II is a rare, X‐linked disease, with very few reports of affected female patients. Natural history data describe a predominantly male population, and appropriate disease characterization in female patients is lacking. This analysis explores the somatic disease burden and clinical progression of female patients with MPS II enrolled in the Hunter Outcome Survey (HOS; NCT03292887), a global disease registry. In total, 15 female patients were identified, representing 1.1% of the total patients in HOS. The median ages at first symptom onset and diagnosis were 1.8 and 3.1 years, respectively. A total of 8/14 (57.1%) of patients had cognitive impairment at the latest visit. X‐chromosome abnormalities were reported in two patients. Most patients (11/15, 73.3%) had received at least one dose of idursulfase, which was generally well tolerated; no serious adverse events during follow‐up were considered treatment‐related. Musculoskeletal and ear symptoms were present in all 14 patients with data recorded. Almost all females also experienced neurological, abdominal/gastrointestinal, and pulmonary disease, similar to the symptomatology reported in males. Most patients underwent surgery (41 procedures in 12 patients). Two participants had a male sibling with MPS II who was also enrolled in HOS. Both sibling sets had missense variants and demonstrated several differences in signs/symptoms between the male and female siblings. Notably, only the female siblings displayed cognitive impairment. This report illustrates the disease burden in female patients with MPS II, helping to inform clinicians about the likely prognosis for this extremely rare subgroup of patients.

This study aimed to assess the performance of the Nelli seizure monitoring system in detecting and classifying seizures during sleep or while at rest in bed in patients with Lennox-Gastaut syndrome (LGS) and Dravet syndrome (DS). We conducted a non-interventional, single-center feasibility study from August 2023 to March 2024, involving 20 patients aged ≥2 years diagnosed with DS or LGS. Participants used Nelli for home-based seizure monitoring during sleep or while at rest in bed for 4 weeks. Seizures were detected and classified by Nelli, and results were compared to epileptologist reviews and seizure diaries. Of 20 enrolled patients, 14 (70%) who experienced seizures at rest were included in the analyses. Among them, Nelli detected 368 seizures, with an accuracy of 97.8%, as confirmed by independent reviewers. Eight seizures (2.2%) detected by Nelli were false positives, identified as part of a single seizure episode. Of the 14 patients, only 35.7% reported experiencing seizures in their diaries, and only 26.1% of the seizures were documented. Seizure durations ranged from 6 to 396 s, with considerable variation. Nelli demonstrated high accuracy in seizure classification (Gwet agreement coefficient [AC1] = .81-1.00) in nine of 14 cases. However, in three of 14 patients, moderate accuracy (AC1 = .41-.60) was observed due to challenges in classifying seizures in patients with high seizure frequency or suboptimal device positioning. The average classification accuracy of Nelli for tonic-clonic seizures was .99 (150/152 seizures), tonic seizures .55 (102/186), clonic seizures 1.00 (3/3), focal motor seizures .89 (16/18), and myoclonic seizures 1.00 (1/1). Nelli demonstrated high sensitivity and classification accuracy for detecting and categorizing seizures in bed in patients with DS and LGS, outperforming seizure diaries and providing a reliable tool for seizure monitoring in home settings.

BackgroundHereditary angioedema (HAE) is a rare disease characterized by unpredictable, recurrent subcutaneous or submucosal swelling that negatively impacts patients’ health-related quality of life (HRQoL). Despite treatment goals aimed at achieving complete control of the disease and normalizing patients' lives, the disease remains poorly controlled for some patients.ObjectivesTo describe the demographic, clinical and treatment characteristics, as well as the HRQoL impairment of patients with sub-optimally controlled HAE type I/II per treating physician's judgment, focusing on understanding the factors influencing the burden of illness.MethodsA chart review was conducted at 32 HAE care centers across 18 European countries, Canada, and Israel between April 2022 and January 2023 in 214 patients aged ≥12 years with HAE type I/II sub-optimally controlled with on-demand treatment (ODT) and/or long-term prophylaxis (LTP). Patients receiving lanadelumab were excluded, as it was not yet widely available during the eligibility period. A cross-sectional survey at patient enrollment included the Angioedema Quality of Life (AE-QoL) and EQ-5D-5L questionnaires to assess the impact of HAE on HRQoL.ResultsPatients with uncontrolled HAE had a mean (standard deviation [SD]) of 9.9 (13) attacks per year, with a mean (SD) duration of 1.9 (1) days per attack. During the one-year observation period, 50.5% of patients were on ODT only, 36.0% used LTP and ODT concurrently, 6.5% used LTP without ODT, and 7.0% were untreated. Attenuated androgens (AA; stanozolol and danazol) in LTP were used by 24.7% of patients, while tranexamic acid (TA) and C1-esterase inhibitor (C1–INH) replacement products were used for LTP by 9.8% and 6.5%, respectively. The mean (SD) AE-QoL total score was 44.4 (24.0), indicating a moderate level of impairment, with women experiencing worse HRQoL (total score of 50.9 [SD 24] vs 37.3 [SD 23] in men) [where the minimal clinically important difference is 6 points] [1]. HRQoL worsened with increasing attack rates, from 41.4 (SD 24.0) among patients with one to 5 attacks/year, still indicating moderate impairment in HRQoL, to 73.0 (SD 27.0) for patients with >40 attacks/year.ConclusionsSuboptimal disease control in HAE was associated with the use of ODT only, as well as LTP mainly with AA/TA. It imposes a substantial burden on patients’ HRQoL, more particularly, but not exclusively, for those with frequent attacks and for women. The results suggest a need for improved HAE management.ClinicalTrial.gov study identifier NCT04957641.

We agree with the commentary that distinguishing between incident and prevalent patients with CeD is important for understanding the disease’s economic implications. However, the limited timeframe of the available data restricts our ability to accurately identify adult CeD patients who are genuinely newly diagnosed, since most individuals with CeD are diagnosed during childhood or adolescence. The available observation period for patients with CeD is not long enough to follow patients from childhood diagnosis until adulthood. Thus, there is a risk of misclassifying incident patients as prevalent cases, but it should be acceptable regarding the overall evaluation, since the probability of incident patients at older age groups is lower.Given our interest in incident patients, we are currently preparing another publication focused specifically on newly diagnosed children with CeD.

Hemophilia A, a bleeding disorder caused by a deficiency of clotting factor VIII (FVIII), is commonly treated with FVIII prophylaxis. Mobile applications help personalize prophylactic regimens by creating individual pharmacokinetic (PK) profiles. This study evaluated how patients with hemophilia A use mobile applications for PK-guided prophylaxis and explored preferences and patterns of usage across different age groups. Between May and September 2022, patients from Bulgaria, Czechia, Hungary, Lithuania, and Romania participated in a cross-sectional survey. The survey collected information on demographics, documentation preferences (mobile applications or paper diaries), usage patterns, and user satisfaction. Of 84 participants, 40.5% used either a mobile application or paper diary exclusively. Czechia had the highest application usage (94.1%), followed by Romania (50.0%). While 84.2% of the application users were satisfied, many suggested improvements including better medication tracking and smartwatch compatibility. No correlation was found between age and documentation type or application preference. Mobile applications were perceived useful, but physician engagement was higher with paper diaries. These findings suggest potential to enhance mobile applications for better patient-physician interaction and user experience.

Abstract Background The use of patient-centric monitoring modalities for assessing therapies, such as vedolizumab (VDZ), are of growing interest to optimize disease outcomes in patients (pts) with Crohn’s disease (CD). Transmural healing is an emerging outcome assessed by intestinal ultrasonography (IUS), which allows frequent evaluation of CD.1,2 Real-world evidence on the effectiveness of current treatments to induce and maintain transmural response to inform treatment decisions is limited. The SUNRISE study aims to describe pts with CD treated with VDZ achieving a composite outcome of complete remission, and transmural response, utilizing IUS. Methods SUNRISE is an ongoing observational, prospective study (NCT05192863) being conducted across 10 sites in Canada, Israel and Italy. Adults with moderately to severely active CD, with a bowel wall thickness of >3 mm based on IUS, and who newly initiated intravenous VDZ are eligible. Complete remission (defined as a composite endpoint of clinically corticosteroid-free [Harvey–Bradshaw Index score of <5 points and no concomitant corticosteroids], biochemical [C-reactive protein and faecal calprotectin normalization] and transmural remission [assessed by IUS]), and transmural response after VDZ treatment are reported after induction with VDZ (Weeks 10/14) and every 6 months until Month 18 or early discontinuation. Methodological details are shown in the Figure. Results This interim analysis included 70 pts; median (interquartile range [IQR]) age was 50.0 (39.0–67.0) years, time since CD diagnosis was 4.0 (0.9–17.2) years and treatment duration (n=69) was 5.0 (3.2–6.1) months. At Month 6, the proportion of pts achieving complete remission, and transmural remission and response were 3/11 (27.3%), 9/28 (32.1%) and 12/28 (42.9%) pts, respectively; data at Weeks 10/14 are shown in the Table. Median (IQR) Short Inflammatory Bowel Disease Questionnaire total score was 4.3 (3.7–5.6) at baseline, 4.5 (3.4–5.3) at Week 10, 4.7 (3.9–5.6) at Week 14 and 5.0 (4.4–6.1) at Month 6. At Month 6, 10/21 pts (47.6%) ranked IUS as their preferred test over colonoscopy, magnetic resonance elastography and computed tomography enterography. Of 40 pts with available data at Month 6, 6 (15.0%) discontinued treatment, 5 (12.5%) switched to subcutaneous VDZ and 1 (2.5%) skipped ≥1 dose of VDZ. During the observation period, 2/70 pts (2.9%) had a CD-related hospitalization, and 1/70 pt (1.4%) each had a CD-related emergency room visit or CD-related surgery (fistula removal). Conclusion The SUNRISE study provides real-world evidence for the use of VDZ to achieve transmural healing in pts with CD and supports pt preference for IUS over other monitoring modalities. Additional follow-up data are required to confirm these findings.

Abstract Background Vedolizumab (VDZ) is a monoclonal antibody approved for adults with moderately to severely active ulcerative colitis (UC) and an inadequate response/intolerance to conventional therapy or anti-tumour necrosis factor (TNF) treatment. There is published evidence supporting the use of VDZ as a first-line biologic in patients with UC, but additional efficacy data for second-line VDZ (after first-line anti-TNF treatment) are required to define its optimal position in the treatment sequence. We conducted a meta-analysis of the efficacy and health-related quality of life (HRQoL) associated with second-line VDZ treatment exposure in patients with UC using data from the randomized, placebo (PBO)-controlled phase 3 GEMINI-1/VISIBLE-1 trials. Methods GEMINI-1 (NCT00783718) evaluated intravenous (IV) VDZ as induction/maintenance treatment in patients with active UC.1 VISIBLE-1 (NCT02611830) assessed IV/subcutaneous maintenance VDZ in patients with moderately/severely active UC.2 Patients who received first-line anti-TNF treatment within 5 years before trial enrolment were included in the meta-analysis. The primary outcome was clinical remission (defined as Adapted Mayo Score [AMS] 1 or 2; Figure). Secondary outcomes included corticosteroid-free remission, mucosal healing and HRQoL (measured via the Inflammatory Bowel Disease Questionnaire and EuroQoL-5 Dimension Visual Analogue Scale). Outcomes were assessed at Week 52. Study-specific treatment effects were estimated using generalized linear models. Efficacy of VDZ vs PBO was compared using fixed-effects models. Regression analyses assessed treatment effects, adjusting for disease location/duration and previous corticosteroid use. Results In total, 137 patients from GEMINI-1/VISIBLE-1 were included (VDZ, n=89; PBO, n=48). Patient characteristics were similar across cohorts, but the mean (standard deviation) disease duration ranged from 6.6 (4.4) years (GEMINI-1 VDZ IV cohort) to 9.9 (10.1) years (VISIBLE-1 PBO cohort). Second-line VDZ was associated with a higher likelihood of achieving clinical remission (AMS 1 and 2; Figure) and all secondary outcomes, including improved HRQoL, at Week 52 vs PBO (Table). Regression analysis showed that patients treated with VDZ were 11.35 (95% confidence interval 3.25–39.63) times more likely to achieve clinical remission (defined as AMS 1) vs PBO. Conclusion Second-line VDZ after first-line anti-TNF treatment significantly increased the likelihood of achieving clinical remission, mucosal healing and improved HRQoL at Week 52 vs PBO in patients with UC. The small sample size and heterogeneity observed in some outcomes warrant further research to strengthen these findings.