Favorable Risk-benefit Profile Research Articles

The long-term safety andtolerability ofanifrolumab forpatients with systemic lupus erythematosus inJapan: TULIP-LTE subgroup analysis.

Evaluate the long-term safety and tolerability of anifrolumab 300 mg, alongside standard therapy, in patients from Japan with systemic lupus erythematosus (SLE) in the TULIP-LTE trial (NCT02794285). TULIP-LTE was a 3-year, randomized, double-blind, placebo-controlled long-term extension (LTE) of the TULIP trials. The primary safety outcome included serious adverse events (SAEs) and AEs of special interest (AESIs) during the LTE period. Exploratory efficacy outcomes included SLE Disease Activity Index 2000 (SLEDAI-2 K) scores and glucocorticoid use. We performed a post hoc subgroup analysis of patients who enrolled in Japan. Exposure-adjusted incidence rates of SAEs during the LTE and follow-up for patients receiving anifrolumab 300 mg (n = 21) were 8.7 per 100 patient-years; AESIs included influenza (6.9) and herpes zoster (3.5). One of three patients receiving placebo had an SAE (13.9). One patient per group discontinued due to an AE. There were no deaths. During the TULIP + LTE period, patients receiving anifrolumab 300 mg (n = 24) had sustained reduction from baseline in mean SLEDAI-2 K scores and cumulative glucocorticoid dosage. Anifrolumab 300 mg showed a favourable benefit-risk profile for the long-term treatment of adult patients with moderate to severe SLE from Japan, with safety, tolerability, and efficacy profiles consistent with the overall population.

The Symphony of Survival: Sacubitril/Valsartan’s Heartfelt Impact on Mortality in Heart Failure: A Systemic Review

Heart failure (HF) is a prevalent and debilitating condition affecting millions worldwide. Over the years, numerous therapeutic strategies have been employed to manage HF, improving patients' quality of life, and reducing morbidity and mortality rates.Sacubitril/valsartan, a novel combination drug, has emerged as a promising therapeutic option in the management of HF with reduced ejection fraction (HFrEF This abstract provides a comprehensive review of the use of sacubitril/valsartan in treating HF patients.It delves into the mechanism of action of both components, examining how sacubitril, a neprilysin inhibitor, and valsartan, an angiotensin receptor blocker, work synergistically to address the complex pathophysiology of HFrEF. The unique combination of these agents has been shown to improve cardiac function, reduce ventricular remodeling, and mitigate neurohormonal activation, leading to better outcomes in HF patients. Several clinical trials and real-world studies have demonstrated the efficacy and safety of sacubitril/valsartan in HF management. These studies have highlighted the drug's ability to reduce HF-related hospitalizations and improve patients' functional status and exercise tolerance. Moreover, the combination therapy has shown a favorable risk-benefit profile, making it a valuable option for HF patients intolerant to angiotensin-converting enzyme (ACE) inhibitors.

Immunogenicity and safety of a pentavalent meningococcal ABCWY vaccine in adolescents and young adults: an observer-blind, active-controlled, randomised trial

Immunogenicity and safety of a pentavalent meningococcal ABCWY vaccine in adolescents and young adults: an observer-blind, active-controlled, randomised trial

Benefit-risk assessment of vaccines

Benefit-risk assessment (BRA) is critical for decision-making throughout the vaccine life cycle. It requires scientific assessment of evidence to make an informed judgment on whether the vaccine has a favourable benefit-risk profile i.e. the benefits of the vaccine outweigh its risks for use in its intended indication. The assessment must also consider data gaps and uncertainties, using sensitivity analyses to show the impact of these uncertainties in the assessment. The BRA field has advanced considerably over the past years, including the use of structured BRA frameworks, quantitative BRA models and use of the patient experience data. Analytical tools and procedures to standardize BRA implementation have become increasingly important. A Benefit-Risk Assessment Module has been prepared to enable the planning, assessment, and communication of relevant BRA information via a structured B-R framework. The module can help facilitate the conduct and communication of defensible BRAs by vaccine developers, funders, regulators and policy makers in high, middle or low-income countries, both for regulatory submissions and in public health responses to infectious diseases, including for epidemics.

Short-Term Treatment Outcomes of Brolucizumab in Patients with Neovascular Age-Related Macular Degeneration: A Multicentre Indian Real-World Evidence Study.

To evaluate the short-term effectiveness and safety outcomes following brolucizumab treatment in patients with neovascular age-related macular degeneration (nAMD) as a part of real-world clinical practice in India. This was a retrospective, observational, multicentre study including patients (≥50 years old) diagnosed with nAMD. Anonymized data of the patients receiving the first dose of brolucizumab intravitreal injection (IVI) who were either treatment-naïve or previously treated with a single or a combination of other anti-VEGF IVIs were included. The present study reported the change in retinal fluid levels from baseline to month 3, best-corrected visual acuity (BCVA), central retinal thickness (CRT), and the number of injections received. The adverse events in the three months after brolucizumab treatment initiation were also monitored. The study included 63 patients (65 eyes) from four study centres across India (mean age: 69.1 ± 9.7 years). A total of 82 brolucizumab injections were administered during the 3 months of study duration, with 52/65 (80.0%) eyes receiving only 1 injection. Resolution of IRF, SRF, and PED was observed in 76.9%, 64.6%, and 67.7% of eyes, respectively. Further, a significant reduction in CRT was observed (baseline: 403.5 ± 118.7 μm; month 3: 308.3 ± 73.8 μm; p < 0.001), and BCVA also improved notably from 0.7 ± 0.5 logMAR at baseline to 0.5 ± 0.4 logMAR at month 3 (p < 0.001). Adverse events (AEs) were reported in 3 eyes from 3 patients; retinal pigment epithelial rip (1) and subretinal hemorrhage (2) after the first injection of brolucizumab, however, none discontinued the treatment. The study reports on the short-term effectiveness and tolerability of brolucizumab therapy in the management of nAMD in both treatment-naïve and switch eyes. Brolucizumab was observed to have a favourable benefit-risk profile, and study results were within the known safety profile, with no instances of intraocular inflammation.

Impact of Dimethylfumarate on Sleep in Multiple Sclerosis Patients: An Actigraphic Study.

Sleep disorders in multiple sclerosis (MS) patients are common. Dimethylfumarate is an oral disease-modifying drug (DMT), whose impact on sleep is unknown. The aim of this study was to characterize actigraphic patterns in MS patients treated with dimethylfumarate. Twenty relapsing-remitting MS patients with low to a mild disability, aged 20-50y, treated with dimethylfumarate for more than 6 months, were enrolled. All subjects had no history of sleep disorders. Actigraphy was used to study sleep patterns during a seven-day period. Sleep quality was assessed by the Pittsburgh Sleep Quality Index (PSQI). Twenty healthy subjects served as controls. Our results showed statistically significant differences between some actigraphic patterns in MS patients treated with dimethylfumarate and healthy subjects, but the values for patients were still within normal limits. PSQI score was higher in MS patients compared to controls. Our findings suggest that dimethylfumarate, an oral DMT with a favourable benefit-risk profile, does not strongly alter sleep patterns in MS patients with low to mild disability and with no history of sleep disorders. Actigraphy is a simple diagnostic tool, able to support an objective measure of sleep parameters. The simplicity of application may allow considering its use for a screening of sleep disorders in MS patients.

Long-term administration of intravenous Trappsol® Cyclo™ (HP-β-CD) results in clinical benefits and stabilization or slowing of disease progression in patients with Niemann-Pick disease type C1: Results of an international 48-week Phase I/II trial

BackgroundNiemann-Pick disease type C (NPC) is a rare, fatal, pan-ethnic, autosomal recessive lysosomal storage disease characterized by progressive major organ failure and neurodegeneration. Preclinical studies confirmed a critical role of systemically administered hydroxypropyl-β-cyclodextrin (HP-β-CD; Trappsol® Cyclo™) in cholesterol metabolism and homeostasis in peripheral tissues of the body, including the liver, and in the central nervous system (CNS). Herein, the pharmacokinetics (PK), safety, and efficacy of HP-β-CD, and biomarkers of NPC were assessed in pediatric and adult patients with NPC1. MethodsThis was a multicenter, Phase I/II, randomized, double-blind, parallel-group, 48-week study (ClinicalTrials.gov identifier NCT02912793) to compare the PK of three different single intravenous (IV) doses of HP-β-CD in pediatric and adult patients with NPC1 and to evaluate the efficacy and tolerability of three different dosages of HP-β-CD in patients with NPC1 after long-term treatment. Twelve patients aged at least 2 years (2–39 years of age) with a confirmed diagnosis of NPC1 were randomized to receive one of three IV doses of HP-β-CD (1500 mg/kg, 2000 mg/kg, or 2500 mg/kg) every 2 weeks for 48 weeks. All patients received HP-β-CD; there was no placebo or other control. PK testing of plasma and cerebrospinal fluid (CSF) was at set times after the first infusion. Pharmacodynamic assessments included biomarkers of cholesterol metabolism (synthesis and breakdown products), N-palmitoyl-O-phosphocholineserine (PPCS), and specific biomarkers of CSF neurodegeneration (including total Tau), CNS inflammation (glial fibrillary acidic protein [GFAP] and tumor necrosis factor α [TNFα]), CNS cholesterol metabolism (24S-hydroxycholesterol) and inflammatory markers. Efficacy measures included clinical disease severity, neurologic symptoms, and clinical impressions of improvement. Safety assessment included physical examination, vital signs, clinical safety laboratory assessment and adverse events (AEs). ResultsNine patients completed the study, 2 in the 1500 mg/kg group, 4 in the 2000 mg/kg group and 3 in the 2500 mg/kg group. Three patients (all in the 1500 mg/kg group) discontinued the study because of either physician decision/site Principal Investigator (PI) discretion, withdrawal by subject/patient/parent/guardian, or other non-safety reasons. In 5 patients who underwent serial lumbar punctures, HP-β-CD was detected in the CSF. Of the 9 patients who completed the study, 8 (88.9%) improved in at least two domains of the 17-Domain Niemann-Pick disease Type C-Clinical Severity Scale (17D-NPC-CSS), and 6 of these patients improved in at least one domain viewed by patients and their caregivers to be key to quality of life, namely, speech, swallow, fine and gross motor skills, and cognition. Of the 9 patients who completed the study, 7 were viewed by their treating physicians as having improved to some degree at the end of the study, and 2 remained stable; both outcomes are highly relevant in a progressive neurodegenerative disease. Some patients and families reported improvement in quality of life.All three doses of HP-β-CD were well tolerated overall, with most treatment-emergent adverse events transient, mild-to-moderate in nature, and considered by the site PIs to be not related to study drug. InterpretationThis 48-week trial is the longest to date to evaluate the safety, tolerability, and efficacy across multiple clinical endpoints of IV administration of Trappsol® Cyclo™ (HP-β-CD) in NPC1 patients. In pediatric and adult patients with NPC, Trappsol® Cyclo™ IV improved clinical signs and symptoms and was generally well tolerated. The findings presented here demonstrate a favorable benefit-risk profile and support the global pivotal trial now underway to evaluate the long-term treatment benefits and the potential of Trappsol® Cyclo™ as a disease-modifying treatment in this patient population.

Population Pharmacokinetics and Exposure-Response Analysis of Tremelimumab 300mg Single Dose Combined with Durvalumab 1500mg Q4W (STRIDE) in Patients with Unresectable Hepatocellular Carcinoma.

A novel single-dose regimen of 300mg tremelimumab in combination with durvalumab (STRIDE) has demonstrated a favorable benefit-risk profile in the phase1/2 Study22 trial (in patients with unresectable hepatocellular carcinoma, uHCC) and in the phase3 HIMALAYA study. The current analysis evaluated the population pharmacokinetics (PopPK) of tremelimumab and durvalumab, and the exposure-response (ER) relationship for efficacy and safety of STRIDE in patients with uHCC. Previous PopPK models for tremelimumab and durvalumab were updated using data from previous studies in various cancers combined with data from Study22 and HIMALAYA. Typical population mean parameters and associated inter- and intra-individual variability were assessed, as was the influence of covariates. Individual exposure metrics were derived from the individual empirical Bayes estimates as drivers for ER analysis related to efficacy and safety from HIMALAYA. The observed pharmacokinetics of tremelimumab in uHCC were well described by a 2-compartment model with both linear and time-dependent clearance. All identified covariates changed tremelimumab PK parameters by <25%, and thus had minimal clinical relevance; similar results were obtained from durvalumab PopPK analysis. None of tremelimumab or durvalumab exposure metrics were significantly associated with overall survival (OS), progression-free survival (PFS), or adverse events. Baseline aspartate aminotransferase and neutrophil-to-lymphocyte ratio (NLR) were associated with OS (P<.001) by the Cox proportional hazards model. No covariate was identified as a significant factor for PFS. No dose adjustment for tremelimumab or durvalumab is needed based on PopPK covariate analyses or ER analyses. Our findings support the novel STRIDE dosing regimen in patients with uHCC.

427 Long-term 4-year safety of upadacitinib in moderate-to-severe atopic dermatitis: results of an integrated analysis of phase 3 studies

Abstract Atopic dermatitis (AD) is a chronic, inflammatory skin disease characterized by intense itch and eczematous skin lesions that can impact individuals at any age across any area of the body. There is a need for safe treatments for AD that provide rapid itch relief and skin clearance and that are suitable for long-term use. Upadacitinib is a selective, reversible oral Janus kinase 1 (JAK1) inhibitor, which is approved in multiple countries for the treatment of adolescents and adults with moderate-to-severe AD. The current analysis assessed the long-term safety for up to 4 years of upadacitinib 15 and 30 mg in adolescents and adults with moderate-to-severe AD, using integrated data from three ongoing global pivotal phase 3 studies. The Measure Up 1, Measure Up 2, and AD Up studies are ongoing pivotal phase 3, randomized, placebo-controlled, multicenter studies evaluating the safety and efficacy of upadacitinib 15 mg and upadacitinib 30 mg in adolescents and adults with moderate-to-severe AD. Patients were randomized 1 : 1 : 1 to receive oral upadacitinib 15 mg, upadacitinib 30 mg or placebo once daily alone (Measure Up 1 and Measure Up 2) or with concomitant topical corticosteroids (AD Up). At Week 16, patients receiving upadacitinib 15 or 30 mg during the double-blinded period continued their assigned treatment in the blinded extension (BE) period, whereas patients receiving placebo were re-randomized 1 : 1 to receive either upadacitinib 15 or 30 mg in the BE period (upadacitinib treatment for up to 260 weeks). A total of 2693 adults and adolescents (upadacitinib 15 mg, 1340; upadacitinib 30 mg, 1353) who received at least one dose of upadacitinib were included in the integrated analysis. Treatment-emergent adverse events of special interest (AESI) were analysed as exposure-adjusted rates per 100 patient-years (PY) for the entire treatment period to adjust for potentially different durations of follow-up. Upadacitinib was well tolerated by both adults and adolescents. For all patients, rates of AESIs were similar at the 1-year analysis and up to 4-year analysis for upadacitinib (15 mg/30 mg) for: serious infections, 2.3 and 2.2/2.8 and 2.8; opportunistic infections, 1.6 and 1.8/1.9 and 2.4; active tuberculosis, &amp;lt;0.1/&amp;lt;0.1 at both time points; herpes zoster, 3.5 and 3.1/5.2 and 5.8; nonmelanoma skin cancer (NMSC), 0.3 and 0.4/0.4 and 0.3; malignancy excluding NMSC, 0.1 and 0.4/0.5 and 0.3; and adverse events leading to death, 0 and 0/&amp;lt;0.1 and &amp;lt;0.1. Rates of adjudicated major adverse cardiovascular events (MACE) were 0.1 and &amp;lt;0.1/&amp;lt;0.1 and &amp;lt;0.1, and for venous thromboembolic events (VTE) were &amp;lt;0.1 for both doses at the 1-year analysis and up to 4-year analysis. Rates of gastrointestinal perforations were 0 for both doses at both timepoint analyses. Rates of serious infections remain low (&amp;lt;3.0 E/100 PY). Based on the integrated analysis of long-term safety data for up to 4 years, rates of AESIs remained low throughout a longer duration of treatment with upadacitinib 15 or 30 mg among adults and adolescents with moderate-to-severe AD. No new safety risks were observed. Findings of the current safety analysis continue to support a favorable benefit-risk profile of upadacitinib in the treatment of adults and adolescents with moderate-to-severe AD for up to 4 years of treatment.

Apremilast Long-Term Safety Up to 5 Years from 15 Pooled Randomized, Placebo-Controlled Studies of Psoriasis, Psoriatic Arthritis, and Behçet's Syndrome.

Since US FDA approval in 2014, apremilast has consistently demonstrated a favorable benefit-risk profile in 706,585 patients (557,379 patient-years of exposure) worldwide across approved indications of plaque psoriasis, psoriatic arthritis, and Behçet's syndrome; however, long-term exposure across these indications has not been reported. The aim of this study was to conduct a pooled analysis of apremilast data from 15 clinical studies with open-label extension phases, focusing on long-term safety. We analyzed longer-term safety and tolerability of apremilast 30 mg twice daily across three indications for up to 5 years, focusing on adverse events of special interest, including thrombotic events, malignancies, major adverse cardiac events (MACE), serious infections, and depression. Data were pooled across 15 randomized, placebo-controlled studies and divided into placebo-controlled or all-apremilast-exposure groups. Treatment-emergent adverse events (TEAEs) were assessed. Overall, 4183 patients were exposed to apremilast (6788 patient-years). Most TEAEs were mild to moderate in the placebo-controlled period (96.6%) and throughout all apremilast exposure (91.6%). TEAE rates of special interest were similar between treatment groups in the placebo-controlled period and remained low throughout all apremilast exposure. Exposure-adjusted incidence rates per 100 patient-years during all apremilast exposure were MACE, 0.30; thrombotic events, 0.10; malignancies, 1.0; serious infections, 1.10; serious opportunistic infections, 0.21; and depression, 1.78. Safety findings were consistent across indications and regions. No new safety signals were identified. The incidence of serious TEAEs and TEAEs of special interest was low despite long-term exposure, further establishing apremilast as a safe oral option for long-term use across indications with a favorable benefit-risk profile. NCT00773734, NCT01194219, NCT01232283, NCT01690299, NCT01988103, NCT02425826, NCT03123471, NCT03721172, NCT01172938, NCT01212757, NCT01212770, NCT01307423, NCT01925768, NCT00866359, NCT02307513.

EV-203: Phase 2 trial of enfortumab vedotin in patients with previously treated advanced urothelial carcinoma in China.

e16574 Background: Enfortumab vedotin (EV), a fully human monoclonal antibody directed against Nectin-4 delivering intracellular monomethyl auristatin E (MMAE) to tumor cells, demonstrated superior overall survival (OS) with manageable safety/tolerability over standard chemotherapy in patients (pts) with previously treated locally advanced or metastatic urothelial carcinoma (la/mUC) in the pivotal EV-301 trial. EV-301 findings led to approval in 41 countries. As EV monotherapy has not been studied in a Chinese population, EV-203 (NCT04995419) assessed efficacy, safety/tolerability, and pharmacokinetics (PK) of EV in pts with la/mUC in China. Methods: In this single-arm, open-label, phase 2 study, Chinese pts with la/mUC previously treated with platinum-based chemotherapy and PD-1/L1 inhibitor therapy received EV 1.25 mg/kg via intravenous infusion on days 1, 8, and 15 of each 28-d cycle at 6 centers. Pts had Eastern Cooperative Oncology Group performance status 0–1 and were excluded if they had preexisting grade ≥2 sensory/motor neuropathy, active central nervous system metastases, clinically significant toxicity associated with prior treatment, or history of uncontrolled diabetes mellitus. Two study centers enrolled pts for a PK cohort. Primary endpoints were confirmed objective response rate (ORR; by Response Evaluation Criteria in Solid Tumors v1.1) by independent review committee (IRC) and PK parameters of antibody–drug conjugate (ADC), total antibody (TAb), and unconjugated MMAE. Secondary endpoints included investigator-assessed confirmed ORR; investigator-/IRC-assessed duration of response (DOR), disease control rate (DCR), and progression-free survival (PFS); OS; and safety/tolerability. Results: A total of 40 Chinese pts were enrolled; 15 were in the PK cohort. Confirmed ORR by IRC was 37.5% (n/N=15/40; 95% CI: 22.7–54.2); best overall response was complete response for 1 (2.5%) pt and partial response for 14 (35.0%) pts. Investigator-assessed ORR was 42.5% (n=17). DCRs were 82.5% (n=33) by investigator and 72.5% (n=29) by IRC. Median DOR by investigator and IRC were not reached. Median PFS were 4.24 mo by investigator and 4.67 mo by IRC. Median follow-up time was 6.5 mo and median OS was not reached. Most treatment-related adverse events (TRAEs) were grade 1–2. Two pts discontinued EV due to TRAE (acute coronary syndrome and hyperglycemia/rash). Serum ADC and TAb concentrations peaked at end of EV infusion; MMAE concentrations had median peak 2–3 d post dose. Minimal ADC, TAb, and MMAE accumulation were observed with repeat EV dosing. Conclusions: EV-203 results show EV has a favorable benefit–risk profile, demonstrating meaningful clinical activity with a manageable safety profile, in pts with previously treated la/mUC in China. EV data are consistent with those from the global population in phase 2–3 EV trials of la/mUC. No new safety signals were identified. Clinical trial information: NCT04995419 .

An age-specific pooled analysis of trastuzumab deruxtecan (T-DXd) in patients (pts) with HER2-positive (HER2+) metastatic breast cancer (mBC) from DESTINY-Breast01, -02, and -03.

1006 Background: T-DXd is approved for use in pts with HER2+ unresectable or mBC after a prior anti-HER2-based regimen in the metastatic or (neo)adjuvant setting, based on the randomized phase 3 DESTINY-Breast03 study (Cortes et al. N Engl J Med 2022). Older pts with HER2+ mBC tend to have worse efficacy and safety outcomes, regardless of treatment (Evans et al. Cancer Res 2021). Outcomes of older pts treated with T-DXd have not been thoroughly examined. Here we report age-specific (&lt;65 vs ≥65 years) efficacy and pooled safety analyses of T-DXd from DESTINY-Breast01, DESTINY-Breast02, and DESTINY-Breast03. Methods: DESTINY-Breast01 (data cutoff [DCO], March 26, 2021) and DESTINY-Breast02 (DCO, June 30, 2022) enrolled pts whose disease progressed on trastuzumab emtansine (T-DM1); DESTINY-Breast02 compared T-DXd to chemotherapy of physician’s choice. DESTINY-Breast03 (DCO, July 25, 2022) included pts previously treated with trastuzumab and taxane; pts received either T-DXd or T-DM1. Results: At baseline, there were 44 (23.9%), 85 (20.9%), and 49 (18.8%) pts ≥65 years of age who received T-DXd in DESTINY-Breast01, DESTINY-Breast02, and DESTINY-Breast03, respectively. At DCO, median pooled treatment duration with T-DXd was 13.1 mo (range, 0.7-44.0) for pts &lt;65 and 12.4 mo (range, 0.7-45.1) for pts ≥65. Key efficacy data are shown in the Table. Any-grade treatment-emergent adverse events (TEAEs), grade ≥3 TEAEs, and serious AEs were observed in 99.6%, 53.6%, and 24.3% of pts &lt;65 and 100%, 65.5%, and 32.2% of pts ≥65, respectively. There were 125 (18.7%) and 45 (25.4%) TEAEs associated with T-DXd discontinuation in pts aged &lt;65 and ≥65, respectively. Any-grade adjudicated drug-related interstitial lung disease/pneumonitis occurred in 11.8% of pts &lt;65 and 17.5% of pts ≥65; grade 5 events occurred in 0.9% and 0.6% of pts &lt;65 and ≥65, respectively. Additional efficacy and safety data will be presented. Conclusions: Results from this pooled analysis further demonstrate that T-DXd has a favorable benefit-risk profile in pts ≥65 years, with slightly increased toxicity, as expected. Clinical trial information: NCT03248492 , NCT03523585 , NCT03529110 . [Table: see text]

Anti-HER2 antibody inetetamab plus camrelizumab and utidelone for pretreated HER2-positive metastatic breast cancer: Final results from the phase 2 ICU trial.

1042 Background: We previously reported (Yan, ASCO 2022) promising efficacy and acceptable safety of anti-HER2 antibody inetetamab in combination with camrelizumab and utidelone regimen in preliminary 20 HER2-positive metastatic breast cancer (MBC) patients who progressed after at least two lines of HER2-directed therapies with trastuzumab and TKIs. Inetetamab is a novel anti-HER2 antibody. Camrelizumab is an anti-programmed death receptor 1 [PD-1] antibody. Utidelone, a genetically engineered epothilone analogue, has shown promising efficacy in heavily pretreated MBC. Here we report the final ICU study results. Methods: In the ICU study (NCT04681287), patients received intravenous camrelizumab (200 mg once every 3 weeks), inetetamab (initial dose of 8 mg/kg, then 6 mg/kg, once every 3 weeks), and utidelone (30 mg/m2, days 1-5, every 3 weeks) until disease progression or intolerable toxicity. The primary endpoint was 3-month progression-free survival (PFS) rate according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary endpoints included objective response rate (ORR), PFS and safety. Simon’s two-stage design was adopted for this study. All AEs were graded according to the grading criteria in the Common Terminology Criteria for the Evaluation of Adverse Events, 5th edition. Results: From Apr 23 2021 to Sept 1 2022, a total of 46 HER2-positive MBC patients were enrolled with median age of 52 (range 43-57). As of Jan 18, 2023, the median follow-up was 11.37 months. There were 12 patients (26.09%) with ER+/PR+, 7 patients (15.22%) with ER+/PR-, one patient (2.17%) with ER-/PR+, 26 patients (56.52%) with ER-/PR-. The median number of previous systemic therapies for advanced disease was three. Previous HER2-targeted therapies included trastuzumab (46 [100%]), TKIs (46 [100%], of which pyrotinib 39 [84.78%] and lapatinib 12 [26.09%]), pertuzumab (13 [28.26%]), and margetuximab (3 [6.52%]), T-DM1 or other HER2-ADC (7 [15.22%]). The 3-month PFS rate in 46 patients was 71.84%. The confirmed ORR was 28% (13/46), include one (2.17%) patient achieved complete response. The median PFS was 5.59 months. The most common treatment-related adverse events (TRAEs) were peripheral neuropathy (40 [86.96%]), capillary proliferation (27 [58.7%]), and alopecia (17 [36.96%]). Grade ≥3 TRAEs included rash (3 [6.52%]), peripheral neuropathy (1 [2.17%]) and AST increase (1 [2.17%]). Moreover, there were no grade 4 or above TRAEs. No related treatment discontinuation or deaths occurred. Conclusions: Final efficacy and safety results were consistent with previous ICU study preliminary analyses. The ICU study showed a favorable benefit-risk profile and is an important option for Chinese patients with HER2-positive MBC after at least two lines of HER2-directed therapies with trastuzumab and TKIs. Clinical trial information: NCT04681287 .

Switching from Sucrose-Formulated rFVIII to Octocog Alfa (BAY 81-8973) Prophylaxis Improves Bleed Outcomes in the LEOPOLD Clinical Trials.

Previous clinical trials established the efficacy and safety of sucrose-formulated recombinant factor (F) VIII (rFVIII-FS/Kogenate FS®/Helixate FS®) and octocog alfa (BAY 81-8973/Kovaltry®; LEOPOLD trials). To report the results of a post hoc subgroup analysis assessing efficacy and safety outcomes in patients with hemophilia A who were receiving rFVIII-FS prior to enrolling into the LEOPOLD I Part B and LEOPOLD Kids Part A clinical trials and switching to octocog alfa. LEOPOLD I Part B (NCT01029340) and LEOPOLD Kids Part A (NCT01311648) were octocog alfa Phase 3, multinational, open-label studies in patients with severe hemophilia A aged 12-65 years and ≤12 years, respectively. Annualized bleeding rate (ABR) was the efficacy endpoint for both studies. Safety endpoints included adverse events (AEs) and development of FVIII inhibitors. Of the 113 patients in both LEOPOLD trials, 40 (35.4%) patients received rFVIII-FS prophylaxis pre-study and had data available for pre-study total ABR. In LEOPOLD I Part B (n = 22, 35.5%), median (Q1; Q3) total ABR decreased from 2.5 (0.0; 9.0) pre-study to 1.0 (0.0; 6.8), and from 1.0 (0.0; 6.0) pre-study to 0.0 (0.0; 6.02) in LEOPOLD Kids Part A (n = 18, 35.3%). Octocog alfa was well tolerated, and no patients had drug-related serious AEs or inhibitors. Treatment with octocog alfa prophylaxis appeared to have a favorable risk-benefit profile compared with rFVIII-FS and thus could be an effective and improved alternative strategy for individualized treatment for children, adolescent and adult patients with severe hemophilia A currently on rFVIII-FS treatment.

Children deserve simple, short, safe, and effective treatment for rifampicin-resistant tuberculosis

Children deserve simple, short, safe, and effective treatment for rifampicin-resistant tuberculosis

Long-Term Efficacy and Safety of Upadacitinib in Patients with Rheumatoid Arthritis: Final Results from the BALANCE-EXTEND Open-Label Extension Study.

Upadacitinib (UPA) is an oral, selective Janus kinase inhibitor that has demonstrated favorable efficacy with an acceptable safety profile across a global, phase 3 program in rheumatoid arthritis (RA). This phase 2 open-label extension investigated the efficacy and safety of UPA through 6years of treatment. Patients from two phase 2b trials (BALANCE-1 and -2) enrolled in BALANCE-EXTEND (NCT02049138) and received open-label UPA 6mg twice daily (BID). Dose increases to 12mg BID were required for patients with < 20% improvement in swollen or tender joint counts at weeks 6 or 12 and permitted for those not achieving Clinical Disease Activity Index (CDAI) low disease activity (LDA; CDAI 2.8 to ≤ 10). Dose reduction to UPA 6mg BID was permitted only for safety or tolerability reasons. After January 2017, the 6/12mg BID doses were replaced by 15/30mg once-daily extended-release equivalents. Efficacy and safety were monitored up to 6years of UPA treatment; outcomes included rates of achievement of LDA or remission. Data were analyzed for patients who received the lower UPA dose throughout; titrated up to the higher UPA dose from weeks 6 or 12; or titrated to the higher UPA dose and back down. Overall, 493 patients entered BALANCE-EXTEND ('Never titrated', n = 306; 'Titrated up', n = 149; 'Titrated up and down', n = 38), and 223 patients (45%) completed the 6-year study. Total cumulative exposure was 1863 patient-years. Rates of LDA and remission were maintained through 6years. Overall, 87%/70%/73% of patients in the 'Never titrated'/'Titrated up'/'Titrated up and down' groups achieved CDAI LDA at week312, while the respective rates of Disease Activity Score28 with C-reactive protein meeting LDA and remission criteria were 85%/69%/70% and 72%/46%/63%. Improvements in patient-reported outcomes were similar among the three groups. No new safety signals were identified. In this open-label extension of two phase 2 studies, UPA demonstrated sustained efficacy and an acceptable safety profile through 6years of treatment in patients who completed the study. These data support a favorable long-term benefit-risk profile of UPA in patients with RA. Trial registration number: NCT02049138.

Early access programs for medicines: comparative analysis among France, Italy, Spain, and UK and focus on the Italian case

Early access programs (EAPs) generally refer to patient access to medicines/indications before marketing authorization, possibly extended to price and reimbursement approval. These programs include compassionate use, which is usually covered by pharmaceutical companies, and EAPs reimbursed by third-party payers. This paper aims at comparing EAPs in four European countries (France, Italy, Spain, UK) and providing empirical evidence on EAPs in Italy. The comparative analysis was conducted through a literature review (including scientific and grey literature), complemented by 30-min semi-structured interviews with local experts. The Italian empirical analysis employed data available on the National Medicines Agency website. Although EAPs are very different across countries, they exhibit some common features: (i) eligibility criteria refer to the absence of valid therapeutic alternatives and a presumed favourable risk–benefit profile; (ii) payers do not allocate a pre-determined budget to these programs; (iii) total spending on EAPs is unknown. The French EAPs seem to be the most structured, financed through social insurance, covering pre-marketing, post-marketing and pre-reimbursement phases and providing for data collection. Italy’s approach to EAPs has been varied, with several programs covered by different payers, including the cohort-based 648 List (for both early access and off-label use), the nominal-based 5% Fund, and Compassionate Use. Most applications to EAPs are from the Antineoplastic and immunomodulating drug class (ATC L). Some 62% of indications in the 648 List are either not under clinical development or have never been approved (pure off-label use). For those subsequently approved, most approved indications coincide with those covered through EAPs. Only the 5% Fund provides data on economic impact (€ 81.2 million in 2021; average cost per patient € 61.5K). Diverse EAPs are a possible source of inequalities in access to medicines across Europe. A harmonization of these programs, though difficult to achieve, could be modelled on the French EAPs and provide key advantages, not least of which a common effort to collect real-world data in parallel with clinical trials and clear separation between EAPs and off-label use programs.

Real-World Effectiveness and Safety of Deutetrabenazine in Combination with Antipsychotic Drugs in Patients With Chorea Associated With Huntington Disease (P2-11.010)

<h3>Objective:</h3> To describe the effectiveness and safety of vesicular monoamine transporter 2 inhibitor deutetrabenazine (DTBZ) combined with antipsychotic agents (APs) in patients with Huntington disease (HD)-related chorea in a real-world setting. <h3>Background:</h3> DTBZ effectiveness and safety for HD-related chorea have been well documented in clinical trials; however, patients receiving APs were not included. Safety and effectiveness data for DTBZ+AP are needed to inform real-world practice. <h3>Design/Methods:</h3> Data were collected from charts of patients with HD-associated chorea who received DTBZ+AP at Vanderbilt University Medical Center from April 3, 2017, until data collection (May–November 2021). Effectiveness was assessed by Total Maximal Chorea (TMC) scores over time. Safety was assessed via adverse drug reactions (ADRs) based on a predefined list of known DTBZ ADRs. <h3>Results:</h3> Among 57 patients treated with DTBZ+AP, 13 started APs first and had TMC scores available within 1 month before and any time after DTBZ addition, and 8 had TMC scores available within 1 month before AP initiation. After initiating APs and before adding DTBZ, TMC scores improved for 2/8 (25%) patients and worsened for 6 (75%). After adding DTBZ, TMC scores further improved for 8/13 (62%) patients, did not change for 1 (8%), and worsened for 4 (31%). In patients with history of tetrabenazine use, TMC scores improved after adding DTBZ for 4/8 (50%), versus 4/5 (80%) patients without history. Among all 57 patients treated with DTBZ+AP, 25 (44%) patients had ≥1 new/continuing ADR, with agitation, akathisia (both n=7; 12%), and somnolence (n=4; 7%) being most frequent; 2 (4%) patients discontinued DTBZ because of ADRs/tolerability issues while receiving combination treatment. <h3>Conclusions:</h3> In this retrospective chart review, adding DTBZ to APs improved motor signs and had a favorable benefit-risk profile. However, prospective, controlled trials investigating the efficacy and safety of DTBZ+AP in patients with HD-related chorea are needed. <b>Disclosure:</b> Dr. Claassen has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Teva Neuroscience. Dr. Claassen has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Spark . The institution of Dr. Claassen has received personal compensation in the range of $50,000-$99,999 for serving as a Consultant for Alterity. Dr. Claassen has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Teva Neuroscience. Dr. Claassen has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for HD Insights. The institution of Dr. Claassen has received research support from NIH. The institution of Dr. Claassen has received research support from CHDI. The institution of Dr. Claassen has received research support from HDSA. The institution of Dr. Claassen has received research support from Department of Defense. The institution of Dr. Claassen has received research support from Griffin Family Foundation. The institution of Dr. Claassen has received research support from Neurocrine. The institution of Dr. Claassen has received research support from Vaccinex. The institution of Dr. Claassen has received research support from AbbVie. The institution of Dr. Claassen has received research support from CHDI. The institution of Dr. Claassen has received research support from Genentech/ Roche. The institution of Dr. Claassen has received research support from Prilenia. The institution of Dr. Claassen has received research support from Neurocrine/ HSG. Dr. Romdhani has nothing to disclose. Rajeev Ayyagari, PhD has received personal compensation for serving as an employee of Analysis Group, Inc. . Debbie Goldschmidt has received personal compensation for serving as an employee of Analysis Group. Ms. Moroz has nothing to disclose. Ms. Hernandez has nothing to disclose. Nayla Chaijale has received personal compensation for serving as an employee of Teva Pharmaceuticals. Dr. Leo has received personal compensation for serving as an employee of Teva Pharmaceutical Industries.

Final Analysis of Pregnancy Outcomes Following Exposure to Dimethyl Fumarate in a Prospective International Registry (S31.004)

Final Analysis of Pregnancy Outcomes Following Exposure to Dimethyl Fumarate in a Prospective International Registry (S31.004)

Design of a Phase 2, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study of Nipocalimab in Participants with Active Idiopathic Inflammatory Myopathies (SPIREA) (P10-5.007)

Design of a Phase 2, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study of Nipocalimab in Participants with Active Idiopathic Inflammatory Myopathies (SPIREA) (P10-5.007)