Safety Profile Research Articles

Rifaximin discontinuation during broad-spectrum antibiotic treatment in critically ill patients with hepatic encephalopathy

Hepatic encephalopathy (HE) is one of the main complications of cirrhosis, characterized by a wide spectrum of neuropsychiatric alterations that lead to an increase in mortality, morbidity and recurrent hospitalizations. Due to the central role in HE pathogenesis of ammonia and other neurotoxins primarily produced by the gut microbiota, the main therapeutic approaches for the treatment of HE are based on the modulation of the gut microbiota. Rifaximin is a non-absorbable broad-spectrum antibiotic, that is effective against ammonia-producing gram-positive, gram-negative, and anaerobic species, approved for the treatment of HE in secondary prophylaxis. The chronic administration of rifaximin in this setting is associated with a lower risk of HE recurrence and mortality, while the role of rifaximin for the treatment of an overt-HE episode in inpatients is still unclear. Limited data exist about the coadministration of rifaximin and broad-spectrum antibiotics commonly used to treat concomitant infections, as patients receiving or recently treated with antibiotics were frequently excluded from clinical trials. In this editorial we comment on the article by Ward et al published in the recent issue of the World Journal of Hepatology . It is a single center, retrospective, quasi-experimental, pharmacist-driven protocol, with the aim to evaluate the feasibility and safety of rifaximin discontinuation in critically ill patients with HE and chronic liver disease receiving broad-spectrum antibiotic therapies in intensive care units. The study revealed no differences between the protocol and control group in terms of primary outcome (days alive and free of delirium and coma to day 14) and secondary outcomes which include: Intensive care mortality, intensive care length of stay, intravenous vasopressor requirement changes and adverse effects rate. Therefore, rifaximin discontinuation during broad-spectrum antibiotic therapy does not appear to negatively impact the clinical status of critically ill liver patients, with a similar safety profile and significant cost savings, as compared to the coadministration of rifaximin and broad-spectrum antibiotics. In agreement with Ward et al , a recently published double-blind, randomized controlled trial provided additional evidence to support the feasibility of withholding rifaximin during broad-spectrum antibiotic therapy in critically ill cirrhotic patients. However, given the limitations of these studies, further multicentric and prospective clinical trials, enrolling a larger sample of non-critically ill patients, are needed to better establish the role of rifaximin in this setting.

The protocol for BROWSE-P (breast reconstruction outcomes with Strattice™ or Artia™ – pre-pectoral): a cohort study to assess long-term outcomes of immediate pre-pectoral implant based breast reconstruction with Strattice™ or Artia™

Introduction: Techniques in implant-based breast reconstruction (IBBR) have evolved over the last 15 years due to the introduction of mesh or acellular dermal matrices (ADMs). Traditionally, total submuscular coverage progressed to upper pole muscle cover with lower pole ADM and now total or anterior ADM cover in the pre-pectoral plane. Data is scarce to support the pre-pectoral technique but, it is suggested to result in less postoperative pain, more natural cosmesis and avoidance of animation deformity. The BROWSE study concluded that subpectoral with Strattice™ IBBR resulted in better cosmesis and lower rates of capsular contracture when compared to the total submuscular technique. The BROWSE-P study aims to assess the safety profile of Artia™ a porcine derived ADM and review the long-term outcomes of pre-pectoral IBBR with Strattice™ and Artia™. Methods and analysis: BROWSE-P is a single center cohort study. Consecutive patients who have undergone immediate pre-pectoral IBBR with Strattice™ or Artia™ from January 2017 to December 2022 will be included. Demographic, operative, oncology, complication, and further surgery data with be collected to assess the rate of revision surgery and safety profile of Artia™. Those who have their implant reconstruction in situ will be invited for clinical assessment to assess for capsular contracture. Participants will also be asked to complete a BREAST-Q post-reconstruction module, to assess patient satisfaction and quality of life, and have medical photographs taken for an assessment of aesthetic outcome by a blinded panel using the 10-point Visser scale. We aim to collect data on 500 reconstructions and complete clinical assessment, patient reported outcomes and aesthetic assessment for 250 patients.

Bimekizumab Efficacy and Safety Through 2 years in Patients with Hidradenitis Suppurativa: Results from the Phase 3 BE HEARD I&II trials and Open-Label Extension BE HEARD EXT

Introduction: Interleukin (IL)-17F and IL-17A play a role in the immunopathogenesis of hidradenitis suppurativa (HS).1–3 Bimekizumab (BKZ) is a humanized IgG1 monoclonal antibody that selectively inhibits IL-17F in addition to IL-17A leading to clinically meaningful improvements in patients (pts) with HS.4,5 Here, BKZ efficacy and safety data (OC) are presented over 2 years (96 weeks [wks]) for the pooled BE HEARD I&II (BHI&II) trials and BE HEARD EXT (BHEXT).5,6 Procedure/Study: In BHI&II, pts with moderate to severe HS were randomized 2:2:2:1 (16wk-initial/32wk-maintenance) to BKZ 320mg every 2 wks (Q2W)/Q2W, BKZQ2W/Q4W, BKZQ4W/Q4W or placebo/BKZQ2W.5 Wk48 completers could enroll in BHEXT and receive open-label BKZQ2W or BKZQ4W based on ≥90% HS Clinical Response (HiSCR90; averaged from Wks36/40/44). We report HiSCR50/75/90/100 rates, percentage change from baseline (%CfB, mean±SD) in International HS Severity Score System (IHS4) and draining tunnel (DT) count, and Dermatology Life Quality Index (DLQI) 0/1 achievement at Wks48/96 for patients randomized to BKZ in BHI&II and entered BHEXT (BKZ Total, observed case). Safety outcomes reported for pts who received ≥1 BKZ dose across BHI&II/BHEXT. Results: 556 pts randomized at baseline to BKZ in BHI&II completed Wk48 and entered BHEXT; 446 pts completed Wk96. At Wk48, HiSCR50/75/90/100 was achieved by 79.9/64.0/42.3/30.2% of pts; responses improved to Wk96: 85.4/77.1/57.6/44.2%. Baseline IHS4 was 35.6±31.5; %CfB at Wk48/96 was –70.3±39.6/−79.8±28.1%. Baseline DTs were 3.8±4.3; the %CfB at Wk48/96 was −57.5±72.9%/−73.7±45.7%. Baseline DLQI was 11.0±6.8; 27.4% (151/551) of pts achieved DLQI 0/1 at Wk48 and 33.9% (149/439) at Wk96. Over 2 years, 917/995 (248.9/100 pt years [PY]) pts experienced a treatment-emergent adverse event (TEAE). Serious TEAEs were reported in 122 (7.2/100 PY) pts; 109 (6.3/100 PY) pts discontinued due to a TEAE. Serious infections occurred in 33 (1.9/100 PY) pts. Safety data were comparable with BHI&II.5 Conclusion: In pts treated with BKZ, clinically meaningful improvements in efficacy outcomes observed at 1 year, including the HiSCR 75/90/100, IHS4, and DT count endpoints, were maintained to 2 years; improvements in quality of life were maintained. No new safety signals were observed; the safety profile over 2 years was consistent with BHI&II and BKZ studies in other indications.5,7–9

Aldosterone synthase inhibitors for cardiorenal protection: ready for prime time?

Background: Aldosterone, through its genomic and non-genomic effects, plays an important role in cardiovascular and renal injury. Steroidal mineralocorticoid receptor antagonists (MRAs) are fundamental to offset the aldosterone-mediated cardiorenal damage, but side effects may limit their use in a substantial proportion of patients. On the other hand, non-steroidal mineralocorticoid receptor antagonists (NS-MRA) showed improved selectivity and safety profile. However, interfering with the MRA could only partially inhibit aldosterone mediated effect both because of escaping mechanisms and potential non-genomic activity. Summary: Inhibiting aldosterone synthesis could be a promising strategy to abolish aldosterone-mediated cardiovascular side effects. Aldosterone is primarily synthesized by the CYP11B2 enzyme, which is very similar to CYP11B1, a key enzyme involved in glucocorticoid production. Lack of specificity for CYP11B2 and consequent off-target effects hampered the development of first-generation aldosterone synthase inhibitors (ASIs). The subsequent development of highly specific ASIs led to successful clinical trials in patients with resistant and uncontrolled hypertension. Key Messages: A recent randomized clinical trial showed a significant benefit of ASIs in patients with chronic kidney disease and albuminuria. However, further outcome based clinical trials are needed to confirm the promising role of ASIs in cardiorenal damage.

Efficacy and Safety of Ruxolitinib Cream for the Treatment of Moderate to Severe Chronic Hand Eczema: Top-Line Results From a 16-Week, Multicenter, Randomized, Double-Blind Study

Hand eczema is a common inflammatory disorder involving skin of the hands. Chronic hand eczema (CHE) is defined as hand eczema that persists for >3 months or recurs ≥2 times within a 12-month period. The efficacy and safety of ruxolitinib (selective Janus kinase [JAK] 1/JAK2 inhibitor) cream was investigated in adults with moderate to severe CHE in a phase 2, randomized, double-blind, vehicle-controlled study (NCT05906628). Patients aged ≥18 years with a diagnosis of CHE for ≥6 months, an Investigator’s Global Assessment (IGA)-CHE score of 3 or 4, and no current or history (≤5 y) of atopic dermatitis were randomized 1:1 to apply twice-daily 1.5% ruxolitinib cream or vehicle cream for 16 weeks of double-blind treatment. Patients (N=186) had a median (range) age of 50.0 (18–80) years, and 59.7% were female. The median (range) Itch numerical rating scale (NRS) score was 6.6 (2.1–10), and 72.6% of patients had an IGA-CHE score of 3. At Week 16, significantly more patients who applied ruxolitinib cream versus vehicle achieved IGA-CHE treatment success (primary endpoint; 53.2% vs 10.9%; P<0.0001), defined as an IGA-CHE score of 0 (clear) or 1 (almost clear) with a ≥2-grade improvement from baseline. Significantly more patients who applied ruxolitinib cream versus vehicle achieved a ≥4-point improvement from baseline in Itch NRS score (Itch NRS4) at Week 4 (46.7% vs 17.6%; P<0.0001; key secondary endpoint) and Week 16 (52.2% vs 23.1%; P<0.0001; key secondary endpoint). Numerical improvements in Itch NRS4 with ruxolitinib cream versus vehicle were observed at Day 2 with statistically significant improvement observed on Day 7 (27.4% vs 9.0%; P=0.0024; key secondary endpoint). Substantially more patients who applied ruxolitinib cream versus vehicle achieved a ≥75% or ≥90% improvement from baseline in Hand Eczema Severity Index (HECSI) score at Week 16 (80.2% vs 26.9% and 64.0% vs 11.5%, respectively). Ruxolitinib cream was generally well tolerated through Week 16 with no new safety signals; no serious infections, major adverse cardiovascular events, malignancies, or thromboses were observed. Application site reactions were infrequent. No treatment-related grade ≥3 treatment-emergent adverse events (TEAEs) were reported, and no patients discontinued owing to a TEAE. In conclusion, ruxolitinib cream demonstrated significant reductions of CHE signs and symptoms versus vehicle through Week 16 and was generally well tolerated, consistent with the known safety profile. (Funding, Incyte Corporation)

A Journey Along the Boulevard of Bioactive Compounds from Natural Sources, with Cosmetic and Pharmaceutical Potential: Bee Venom, Cobra Venom, Ficus carica

Animal venom and plant extracts have been used since ancient times in traditional medicine worldwide. Natural components, valued for their safety and effectiveness, have been consistently used in cosmetic and pharmaceutical applications. We propose a journey along the boulevard of active compounds from natural sources, where bee venom (BV), cobra venom (CV), and Ficus carica reveal their individual therapeutic and cosmetic properties. The originality of this review lies in exploring the synergy of these bioactive sources, an approach that has not been presented in the literature. Although BV, CV, and Ficus carica have different origins and compositions, they have multiple common pharmacological and cosmetic actions, which make them ideal for inclusion in various products that can be used for skin care and health in general. Their anti-inflammatory, antioxidant, immunomodulatory, antimicrobial, neuroprotective, and regenerative properties give them an essential role in the creation of potential innovative and effective products in the pharmaceutical and cosmetics industry. Although many plant extracts have antioxidant and anti-inflammatory properties, Ficus carica was chosen due to its complex biochemical composition, which provides valuable benefits in skin regeneration and protection against oxidative stress. According to the International Nomenclature of Cosmetic Ingredients (INCI), Ficus carica is used in the form of an extract of fruits, leaves, juice, bark or stem, each having specific applicability in topical formulations; due to the diversity of bioactive compounds, it can amplify the effectiveness of BV and CV, helping to enhance their beneficial effects and reducing the risk of adverse effects, due to its well-tolerated nature. Thus, this combination of natural ingredients opens up new perspectives in the development of innovative products, optimizing efficiency and maintaining a favorable safety profile. In this context, due to the reported experimental results, the three natural sources caught our attention, and we conceived the present work, which is a review made following the analysis of the current progress in the study of the bioactive compounds present in BV, CV, and Ficus carica. We focused on the novelties regarding pharmacological and cosmetic actions presented in the literature, and we highlighted the safety profile, as well as the modern approaches regarding the delivery and transport systems of the active substances from the three natural sources, and we evaluated their prospects in therapeutic and cosmetic use. This paper not only expands our knowledge of bioactive compounds, but it can also generate new ideas and motivations for the research and development of innovative treatments and skincare methods.

Orange Peel Lactiplantibacillus plantarum: Development of A Mucoadhesive Nasal Spray with Antimicrobial and Anti-Inflammatory Activity

Background/Objectives: Due to the high frequency and severity of upper respiratory bacterial infections, probiotics could offer a new medical approach. We explored the antibacterial and anti-inflammatory properties of the new strain Lactiplantibacillus plantarum BIA and formulated a nasal spray. Methods: L. plantarum BIA was isolated from orange peel and taxonomically identified through 16S rRNA gene sequencing. Its antibacterial activity was tested against Pseudomonas aeruginosa, Streptococcus pyogenes, Bacillus subtilis, Escherichia coli, and Staphylococcus aureus, while anti-inflammatory potential was evaluated by Griess assay. BIA genome was fully sequenced and analyzed to assess its safety. BIA was formulated in a freeze-dried matrix, containing prebiotics and cryoprotectants, to be reconstituted with a polymer solution. Solutions containing two types of hydroxypropyl methylcellulose (HPMC) and hyaluronic acid were evaluated as resuspending media and compared in terms of pH, viscosity, and mucoadhesion ability. The biological activity of BIA formulated as nasal spray was verified together with the stability of the selected formulations. Results: L. plantarum BIA inhibited human pathogens’ growth and showed anti-inflammatory activity and a safe profile. In the best-performing formulation, the probiotic is lyophilized in 10% fructooligosaccharides, 0.1% ascorbic acid, and 0.5% lactose and reconstituted with HPMC high viscosity 1% w/v. This composition ensured the probiotic’s viability for up to six months in its dried form and one week after reconstitution. It also allowed interaction with the nasal mucosa, preserving its antimicrobial and anti-inflammatory activities. Conclusion: The developed nasal spray could become a promising formulation in the field of nasal infectious and inflammatory diseases.

Pharmacodynamic effects and exploratory efficacy of afimetoran, a TLR7/8 inhibitor, in patients with cutaneous lupus erythematosus

Background: Cutaneous lupus erythematosus (CLE) is a chronic inflammatory skin condition occurring alone or as a manifestation of systemic lupus erythematosus (SLE). There is an unmet need for safe and effective CLE-focused treatments. Afimetoran is an investigational, first-in-class, potent oral inhibitor of toll-like receptors (TLRs) 7/8. Given the involvement of TLRs 7/8 in SLE, afimetoran may have therapeutic potential for CLE. A phase 1b randomized, double-blind, placebo-controlled study (NCT04493541) demonstrated preliminary safety and efficacy of afimetoran in patients with active CLE. We assessed the pharmacodynamics, safety, and efficacy of afimetoran and its impact on CLE pathobiology. Methods: Patients aged 18–65 years with SLE and cutaneous manifestations by EULAR/ACR 2019 classification criteria or biopsy-proven CLE, and modified CLE Disease Area and Severity Index-Activity (CLASI-A) score ≥6, were randomized 2:1 to once-daily afimetoran (30 mg) or placebo for 16 weeks with a 4-week post-treatment follow-up period. The primary endpoints were safety and tolerability; efficacy was exploratory. Transcriptomics and cytokine analyses were performed using peripheral whole blood and serum, respectively, at baseline (pre-dose) and each study visit (weeks 1, 2, 4, 8, 12, 16, and 20 [post-dose]). Statistical analyses compared data from the 13 randomized patients with thirteen age-, ethnicity-, and gender-matched healthy volunteers. Treatment responses were evaluated longitudinally in each treatment arm. The dataset was analyzed using a linear regression model. Gene set variation analysis (GSVA) was performed for pathway enrichment. Results: 13 patients with CLE were randomized (afimetoran, n=8; placebo, n=5); 12 patients completed 16 weeks of treatment and 1 discontinued after 6 weeks due to COVID-19. Compared with placebo, afimetoran demonstrated a favorable safety profile with no serious adverse events, and showed a greater reduction in CLASI-A scores as early as week 4, which persisted to week 20. Improvement in the molecular disease profile was rapid (week 1), sustained through the 16-week treatment period, and the 4-week post-treatment follow-up period. Expression of interferon (IFN) pathway genes was significantly reduced with afimetoran compared with baseline (ΔGSVA enrichment score [ES]=1.57, P<0.0001) and placebo (ΔGSVA ES=0.56, P<0.01); this effect was maintained through week 16 and ≥4 weeks post-treatment. Expression of TLR7 and TLR8 pathway genes and key cytokines (interleukin [IL]-6, tumor necrosis factor α, IL-18, IFNγ, macrophage inflammatory protein-1 alpha [CCL3/MiP1α] or beta [CCL4/MiP1β]) were greatly reduced with afimetoran treatment. GSVA demonstrated robust pharmacodynamic activity on immune cell populations, including immature and activated dendritic cells, macrophages, and inflammatory pathway signatures. Conclusion: In patients with CLE, afimetoran was safe, well tolerated, and demonstrated durable efficacy beyond the treatment period. Afimetoran’s clinical effects and potent pharmacodynamic impact on the molecular disease profile suggest a substantial therapeutic benefit for patients with CLE.

Cleistopholis patens root bark extract exerts cardioprotective effect against doxorubicin-induced myocardial toxicity in rats

Abstract Background Myocardial Infarction still persists as the most prevalent cardiovascular disease and is a top cause of morbidity and mortality in doxorubicin treated cancer patients. This study evaluated the prophylactic effect of the ethanol root bark extract of Cleistopholis patens (ERBECP) against doxorubicin-induced myocardial infarction in wistar rats. Extraction, preliminary phytochemical analysis, acute toxicity study and body weight (b.w.) of ERBECP were achieved using standard methods. Phyto-constituents in ERBECP were indentified using Gas Chromatography-Mass Spectrometry (GC–MS) technique. Thirty (30) male albino Wistar rats of average b.w. ranging between 100 and 130 g were divided into six groups of five rats each. Groups I, II and III served as normal, doxorubicin (DOX) and standard (Vasoprin 150 mg/kg b.w) controls respectively, while groups IV, V and VI were orally pre-treated with the extract (200, 400 and 600 mg/kgb.w) for two weeks prior to intraperitoneal induction of cardiotoxicity with DOX (20 mg/kg bw) on day 14. Results Disturbances in serum cardiac function bio-markers such as; Cardiac Troponin-I (CTnI), Creatine Kinase (CK), Lactate Dehydrogenase (LDH), Aspartate aminotransferase (AST), Alanine aminotransferase (ALT). Lipid profile markers such as; Total cholesterol (TC), Triacylglycerol (TAG), Low Density Lipoprotein (LDL), High Density Lipoprotein (HDL). Oxidative stress markers such as; Malondialdehyde (MDA), Superoxide Dismutase (SOD), Catalase (CAT), Glutathione (GSH) confirmed the induction of myocardial infarction. Histological assessment of heart tissues was performed to validate biochemical results. The GC–MS analysis of ERBECP identified a total of 69 compounds. Safety profile of the aqueous extract was safe for the animals up to the highest dose of 5000 mg/kg b.w. Pre-treatment of DOX group with ERBECP could significantly increase the b.w. compared to the DOX-treated group during the experimental period of 2 weeks. There were significant (p < 0.05) alterations in the levels of CTnI, CK, LDH, AST, ALT and lipid profile indices in the DOX control rats. Also, significant (p < 0.05) increase was observed in MDA and decrease in SOD, CAT and GSH in the DOX control rats. However, administration of the extract significantly (p < 0.05) normalized these alterations and reversed the architectural changes in the heart. The 69 compounds were screened against the target protein (CBR1); we identified seven hits based on the docking score and interactions with the active site residues. All the C. patens constituents had MW (g/mol) less than 500, HBA < 10 and HBD not more than 5. Apart, 9-Octadecenoic acid (Z)-, 2,3-dihydroxy propyl ester and Estra-1,3,5(10)-trien-17. beta. -ol, all the constituents had LD50 lower than 2000 mg/kg. Conclusions The findings reveals ERBECP demonstrated promising potential and can be exploited in the development novel cardiac therapeutic agents.

Deucravacitinib, an Oral Selective Tyrosine Kinase 2 (TYK2) Inhibitor, in Patients with Moderate to Severe Scalp Psoriasis: Efficacy and Safety Results of a Phase 3b/4, Multicenter, Randomized, Double-blinded, Placebo-controlled Trial (PSORIATYK SCALP)

Introduction: Deucravacitinib, an oral, selective, allosteric TYK2 inhibitor, is approved in multiple countries for treatment of adults with moderate to severe plaque psoriasis who are candidates for systemic therapy. PSORIATYK SCALP, an ongoing, 52-week, phase 3b/4, multicenter, randomized, double-blinded, placebo-controlled trial, evaluated deucravacitinib efficacy/safety in patients with moderate to severe scalp psoriasis, including those with more limited overall psoriasis. Methods: Adults with moderate to severe scalp psoriasis defined by more focused and objective inclusion criteria (ss-PGA ≥3, scalp surface area involvement ≥20%, and PSSI ≥12 at baseline) and BSA involvement ≥3% were randomized 1:2 to oral placebo or deucravacitinib 6 mg once daily through Week 16. The primary efficacy outcome was ss-PGA 0/1; key secondary outcomes were PSSI 90, change from baseline in scalp-specific itch numeric rating scale (NRS), and sPGA 0/1 at Week 16. Efficacy outcomes were evaluated at Week 16 for the overall population and the subpopulation with global sPGA ≥3. Nonresponder imputation and modified baseline observation carried forward were used for patients who discontinued or had missing data for binary and continuous outcomes, respectively. Results: 154 patients were randomized (placebo, n=51; deucravacitinib, n=103). Baseline characteristics were similar in each group (placebo: mean BSA 10.0%, PASI 9.4, PSSI 32.2; deucravacitinib: mean BSA 10.5%, PASI 10.2, PSSI 33.5). In the overall population, a higher proportion of patients receiving deucravacitinib versus placebo achieved ss-PGA 0/1 at Week 16 (48.5% vs 13.7%; P<0.0001). Deucravacitinib was superior to placebo for PSSI 90 (38.8% vs 2.0%; P<0.0001) and mean change from baseline in scalp-specific itch NRS (−3.2 vs −0.7; P<0.0001). In the subpopulation (sPGA ≥3), a greater proportion achieved sPGA 0/1 with deucravacitinib versus placebo (51.0% vs 4.3%; P<0.0001). The most common adverse events (AEs) in the deucravacitinib group (≥5%) were nasopharyngitis (14.6%), upper respiratory tract infection (11.7%), acne (9.7%), headache (7.8%), COVID-19 (5.8%), and pustular acne (5.8%). Two serious AEs were reported (1/group); neither was considered treatment related or led to discontinuation. Conclusion: Deucravacitinib was efficacious and well tolerated in patients with moderate to severe scalp psoriasis, including those with less extensive overall psoriasis (BSA ≥3%). The overall psoriasis response rate (sPGA 0/1) was consistent with POETYK trial results, despite including patients with more limited BSA involvement. Safety findings were consistent with the known deucravacitinib safety profile.

Real-world safety of spesolimab in generalized pustular psoriasis: Evidence from an expanded access program in Argentina

Introduction: Generalized pustular psoriasis (GPP) is a heterogeneous, systemic, neutrophilic, inflammatory disease associated with chronic symptoms and periods of flaring. Spesolimab is an anti-interleukin-36 receptor monoclonal antibody approved for the treatment of flares in adult patients with GPP in Argentina (17 Aug 2023).1 Here, we present safety data from a real-world expanded access program (EAP: 22 Feb 2023–10 Jan 2024) in Argentina which provided early access to spesolimab intravenous (IV) for GPP patients presenting with a flare with no other treatment options. Methods: Patients (18–75 years old) diagnosed with GPP received a 900mg dose of spesolimab IV for flare treatment, with an optional second dose after 1 week for persistent flare symptoms. Adverse events (AEs), serious AEs (SAEs), and AEs of special interest (AESIs) were recorded for up to 16 weeks after the last spesolimab infusion.Results: Six female patients were treated with spesolimab IV (1 dose, n=2; 2 doses, n=4).Mean (standard deviation [SD]) age: 49.3 (11.5) years (range: 30–60 years), mean (SD) body mass index: 28.1 (5.8) kg/m2, and mean (SD) follow-up: 3.85 (0.11) months. At baseline, GPP had been diagnosed within ≤1 year (n=2), >1–≤5 years (n=1), and >10 years (n=3). Reported flare triggers were stress (n=2), treatment withdrawal (n=1), heat (n=1), lack of current treatment efficacy (n=1), and unknown (n=1). At baseline, 4 patients had ≥1 comorbidity, including hypertension (n=2), tachycardia, hypothyroidism, chronic gastritis, arthritis, and epilepsy (each n=1). Five patients reported use of ≥1 concomitant medication (including immunosuppressants and corticosteroids) during the EAP; 1 patient had discontinued ustekinumab (biologic). Three patients had signs of plaque psoriasis within the past year and had received treatment for plaque psoriasis; 1 patient had ongoing plaque psoriasis. In total, 4 patients had any AEs (all 4 patients had mild AEs [influenza, catarrh, pruritis, rash, pain] and 1 of these patients also had a moderate AE [headache]). Two drug-related AEs (pruritus and rash) were reported in 1 patient. The hypersensitivity event (rash) was non-serious. There were no reports of SAEs, AESIs, or AEs that led to discontinuation/death. Conclusion: Spesolimab showed a favorable safety profile in patients with GPP, including patients with comorbidities and those taking concomitant medication. Findings were comparable with a Phase 2a randomized controlled trial in patients with GPP flares (EFFISAYIL 1).

Bimekizumab Efficacy and Safety in Patients With Psoriatic Arthritis Who Had Skin and Nail Psoriasis at Baseline: Up to 2-year Results From Two Phase 3 Studies

Introduction: Bimekizumab (BKZ), a humanized anti-IL17F anti-IL17A antibody has demonstrated efficacy and tolerability to 1 year in patients with psoriatic arthritis (PsA) and psoriasis.1 Nail psoriasis is associated with increased PsA risk, more severe disease and decreased quality of life, in patients with psoriasis.2,3 Here, efficacy and safety of BKZ treatment are reported to 2 years in patients with PsA, skin involvement and nail psoriasis in two phase 3 trials. Methods: BE OPTIMAL (NCT03895203; bDMARD-naïve) and BE COMPLETE (NCT03896581; TNFi‑IR) assessed subcutaneous BKZ 160 mg Q4W in patients with PsA. Placebo (PBO) patients switched to BKZ (PBO/BKZ) at Wk16. BE OPTIMAL included a reference arm (adalimumab [ADA] 40 mg Q2W); ADA patients switched to BKZ at Wk52 (ADA/BKZ). BE OPTIMAL Wk52 and BE COMPLETE Wk16 completers could enter BE VITAL (open-label extension; NCT04009499), where all patients received BKZ. Post-hoc data reported for patients with baseline skin involvement (≥3% body surface area) and nail psoriasis (modified Nail Psoriasis Severity Index >0). Efficacy reported to Wk104 of BE OPTIMAL/Wk100 of BE COMPLETE. Missing data imputed using non‑responder, multiple or worst-category imputation. Safety data are reported for all patients treated with BKZ. Results: Of 263/852 (30.9%) bDMARD-naïve and 159/400 (39.8%) TNFi-IR patients with baseline skin and nail psoriasis, 230 (87.5%) and 136 (85.5%) patients completed Wk104/Wk100. Efficacy responses at Wk52 on BKZ were sustained to Wk104/Wk100 across joint, skin, nail, physical function and composite outcomes. ADA/BKZ cohort showed sustained responses after switch. For bDMARD-naïve and TNFi-IR patients on BKZ, the exposure-adjusted incidence rates per 100 patient-years (EAIR/100 PY) for ≥1 treatment-emergent adverse event (TEAE) were 154.9 and 78.8, respectively; and for serious TEAEs, 6.6 and 5.2 respectively. None of the reported Candida infections were serious or systemic; all 3 deaths were deemed unrelated to treatment. Conclusions: BKZ treatment demonstrated sustained clinical efficacy to 2 years in patients with PsA, skin involvement and nail psoriasis, regardless of prior TNFi treatment. BKZ was well tolerated; consistent safety profile to previous reports.1

Switching from Dupilumab to Upadacitinib in Adults and Adolescents with Moderate-to-Severe Atopic Dermatitis and Inadequate Response to Dupilumab: Efficacy and Safety Results from the Phase 3b/4 LEVEL UP Study

Atopic dermatitis (AD) is a chronic skin disease characterized by intense itch and eczematous skin lesions. Upadacitinib (UPA), a selective oral Janus kinase (JAK) inhibitor, and dupilumab (DUPI), a monoclonal antibody targeting interleukin-4 and interleukin-13 signaling, are both approved treatments for moderate-to-severe AD. LEVEL UP is a phase 3b/4 efficacy assessor blinded monotherapy study comparing UPA to DUPI for treatment of moderate-to-severe AD in adults and adolescents over a 16-week period (Period 1). Patients not achieving ≥75% improvement in the Eczema Area and Severity Index (EASI 75) from baseline at Week 16 entered an additional 16-week extension phase (Period 2). In Period 2, patients either continued/escalated to UPA 30 mg (UPA/UPA 30) or switched from DUPI to UPA 15 mg (DUPI/UPA), with the potential to escalate to 30 mg based on clinical response. Efficacy for skin and itch outcomes in Period 2 were assessed using observed case analysis while on treatment, without statistical comparisons. Here we report efficacy and safety results for the DUPI/UPA switch group. A total of 355 patients who did not achieve EASI 75 at Week 16 entered Period 2 of the study (DUPI/UPA, N=208). At Week 32, response rates in the DUPI/UPA group were: 79.6%, 58.7%, and 19.9% achieving EASI 75, EASI 90, and EASI 100, respectively; 60.2% achieving WP-NRS improvement ≥4 among those with baseline WP-NRS ≥4; 37.0% achieving WP-NRS 0/1 among those with baseline WP-NRS >1; and 26.8% simultaneously achieving EASI 90 and WP-NRS 0/1 by Week 32. Clinically meaningful outcomes were also observed at an earlier visit (Week 20). No new safety signals through Week 32 were identified compared to the established safety profile of UPA. Most patients with an inadequate response to DUPI at Week 16 experienced clinically meaningful improvements in skin clearance and itch at 4 weeks post-switch to UPA, with additional patients achieving these outcomes by 16 weeks post-switch. These findings suggest that switching from DUPI to UPA is an effective treatment strategy for patients who do not meet moderate or optimal treatment targets with DUPI.

Deucravacitinib in Plaque Psoriasis: 4-year Safety and Efficacy Results from the Phase 3 POETYK PSO-1, PSO-2, and LTE Trials

Introduction: Deucravacitinib, an oral, selective, allosteric TYK2 inhibitor, is approved in multiple countries for treatment of adults with moderate to severe plaque psoriasis who are candidates for systemic therapy. Deucravacitinib was superior to placebo and apremilast in the global, 52-week, phase 3 POETYK PSO-1 and PSO-2 parent trials in moderate to severe plaque psoriasis. Upon completion, patients could enroll in the ongoing POETYK long-term extension (LTE) trial. Here, deucravacitinib safety/efficacy are reported through 4 years. Methods: PSO-1/PSO-2 randomized patients 1:2:1 to oral placebo, deucravacitinib 6 mg once daily, or apremilast 30 mg twice daily. At Week 52, patients enrolled in the LTE received open-label deucravacitinib. Safety was evaluated in patients receiving ≥1 deucravacitinib dose. Exposure-adjusted incidence rate (EAIR) per 100 person-years (PY) was used to assess adverse events (AEs). Efficacy outcomes included PASI 75, PASI 90, and sPGA 0/1 and were analyzed using mNRI in LTE patients receiving continuous deucravacitinib from Day 1 of the parent trials. Results: 1519 patients received ≥1 deucravacitinib dose; cumulative exposure was 4392.8 PY. EAIRs/100 PY were decreased/comparable from the 1-year to 4-year cumulative period, respectively, for AEs (229.2, 131.7), serious AEs (5.7, 5.0), deaths (0.2, 0.3), discontinuation due to AEs (4.4, 2.2), herpes zoster (0.8, 0.6), malignancies (1.0, 0.9), major adverse cardiovascular events (0.3, 0.3), and venous thromboembolism (0.2, 0.1). Clinical response rates with continuous deucravacitinib (n=513) were maintained from Year 3 (PASI 75, 73.8% [95% CI, 69.6-78.0]; PASI 90, 49.0% [44.4-53.7]; sPGA 0/1, 55.2% [50.5-59.9]) to Year 4 (PASI 75, 71.7% [67.0-76.3]; PASI 90, 47.5% [42.6-52.4]; sPGA 0/1, 57.2% [52.1-62.2]) by mNRI. Conclusion: Deucravacitinib demonstrated a safety profile through 4 years consistent with 3 years with no emergence of new or long-term safety signals. Efficacy was maintained through 4 years in patients receiving continuous deucravacitinib from Day 1 in PSO-1/PSO-2.

First-in-Human Phase I Trial to Assess the Safety and Immunogenicity of an Orf Virus-Based COVID-19 Vaccine Booster

The emergence of SARS-CoV-2 has necessitated the development of versatile vaccines capable of addressing evolving variants. Prime-2-CoV_Beta, a novel Orf virus-based COVID-19 vaccine, was developed to express the SARS-CoV-2 spike and nucleocapsid antigens. This first-in-human, phase I, dose-finding clinical trial was conducted to assess the safety, reactogenicity, and immunogenicity of Prime-2-CoV_Beta as a booster in healthy adults. From June 2022 to June 2023, 60 participants in Germany received varying doses of Prime-2-CoV_Beta. The study demonstrated a favorable safety profile, with no serious adverse events (AEs) reported. All AEs were mild (107) or moderate (10), with the most common symptoms being pain at the injection site, fatigue, and headache. Immunogenicity assessments revealed robust vaccine-induced antigen-specific immune responses. High doses notably elicited significant increases in antibodies against the spike and nucleocapsid proteins as well as neutralizing antibodies against SARS-CoV-2 and its variants. Additionally, the vaccine did not induce ORFV-neutralizing antibodies, indicating the potential for repeated administration. In conclusion, Prime-2-CoV_Beta was safe, well tolerated, and immunogenic, demonstrating potential as a broadly protective vaccine against SARS-CoV-2 and its variants. These promising results support further evaluation of higher doses and additional studies to confirm efficacy and long-term protection. This trial was registered at ClinicalTrials, NCT05389319.

Results of a Phase 2 Multicenter Study Evaluating the Safety and Tolerability of VP-315, an Investigational Therapy for Basal Cell Carcinoma

Introduction VP-315 is an intratumorally injected, chemotherapeutic oncolytic peptide in development as a non-surgical immunotherapeutic agent to be utilized as first line therapy in a primary or neoadjuvant setting for patients with basal cell carcinoma (BCC). Objective In Part 2 of this study, the primary objective was to determine the optimal dosing regimen for VP-315 by exploring the effects of various dosing schemes on the safety and tolerability of VP-315 in a larger population of subjects with biopsy proven BCC. Methods Eighty-two (82) subjects with up to 2 target BCC tumors (total 91 tumors) were treated intratumorally with VP-315 for up to 2 weeks. Cohort 3 was not enrolled based on results from Cohorts 1-2. Each 7-day treatment week was comprised of 2 or 3 consecutive treatment days followed by a no-treatment period of at least 4 days. Dosing scheme: Cohort 1: (n=6) Tumor injected 3 days consecutively (3X/week 4 mg loading dose Day 1 followed by 8 mg dose). Cohort 2: (n=3) Tumor injected 3 days consecutively (3X/week 8 mg dose). Cohort 4: (n=36) Each tumor was injected 2 days consecutively (2X/week 8 mg split dose*). Cohort 5: (n=37) Each tumor was injected 3 days consecutively (3X/week 8 mg split dose*). * Dose split into 2 injections, 30% injected initially; 70% injected 15-30 minutes later. Safety and tolerability were assessed by documenting the occurrence of Treatment Related Adverse Events (TRAEs), including those of special interest, Treatment Related Serious Adverse Events (TRSAEs), discontinuations due to AEs and expected treatment-related cutaneous reactions including tumor necrosis. Results All 82 subjects completed one of the VP-315 treatment regimens for BCC. TRAEs were mostly mild to moderate. AEs included injection site pain (mild 13.4%, moderate 12.2%, severe 1.2%), hypertension (mild 4.9%), hypotension (mild 4.9%), erythema (mild 1.2%, moderate 2.4%), and headache (mild 2.4%). Expected cutaneous reactions were observed. No TRSAEs were reported. Conclusion VP-315 treatment was shown to be safe and well-tolerated when administered once daily 2-3 times per week per tumor for up to 2 weeks using a split dose approach. Given its favorable safety profile, VP-315 warrants continued research as a potential non-surgical immunotherapy for BCC as a first line therapy in a primary or neoadjuvant setting. Sponsored by Verrica Pharmaceuticals Inc.

Abstract C047: AGX101: Preclinical evaluation of a TM4SF1-directed tubulin inhibitor conjugate with ongoing first-in-human trial

Abstract Introduction: TM4SF1 (Transmembrane-4 L-Six-Family-Member-1) is an endothelial marker with critical roles in angiogenesis, as well as a tumor cell antigen that contributes significantly to invasion and metastasis. TM4SF1 is upregulated 20-fold in angiogenic tumor vascular endothelium compared to normal vasculature endothelium and exhibits a unique nuclear internalization pathway. AGX101 is a novel tubulin inhibitor conjugate specifically directed against TM4SF1, delivering a potent maytansinoid payload directly to the nucleus of cells within the tumor microenvironment. Delivery to both the vascular and tumor cell compartments of the tumor results in three mechanisms of action (MoAs): (1) activation of tumor immune surveillance, (2) tumor blood supply deprivation, and (3) direct tumor cell killing. Methods: TM4SF1 expression was assessed across solid tumor samples using immunohistochemistry. Safety and pharmacokinetics of AGX101 were evaluated in non-human primates, with escalating doses to determine the highest non-severely toxic dose (HNSTD). Efficacy studies were also conducted in mouse models, enabling assessment of the minimum effective dose (MED) needed to engage each of the three MoAs. The combination of HNSTD and MED enables calculation of a therapeutic index (TI). Preclinical efficacy studies used either AGX101 (in human tumor xenograft models, to study the tumor cell killing MoA) or AGXB01, a rodent surrogate of AGX101, to study vascular and immune MoAs and all three MoAs in syngeneic mouse cancer models. The potential for synergy with immune checkpoint inhibitors (ICIs) was also investigated. A first-in-human study of AGX101 in patients with advanced solid tumors with the primary objective of safety and dose-limiting toxicities (DLTs) has initiated. Results: TMFS41 is broadly expressed across solid tumors with increasing scoring intensity in higher grade tumors. In non-human primates, AGX101 exhibited a favorable safety profile, being tolerated at relatively high doses and with dose dependent, monitorable, and reversible effects. In preclinical efficacy studies, AGXB01 and AGX101 as monotherapies demonstrated robust efficacy through each of the three MoAs in multiple syngeneic, xenograft, and orthotopic tumor models in mice and rats as well as non-tumor models of angiogenesis. Measured by exposure, TI was large. Additionally, AGXB01 was shown to potentiate the effects of ICIs in syngeneic mouse models (CT26, Renca, and B16-F10), suggesting a potential synergistic approach in cancer therapy. The first dose level of AGX101 monotherapy in humans has cleared without DLTs. Conclusion: AGX101, targeting the TM4SF1 antigen, represents a promising new approach in cancer therapy. The preclinical data suggest that AGX101 could provide a significant therapeutic benefit by novel and differentiated mechanisms of action, namely selectively targeting the tumor vasculature and potentiating immune-based therapies. Further clinical development of AGX101 is ongoing. Citation Format: Ildefonso Ismael Rodriguez Rivera, Meredith S. Pelster, Shou-Ching Jaminet, Paul Jaminet, Glen J. Weiss. AGX101: Preclinical evaluation of a TM4SF1-directed tubulin inhibitor conjugate with ongoing first-in-human trial [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr C047.

Abstract C020: Discovery & characterization of small molecules to enhance Natural Killer cell cytotoxicity against solid tumors

Abstract While adoptive cellular therapies (ACT) such as CAR-T and NK therapy have shown clinical efficacy against hematologic malignancies, their use against solid tumors (such as ovarian or pancreatic cancer) has had limited success to date. In particular, CAR-T therapy for solid cancers has led to severe toxicities, including on-target, off-tumor killing of healthy cells and graft vs. host disease (GVHD) with allogeneic transplant. NK cell therapies, in contrast, have fewer associated toxicities due to specific and innate recognition/killing of cancer cells. This greater safety profile makes NK therapies an attractive treatment option for solid cancers. NK therapies are currently limited by insufficient in vivo tumor clearance, caused largely by their lower cytotoxicity and in vivo expansion compared to CAR-T cells. To address this, we have screened 300,000 small molecule compounds for their ability to enhance NK cytotoxicity against ovarian cancer (OVCAR) cells. Our primary screen identified 11 lead compounds which increase NK killing activity against OVCAR cells >= 10% over baseline (vehicle-treated control). Secondary in vitro assays have confirmed that at least 3 out of 11 lead compounds enhance NK cytotoxicity by at least 10% over baseline. As such, we hypothesize that our lead compounds will increase in vivo NK cytotoxicity and tumor clearance, through mechanisms which might include I) upregulation of NK activating receptors, II) downregulation of NK inhibitory receptors, and/or III) modulation of NK metabolism in the immunosuppressive tumor microenvironment. Immediate future studies include in vivo testing of our lead compounds’ ability to enhance NK cytotoxicity, using immunodeficient mouse models of subcutaneous OVCAR tumors. Moreover, we will utilize 2D and 3D in vitro culture techniques alongside flow cytometry and RNA sequencing to identify how lead compounds impact markers of NK activation and metabolism. This will include expression of activating/inhibitory receptors, exhaustion markers, and key metabolic factors. Finally, we will assess the effect of lead compounds on NK function within an immunosuppressive tumor environment. Our findings will contribute to effective future NK cell therapies for solid tumors. Citation Format: Indrani Das, Olubukola Abiona, Riufu Liu, Grace K. Lee, David N. Wald. Discovery & characterization of small molecules to enhance Natural Killer cell cytotoxicity against solid tumors [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr C020.

Risk Factors for Eye and Orbital Injuries Related to Electric Scooters and Off-Road Vehicles

ABSTRACT Purpose Electric scooters (e-scooters) have rapidly become a mainstream method of transportation in the U.S. but there is consequently limited data on their safety profile. This study evaluates ophthalmic injuries related to e-scooters compared to non-motorized scooters and off-road vehicles (ORV). Methods This retrospective study uses the National Electronic Injury Surveillance System (2014 to 2023). Ocular injury profiles associated with conventional scooters, e-scooters, and off-road vehicles were included. Results E-scooter ocular injuries rose by 1950% between 2014 and 2023. E-scooter riders were 4.3 times more likely to sustain orbital fractures and 2.7 times more likely to be hospitalized than non-motorized scooter riders. ORV and e-scooter riders had comparable injury and hospitalization patterns. Alcohol use and lack of helmet use were significant contributors to injury severity. Conclusions and Relevance Injury patterns and hospitalization rates in e-scooter accidents resemble those of ORV incidents. Findings highlight the need for public health interventions to reduce the burden of e-scooter-related injuries.

Evaluating the drug-drug interactions of SHR4640 on repaglinide and midazolam in healthy subjects

ABSTRACT Background SHR4640, a highly selective URAT1 inhibitor, was evaluated to investigate its inhibitory effects on CYP2C8 and CYP3A4 in vivo clinical trial. This study assessed the pharmacokinetic (PK) impact of SHR4640 when co-administered with the CYP2C8 probe substrate repaglinide and the CYP3A4 probe substrate midazolam. Research design and methods In this single-center, randomized, double-blind, placebo-controlled study, participants were randomly allocated in a 1:1:1 ratio to SHR4640 Group A, SHR4640 Group B, and placebo group and received oral repaglinide, midazolam, SHR4640 or placebo at specific times. The primary endpoints included the main PK parameters of repaglinide and midazolam, both alone and in combination with SHR4640 (AUC0-inf, AUC0-t, and Cmax). Results The increase in the area under the concentration-time curve (AUC) for repaglinide, when co-administered with SHR4640, was less than 1.25-fold, while the AUC for midazolam exhibited a slight increase of 46%. Conclusions SHR4640 exerts a weak inhibitory effect on the AUC of CYP enzyme probe substrates and has minimal potential for drug-drug interactions and presents a favorable safety profile. Clinical trial registration www.clinicaltrials.gov identifier is NCT06196580 (Name: PK Effects of SHR4640 on Repaglinide and Midazolam, and the Impact of SHR4640 on QT Interval).