Ruxolitinib 1.5% Topical Cream for the Treatment of Pediatric Alopecia Areata.

Alopecia areata (AA) is a common autoimmune disorder. Although its pathogenesis is not fully understood, AA involves CD8 T cell-mediated destruction of the hair follicle. Several treatment options exist; however, there is minimal evidence in the pediatric population. Currently, there are no curative treatments for AA. The literature suggests that Janus kinase (JAK) inhibitors may be an effective treat-ment for AA, but evidence in pediatric patients is limited. Here, we report a case of severe pediatric AA treated with topical ruxolitinib, a JAK inhibitor. J Drugs Dermatol. 2024;23(5):378-379. doi:10.36849/JDD.7782.

QbD Enabled Development and Evaluation of Pazopanib Loaded Nanoliposomes for PDAC Treatment.

Pancreatic ductal adenocarcinoma (PDAC) is one of the highly fatal types of cancer with high mortality/incidence. Considering the crucial role of vascular endothelial growth factor (VEGF) in PDAC progression, its inhibition can be a viable strategy for the treatment. Pazopanib, a second-generation VEGF inhibitor, is approved for the treatment of various oncological conditions. However, due to associated limitations like low oral bioavailability (14-39%), high inter/intra-subject variability, stability issues, etc., high doses (800 mg) are required, which further lead to non-specific toxicities and also contribute toward cancer resistance. Thus, to overcome these challenges, pazopanib-loaded PEGylated nanoliposomes were developed and evaluated against pancreatic cancer cell lines. The nanoliposomes were prepared by thin-film hydration method, followed by characterization and stability studies. This QbD-enabled process design successfully led to the development of a suitable pazopanib liposomal formulation with desirable properties. The % entrapment of PZP-loaded non-PEGylated and PEGylated nanoliposomes was found to be 75.2% and 84.9%, respectively, whereas their particle size was found to be 129.7 nm and 182.0 nm, respectively. The developed liposomal formulations exhibited a prolonged release and showed desirable physicochemical properties. Furthermore, these liposomal formulations were also assessed for in vitro cell lines, such as cell cytotoxicity assay and cell uptake. These studies confirm the effectiveness of developed liposomal formulations against pancreatic cancer cell lines. The outcomes of this work provide encouraging results and a way forward to thoroughly investigate its potential for PDAC treatment.

Bioequivalence and the food effect of macitentan/tadalafil 10/20 fixed-dose combination tablets versus the use of single-component tablets in healthy subjects.

The primary aim was to demonstrate bioequivalence between the 10/20 mg fixed-dose combination (FDC) of macitentan/tadalafil in a single tablet and the free combination of both drugs, and to evaluate the food effect on the 10/20 mg FDC in healthy participants. In this single-center, randomized, open-label, 3-way crossover, single-dose Phase 1 study in healthy adult participants, macitentan/tadalafil was administered as a 10/20 mg FDC formulation and compared with the free combination of macitentan and tadalafil. The food effect on the FDC was also evaluated. Pharmacokinetic sampling (216 h) was conducted. The 90% confidence intervals (CIs) for the geometric mean ratios of maximum observed plasma analyte concentration (Cmax) and area under the plasma analyte concentration-time curves (AUCs) for Treatment A (FDC, fasted) versus C (free combination, fasted) were within bioequivalence limits demonstrating that the FDC formulation can be considered bioequivalent to the free combination. The 90% CIs for the geometric mean ratios of Cmax and AUC for Treatment B (FDC, fed) versus A (FDC, fasted) were contained within bioequivalence limits demonstrating that there was no food effect. The administration of the 10/20 mg FDC was generally safe and well tolerated in healthy participants. This study demonstrated bioequivalence between the FDC of macitentan/tadalafil (10/20 mg) in a single tablet and the free combination of both drugs in healthy participants, and that the FDC can be taken without regard to food, similarly to the individual components. The FDC was generally safe and well tolerated.

Enabling superior drug loading in lipid-based formulations with lipophilic salts for a brick dust molecule: Exploration of lipophilic counterions and in vitro-in vivo evaluation.

Lipid-based formulations (LbFs) are an extensively used approach for oral delivery of poorly soluble drug compounds in the form of lipid suspension and lipid solution. However, the high target dose and inadequate lipid solubility limit the potential of brick dust molecules to be formulated as LbFs. Thus, the complexation of such molecules with a lipophilic counterion can be a plausible approach to improve the solubility in lipid-based solutions via reducing drug crystallinity and polar surface area. The study aimed to enhance drug loading in lipid solution for Nilotinib (Nil) through complexation or salt formation with different lipophilic counterions. We synthesized different lipophilic salts/ complexes via metathesis reactions and confirmed their formation by 1H NMR and FTIR. Docusate-based lipophilic salt showed improved solubility in medium-chain triglycerides (∼7 to 7.5-fold) and long-chain triglycerides (∼30 to 35-fold) based lipids compared to unformulated crystalline Nil. The increased lipid solubility could be attributed to the reduction in drug crystallinity which was further confirmed by the PXRD and DSC. Prototype LbFs were prepared to evaluate drug loading and their physicochemical characteristics. The findings suggested that structural features of counterion including chain length and lipophilicity affect the drug loading in LbF. In addition, physical stability testing of formulations was performed, inferring that aliphatic sulfate-based LbFs were stable with no sign of drug precipitation or salt disproportionation. An in vitro lipolysis-permeation study revealed that the primary driver of absorptive flux is the solubilization of the drug and reduced amount of lipid. Further, the in vivo characterization was conducted to measure the influence of increased drug load on oral bioavailability. Overall, the results revealed enhanced absorption of lipophilic salt-based LbF over unformulated crystalline Nil and conventional LbF (drug load equivalent to equilibrium solubility) which supports the idea that lipophilic salt-based LbF enhances drug loading, and supersaturation-mediated drug solubilization, unlocking the full potential of LbF.

Successful treatment with tofacitinib for anti-melanoma differentiation-associated gene 5 antibody-positive juvenile dermatomyositis: case reports and review of the literature.

Although the clinical efficacy of tofacitinib has been reported in adult patients with anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive (Ab+) dermatomyositis, data on its use in refractory juvenile dermatomyositis (JDM) are scarce. We describe two female Japanese patients with anti-MDA5 Ab + JDM and rapidly progressive interstitial lung disease who achieved remission by adding tofacitinib to existing immunosuppressive drugs and present a literature review. While both patients received various immunosuppressive or anti-inflammatory treatments for induction therapy, remission could not be achieved. Subsequently, tofacitinib was administered to reduce the Krebs von den Lungen-6 level 5 months after diagnosis in one patient; the other patient received tofacitinib 4 months after diagnosis to reduce ferritin levels and skin manifestations. Subsequently, both patients achieved remission, and prednisolone was withdrawn. Tofacitinib reduced the interferon signature associated with dermatomyositis/JDM disease progression and exerted a therapeutic effect on dermatomyositis/JDM. We found six published cases from five articles of tofacitinib for refractory anti-MDA5 Ab + JDM. Except for one case of herpes simplex meningitis, the other cases, including ours, had improved disease activity without severe adverse events, and steroids and immunosuppressive medicines could be tapered. Tofacitinib could be considered an available therapy for refractory anti-MDA5 Ab + JDM.

Nanomodulators targeting endothelial WNT and pericytes to reversibly open the blood-tumor barrier for boosted brain tumor therapy.

The blood-brain barrier (BBB)/blood-tumor barrier (BTB) impedes brain entry of most brain-targeted drugs, whether they are water-soluble or hydrophobic. Endothelial WNT signaling and neoplastic pericytes maintain BTB low permeability by regulating tight junctions. Here, we proposed nitazoxanide (NTZ) and ibrutinib (IBR) co-loaded ICAM-1-targeting nanoparticles (NI@I-NPs) to disrupt the BTB in a time-dependent, reversible, and size-selective manner by targeting specific ICAM-1, inactivating WNT signaling and depleting pericytes in tumor-associated blood vessels in breast cancer brain metastases. At the optimal NTZ/IBR mass ratio (1:2), BTB opening reached the optimum effect at 48-72 h without any sign of intracranial edema and cognitive impairment. The combination of NI@I-NPs and chemotherapeutic drugs (doxorubicin and etoposide) extended the median survival of mice with breast cancer brain metastases. Targeting BTB endothelial WNT signaling and tumor pericytes via NI@I-NPs could open the BTB to improve chemotherapeutic efficiency against brain metastases.

Incidence of pleural effusion with dasatinib and the effect of switching therapy to a different TKI in patients with chronic phase CML.

Dasatinib is one of the second generation tyrosine kinase inhibitors (TKI) which is approved for the treatment of patients with chronic phase CML (CP-CML) both in the front line and in the second line setting. Pleural effusion (PE) is a unique toxicity associated with dasatinib use. Our aim was to study the incidence of pleural effusion in our cohort of patients who were treated with dasatinib for CP-CML and the safety upon TKI switch. A total of 390 patients were treated with dasatinib during their course of treatment for CP-CML. A total of 69 patients (17.6%) developed any grade of PE. About 33 (48%) patients developed CTCAE grade 2 PE, 34 (49%) grade 3 and only 1 patient developed grade 4 PE. Recurrence of PE was observed in 34 (49%) patients. While only 12 patients (17.3%) continued using dasatinib after development of PE, dasatinib was discontinued in the other 57 patients. Therapy was switched to bosutinib in 13 patients out of which 6 (46%) patients re-developed PE. While only 12.5% patients developed re-accumulation of pleural fluid in patients switched to imatinib, none of the patients switched to nilotinib re-developed PE. A change in TKI to bosutinib was associated with a 46% risk of recurrence of PE in patients who develop PE on dasatinib for the treatment of CP-CML. The incidence of recurrent PE was markedly lower in patient switched to imatinib or nilotinib.

Tofacitinib Treatment for Pretibial Myxedema.

This case report describes tofacitinib treatment for 2 patients with pretibial myxedema.

Comparative Effectiveness of Tofacitinib and Adalimumab in Axial Spondyloarthritis: A Real-World Clinical Context Multicenter Study.

INTRODUCTION: Tofacitinib, an oral Janus kinase inhibitor, is a putative choice in the treatment of axial spondyloarthritis (AxSpA). The objective of this study was to compare the effectiveness and tolerability of tofacitinib with adalimumab, in AxSpA, in a real-world clinical setting. METHODS: In this multicentric medical records review study, adult patients with active AxSpA treated with either tofacitinib 5 mg twice daily or adalimumab 40 mg subcutaneously fortnightly were recruited. Effectiveness was measured with Ankylosing Spondylitis Disease Activity Score (ASDAS) and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). Drug-cost analysis was calculated with Incremental Cost-Effectiveness Ratio (ICER drug ). RESULTS: Among the 266 patients, 135 were treated with tofacitinib and 131 with adalimumab (follow-up: 6.5 ± 1.6 months). Mean improvement of BASDAI (3.39 ± 0.09 vs. 3.14 ± 1.16, respectively) and that of ASDAS (1.78 ± 0.68 vs. 2.07 ± 2.08, respectively) were comparable between the adalimumab and tofacitinib groups. A higher proportion of patients achieved BASDAI50 response in the second (49.5% vs. 31.6%) and fourth month (83.9% vs. 62.8%) and ASDAS low disease activity in the fourth month (71.6% vs. 47.9%) in the adalimumab group. All disease activity measurements were similar by the sixth month in both groups. A higher proportion of patients in the tofacitinib group than in the adalimumab group required change in therapy (14.8% vs. 7.6%, respectively). ICER drug for adalimumab compared with tofacitinib was US $188.8 per patient in the adalimumab group for each person-month with BASDAI <4. CONCLUSIONS: Tofacitinib showed comparable effectiveness with adalimumab in patients with AxSpA at the sixth month, despite lesser response in the initial months, with favorable ICER drug .

Assessment of the Effects of Abrocitinib on the Pharmacokinetics of Probe Substrates of Cytochrome P450 1A2, 2B6 and 2C19 Enzymes and Hormonal Oral Contraceptives in Healthy Individuals.

BACKGROUND AND OBJECTIVE: Abrocitinib is an oral small-molecule Janus kinase (JAK)-1 inhibitor approved for the treatment of moderate-to-severe atopic dermatitis. In vitro studies indicated that abrocitinib is a weak time-dependent inhibitor of cytochrome P450 (CYP) 2C19/3A and a weak inducer of CYP1A2/2B6/2C19/3A. To assess the potential effect of abrocitinib on concomitant medications, drug-drug interaction (DDI) studies were conducted for abrocitinib with sensitive probe substrates of these CYP enzymes. The impact of abrocitinib on hormonal oral contraceptives (ethinyl estradiol and levonorgestrel), as substrates of CYP3A and important concomitant medications for female patients, was also evaluated. METHODS: Three Phase 1 DDI studies were performed to assess the impact of abrocitinib 200 mg once daily (QD) on the probe substrates of: (1) 1A2 (caffeine), 2B6 (efavirenz) and 2C19 (omeprazole) in a cocktail study; (2) 3A (midazolam); and (3) 3A (oral contraceptives). RESULTS: After multiple doses of abrocitinib 200 mg QD, there is a lack of effect on the pharmacokinetics of midazolam, efavirenz and contraceptives. Abrocitinib increased the area under the concentration time curve from 0 to infinity (AUCinf) and the maximum concentration (Cmax) of omeprazole by approximately 189 and 134%, respectively. Abrocitinib increased the AUCinf of caffeine by 40% with lack of effect on Cmax. CONCLUSIONS: Based on the study results, abrocitinib is a moderate inhibitor of CYP2C19. Caution should be exercised when using abrocitinib concomitantly with narrow therapeutic index medicines that are primarily metabolized by CYP2C19 enzyme. Abrocitinib is a mild inhibitor of CYP1A2; however, the impact is not clinically relevant, and no general dose adjustment is recommended for CYP1A2 substrates. Abrocitinib does not inhibit CYP3A or induce CYP1A2/2B6/2C19/3A and does not affect the pharmacokinetics of contraceptives. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov registration IDs: NCT03647670, NCT05067439, NCT03662516.

Brigatinib combined with cetuximab in the fifth-line treatment of non-small cell lung cancer with EGFR p.C797S mutation in critically ill patients: a report of two cases and literature review.

For critically ill patients with non-small cell lung cancer (NSCLC) in need of life-saving treatment, there is currently no reported evidence regarding the use of medication specifically targeting epidermal growth factor receptor ( EGFR ) p.C797S mutation, which is known to cause resistance to third-generation tyrosine kinase inhibitors (TKIs). Our report aims to investigate and explore treatment strategies to overcome resistance associated with EGFR p.C797S mutation in order to provide potential therapeutic options for these patients. Here, we reported two cases with NSCLC who initially harbored an EGFR -sensitive mutation and were both treated with osimertinib, a third-generation TKI. Next-generation sequencing tests conducted prior to the initiation of fifth-line therapy in critically ill patients revealed the presence of EGFR p.C797S mutations in both patients, suggesting acquired resistance. In the course of fifth-line therapy, the administration of a combination of brigatinib and cetuximab proved vital in saving critically ill patients, moderately extending their overall survival period. Our findings suggested that a combined regimen of brigatinib and cetuximab could serve as a potentially life-saving therapeutic strategy for critically ill patients with NSCLC, particularly those demonstrating EGFR p.C797S-mediated resistance. Further studies, however, are required to validate and expand upon these promising findings.

Riociguat in patients with sickle cell disease and hypertension or proteinuria (STERIO-SCD): a randomised, double-blind, placebo controlled, phase 1-2 trial.

BACKGROUND: Although nitric oxide based therapeutics have been shown in preclinical models to reduce vaso-occlusive events and improve cardiovascular function, a clinical trial of a phosphodiesterase 5 inhibitor increased rates of admission to hospital for pain. We aimed to examine if riociguat, a direct stimulator of the nitric oxide receptor soluble guanylate cyclase, causes similar increases in vaso-occlusive events. METHODS: This was a phase 1-2, randomised, double blind, placebo-controlled trial. Eligible patients were 18 years or older, had confirmed sickle cell disease documented by haemoglobin electrophoresis or HPLC fractionation (haemoglobin SS, SC, Sß-thalassemia, SD, or SO-Arab), and stage 1 hypertension or proteinuria. Participants were randomly assigned 1:1 to receive either riociguat or matching placebo via a web-based system to maintain allocation concealment. Both treatments were administered orally starting at 1·0 mg three times a day up to 2·5 mg three times a day (highest tolerated dose) for 12 weeks. Dose escalation by 0·5 mg was considered every 2 weeks if systolic blood pressure was greater than 95 mm Hg and the participant had no signs of hypotension; otherwise, the last dose was maintained. The primary outcome was the proportion of participants who had at least one adjudicated treatment-emergent serious adverse event. The analysis was performed by the intention-to-treat. This trial is registered with ClinicalTrials.gov (NCT02633397) and was completed. FINDINGS: Between April 11, 2017, and Dec 31, 2021, 165 participants were screened and consented to be enrolled into the study. Of these, 130 participants were randomly assigned to either riociguat (n=66) or placebo (n=64). The proportion of participants with at least one treatment-emergent serious adverse event was 22·7% (n=15) in the riociguat group and 31·3% (n=20) in the placebo group (difference -8·5% [90% CI -21·4 to 4·5]; p=0·19). A similar pattern emerged in other key safety outcomes, sickle cell related vaso-occlusive events (16·7 [n=11] vs 21·9% [n=14]; difference -5·2% [-17·2 to 6·5]; p=0·42), mean pain severity (3·18 vs 3·32; adjusted mean difference -0·14 [-0·70 to 0·42]; p=0·69), and pain interference (3·15 vs 3·12; 0·04 [-0·62 to 0·69]; p=0·93) at 12 weeks were similar between groups. Regarding the key clinical efficacy endpoints, participants taking riociguat had a blood pressure of -8·20 mm Hg (-10·48 to -5·91) compared with -1·24 (-3·58 to 1·10) in those taking placebo (-6·96 mm Hg (90% CI -10·22 to -3·69; p<0·001). INTERPRETATION: Riociguat was safe and had a significant haemodynamic effect on systemic blood pressure. The results of this study provide measures of effect and variability that will inform power calculations for future trials. FUNDING: Bayer Pharmaceuticals.

Real-world characteristics and use patterns of patients treated with vericiguat: A nationwide longitudinal cohort study in Germany.

PURPOSE: Vericiguat reduced clinical endpoints in patients experiencing worsening heart failure in clinical trials, but its implementation outside trials is unclear. METHODS: This retrospective analysis of longitudinally collected data was based on the IQVIA™ LRx database, which includes ~ 80% of the prescriptions of the 73 million people covered by the German statutory health insurance. RESULTS: Between September 2021 and December 2022, vericiguat was initiated in 2916 adult patients. Their mean age was 73 ± 13 years and 28% were women. While approximately 70% were uptitrated beyond 2.5 mg, only 36% reached 10 mg. Median time to up-titration from 2.5 mg to 5 mg was 17 (quartiles: 11-33) days, and from 2.5 to 10 mg 37 (25-64) days, respectively. In 87% of the patients, adherence to vericiguat was high as indicated by a medication possession ratio of  ≥ 80%, and 67% of the patients persistently used vericiguat during the first year. Women and older patients reached the maximal dose of 10 mg vericiguat less often and received other substance classes of guideline-recommended therapy (GDMT) less frequently. The proportion of patients receiving four pillars of GDMT increased from 29% before vericiguat initiation to 44% afterwards. CONCLUSION: In a real-world setting, despite higher age than in clinical trials, adherence and persistence of vericiguat appeared satisfactory across age categories. Initiation of vericiguat was associated with intensification of concomitant GDMT. Nevertheless, barriers to vericiguat up-titration and implementation of other GDMT, applying in particular to women and elderly patients, need to be investigated further.

Safety and efficacy of zandelisib plus zanubrutinib in previously treated follicular and mantle cell lymphomas.

The combination of the phosphatidylinositol 3-kinase delta (PI3Kδ) inhibitor zandelisib with the Bruton's tyrosine kinase (BTK) inhibitor zanubrutinib was hypothesized to be synergistic and prevent resistance to single-agent therapy. This phase 1 study (NCT02914938) included a dose-finding stage in patients with relapsed/refractory (R/R) B-cell malignancies (n = 20) and disease-specific expansion cohorts in follicular lymphoma (FL; n = 31) or mantle cell lymphoma (MCL; n = 19). The recommended phase 2 dose was zandelisib 60 mg on Days 1-7 plus zanubrutinib 80 mg twice daily continuously in 28-day cycle. In the total population, the most common adverse events (AEs; all grades/grade 3-4) were neutropenia (35%/24%), diarrhoea (33%/2%), thrombocytopenia (32%/8%), anaemia (27%/8%), increased creatinine (25%/0%), contusion (21%/0%), fatigue (21%/2%), nausea (21%/2%) and increased aspartate aminotransferase (24%/6%). Three patients discontinued due to AEs. The overall response rate was 87% (complete response [CR] = 33%) for FL and 74% (CR = 47%) for MCL. The median duration of response and progression-free survival (PFS) were not reached in either group. The estimated 1-year PFS was 72.3% (95% confidence interval [CI], 51.9-85.1) for FL and 56.3% (95% CI, 28.9-76.7) for MCL (median follow-up: 16.5 and 10.9 months respectively). Zandelisib plus zanubrutinib was associated with high response rates and no increased toxicity compared to either agent alone.

Diuretic use and outcomes in patients with heart failure with reduced ejection fraction: Insights from the VICTORIA trial.

AIMS: In VICTORIA, vericiguat compared with placebo reduced the risk of cardiovascular death (CVD) and heart failure hospitalization (HFH) in patients enrolled after a worsening heart failure (WHF) event. We examined clinical outcomes and efficacy of vericiguat as it relates to background use of loop diuretics in patients with WHF. METHODS AND RESULTS: We calculated the total daily loop diuretic dose equivalent to furosemide dosing at randomization and categorized these as: no loop diuretic, 1-39, 41-80, 40, and >80 mg total daily dose (TDD). The primary composite outcome of CVD/HFH and its components were evaluated based on TDD loop diuretic and expressed as adjusted hazard ratios with 95% confidence intervals. Post-randomization rates of change in TDD were also examined. Of 4974 patients (98% of the trial) with diuretic dose information available at randomization, 540 (10.8%) were on no loop diuretic, 647 (13.0%) were on 1-39, 1633 (32.8%) were on 40, 1185 (23.8%) were on 41-80, and 969 (19.4%) were on >80 mg TDD. Patients with higher TDD had a higher rate of primary and secondary clinical outcomes. There were no significant interactions with TDD at randomization and efficacy of vericiguat versus placebo for any outcome (all pinteraction > 0.5). Post-randomization diuretic dose changes for vericiguat and placebo showed similar rates of up-titration (19.6 and 20.2/100 person-years), down-titration (16.8 and 18.1/100 person-years), and stopping diuretics (22.9 and 24.2/100 person-years). CONCLUSIONS: Loop diuretic TDD at randomization was independently associated with worse outcomes in this high-risk population. The efficacy of vericiguat was consistent across the range of diuretic doses.

The effect of concomitant beta-blocker use on survival in patients with metastatic renal cell carcinoma treated with a vascular endothelial growth factor receptor inhibitors in the first line.

PURPOSE: Vascular endothelial growth factor (VEGF) inhibition is one of the cornerstones of treatment in the treatment of metastatic renal cell carcinoma (mRCC). Since RCC is a disease of advanced age and hypertension as a side effect of VEGF receptor inhibitors, beta-blocker use is common in these patients. We aimed to compare the treatment efficacy and survival results in case of concomitant use of these two drugs due to the inhibition of VEGF in beta-blockers. METHODS: A total of 121 patients with a diagnosis of mRCC who used sunitinib or pazopanib in first-line therapy were included in the study. These patients were divided into two groups as those using concomitant beta-blockers and those not using them. RESULT: The median overall survival (mOS) of the patient using sunitinib or pazopanib and concomitant beta-blocker was 47 (95% CI 29.0-65.0) months, and the mOS of those not using concomitant beta-blocker was 18 (95% CI 8.9-27.1) months (p < 0.001). The median progression-free survival (mPFS) of the patients using sunitinib or pazopanib and concomitant beta-blocker was 20.4 (95% CI 4.5-40.1) months, and the mPFS of those not using it was 11.4 (95% CI 5.9-16.9) months (p = 0.042). Concomitant beta-blocker use was found to be a good prognostic factor for OS in the multivariate analysis (p = 0.029). In the multivariate analysis, concomitant beta-blocker use had a trend towards statistical significance for PFS (p = 0.062). CONCLUSION: Concomitant use of betablockers with sunitinib or pazopanib is associated with longer overall survial and progression free survival.

Safety and pharmacokinetics of ONC201 (dordaviprone) administered two consecutive days per week in pediatric patients with H3 K27M-mutant glioma.

BACKGROUND: This study evaluated the safety and pharmacokinetics (PK) of oral ONC201 administered twice-weekly on consecutive days (D1D2) in pediatric patients with newly diagnosed DIPG and/or recurrent/refractory H3 K27M glioma. METHODS: This phase 1 dose-escalation and expansion study included pediatric patients with H3 K27M-mutant glioma and/or DIPG following ≥1 line of therapy (NCT03416530). ONC201 was administered D1D2 at 3 dose levels (DLs; -1, 1, and 2). The actual administered dose within DLs was dependent on weight. Safety was assessed in all DLs; PK analysis was conducted in DL2. Patients receiving once-weekly ONC201 (D1) served as a PK comparator. RESULTS: Twelve patients received D1D2 ONC201 (DL1, n = 3; DL1, n = 3; DL2, n = 6); no dose-limiting toxicities or grade ≥3 treatment-related adverse events occurred. PK analyses at DL2 (D1-250 mg, n = 3; D1-625 mg, n = 3; D1D2-250 mg, n = 2; D1D2-625 mg, n = 2) demonstrated variability in Cmax, AUC0-24, and AUC0-48, with comparable exposures across weight groups. No accumulation occurred with D1D2 dosing; the majority of ONC201 cleared before administration of the second dose. Cmax was variable between groups but did not appear to increase with D1D2 dosing. AUC0-48 was greater with D1D2 than once-weekly. CONCLUSIONS: ONC201 given D1D2 was well tolerated at all DLs and associated with greater AUC0-48.

Managing Risks with Newer Oral Small Molecules in Patients with Inflammatory Bowel Diseases.

PURPOSE OF REVIEW: Treatment of Inflammatory Bowel Diseases (IBD) is challenging; thus, the need for newer therapeutic options with an oral route of administration has led to the development of novel small molecules drugs (SMDs). We aim to highlight the most common Adverse events (AEs) associated with SMDs and recommendations on monitoring for AEs before and during treatment. RECENT FINDINGS: SMDs, such as Tofacitinib, a JAK inhibitor, have been associated with laboratory abnormalities, infections, and risk of thromboembolic events. Therefore, oral agents with greater selectivity in JAK inhibition, such as tofacitinib and upadacitinib, were later developed. Ozanimod and etrasimod, S1PR agonists, require closer safety profile monitoring by clinicians. Multiple therapies have been recently developed with variable efficacy. However, they have been associated with AEs, and some require close monitoring prior to and during therapy. Clinicians should highlight these adverse events to patients while reassuring the safety profile of these novel SMDs for IBD is favorable.