Oral Selective Inhibitor Research Articles

Fedratinib combined with ropeginterferon alfa-2b in patients with myelofibrosis (FEDORA): study protocol for a multicentre, open-label, Bayesian phase II trial

BackgroundMyelofibrosis (MF) is a clonal haematopoietic disease, with median overall survival for patients with primary MF only 6.5 years. The most frequent gene mutation found in patients is JAK2V617F, causing constitutive activation of the kinase and activation of downstream signalling. Fedratinib is an oral selective JAK2 inhibitor. It has shown activity in MF and is well-tolerated, but combination with other therapies is likely needed to achieve clonal remission. Combining a JAK2 inhibitor with an interferon may be synergistic, as haematopoietic cells are activated from quiescence (a typical kinase resistance mechanism) rendering them more sensitive to inhibition.Ropeginterferon alfa-2b is a next generation pegylated interferon-α-2b with high tolerability and clinical activity in patients with MF, however, evidence of tolerability and activity in combination with fedratinib is lacking in this setting. The aim of the FEDORA trial is to assess tolerability, safety, and activity of fedratinib with ropeginterferon alfa-2b in patients with MF who require treatment to justify further investigation in a phase III trial.MethodsFEDORA is a single arm, multicentre, open-label, Bayesian phase II trial to assess tolerability, safety, and activity of fedratinib with ropeginterferon alfa-2b aiming to recruit 30 patients. Patients with JAK2V617F positive primary or secondary MF, who are aged ≥ 18 years, have intermediate-1 with palpable splenomegaly of > 5cm, intermediate-2, or high-risk disease according to the Dynamic International Prognostic Scoring System (DIPSS), and who require treatment are eligible. The primary outcome is tolerability, whereby the combination is deemed intolerable in a patient if drug-related toxicities in the first four months of treatment lead to: either drug being discontinued; delays in treatment exceeding 28 consecutive days; or death. FEDORA uses a within-patient dose escalation regimen to ensure each patient reaches a personalised dose combination that is acceptable.DiscussionFEDORA is using a Bayesian trial design and aims to provide evidence of the tolerability, safety, and activity of combining fedratinib with ropeginterferon alfa-2b upon which the decision as to whether a phase III trial is warranted will be based.Trial registrationEudraCT number: 2021–004056-42.ISRCTN: 88,102,629.

Effect of Oral Posaconazole on Venetoclax Plasma Concentration and its Efficacy in Patients with Acute Myeloid Leukemia.

BCL-2 was the first gene identified to have antiapoptotic effects, and venetoclax is an oral selective BCL-2 inhibitor, which has great potential in the treatment of patients with acute myeloid leukemia (AML) who are not candidates for intensive therapy. Notably, posaconazole, an oral antifungal drug, is also a strong factor that can affect blood venetoclax concentrations. To the best of our knowledge, the relationship between BCL-2 expression, posaconazole, and venetoclax, as well as their influence on treatment efficacy and the prognosis of patients with AML, has not been reported. In this single-center retrospective study, the relationship between BCL-2 expression and blood venetoclax concentration was analyzed in 35 patients with AML. After that, we explored the differences in curative effect, adverse reactions, and outcomes between patients with different BCL-2 expression levels and patients with different venetoclax concentration levels, respectively. BCL-2 mRNA expression levels were examined by reverse transcription quantitative PCR. Blood venetoclax concentrations were measured using high-performance liquid chromatography- tandem mass spectrometry. The results revealed that among patients with AML, those with lower primary BCL-2 expression had a higher complete remission (CR) rate (p =0.005), overall response (OR) rate (p <0.0001), and progression-free survival time (p =0.04). Posaconazole was revealed to be a strong factor that was able to increase blood venetoclax concentration (p <0.001) and CR rate in the venetoclax plus posaconazole group compared to that in the venetoclax monotherapy group (p =0.002); however, no significant difference was identified in the occurrence of adverse reactions between these groups. Among low and high-blood venetoclax concentration groups, the event-free survival of the former group was significantly higher (p =0.013). Higher levels of BCL-2 expression at initial diagnosis may have adverse effects on the efficacy and prognosis of patients, and higher levels of venetoclax concentration may advance the time of adverse reactions in patients, thus adversely affecting event-free survival (EFS).

P94 REX-7117 is a highly potent and selective oral STAT3 inhibitor that has demonstrated potential efficacy and safety differentiation versus JAK/TYK2 targeting in preclinical models of psoriasis

Abstract Inhibition of key cytokine pathways, including IL-23 and IL-17, has translated into transformative efficacy in plaque psoriasis, psoriatic arthritis and other inflammatory diseases. There is a strong unmet need to develop oral medicines which match the efficacy of biologics. Additionally, current small molecule JAK/TYK2 inhibitors are associated with on-target safety signals, including opportunistic infections and dysregulated haematologic homeostasis (anaemia, thrombocytopenia). Oral selective STAT3 inhibitors represent an opportunity to target psoriatic pathogenesis by inhibiting clinically validated inflammatory mediators, such as IL-23 and IL-6 cytokines. The STAT3 SH2 domain mediates both binding to the cytokine receptor and transcriptional activity, and therefore is an attractive therapeutic target. Recludix has developed an innovative and proprietary SH2 domain platform that has enabled the discovery of a new class of small molecule inhibitors of these previously undruggable protein domains. REX-7117 is the first orally available, reversible, SH2 domain-targeting STAT3 inhibitor. REX-7117 demonstrates low nanomolar potency in biochemical and primary human cellular assays, is highly selective across the SH2 family, including other STAT proteins, and inhibits IL-6 and IL-23 driven Th17 cell function. Unlike JAK1/2 and TYK2 inhibitors, REX-7117 does not impair broader immune responses, such as Th1 cell activity, innate interferon-dependent anti-viral immunity, or growth factor signalling critical for haematologic homeostasis. In dogs and mice, REX-7117 achieves deep, durable, and selective STAT3 inhibition at clinically relevant oral doses and exhibits comparable efficacy to an IL-17 antibody in rodent models of plaque psoriasis. Selective STAT3 inhibition has the potential to combine the efficacy of clinically validated biologics with the convenience of oral administration, while avoiding known safety concerns observed with the broader activity of JAK and TYK2 inhibitors.

Pharmacokinetics of infigratinib and its active metabolites in Chinese patients with advanced gastric cancer harboring FGFR2 gene amplification.

Infigratinib, an FGFR1-3 selective oral tyrosine kinase inhibitor, has shown clinical activity in cancers with FGFR alterations. The pharmacokinetics (PK) of infigratinib and its major metabolites have been characterized in global populations. This study examined the PK profile of infigratinib and its metabolites in Chinese patients. In this phase II, open-label, single-arm study in China, patients with advanced gastric cancer (GC) or gastroesophageal junction adenocarcinoma (GEJ) harboring FGFR2 gene amplification received 125 mg infigratinib orally once daily in a "3 weeks on, 1 week off" schedule for 28-day cycles. Plasma PK parameters were calculated with a non-compartmental model. Data were available from 21 patients (19 GC and two GEJ). After a single dose, peak infigratinib plasma concentration was reached at a median time of 3.1 h, with geometric mean Cmax of 85.9 ng/mL and AUC0-t of 637 h*ng/mL. After 21-day dosing, geometric mean infigratinib Cmax,ss of 204 ng/mL was reached at a median of 4.0 h; geometric mean AUC0-24,ss was 3060 h*ng/mL. The geometric mean Rac,Cmax (%CV) and Rac,AUC0-24 (%CV) of infigratinib was 2.5 (113.8) and 5.1 (138.2), respectively. A steady state of infigratinib was reached after continuous dosing for 15 days. The metabolites accounting for >10% of infigratinib were BHS697 and CQM157. The PK profiles of infigratinib and its metabolites in Chinese patients with GC or GEJ were largely consistent with known PK profiles of infigratinib from global populations.

Worldwide Clinical and Real-World Exposure to Baricitinib

Introduction: Baricitinib (BARI), an oral selective JAK inhibitor, is approved in many geographies for adults with rheumatoid arthritis or alopecia areata and for patients as young as age 2 years with atopic dermatitis or juvenile idiopathic arthritis. It is also approved in the US for hospitalized patients with COVID-19 infection. We report the worldwide clinical trial and real-world exposure to BARI across a range of diseases, ages and racial backgrounds. Methods: Real-world patient exposure estimates were calculated based on total mg sold, average daily dose, and average length of therapy as reported to regulatory agencies through the cumulative timeframe ending Jan. 31, 2024. Clinical trial exposures were based on actual exposures from completed trials through Feb. 13, 2024, and estimates were made for ongoing blinded trials based on the enrolment/randomization schemes Results: In the real-world setting, an estimated 1,836,600 patients have been exposed to the following BARI doses: 1 mg, ~2,000 (0.1%); 2 mg, ~524,900 (28.6%); 4 mg, ~1,309,600 (71.3%). Of these estimated exposures, ~ 57% were for COVID-19 with the remaining for all other indications combined. Across 59 clinical trials (completed and ongoing), an estimated 14,660 subjects (548 healthy volunteers and 14,112 patients) have received BARI since June 2008. Exposures from completed studies include 10,276 patients (62% female), 399 of whom were &lt;18 yrs of age (≤1 month, N=4; 1 month - ≤2 yrs, N=24; &gt;2 - ≤12 yrs, N=111; &gt;12 - ≤18 yrs, N=260), 8820 were &gt;18 to ≤65 yrs, 1027 were &gt;65 yrs, and 30 had age unknown. An additional 467 adolescent and pediatric patients down to the age of 2 have been treated with BARI for atopic dermatitis in an ongoing clinical trial, bringing the total number of patients &lt;18 years of age to 866 across dermatologic, rheumatologic, other autoimmunologic, and acute infectious diseases (excluding alopecia areata for which there is an ongoing pediatric trial). Clinical trial exposures by racial and ethnic background are as follows: Asian, N=2,491; Black, N=450; Caucasian, N=6,237; other, N=496; multiple, N=135; unknown, N=467. Conclusion: There has been extensive real-world exposure to BARI across indications and populations, and BARI is a well-studied molecule in clinical trials, across varied disease states, racial populations and ages. Since average daily dose and length of therapy may vary over time, real-world exposures are only an estimate of total patients receiving BARI. Exposures in clinical trials include patients as young as less than 1 month of age up to patients over the age of 65 years. While these exposures do not indicate efficacy or safety, they provide data to establish the overall profile of the drug and can inform on its performance over time across a variety of populations.

Long-Term Maintenance of Optimal Treatment Targets for Skin and Itch Outcomes With Upadacitinib in Moderate-to-Severe Atopic Dermatitis: 140-Week Results From the Phase 3 Measure Up 1 and 2 Studies

Introduction: Despite undergoing prolonged systemic therapy, many patients with moderate-to-severe atopic dermatitis (AD) do not achieve optimal targets for skin and itch outcomes as defined by Aiming High in Eczema/AD (AHEAD) recommendations (eg, ≥90% improvement from baseline in Eczema Area and Severity Index [EASI 90] and Worst Pruritus Numerical Rating Scale [WP-NRS] score of 0/1 [no/minimal itch]). We evaluated long-term maintenance of optimal treatment targets with upadacitinib, an oral selective JAK inhibitor approved for moderate-to-severe AD in adolescents and adults. Methods: This 140-week interim analysis included adolescents and adults with moderate-to-severe AD who were randomized at baseline to upadacitinib 15 mg (UPA15) or 30 mg (UPA30) in the ongoing, phase 3, double-blind Measure Up 1 and 2 studies. Assessments included the proportion of patients (at the population level) who maintained EASI 90, WP-NRS 0/1, or simultaneous achievement of EASI 90 + WP-NRS 0/1 responses from week 16 (end of the placebo-controlled period) onwards. Data are reported as observed cases with no imputation for missing data. Results: Among patients who achieved EASI 90 at week 16 (UPA15, n=298; UPA30, n=384), EASI 90 was maintained by 79.8% (UPA15) and 83.7% (UPA30) at week 52, 76.7% (UPA15) and 83.0% (UPA30) at week 100, and 74.0% (UPA15) and 84.2% (UPA30) at week 140. Of patients achieving WP-NRS 0/1 at week 16 (UPA15, n=193; UPA30, n=281), WP-NRS 0/1 was maintained by 69.4% (UPA15) and 72.0% (UPA30) at week 52, 65.6% (UPA15) and 68.4% (UPA30) at week 100, and 62.3% (UPA15) and 66.0% (UPA30) at week 140. Of patients simultaneously achieving EASI 90 + WP-NRS 0/1 at week 16 (UPA15, n=156; UPA30, n=243), maintenance was achieved by 68.1% (UPA15) and 70.8% (UPA30) at week 52, 62.7% (UPA15) and 66.5% (UPA30) at week 100, and 58.7% (UPA15) and 64.4% (UPA30) at week 140. Among patients who did not maintain optimal outcomes, most still achieved clinically meaningful responses. Conclusion: Most patients maintained optimal skin and itch outcomes through 140 weeks of upadacitinib treatment, demonstrating its potential to provide sustained long-term disease control in atopic dermatitis.

Pharmacokinetics, Efficacy, and Safety of Upadacitinib in Pediatric Patients With Polyarticular-Course Juvenile Idiopathic Arthritis: An Interim Analysis of an Open-Label, Phase 1 Trial.

This work aimed to evaluate the pharmacokinetics, efficacy, and safety of upadacitinib, an oral selective JAK inhibitor, in pediatric patients with polyarticular-course juvenile idiopathic arthritis (pcJIA). In an open-label, phase 1 study (SELECT-YOUTH), enrolled patients, aged 2 to <18 years with pcJIA, received body weight-based upadacitinib doses using a twice-daily oral solution or once-daily extended-release tablet based on their body weight and ability to swallow tablets. The study included a 7-day pharmacokinetic assessment, followed by a long-term efficacy and safety evaluation for up to 156 weeks, including an additional long-term safety cohort. This interim analysis included available pharmacokinetic and safety data and efficacy data collected through week 48. A total of 57 patients received upadacitinib. The median time to maximum upadacitinib concentration was approximately three hours and one hour for the tablet and oral solution regimens, respectively; the harmonic mean functional half-life was approximately five hours and two hours, respectively. Juvenile idiopathic arthritis American College of Rheumatology 30, 50, 70, 90, and 100 responses at week 12 were 91.8%, 89.8%, 69.4%, 49.0%, and 32.7%, respectively. Efficacy was generally maintained through week 48, and improvement in additional efficacy end points was also observed. At a median exposure duration of 412 days, 52 of 57 patients reported adverse events; of these, 6 experienced serious adverse events. Adverse events were predominately mild to moderate in severity and consistent with the known safety profile of upadacitinib. This interim analysis demonstrates that the bodyweight-based dosing regimen of upadacitinib was well tolerated and efficacious in pediatric patients with pcJIA.

PDE4 Inhibitors and their Potential Combinations for the Treatment of Chronic Obstructive Pulmonary Disease: A Narrative Review

Chronic Obstructive Pulmonary Disease (COPD) is associated with cough, sputum production, and a reduction in lung function, quality of life, and life expectancy. Currently, bronchodilator combinations (β2-agonists and muscarinic receptor antagonists, dual therapy) and bronchodilators combined with inhaled corticosteroids (ICS), triple therapy, are the mainstays for the management of COPD. However, the use of ICS in triple therapy has been shown to increase the risk of pneumonia in some patients. These findings have laid the foundation for developing new therapies that possess both anti-inflammatory and/or bronchodilation properties. Phosphodiesterase-4 (PDE4) inhibitors have been reported as an effective therapeutic strategy for inflammatory conditions, such as asthma and COPD, but their use is limited because of class-related side effects. Efforts have been made to mitigate these side effects by targeting the PDE4B subtype of PDE4, which plays a pivotal role in the anti-inflammatory effects. Unfortunately, no selective oral PDE4B inhibitors have progressed to clinical trials. This has led to the development of inhaled PDE4 inhibitors to minimize systemic exposure and maximize the therapeutic effect. Another approach, the bronchodilation property of PDE3 inhibitors, is combined with anti-inflammatory PDE4 inhibitors to develop dual inhaled PDE4/PDE3 inhibitors. A few of these dual inhibitors have shown positive effects and are in phase 3 studies. The current review provides an overview of various PDE4 inhibitors in the treatment of COPD. The possibility of studying different selective PDE4 inhibitors and dual PDE3/4 inhibitors in combination with currently available treatments as a way forward to increase their therapeutic effectiveness is also emphasized.

A real-world pharmacovigilance study of FDA Adverse Event Reporting System events for pralsetinib.

Pralsetinib, a selective oral inhibitor of rearranged during transfection (RET) fusion proteins and oncogenic RET mutants, has shown significant efficacy in treating RET fusion-positive non-small cell lung cancer and thyroid cancer. However, since pralsetinib was approved in the United States in September 2020, there have been limited reports of post-marketing adverse events (AEs). In this study, we aimed to analyze the AE signals with pralsetinib on the basis of the United States Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) to provide instructions in clinical practice. All AE reports were obtained from the FAERS database from the first quarter (Q3) of 2020 to the second quarter (Q2) of 2024. Various signal quantification techniques were used for analysis, including reporting odds ratios, proportional reporting ratios, Bayesian confidence propagation neural network, and multi-item gamma Poisson shrinker (MGPS)-based empirical Bayesian geometric mean. Out of 8,341,673 case reports in the FAERS database, 1,064 reports of pralsetinib as the "primary suspected (PS)" AEs were recorded, covering 26 system organ classes and 256 preferred terms. Of the reports, 62.5% were from consumers rather than healthcare professionals. The most common systems were general disorders and administration site conditions (n = 704), investigations (n = 516), and gastrointestinal disorders (n = 405). A total of 95 significant disproportionality preferred terms (PTs) conformed to the four algorithms simultaneously. AEs that ranked the top three at the PT level were hypertension (n = 80), asthenia (n = 79), and anemia (n = 65). Of the 95 PTs with significant disproportionation, unexpected significant AEs such as increased blood calcitonin, increased myocardial necrosis marker, and bacterial cystitis were observed, which were not mentioned in the drug's instructions. The median onset time of pralsetinib-associated AEs was 41 days [interquartile range (IQR) 14-86 days]. The majority of the AEs occurred in 30 days (42.86%). Our pharmacovigilance analysis of real-world data from the FEARS database revealed the safety signals and potential risks of pralsetinib usage. These results can provide valuable evidence for further clinical application of pralsetinib and are important in enhancing clinical medication safety.

CTNI-82. BELZUTIFAN TREATMENT OF VHL-ASSOCIATED CENTRAL NERVOUS SYSTEM HEMANGIOBLASTOMA

Abstract Von Hippel-Lindau (VHL) disease is caused by pathogenic variants in the VHL gene. Abnormal function of VHL protein leads to accumulation of HIF-α and the engagement of hypoxia-sensitive genes with oncogenic effects. VHL is associated with tumors in multiple organs. Belzutifan is an oral selective inhibitor of hypoxia-inducible factor 2 alpha. Belzutifan was approved in 2021 as a targeted therapy for VHL-associated CNS hemangioblastomas, renal cell carcinomas, and pancreatic neuroendocrine tumors. Here, we report on our institutional clinical experience with belzutifan for VHL-associated CNS hemangioblastomas. From October 2021 to May 2024, thirteen adults (9 female, 4 male, median age 40) were treated. Median duration of therapy was 24 months. Seven had a partial radiographic response after median of 3 months; one patient had a partial response; 1 patient had progressive disease on belzutifan. Four patients have been taking belzutifan for less than 3 months, and do not have follow-up imaging to assess response. The most common adverse effect was fatigue (7 patients). Four patients experienced anemia and 2 experienced hypoxia. Three patients discontinued belzutifan due to adverse effects. One patient had to take multiple medication pauses, due to seizure and kidney injury, but resumed treatment with dose reduction. Nine patients remain on therapy. Based on this data, belzutifan is often well-tolerated and associated with durable radiographic responses. Toxicity profile among our patients was similar to that encountered in the clinical trial leading to approval of the agent. These findings provide real-world data supporting continued use of belzutifan in this patient population, with an awareness of potential adverse reactions. Future studies should assess continued radiographic response, sex differences, and effects after long-term use.

Longer-term safety and efficacy of baricitinib for atopic dermatitis in pediatric patients 2 to

Background Baricitinib, an oral selective Janus kinase inhibitor, improved clinical signs and symptoms of moderate-to-severe atopic dermatitis (AD) at week 16 in the phase 3 pediatric study BREEZE-AD-PEDS. Objective To assess longer-term efficacy and safety of baricitinib in pediatric patients aged 2 to <18 years. Methods In BREEZE-AD-PEDS long-term extension, responders and partial responders (validated Investigator Global Assessment-Atopic Dermatitis [vIGA-AD®] 0/1/2) at Week 16 remained on double-blind treatment to which they were randomized (placebo, baricitinib [1-mg equivalent, 2-mg equivalent, or 4-mg equivalent); non-responders (vIGA-AD 3 or 4) at Week 16 transitioned to open-label baricitinib 4-mg equivalent. Safety was summarized for all randomized patients who received ≥1 dose of study treatment. Results In total 467 patients received baricitinib for 750.7 patient-years. Proportion of responders/partial responders (at Week 16) who achieved vIGA-AD 0/1 at Week 52 was greater for baricitinib 4-mg equivalent (56.8%) versus all other treatment groups (42.2%, 47.7%, and 39.7% for 2-mg equivalent, 1-mg equivalent, and placebo, respectively). Most treatment-emergent adverse events were mild/moderate in severity. No deaths, pulmonary emboli, deep vein thromboses or arterial thrombotic events, major adverse cardiovascular events, malignancies, tuberculosis events, or gastrointestinal perforations were reported. Conclusions Baricitinib demonstrated sustained long-term efficacy. No new safety signals were identified. Trial Registration ClinicalTrials.gov Identifier: NCT03952559

Combined Targeting of SYK and BCL-2 in Acute Myeloid Leukaemia and Mechanism Study

Acute myeloid leukemia (AML) is a highly heterogeneous haematological malignancy and is the most common acute leukaemia in adults, with a median age of onset of 68 years and a 5-year survival rate of only 30%. Only 60-80% of adult AML patients can achieve complete remission with the first induction chemotherapy, and 50-80% of AML patients ultimately relapse with the “3+7” first-line treatment regimen based on anthracycline and cytarabine (Ara-C), so there is an urgent need to find safer and more effective targeted therapies. There is an urgent need to find safer and more effective targeted therapies. Venetoclax (ABT-199) is an FDA-approved oral selective Bcl-2 inhibitor with limited anti-leukaemia activity as a single agent, and mechanisms of resistance include up-regulation of anti-apoptotic proteins, compensation of multiple metabolic pathways such as OXPHOS glycolysis, and mutations in BCL-2 and BAX.In 2018, the FDA approved the use of Venetoclax in combination with demethylating drugs (azacitidine ( AZA) or low-dose azacitidine AraC (LDAC)) in combination for newly diagnosed AML in older adults aged 75 years and older, and while this combination greatly improves remission rates, most patients relapse within 18 months. It has been suggested that direct or indirect inhibition of oxidative phosphorylation (OXPHOS) may be able to circumvent adaptive resistance of AML to Venetoclax+ AraC combination therapy. Therefore, an ideal candidate therapy in combination with Venetoclax should be able to antagonise its resistance mechanisms from metabolic pathways and down-regulation of MCL-1. Purpose To investigate the efficacy and related mechanisms of co-targeting SYK with BCL-2 for the treatment of acute myeloid leukaemia (AML). Experimental Design AML cell lines and primary patient samples were collected for cell proliferation assays. Firstly, cell activity was detected by MTS colorimetric assay, by Compusyn calculation software, the joint index CI value was calculated, apoptosis was detected by flow cytometry, mitochondrial membrane potential was altered, gene expression was detected by transcriptome sequencing, and the signalling pathways were analysed, followed by apoptosis-related proteins, BCL-2-related proteins by Western Blot, and glucose was detected by metabolism kit. sugar consumption,ATP and lactate content. The in vivo efficacy of the combination of Venetoclax and Entospletinib was assessed using an MV4-11-derived xenograft mouse model. Results SYK is highly expressed in AML and is associated with poor prognosis. ...The combination of Venetoclax and Entospletinib in AML cell lines and AML primary patient cells had significant synergistic growth inhibitory and apoptosis-inducing effects...Venetoclax in combination with Entospletinib down-regulated the expression of anti-apoptotic proteins, MCL-1, and BCL-XL, and down-regulated phosphorylated ERK expression, thereby affecting MCL1 post-translational protein stability rather than transcriptional levels.... Venetoclax in combination with Entospletinib downregulated the expression of anti-apoptotic proteins MCL-1, BCL-XL and phosphorylated ERK, thereby affecting the post-translational protein stability of MCL1, but not the transcriptional level. Conclusions The combination of Venetoclax and Entospletinib had significant synergistic killing effects in both AML cell lines and AML primary patient cells.Venetoclax in combination with Entospletinib exerts synergistic therapeutic effects on AML through down-regulation of ERK phosphorylation affecting the expression of anti-apoptotic proteins MCL-1, BCL-XL and reprogramming of glucose metabolism.

Symptom management in isocitrate dehydrogenase mutant glioma.

According to the 2021 World Health Organization classification of CNS tumors, gliomas harboring a mutation in isocitrate dehydrogenase (mIDH) are considered a distinct disease entity, typically presenting in adult patients before the age of 50 years. Given their multiyear survival, patients with mIDH glioma are affected by tumor and treatment-related symptoms that can have a large impact on the daily life of both patients and their caregivers for an extended period of time. Selective oral inhibitors of mIDH enzymes have recently joined existing anticancer treatments, including resection, radiotherapy, and chemotherapy, as an additional targeted treatment modality. With new treatments that improve progression-free and possibly overall survival, preventing and addressing daily symptoms becomes even more clinically relevant. In this review we discuss the management of the most prevalent symptoms, including tumor-related epilepsy, cognitive dysfunction, mood disorders, and fatigue, in patients with mIDH glioma, and issues regarding patient's health-related quality of life and caregiver needs in the era of mIDH inhibitors. We provide recommendations for practicing healthcare professionals caring for patients who are eligible for treatment with mIDH inhibitors.

Outcomes of down-titration in patients with severe scalp alopecia areata initially treated with baricitinib 4-mg: Week 152 data from BRAVE-AA2

BackgroundBaricitinib, an oral selective Janus kinase inhibitor, is approved to treat adults with severe alopecia areata (AA). ObjectiveTo report the Week 152 efficacy results from the Phase 3 trial BRAVE-AA2 down-titration sub-study. MethodsBRAVE-AA2 enrolled 546 adults with severe AA (Severity of Alopecia Tool [SALT] score ≥50). Baricitinib 4-mg treated patients achieving a clinical response (SALT score ≤20) at Week 52 were rerandomized 1:1 to stay on 4-mg or down-titrate to 2-mg. Last observation carried forward was used to impute missing or censored data. ResultsAt Week 52, 86/234 (36.8%) baricitinib 4-mg treated patients were eligible for down-titration; 44 remained on 4-mg while 42 down-titrated to 2-mg. At Week 152, 39/44 (88.6%) 4-mg treated patients had maintained clinical response, compared to 24/41 (58.5%) down-titrated patients. Among down-titrated patients, loss of treatment benefit was less frequent in those with sustained response and SALT score ≤5 at Week 52. LimitationsMethod and timing of down-titration were pre-specified in the protocol based on Week 52 responder status and not on other clinical factors. ConclusionMore than half of down-titrated patients maintained response. Sustained treatment response and/or near-total regrowth may be associated with a greater likelihood of response maintenance after down-titration.

Effectiveness and safety of upadacitinib in acute severe ulcerative colitis patients from single Chinese IBD Center: a monocentric study

Upadacitinib is an oral new selective JAK1 inhibitor that has been approved for treating adult patients with moderately to severely active ulcerative colitis. However, a growing number of studies are needed on the effectiveness of upadacitinib in the treatment of acute severe ulcerative colitis. This study was mainly aimed to describe the clinical and endoscopic effectiveness of upadacitinib 45 mg in Chinese acute severe ulcerative colitis patients following eight weeks of treatment. In this study, we examined all patients with acute severe ulcerative colitis from Xijing IBD Center, Xi’an, China, with acute severe ulcerative colitis. All patients were initially given oral upadacitinib 45 mg. Clinical indicators, C-reactive protein, and erythrocyte sedimentation rates were collected. Clinical response and clinical remission were assessed using modified Mayo. Endoscopic evaluation was performed carried out using the Mayo Endoscopic Score and Ulcerative colitis endoscopic index of severity score. A total of 14 patients who received upadacitinib were included in the study period. All patients exhibited a clinical response to 45 mg upadacitinib initially. All patients completed the 8-week induction. The clinical remission rate was 28.6% after eight weeks. Two patients revealed endoscopic remission at 14.3%. The pathology improved in 50.0% of patients. The 8-week surgical resection rate was 7.1%, with the 16-week surgical resection rate being 14.3%. Adverse events included herpes simplex virus infection and increased thrombin time. The results of our study support the short-term effectiveness and safety of upadacitinib in acute severe ulcerative colitis, providing new choices for patients’ treatment. However, more extended investigation needs to be performed on the long-term effectiveness and safety.

Ziftomenib in relapsed or refractory acute myeloid leukaemia (KOMET-001): a multicentre, open-label, multi-cohort, phase 1 trial

Ziftomenib (KO-539) is an oral selective menin inhibitor with known preclinical activity in menin-dependent acute myeloid leukaemia models. The primary objective of this study was to determine the recommended phase 2 dose in patients with relapsed or refractory acute myeloid leukaemia based on safety, pharmacokinetics, pharmacodynamics, and preliminary activity. KOMET-001 is a multicentre, open-label, multi-cohort, phase 1/2 clinical trial of ziftomenib in adults with relapsed or refractory acute myeloid leukaemia. Results of the phase 1 study, conducted at 22 hospitals in France, Italy, Spain, and the USA, are presented here and comprise the dose-escalation (phase 1a) and dose-validation and expansion (phase 1b) phases. Eligible patients were aged 18 years or older, had relapsed or refractory acute myeloid leukaemia, and had an Eastern Cooperative Oncology Group performance status of 2 or less. For phase 1a, patients (all molecular subtypes) received ziftomenib (50-1000 mg) orally once daily in 28-day cycles. For phase 1b, patients with NPM1 mutations or with KMT2A rearrangements were randomly assigned (1:1) using third-party interactive response technology to two parallel dose cohorts (200 mg and 600 mg ziftomenib). Primary endpoints were maximum tolerated dose or recommended phase 2 dose in phase 1a, and safety, remission rates, and pharmacokinetics supporting recommended phase 2 dose determination in phase 1b. Analyses were performed in all patients who received at least one dose of ziftomenib (modified intention-to-treat population). Phase 1a/1b is complete. This trial is registered with ClinicalTrials.gov, NCT04067336, and the EU Clinical Trials register, EudraCT 2019-001545-41. From Sept 12, 2019, to Aug 19, 2022, 83 patients received 50-1000 mg ziftomenib (39 [47%] were male and 44 [53%] were female). Median follow-up was 22·3 months (IQR 15·4-30·2). Of 83 patients, the most common grade 3 or worse treatment-emergent adverse events were anaemia (20 [24%]), febrile neutropenia (18 [22%]), pneumonia (16 [19%]), differentiation syndrome (12 [15%]), thrombocytopenia (11 [13%]), and sepsis (ten [12%]). Overall, 68 of 83 patients had serious adverse events, with two reported treatment-related deaths (one differentiation syndrome and one cardiac arrest). Differentiation syndrome rate and severity influenced the decision to halt enrolment of patients with KMT2A rearrangements. In Phase 1b, no responses were reported in patients treated at the 200 mg dose level. At the recommended phase 2 dose of 600 mg, nine (25%) of 36 patients with KMT2A rearrangement or NPM1 mutation had complete remission or complete remission with partial haematologic recovery. Seven (35%) of 20 patients with NPM1 mutation treated at the recommended phase 2 dose had a complete remission. Ziftomenib showed promising clinical activity with manageable toxicity in heavily pretreated patients with relapsed or refractory acute myeloid leukaemia. Phase 2 assessment of ziftomenib combination therapy in the upfront and relapsed or refractory setting is ongoing. Kura Oncology.

Discovery of TYRA-300: First Oral Selective FGFR3 Inhibitor for the Treatment of Urothelial Cancers and Achondroplasia.

Activating FGFR3 alterations have been identified in up to 15-20% of muscle-invasive bladder cancer and metastatic urothelial carcinoma (mUC), and as high as 80% in nonmuscle invasive bladder cancers. FGFR3 germline mutations have also been associated with a variety of skeletal dysplasias. Achondroplasia, the most common form of dwarfism in humans, results from a G380R mutation in FGFR3. The pan-FGFR inhibitor erdafitinib was approved for the treatment of mUC with FGFR3 alterations but is limited due to FGFR isoform off-target toxicities and the development of on-target gatekeeper resistance mutations. TYRA-300 (22) was conceived using a structure-based approach as a potent FGFR3-selective inhibitor to avoid the toxicities associated with inhibition of FGFR1, FGFR2, and FGFR4, and to be agnostic for the FGFR3 gatekeeper mutations. TYRA-300 is being evaluated in a Phase 1 clinical trial in urothelial cancers and solid tumors, with intention to initiate Phase 2 studies in urothelial cancers and achondroplasia.

Abstract P440: Discovery of clinical candidate GSC002219, a highly selective oral CYP11B2 inhibitor for hypertension

Background: Aldosterone is an important mediator of hypertension and its aberration could contribute to heart and kidney diseases. Aldosterone synthase inhibitors (ASI) attenuate the production of aldosterone directly and have been proposed as an alternative to mineralocorticoid receptor antagonists (MRA) for treatment of resistant hypertension and chronic renal disease. GSC002219 is a potent inhibitor of aldosterone synthase (CYP11B2) with high selectivity over the closely related enzyme CYP11B1. The aim of the study was to evaluate the effect of GSC002219 on aldosterone and blood pressure. Methods: The inhibitory effect of GSC002219 against CYP11B2 and CYP11B1 proteins was assessed in human renal leiomyoblastoma cells expressing recombinant human / cynomolgus CYP11B1or CYP11B2 enzymes, respectively. GSC002219 was further evaluated in Synacthen (ACTH) challenged cynomolgus monkey model for its effects against various related key biomarkers including cortisol, aldosterone and precursors. The effects of GSC002219 on systolic blood pressure (SBP) and diastolic blood pressure (DBP) were evaluated in stroke-prone spontaneously hypertensive rat (SHRSP) model. Results: GSC002219 potently inhibits CYP11B2 with an IC 50 of 27nM, while maintains a &gt;150-fold selectivity over CYP11B1. In ACTH challenged cynomolgus monkey model, single oral doses of GSC002219 at 0.03 mg/kg and 0.1 mg/kg could suppress aldosterone production to 80% and 93%, respectively, comparing to vehicle-treated animals without any effect towards cortisol levels. In the rat SHRSP hypertension model, GSC002219 could effectively lower both SBP and DBP. GSC002219 has an excellent in vitro ADME and toxicology profile as well as a balanced physicochemical property. In 14-day rat and monkey toxicology studies, GSC002219 displayed good tolerance, excellent PK profile and a great safety window (&gt;100 fold). Conclusions: Taken together, GSC002219 is a safe and potent inhibitor of CYP11B2 and efficacious in various disease models of hypertension. GSC002219 is under IND-enabling study and may enter the clinical development early 2025.

644 - Effectiveness and safety of upadacitinib in adolescent and adult patients with atopic dermatitis: an interim analysis of week 20-32 data from a real-world multicenter retrospective review

Abstract Introduction While clinical trial data demonstrates the efficacy and safety of upadacitinib (UPA), a selective oral Janus kinase inhibitor (JAKi) for atopic dermatitis (AD), there is still a lack of real-world evidence. Objectives Our study evaluated the real-world effectiveness and safety of UPA for AD at weeks 20-32. Methods We conducted a multicenter retrospective review at three practices in Canada. Effectiveness endpoints evaluated at weeks 20-32 included Investigator Global Assessment (IGA) score of clear or almost clear (IGA 0/1) as well as improvements in Eczema Area and Severity Index (EASI), body surface area (BSA), IGAxBSA, and Dermatology Life Quality Index (DLQI)/Children’s DLQI (CDLQI). Safety was ­determined via incidence of treatment-related adverse events (AEs). Results A total of 131 patients were included in the analysis. Mean age was 44.3 ± 17.5 (range: 12-78) years; 53.4% (70/131) were female. UPA doses were 15 mg (43.5%, 57/131) or 30 mg (56.5%, 74/131) once daily. Previous treatments included: topical therapy (100%, 131/131), phototherapy (29%, 38/131), systemic non-biologic therapy (75.6%, 99/131), and systemic biologic/JAKi therapy (38.9%, 51/131). At weeks 20-32: 85.5% (112/131) of patients achieved IGA 0/1; 84.3% (59/70), 75.7% (53/70), and 62.9% (44/70) of patients achieved EASI improvements of 75% (EASI75), 90% (EASI90), and 100% (EASI100), respectively; mean EASI was reduced from 12.7 to 0.7 (p=0.0001; mean EASI improvement = 88.8%); 94.3% (66/70), 92.9% (65/70), 90% (63/70), and 77.1% (54/70) of patients achieved absolute EASI scores &amp;lt;7, 5, &amp;lt;3, and &amp;lt;1, respectively; mean BSA was reduced from 16.4% to 0.9% (p=0.0001; mean BSA improvement=92.5%); mean IGAxBSA was reduced from 53.5 to 1.6 (p=0.0001; mean IGAxBSA improvement=95.7%); and mean DLQI/CDLQI was reduced from 13 to 1.2 (p=0.0001; mean DLQI/CDLQI improvement=90.5%), with 84.6% (55/65) of patients achieving DLQI/CDLQI 0/1. UPA monotherapy was utilized in 38.9% (51/131) of cases. Common concomitant therapies included topical corticosteroids (56.5%, 74/131), systemic corticosteroids (5.3%, 7/131), and topical calcineurin inhibitors (3.8%, 5/131). Frequent AEs included: acne (18.3%, 24/131), hypertriglyceridemia (18.3%, 24/131), elevated creatine phosphokinase (12.2%, 16/131), herpes simplex (5.3%, 7/131), and transaminitis (5.3%, 7/131). Five patients (3.8%) discontinued UPA due to treatment-related AEs (myalgia/arthralgia [n=2]; gastrointestinal discomfort [n=1]; venous thromboembolism [n=1]; folliculitis [n=1]). No serious infections, tuberculosis, major adverse cardiovascular events, gastrointestinal perforation, or malignancy were observed in 67.4 patient-years of safety follow-up. Conclusions Our real-world study shows that UPA is an effective and safe therapy for AD, with high levels of skin clearance and a favorable safety profile between weeks 20-32. These results indicate that UPA may perform better in the real-world versus clinical trial setting, as compared to the Heads Up and Rising Up studies at week 24, specifically for IGA 0/1 and EASI75/EASI90/EASI100 achievement. This may be explained by less severe baseline disease severity in our study. Limitations of this study include its sample size and retrospective nature.

Phase IB Study of Oral Selinexor in Combination with Rituximab and Platinum Chemotherapy in Patients with Relapsed/Refractory B-Cell Lymphoma-Final Analysis.

Selinexor is an oral selective inhibitor of exportine-1 (XPO1) with efficacy as a single agent in heavily pretreated diffuse large B-cell lymphoma (DLBCL). We conducted a study investigating the combination of selinexor with rituximab and platinum-based chemotherapy in B-cell lymphoma. We conducted a phase 1b, dose-escalation, and expansion trial, which enrolled patients with relapsed or refractory B-cell non-Hodgkin lymphoma. Patients received oral selinexor according to a 3 + 3 design in combination with rituximab and dexamethasone, high-dose cytarabine, oxaliplatine (DHAOX) or gemcitabine, dexamethasone, and cisplatin (GDP) chemotherapy. A total of 39 patients were enrolled, 27 during the escalation phase and 12 during the expansion phase. Most patients had diffuse large B-cell lymphoma (DLBCL; 77%). Group R-DHAOX was prematurely closed to inclusion due to a recommendation from the French drug agency, independent of this trial. A recommended phase 2 dose (RP2D) of selinexor in association with R-GPD was established at 40 mg on days 1, 8, and 15 of each 21-day cycle. In a population of 18 patients treated at this dose of selinexor, the most frequent grade 3-4 adverse events were hematological. With this regimen, seven obtained a complete metabolic response and five a partial response. The median PFS was 5.8 months. Among the patients with R/R B-cell lymphoma, selinexor at a weekly dose of 40 mg with R-GDP is feasible for outpatients, with a generally acceptable safety profile.