Favorable Safety Profile Research Articles

Momelotinib in myelofibrosis.

Myelofibrosis (MF) is a hematologic disease characterized by bone marrow fibrosis, cytopenias, splenomegaly, and constitutional symptoms. Recent years have seen the emergence of novel therapeutic agents, notably ruxolitinib and fedratinib, which target the Janus kinases (JAK) pathway. However, their myelosuppressive effect coupled with the persistence, and even worsening anemia remains a significant challenge, leading usually to treatment discontinuation. This review focuses on Momelotinib (MMB), a unique JAK inhibitor that has shown promise in MF treatment, particularly in improving anemia. MMB inhibits type 1 kinase activin A receptor or activin receptor-like kinase-2 (ACVR1/ALK2), with consequent rebalancing of the SMAD pathways and reduced transcription of hepcidin. Moreover, it seems that MMB could reduce the serum levels of several inflammatory cytokines responsible for anemia. Clinical trials have demonstrated MMB's efficacy in reducing spleen size, alleviating symptoms, and improving anemia, with a favorable safety profile compared to other JAK inhibitors, both in treatment-naïve and in pre-treated patients. Due to its mechanism of action, MMB represents a valuable therapeutic option in MF, addressing the clinical challenge of anemia and potentially improving outcomes for patients with hematologic malignancies. Ongoing research explores MMB's potential in acute myeloid leukemia and combination therapies.

Laser interstitial thermal therapy for recurrent glioblastomas: a systematic review and meta-analysis.

We aim to investigate the efficacy and safety of laser interstitial thermal therapy (LITT) in treating recurrent glioblastomas (rGBMs). A comprehensive search was conducted in four databases to identify studies published between January 2001 and June 2022 that reported prognosis information of rGBM patients treated with LITT as the primary therapy. The primary outcomes of interest were progression-free survival (PFS) and overall survival (OS) at 6 and 12 months after LITT intervention. Adverse events and complications were also evaluated. Eight eligible non-comparative studies comprising 128 patients were included in the analysis. Seven studies involving 120 patients provided data for the analysis of PFS. The pooled PFS rate at 6 months after LITT was 25% (95% CI 15-37%, I2 = 53%), and at 12 months, it was 9% (95% CI 4-15%, I2 = 24%). OS analysis was performed on 54 patients from six studies, with an OS rate of 92% (95% CI 84-100%, I2 = 0%) at 6 months and 42% (95% CI 13-73%, I2 = 67%) at 12 months after LITT. LITT demonstrates a favorable safety profile with low complication rates and promising tumor control and overall survival rates in patients with rGBMs. Tumor volume and performance status are important factors that may influence the effectiveness of LITT in selected patients. Additionally, the combination of LITT with immune-based therapy holds promise. Further well-designed clinical trials are needed to expand the application of LITT in glioma treatment.

Unveiling the Potential of Ent-Kaurane Diterpenoids: Multifaceted Natural Products for Drug Discovery

Natural products hold immense potential for drug discovery, yet many remain unexplored in vast libraries and databases. In an attempt to fill this gap and meet the growing demand for effective drugs, this study delves into the promising world of ent-kaurane diterpenoids, a class of natural products with huge therapeutic potential. With a dataset of 570 ent-kaurane diterpenoids obtained from the literature, we conducted an in silico analysis, evaluating their physicochemical, pharmacokinetic, and toxicological properties with a focus on their therapeutic implications. Notably, these natural compounds exhibit drug-like properties, aligning closely with those of FDA-approved drugs, indicating a high potential for drug development. The ranges of the physicochemical parameters were as follows: molecular weights—288.47 to 626.82 g/mol; number of heavy atoms—21 to 44; the number of hydrogen bond donors and acceptors—0 to 8 and 1 to 11, respectively; the number of rotatable bonds—0 to 11; fraction Csp3—0.65 to 1; and TPSA—20.23 to 189.53 Ų. Additionally, the majority of these molecules display favorable safety profiles, with only 0.70%, 1.40%, 0.70%, and 46.49% exhibiting mutagenic, tumorigenic, reproduction-enhancing, and irritant properties, respectively. Importantly, ent-kaurane diterpenoids exhibit promising biopharmaceutical properties. Their average lipophilicity is optimal for drug absorption, while over 99% are water-soluble, facilitating delivery. Further, 96.5% and 28.20% of these molecules exhibited intestinal and brain bioavailability, expanding their therapeutic reach. The predicted pharmacological activities of these compounds encompass a diverse range, including anticancer, immunosuppressant, chemoprotective, anti-hepatic, hepatoprotectant, anti-inflammation, antihyperthyroidism, and anti-hepatitis activities. This multi-targeted profile highlights ent-kaurane diterpenoids as highly promising candidates for further drug discovery endeavors.

Tirbanibulin 1% Ointment Effectiveness for Actinic Keratosis Treatment Evaluated by Dynamic Optical Coherence Tomography

Background. Actinic keratosis (AK) is a common premalignant skin condition. Its diagnosis is based on a clinical and sometimes dermoscopic examination, but, in some situations, a skin biopsy may be necessary. Dynamic optical coherence tomography (D-OCT) can often bypass this need, by noninvasive evaluation of skin morphology. Early and effective treatment of AKs is important to prevent the progression to invasive squamous cell carcinoma (iSCC). Tirbanibulin 1% ointment, a new topical field therapy for AKs, has recently been introduced. Objectives. The aim of this study was to evaluate the efficacy and safety of tirbanibulin 1% ointment for the field treatment of nonhyperkeratotic, nonhypertrophic AKs (Olsen grade 1) on the face and/or scalp in adults, using D-OCT technology. Methods. Patients, presenting multiple, mild to moderate AKs on the face and scalp, in treatment with tirbanibulin 1% ointment for five consecutive days of an area measuring 25 cm2, were evaluated with videodermoscopy (V-track Vidix 4.0) and D-OCT (VivoSight Dx, Michelson Diagnostics Ltd., Kent, England, United Kingdom), as normal clinical practice. The lesions were staged according to the Olsen classification, excluding the most aggressive lesions. Results. We retrospectively evaluated 50 patients (27 males and 23 females, mean age 76 ± 7.9 years). At 57 days posttreatment, the complete clearance rate was 68% (n = 34) and partial clearance rate was 76% (n = 38). D-OCT showed markedly improved morphology, including a better recognizable dermal-epidermal junction (DEJ), associated with reduced inflammation. The most common adverse events reported were erythema and scaling, which were mostly mild and self-limiting. Conclusions. This study demonstrated that tirbanibulin may be considered an effective and well-tolerated treatment option for nonhyperkeratotic, nonhypertrophic AKs. It showed a favorable safety profile, with mostly mild adverse events. D-OCT can be considered a useful tool for personalizing AK treatment and monitoring.

Current state of endothelial cell therapy.

Currently, there is heightened interest surrounding endothelial cell therapy for the treatment of corneal edema. The purpose of this review article is to describe and summarize the background information as well as the research surrounding the emerging treatment modalities for endothelial cell therapy. Marked advancements have been made in the translational research in this area, and increasing refinements have been demonstrated in the treatment protocols for cell therapy. Human clinical trials in this field are ongoing, specifically, in the area of injected human corneal endothelial cells (HCECs), with early results showing favorable safety and efficacy profiles. Efficient and effective delivery of HCECs to patients with corneal edema and dysfunction now appears feasible, and the results from ongoing human clinical trials are much anticipated. Adjunct therapeutics-in the form of pharmacological agents and/or surgical techniques, such as descemetorhexis-will likely continue to play an important role in defining the future of endothelial cell therapy.

Pegunigalsidase alfa: a novel, pegylated recombinant alpha-galactosidase enzyme for the treatment of Fabry disease

Fabry disease, a rare X-linked genetic disorder, results from pathogenic variants in GLA, leading to deficient lysosomal α-galactosidase A enzyme activity and multi-organ manifestations. Since 2001, enzyme replacement therapy (ERT), using agalsidase alfa or agalsidase beta, has been the mainstay treatment, albeit with limitations such as rapid clearance and immunogenicity. Pegunigalsidase alfa, a novel PEGylated recombinant alpha-galactosidase, offers promise as an alternative. Produced in plant cells, pegunigalsidase alfa exhibits enhanced stability, prolonged half-life, and reduced immunogenicity due to pegylation. A phase 1/2 clinical trial demonstrated Gb3 clearance from renal capillary endothelial cells and its 48-month extension study revealed notable outcomes in renal function preservation. Three phase 3 clinical trials (BRIDGE, BRIGHT, and BALANCE) have shown favorable efficacy and safety profile, although caution is warranted in interpreting the results of BRIDGE and BRIGHT which lacked control groups. In BALANCE, the pivotal phase 3 trial comparing pegunigalsidase alfa with agalsidase beta, an intention-to-treat analysis of the eGFR decline over 2 years showed that the intergroup difference [95%confidence interval] in the median slope was −0.36 mL/min/1.73 m2/year [−2.44; 1.73]. The confidence interval had a lower limit above the prespecified value of −3 mL/min/1.73 m2/year and included zero. Despite challenges such as occasional hypersensitivity reactions and immune-complex-mediated glomerulonephritis, pegunigalsidase alfa approval by the European Medicines Agency and the Food and Drug Administration represents a significant addition to Fabry disease therapeutic landscape providing an option for patients in whom enzyme replacement therapy with current formulations is poorly tolerated or poorly effective.

Apilimod dimesylate in C9orf72 amyotrophic lateral sclerosis: a randomized phase 2a clinical trial.

Apilimod dimesylate is a first-in-class phosphoinositide kinase, FYVE-type zinc finger containing (PIKfyve) inhibitor with favourable clinical safety profile and has demonstrated activity in preclinical C9orf72 and TDP-43 amyotrophic lateral sclerosis models. In this amyotrophic lateral sclerosis clinical trial, the safety, tolerability, CNS penetrance, and modulation of pharmacodynamic target engagement biomarkers were evaluated. This Phase 2a, randomized, double-blind, placebo-controlled, biomarker-endpoint clinical trial was conducted in four USA centres (ClinicalTrials.gov NCT05163886). Participants with C9orf72 repeat expansion were randomly assigned (2:1) to receive twice-daily oral treatment of 125 mg apilimod dimesylate capsules or matching placebo for 12 weeks, followed by a 12-week open-label extension. Safety was measured as the occurrence of treatment-emergent adverse or serious adverse events attributable to study drug, and tolerability as trial completion on treatment over 12 weeks. Changes from baseline in plasma and CSF and concentrations of apilimod and its active metabolites and of pharmacodynamic biomarkers of PIKfyve inhibition (soluble glycoprotein nonmetastatic melanoma protein B [sGPNMB] upregulation) and disease-specific CNS target engagement (poly[GP]). Between Dec 16, 2021, and Jul 7, 2022, 15 eligible participants were enrolled. There were no drug-related serious adverse events reported in the trial. Fourteen (93%) participants completed the double-blind period with 99% dose compliance (N=9 [90%] apilimod dimesylate; N=5 [100%] placebo). At Week 12, apilimod dimesylate was measurable in CSF at 1.63 ng/mL (SD: 0.937). At Week 12, apilimod dimesylate increased plasma sGPNMB by > 2.5-fold (p < 0.001) indicating PIKfyve inhibition and lowered CSF poly(GP) protein levels by 73% (p < 0.001) indicating CNS tissue-level proof of mechanism. Apilimod dimesylate met prespecified key safety and biomarker endpoints in this Phase 2a trial and demonstrated CNS penetrance and pharmacodynamic target engagement. Apilimod dimesylate was observed to have the greatest reduction in CSF poly(GP) levels observed to date in C9orf72 clinical trials.

Use of Darvadstrocel (Allogenic Stem Cell Therapy) for Crohn's Fistulas in Real Clinical Practice: The National Project to Implement Mesenchymal Stem Cell for the Treatment of Perianal Crohn's Fistula (the PRIME Study).

Perianal fistulas may affect 15-50% of patients with Crohn's disease. Treatment is complex, requiring a multidisciplinary approach. Darvadstrocel (allogenic mesenchymal cells obtained from lipoaspirates) was approved in 2018 by the European and Spanish Agencies of Medicines and Medical Products as a treatment for fistulas in Crohn's disease. Recent European Crohn's and Colitis Organisation and Spanish Working Group on Crohn's Disease and Ulcerative Colitis guidelines state that darvadstrocel is effective with a favorable safety profile and a strong level of evidence (2). Presenting real-world effectiveness data for darvadstrocel in a Spanish population. Observational retrospective cohort study with prospective data gathering. Fourteen institutions. From November 2019-April 2022, all patients (73) treated with darvadstrocel in these institutions were included, fulfilling the following criteria: 1) complex fistula/s in a patient with Crohn's disease; 2) failure of conventional and antitumor necrosis factor treatment; 3) absence of collections >2 cm confirmed by pelvic MRI scan at the time of surgery. Darvadstrocel treatment. Clinical response (closure of ≥50% of external openings), complete clinical closure (100% of external openings) and radiological closure (no fluid collection >2 cm, no edema or inflammation) evaluated 6 months after treatment. Clinical response was observed in 63 patients (86.3%), complete clinical closure in 50 patients (68.5%) and radiological closure in 45 patients (69.2%). Combined clinical and radiological response was observed in 41 patients (63.1%). Not all clinically healed patients had radiological closure and vice versa. No serious adverse events were reported. Retrospective. Study results were consistent with those reported in previous clinical trials, real-world efficacy findings from the INSPIRE study (assessing darvadstrocel effectiveness in Europe, Israel, Switzerland, UK, and Japan) and previously published literature. Darvadstrocel was effective and demonstrated a favorable safety profile when used in normal clinical practice for treatment of fistulas in Crohn's disease. See Video Abstract.

In vitro pharmacokinetics/pharmacodynamics of FL058 (a novel beta-lactamase inhibitor) combined with meropenem against carbapenemase-producing Enterobacterales

Objective: FL058 is a novel beta-lactamase inhibitor with a broad spectrum of activity and a favorable safety profile. The objective of this study was to evaluate pharmacokinetic/pharmacodynamic (PK/PD) relationships for the combination of FL058 and meropenem in an in vitro infection model.Methods: By simulating human concentration-time profiles in the in vitro model, meropenem combined with FL058 when administered 1 g/0.5 g, 1 g/1 g, 2 g/1 g, and 2 g/2 g q8h by 3-h infusion achieved approximately 2- and 4-log10 kill to KPC/OXA-producing Klebsiella pneumoniae and Escherichia coli; the combination therapy could not inhibit NDM-producing K. pneumoniae but could maintain NDM-producing E. coli around a baseline.Results: The PK/PD indexes that best described the bacterial killing from baseline in log10 CFU/mL at 24 h were the percent time of free drug above the minimal inhibitory concentration (MIC) (%fT &amp;gt; MIC, MIC with FL058 at 4 mg/L) for meropenem and the percent time of free drug above 1 mg/L (%fT &amp;gt; 1 mg/L) for FL058. The targets for achieving a static effect and the 1- and 2-log10 kill were 74, 83, and 99 for %fT &amp;gt; MIC of meropenem and 40, 48, and 64 for %fT &amp;gt; 1 mg/L of FL058, respectively. The PK/PD index of %fT &amp;gt; 1 mg/L can provide a basis for evaluating clinical dosing regimens for FL058 combined with meropenem.Conclusion: FL058 combined with meropenem might be a potential treatment for KPC- and/or OXA-48-producing Enterobacterales infection.

Thoracic spinal anesthesia with intrathecal sedation for lower back surgery: a retrospective cohort study

BackgroundSpinal anesthesia (SA) is a good alternative to general anesthesia (GA) for spine surgery. Despite that, a few case series concern the use of thoracic spinal anesthesia for short-duration surgical interventions. In search of an alternative approach to GA and a better opioid-free modality, we aimed to investigate the safety, feasibility, and patient satisfaction of thoracic SA for spine surgery.Materials and methodsWe analyzed retrospectively a cohort of 24 patients operated on for a degenerative and osteoporotic pathology of the lower thoracic and lumbar spine. Data was collected from medical records, including clinical notes, operative and anesthesia records, and patient questionnaires.ResultsTwenty-one surgeries for herniated discs, two for degenerative spinal stenosis, and one for multi-level osteoporotic vertebral body fractures were performed under spinal anesthesia with intrathecal sedation. In all cases, we applied 0.5% isobaric bupivacaine and the following adjuvants: midazolam, clonidine or dexmedetomidine, and dexamethasone. We boosted the anesthesia with local ropivacaine due to inefficient sensory block in two patients. Nobody in the cohort received intravenous opioids, non-steroidal anti-inflammatory drugs, or additional sedation intraoperatively. Postoperative painkillers were upon the patient’s request. No significant complications were detected.ConclusionThoracic spinal anesthesia incorporating adjuvants such as midazolam, clonidine or dexmedetomidine, and dexamethasone demonstrates not only efficient conditions for spine surgery, a favorable safety profile, high patient satisfaction, and intrathecal sedation but also effective opioid-free pain management.

Reappraising the Use of Systemic Immunomodulators for Psoriasis and Eczema in the Military.

Psoriasis and atopic dermatitis are chronic, immune-mediated skin disorders that are disqualifying for entrance into the military. Both conditions can cause difficulty wearing body armor and other protective equipment when poorly controlled, limiting a service member's ability to train and deploy worldwide. In addition, these conditions may be exacerbated by military service because of increased exposure to austere environments, extreme temperatures, stress, skin injury, bug bites, and vaccinations Service members have limited treatment options because of restrictions on systemic medications that can be used while deployed. Newer systemic medications-in particular, biologics and oral immunomodulators-have evolved to be both extremely effective and safe. We review more recent treatment options for psoriasis and atopic dermatitis in the context of DoD's regulations guiding entry and retention of personnel with psoriasis and eczema and make recommendations regarding updating DoD policy for systemic treatment options. A literature search was performed using PubMed, Embase, and Ovid with the last search done in the fall of 2023 from all years to date. These articles were further screened based on inclusion and exclusion criteria. In total, 25 articles were included in this review. An Internet search was also performed on the DoD's regulations guiding entry and retention of personnel with psoriasis and eczema. In addition, we examined medical requirements for deployment to the U.S. Central Command and U.S. European Command. Currently, U.S. Central Command and U.S. European Command do not allow the use of medications with special storage and handling requirements on deployments. Newer biologics are safe and efficacious but require refrigeration, although other immunomodulators like deucravacitinib and apremilast are oral pills and do not have cold-storage requirements. However, the use of biologics in austere environments may be feasible because of increased intervals between dosing and the ability to store refrigerated medical supplies in most deployed environments. For military service members with psoriasis, risankizumab and deucravacitinib are excellent options given their favorable safety and efficacy profiles. Of the biologics available for atopic dermatitis, dupilumab is the safest and effective systemic medication available. The Janus kinase inhibitors have also demonstrated excellent efficacy in treating atopic dermatitis, but more safety data are needed because of potential adverse events to include heart-related events, blood clots, and cancers. Systemic treatments have evolved to become highly specific for both eczema and psoriasis. These newer biologics and immunomodulators may be compatible with use in the deployed setting, especially those that have long dosing intervals and proven efficacy and safety. Of the biologics, dupilumab and risankizumab offer the best efficacy, safety, and dosing intervals for atopic dermatitis and psoriasis, respectively. Deucravcitinib is a recently FDA-approved oral immunomodulator for psoriasis that has an excellent safety profile and efficacy. Allowing the use of these medications on deployments will enable more people with moderate to severe psoriasis and eczema to join and remain in the military while receiving effective treatment.

Costs associated with adverse events during treatment episodes for adult attention-deficit/hyperactivity disorder

ABSTRACT Aims: Attention-deficit/hyperactivity disorder (ADHD) medication is frequently associated with adverse events (AEs), but limited real-world data exist regarding their costs from a payer’s perspective. Therefore, this study evaluated the healthcare costs associated with common AEs among adult patients treated for ADHD in the US. Materials and methods: Eligible adults treated for ADHD were identified from a large US claims database (10/1/2015─9/30/2021). A retrospective cohort study design was used to assess excess healthcare costs and costs directly related to AE-specific claims per-patient-per-month (PPPM) associated with 10 selected AEs during ADHD treatment. To account for all costs associated with the AE, treatment episodes with a given AE were compared to similar treatment episodes without this AE. Entropy balancing was used to create cohorts with similar characteristics. Studied AEs were selected based on their prevalence in clinical trials for common ADHD medications and were identified from ICD-10-CM diagnosis codes recorded in claims. Results: Among the 461,464 patients included (mean age: 34.2 years; 45.5% male), 49.4% had ≥1 AE during their treatment episode. Treatment episodes with AEs were associated with statistically significant AE-specific medical costs (erectile dysfunction: $57; fatigue: $82; dry mouth: $90; diarrhea: $162; insomnia: $147; anxiety: $281; nausea: $299; constipation: $356; urinary hesitation: $491; feeling jittery: $723) and excess healthcare costs PPPM (erectile dysfunction: $120, fatigue: $248, insomnia: $265, anxiety: $380, diarrhea: $441, dry mouth: $485, nausea: $709, constipation: $802, urinary hesitation: $1,105, feeling jittery: $1,160; p < 0.05). Limitations: AEs were identified based on recorded diagnosis on medical claims and likely represent more severe AEs. Therefore, costs may not be representative of milder AEs. Conclusions: This study found that AEs occurring during ADHD treatment episodes are associated with significant healthcare costs. This highlights the potential of treatments with favorable safety profiles to alleviate the burden experienced by patients and the healthcare system.

Differential Susceptibility to Propofol and Ketamine in Primary Cultures of Young and Senesced Astrocytes

The adverse effects of general anesthesia on the long-term cognition of young children and senior adults have become of concern in recent years. Previously, mechanistic and pathogenic investigations focused on neurons, and little is known about the effect of commonly used intravenous anesthetics such as propofol and ketamine on astrocytes. Recently, astrocyte dysfunction has been implicated in a wide range of age-related brain diseases. In this study, we examined the survival and viability of both young and senescent astrocytes in culture after adding propofol and ketamine to the media at varying strengths. Oxidative stimulus was applied to commercially available fetal cell lines of human astrocytes in vitro to induce morphological changes in cellular senescence. Our results indicate that propofol reduces the survival of young astrocytes as compared to controls, as well as to ketamine. These effects were seen in comparisons of total cell count and at both high and low dose concentrations. High doses of propofol also significantly reduced cell viability compared to those exposed to baseline controls and ketamine. Senescent astrocytes, on the other hand, demonstrated cell count reductions as compared to baseline controls and ketamine when exposed to either DMSO or propofol. The data show differential susceptibility of young astrocytes to propofol than to ketamine. The observed cell count reduction may be related to the adverse effects of propofol on mitochondrial function and free radical production, as described in previous studies. We speculate that ketamine may have a more favorable safety profile in infants and young children.

First-in-human study of GFH018, a small molecule inhibitor of transforming growth factor-β receptor I inhibitor, in patients with advanced solid tumors

BackgroundTransforming growth factor-β (TGF-β) is a cytokine with multiple functions, including cell growth regulation, extracellular matrix production, angiogenesis homeostasis adjustment and et al. TGF-β pathway activation promotes tumor metastasis/progression and mediates epithelial-mesenchymal transmission suppressing immunosurveillance in advanced tumors. GFH018, a small molecule inhibitor blocking TGF-β signal transduction, inhibits the progression and/or metastasis of advanced cancers. This first-in-human study evaluated the safety, tolerability, pharmacokinetics (PK), and efficacy of GFH018 monotherapy in patients with advanced solid tumors.MethodsThis phase I, open-label, multicenter study used a modified 3+3 dose escalation and expansion design. Adult patients with advanced solid tumors failing the standard of care were enrolled. Starting at 5 mg, eight dose levels up to 85 mg were evaluated. Patients received GFH018 BID (14d-on/14d-off) starting on the 4th day after a single dose on cycle 1, day 1. Subsequent cycles were defined as 28 days. The study also explored the safety of 85 mg BID 7d-on/7d-off. Adverse events were graded using NCI criteria for adverse events (NCI-CTCAE v5.0). PK was analyzed using a noncompartmental method. Efficacy was evaluated using RECIST 1.1. Blood samples were collected for biomarker analysis.ResultsFifty patients were enrolled and received at least one dose of GFH018. No dose-limiting toxicity occurred, and the maximum tolerated dose was not reached. Forty-three patients (86.0%) had at least one treatment-related adverse event (TRAE), and three patients (6.0%) had ≥ G3 TRAEs. The most common TRAEs (any grade/grade ≥3) were AST increased (18%/0%), proteinuria (14%/2%), anemia (14%/2%), and ALT increased (12%/0%). No significant cardiotoxicity or bleeding was observed. GFH018 PK was linear and dose-independent, with a mean half-life of 2.25–8.60 h from 5 – 85 mg. Nine patients (18.0%) achieved stable disease, and one patient with thymic carcinoma achieved tumor shrinkage, with the maximum target lesion decreased by 18.4%. Serum TGF-β1 levels were not associated with clinical responses. The comprehensive recommended dose for Phase II was defined as 85 mg BID 14d-on/14d-off.ConclusionsGFH018 monotherapy presented a favorable safety profile without cardiac toxicity or bleeding. Modest efficacy warrants further studies, including combination strategies.Trial registrationClinicalTrial. gov (https://www.clinicaltrials.gov/), NCT05051241. Registered on 2021-09-02.

Troriluzole Exhibits Favorable Hepatic Safety Profile Across a Diverse Range of Disorders (P4-4.013)

Troriluzole Exhibits Favorable Hepatic Safety Profile Across a Diverse Range of Disorders (P4-4.013)

Janus kinase inhibitors and tumour necrosis factor inhibitors show a favourable safety profile and similar persistence in rheumatoid arthritis, psoriatic arthritis and spondyloarthritis: real-world data from the BIOBADASER registry

ObjectivesTo compare the safety of Janus kinase inhibitors (JAKi) with that of tumour necrosis factor inhibitors (TNFi) and determine drug persistence among patients with rheumatoid arthritis (RA) and spondyloarthritis (SpA).MethodsWe...

Abstract LB425: A tumor microenvironment-targeting CD98-directed ADC confers robust anti-tumor activity in multiple cancers with favorable pharmacokinetics and safety profiles in preclinical models

Abstract CD98, a subunit of the LAT1/CD98 amino acid transporter complex, is intimately involved in cell adhesion, migration, proliferation, and signal transduction by enhancing amino acid transport and amplifying integrin signaling. CD98 is expressed at aberrantly high levels in many solid tumors and hematological malignancies, and this is frequently associated with poor prognosis, highlighting its potential as a cancer therapy target. However, CD98 is also expressed in various normal tissues hence complicating the development of antibody-based therapies owing to lack of tumor selectivity, poor pharmacokinetics (PK), and safety issues. We previously reported a pH-dependent anti-CD98 monoclonal antibody (mAb) that selectively targets the acidic tumor microenvironment (Tian, X., et al. Nat Biomed Eng 7(1): 8-23.). In the present report, we further developed that mAb into an antibody-drug conjugate (ADC; HH018-sesutecan), in which the mAb is conjugated to a topoisomerase I inhibitor-based linker-drug, sesutecan, at a drug:antibody ratio (DAR) of approximately 8. Sesutecan previously demonstrated promising characteristics in preclinical studies with multiple targets and conferred an encouraging benefit:risk profile in the clinic with a FRα-directed ADC (rinatabart sesutecan). HH018-sesutecan exhibited similar pH-dependent binding as its parental mAb in vitro, and markedly improved PK compared to the non-pH-dependent ADC control in CD98-humanized C57BL/6 mice. HH018-sesutecan demonstrated potent cytotoxicity against CD98-expressing cancer cell lines, strong bystander effect, as well as dose-dependent anti-tumor activity in mouse models representing multiple tumor types (colorectal cancer, ovarian cancer, renal cell carcinoma, lymphoma, hypopharyngeal carcinoma, and oral adeno-squamous carcinoma). Notably, sustained tumor regression was achieved with a single dose of 3-5 mg/kg in ~8 tumor models. A pilot toxicity study was conducted for HH018-sesutecan at two repeat-dose of 30 mg/kg in cynomolgus monkeys. HH018-sesutecan was well-tolerated with the principal toxicity (myelosuppression) being payload driven and reversible, accompanied with a favorable PK profile (half-life of 7-9 days). In summary, our studies demonstrate that the pH-dependent CD98-directed HH018- sesutecan exerts wide-ranging and potent anti-tumor efficacy, as well as favorable PK and safety profiles in preclinical models. HH018-sesutecan is a promising agent for further development in a broad range of CD98-expressing tumors. Citation Format: Fang Yang, Lei Wang, Xinxin Tian, Xuan Qiu, Jianhe Chen, Wenke Qi, Guangyu Li, Haidong Liu, Juan Liu, Suping Huang, Bin Ye, Qilin Wu, Baiteng Zhao, Wenhui Li, Jianhua Sui, Zhu Chen. A tumor microenvironment-targeting CD98-directed ADC confers robust anti-tumor activity in multiple cancers with favorable pharmacokinetics and safety profiles in preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB425.

Abstract CT206: Efficacy and safety of SV-BR-1-GM after progression on ADC in metastatic breast cancer patients

Abstract Background: Antibody-drug conjugate (ADC) sequencing raises concerns of cross-resistance due to their shared cytotoxic payloads. Consequently, there is a pressing need for treatments after ADCs, especially in heavily pretreated patients. Immunization with irradiated SV-BR-1-GM, a GM-CSF secreting, antigen-presenting immortalized breast cancer cell line, has emerged as a potential post ADC solution based on a different mechanism of action. This retrospective analysis aims to assess the overall efficacy and safety of SV-BR-1-GM in a subset of ADC treated patients. Methods: Post-hoc subset analysis of the ongoing randomized Phase 2 study identified 23 advanced MBC patients who failed prior ADC therapy. Bria-IMT™ (irradiated SV-BR-1-GM ~20x106 cells, intradermally 48-72 hours after cyclophosphamide (300 mg/m2), followed by interferon-alpha at the inoculation sites 2 days later) was administered q3wks with a CPI. Endpoints included PFS, OS and disease control rate (the proportion of patients with stable disease, partial or complete responses) using the KM method censored to the data-cut date prior to data lock. Adverse events were classified according to their severity and relationship to treatment regimen. Results: All pts were heavily pretreated (median 6 prior lines, range 3 - 13). Median age was 62 (41-83). 14 pts had HR+/HER2-, 5 TNBC, and 2 HR+/HER2+ MBC. The remaining pts were HR-/HER2low or HR-/HER2+. Prior ADCs included: 4 ado-trastuzumab emtansine, 14 trastuzumab deruxtecan, 13 sacituzumab govitecan; 8 pts received &amp;gt; 1 ADC. 7 pts had also received ≥ 1 prior CPI line. To date, pts received a median 3 cycles of Bria-IMT™ + CPI (2-7). Kaplan-Meier analysis revealed a median OS of 42 weeks with survival of 69% at 6 months. The subset experienced a median PFS of 74 days with 40% of pts demonstrating a Bria-IMT PFS (PFS2) similar to or &amp;gt; their prior line PFS (PFS1). 39% of pts experienced a PFS2 ≥ their most recent line of ADC PFS. The disease control rate was 40% among evaluable pts. 43% of pts had a reduction in cancer-associated macrophage-like cell (CAML) levels; median reduction was 36% (22-98%) after 1 cycle. There were no toxicity-related treatment discontinuations. 43% (10/23) reported grade 3 or 4 AEs, independent of study drug causality. No interstitial lung disease (ILD) reported. AEs included injection site reaction (39%), fatigue (26%), and nausea/vomiting (43%), mostly mild to moderate. One case of elevated lipase was the most clinically significant grade 4 AE. Conclusion: The retrospective analysis of the Bria-IMT™ regimen in ADC refractory MBC patients suggests a potential treatment option for this patient population. The absence of serious AEs, notably ILD, and no toxicity-related treatment discontinuations, underscores the regimen's favorable safety profile. Future studies are warranted to confirm these results and explore the potential of Bria-IMT™ in broader clinical settings. Citation Format: Chaitali Nangia, Carmen Calfa, Blaise Bayer, Mingjin Chang, William Williams, Giuseppe Del Priore, Charles Wiseman, Saranya Chumsri. Efficacy and safety of SV-BR-1-GM after progression on ADC in metastatic breast cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT206.

Efficacy and Safety of PEGylated Interferons for Relapsing-Remitting Multiple Sclerosis in Adult Patients: Results of Matching-Adjusted Indirect Comparison

Introduction. Beta interferons are effective and safe agents for the treatment of relapsing-remitting multiple sclerosis (RRMS). PEGylated interferons have been developed in order to increase patient adherence. Direct comparisons of the efficacy and safety of PEGylated interferons have not yet been conducted.&#x0D; Our objective was to evaluate the efficacy and safety of SamPEG-IFN-β1a versus PEG-IFN-β1a in adult patients with RRMS.&#x0D; Materials and methods. We conducted a systematic search of randomized clinical trials (RCTs) using the PubMed, Embase and eLIBRARY.RU databases. Efficacy was assessed based on the proportion of patients with disease relapses and the annualized relapse rate (ARR) during the 1st and the 2nd years of treatment. Safety was assessed by the number of patients with adverse events (AEs), serious AEs (SAEs), and any AEs that led to the treatment discontinuation. We conducted pairwise matching-adjusted indirect comparison (MAIC) to assess comparative efficacy of PEGylated IFNs. To evaluate the efficacy, hypotheses of non-inferiority of SamPEG-IFN-β1a to PEG-IFN-β1a and superiority of SamPEG-IFN-β1a over PEG-IFN-β1a were tested.&#x0D; Results. Based on results of the systematic review, four articles were selected wherein the results of phase 3 clinical trial of PEG-IFN-β1a and phase 2–3 clinical trial of SamPEG-IFN-β1a were described. In PEG-IFN-β1a group (n = 512) the agent was administered once every 2 weeks, in SamPEGIFN-β1a group (n = 114) the agent was administered at a dose of 240 μg. The analysis results confirmed the hypothesis of SamPEG-IFN-β1a non-inferiority to PEG-IFN-β1a in efficacy, while SamPEG-IFN-β1a superiority over PEG-IFN-β1a in efficacy was not confirmed. The hypothesis of SamPEG-IFN-β1a superiority over PEG-IFN-β1a in safety was also confirmed based on a significantly lower incidence of SAEs and any AEs that led to treatment discontinuation.&#x0D; Conclusions. The proportion of patients with relapses and the ARR in 1 year and in 2 years of therapy indicates that SamPEG-IFN-β1a is non-inferior to PEG-IFN-β1a in efficacy. SamPEG-IFN-B1a demonstrated a more favourable safety profile than PEG-IFN-B1a as showing less odds of SAEs and AEs leading to treatment discontinuation.

Abstract ND08: M3554, a novel anti-GD2 antibody drug conjugate

Abstract The glycosphingolipid GD2 is a cell membrane component of a limited number of normal tissues including nerve cells, melanocytes or lymphocytes. However, in some tumor types as neuroblastoma, osteosarcoma, glioma, or soft tissue sarcoma, GD2 is found on cell membranes with high levels. This tumor associated expression pattern makes GD2 an attractive target for therapeutic antibodies like dinutuximab (ch14.18) and naxitamab, which have been approved for neuroblastoma. M3554 is designed a be novel anti-GD2 ADC based on the humanized ch14.18 anti-GD2 antibody. The payload linker consists of the Topoisomerase I inhibitor (TOP1i) payload exatecan and a cleavable beta-glucuronide linker structure, which demonstrated higher potency, better bystander effects and improved activity in multidrug resistant cancer cells compared to other TOP1i payloads. While the antitumor effect of approved anti-GD2 antibodies is presumably related to Antibody-Dependent Cellular Cytotoxicity (ADCC) and Complement- Dependent Cytotoxicity (CDC), M3554 will exploit the high antigen density for direct tumor cytotoxicity by the payload. As the ADCC and CDC effector functions are believed to cause side effects for the approved GD2 antibodies, we have modified the M3554 antibody moiety with mutations in the Fc-region to reduce or eliminate these Fcγ receptor mediated functions. The cytotoxicity of M3554 was in the subnanomolar IC50 range for the GD2-positive neuroblastoma cell line CHP134. M3554 showed strong in vivo antitumor activity with tumor regressions in the CHP134 xenograft model and in patient-derived xenografts from neuroblastoma, osteosarcoma or glioma at doses ranging from 3 to 10 mg/kg. In addition, M3554 showed favorable pharmacokinetics in rats and monkeys, indicating a very stable linker-payload, and a favorable safety profile. In conclusion, M3554 represents a novel therapeutic approach for oncology indications with a high unmet medical need and high GD2 prevalence. Disclosures: Christiane Amendt, Christine Knuehl, Willem Sloot, Stanley Sweeney-Lasch, Joao NS Pereira, Julia Dotterweich, Hans-Henning Boehm and Jan Anderl are employees of the healthcare business of Merck KGaA, Darmstadt, Germany. Timothy Crandall is an employee of EMD Serono. Mira Toister-Achituv is an employee of Inter-Lab Ltd., Yavne, Israel, an affiliate of Merck KGaA, Darmstadt, Germany.Sponsor: This study was sponsored by the healthcare business of Merck KGaA, Darmstadt, Germany (CrossRef Funder ID: 10.13039/100009945). Citation Format: Christiane Amendt, Christine Knuehl, Timothy Crandall, Willem Sloot, Mira Toister-Achituv, Stanley Sweeney-Lasch, Joao NS Pereira, Julia Dotterweich, Hans_Henning Boehm, Jianguo Ma, Jan Anderl. M3554, a novel anti-GD2 antibody drug conjugate [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr ND08.