The worldwide epidemics of obesity, hypertriglyceridemia, dyslipidemia, type 2 diabetes, and metabolic dysfunction-associated steatotic liver disease (MASLD) / metabolic dysfunction-associated steatohepatitis (MASH) represents a major economic burden on healthcare systems. At-risk MASH patients, defined as MASH with moderate or significant fibrosis are at higher risk of comorbidity / mortality with a significant risk of cardiovascular diseases and/or major adverse liver outcomes. Despite a high unmet medical need, there is no approved therapy to date. Several drug candidates have reached the phase 3 development stage and could lead to several potential conditional drug approvals in the coming years. Within the armamentarium of future treatment options, FGF21 analogs exhibit an interesting positioning thanks to their pleiotropic effects in addition to their significant effect on both MASH resolution and fibrosis improvement. In this review, we summarize preclinical and clinical data from FGF21 analogs for MASH and explore additional potential therapeutic indications. 

FGF21 Agonists: An Emerging Therapeutic for Metabolic Dysfunction-Associated Steatohepatitis and Beyond.

Drugs with a long residence time at their target sites are often more efficacious in disease treatment. The mechanism, however, behind prolonged retention at the site of action is often difficult to understand for non-covalent agents. In this context, we focus on epichaperome agents, such as zelavespib and icapamespib, which maintain target binding for days despite rapid plasma clearance, minimal retention in non-diseased tissues, and rapid metabolism. They have shown significant therapeutic value in cancer and neurodegenerative diseases by disassembling epichaperomes, which are assemblies of tightly bound chaperones and other factors that serve as scaffolding platforms to pathologically rewire protein–protein interactions. To investigate their impact on epichaperomes in vivo, we conducted pharmacokinetic and target occupancy measurements for zelavespib and monitored epichaperome assemblies biochemically in a mouse model. Our findings provide evidence of the intricate mechanism through which zelavespib modulates epichaperomes in vivo. Initially, zelavespib becomes trapped when epichaperomes bound, a mechanism that results in epichaperome disassembly, with no change in the expression level of epichaperome constituents. We propose that the initial trapping stage of epichaperomes is a main contributing factor to the extended on-target residence time observed for this agent in clinical settings. Zelavespib’s residence time in tumors seems to be dictated by target disassembly kinetics rather than by frank drug–target unbinding kinetics. The off-rate of zelavespib from epichaperomes is, therefore, much slower than anticipated from the recorded tumor pharmacokinetic profile or as determined in vitro using diluted systems. This research sheds light on the underlying processes that make epichaperome agents effective in the treatment of certain diseases.

Unraveling the Mechanism of Epichaperome Modulation by Zelavespib: Biochemical Insights on Target Occupancy and Extended Residence Time at the Site of Action

Human fungal pathogens cause a broad plethora of infections, spanning cutaneous dermatophytoses to invasive infections in immunocompromised hosts. As eukaryotic pathogens are capable of morphotype switching, they present unique challenges both for drug development and the immunological response. Whilst current antifungal therapies are limited to the orally available triazoles, intravenous echonocandins and polyenes, and flucytosine and terbinafine, there has been recent significant progress in the antifungal armamentorium with ibrexafungerp, a novel orally available terpanoid that inhibits 1,3‐beta‐D‐glucan‐approved by Food and Drug Administration in 2021, and fosmanogepix, an orally available pro‐drug of manogepix, which targets glycosylphosphatidylinositol‐anchored protein maturation entering Phase 3 studies for candidaemia. A number of further candidates are in development. There has been significant use of existing immunotherapies such as recombinant interferon‐γ and G‐CSF for fungal disease in immunocompromised patients, and there are emerging opportunities for monoclonal antibodies targeting TH2 inflammation. Omalizumab, an anti‐IgE monoclonal antibody in asthma, is now used routinely for the treatment of allergic bronchopulmonary aspergillosis, and further agents targeting IL‐4 and IL‐5 are being evaluated. In addition, T‐cell CAR therapy is showing early promise for fungal disease. Thus, we are likely to see rapid advances to our approach to the management of fungal disease in the near future.

Antifungal chemotherapies and immunotherapies for the future

Sickle cell disease (SCD) is the most common genetic blood disorder in the United States, with over 100,000 people suffering from this debilitating disease. SCD is caused by abnormal hemoglobin (Hb) variants that interfere with normal red blood cell (RBC) function. Research on SCD has led to the development and approval of several new SCD therapies in recent years. The recent FDA-approved novel gene therapies are potentially curative, giving patients an additional option besides a hematopoietic bone marrow transplant. Despite the promise of existing therapies, questions remain regarding their long-term pharmacological effects on adults and children. These questions, along with the exorbitant cost of the new gene therapies, justify additional research into more effective therapeutic options. Continual research in this field focuses on not only developing cheaper, more effective cures/treatments but also investigating the physiological effects of the current therapies on SCD patients, particularly on the brain and kidneys. In this article, we undertake a comprehensive review of ongoing clinical trials with completion dates in 2024 or later. Our exploration provides insights into the landscape of current therapeutics and emerging novel therapies designed to combat and potentially eradicate SCD, including the latest FDA-approved gene therapies.

Current and Future Therapeutics for Treating Patients with Sickle Cell Disease

Rezafungin is a novel echinocandin being developed for the treatment and prevention of invasive fungal infections. The objectives of this randomized, double‐blind study in healthy adults were to determine the safety, tolerability, and pharmacokinetics of rezafungin after subcutaneous (s.c.) administration. The study design consisted of six sequential cohorts of eight subjects, except for the first cohort with four subjects. The subjects were randomized in a 3:1 ratio of rezafungin to placebo and were to receive a single dose of 1, 10, 30, 60, 100, or 200 mg. The most common adverse events (AEs) were increased alanine aminotransferase and sinus bradycardia (unsolicited) and erythema at the injection site (solicited). Unsolicited AEs were generally mild to moderate and not rezafungin‐related. Although the study was terminated after the 10 mg dose cohort due to concerns of potential increased severity of injection site reactions, no predetermined dose escalation halting criteria were met. Following the 10 mg single s.c. dose of rezafungin (n = 6), the geometric mean (GM) maximum concentration (Cmax) was 105.0 ng/ml and the median time to Cmax was 144 h. The GM area under the concentration‐time curve was 32,770 ng*h/ml. The median estimated terminal half‐life was 193 h. The GM apparent oral clearance was 0.255 L/h and the GM apparent volume of distribution was 68.5 L. This study demonstrates that a single s.c. dose of rezafungin in healthy adult subjects: (1) did not result in serious AEs, death, or withdrawal from the study due to an AE; and (2) produced a pharmacokinetic profile with long exposure period postadministration. In an effort to reduce the occurrence of injection site reactions, a re‐evaluation of the rezafungin s.c. formulation could be considered in the future.

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1111/cts.13286

A phase I randomized, double‐blind, single subcutaneous dose escalation study to determine the safety, tolerability, and pharmacokinetics of rezafungin in healthy adult subjects

Neurodegenerative diseases are devastating conditions that most commonly affect individuals 65 years and older. Currently there are no effective treatments or cures for neurodegenerative diseases, and therapeutics that selectively target the underlying causes of these diseases are needed. Epichaperomes play a major role in the maintenance and progression of neuronal pathology. Inhibiting epichaperomes induces degradation of disease associated proteins and is a promising therapeutic approach to treat neurodegenerative diseases, in particular Alzheimer’s Disease and amyotrophic lateral sclerosis. This Phase 1 clinical study evaluated the safety, tolerability, pharmacokinetics, and bioavailability of icapamespib, a purine scaffold inhibitor of epichaperomes that is specific to epichaperomes, in healthy subjects. Double-blind, placebo-controlled dose escalating single ascending dose and multiple ascending doses and an unblinded two-period cross-over bioavailability study design. Single site in the United States. Healthy men or women of 18 to 60 years of age, inclusive, for Part 1 (single ascending dose), ≥ 60 years of age for Part 2 (multiple ascending dose), or 18 to 49 years of age for Part 3 (bioavailability). In the single ascending dose group, oral single doses (10, 20, and 30 mg icapamespib or placebo) were administered to healthy non-elderly subjects. In the multiple ascending dose group, multiple doses (20 and 30 mg icapamespib once daily for 7 days or placebo) were administered to healthy elderly subjects. In the bioavailability group, the bioavailability of once daily oral icapamespib solution and tablet was assessed in healthy non elderly subjects. Safety was evaluated based on assessments of treatment-emergent adverse events, physical examinations, clinical laboratory tests (hematology, clinical chemistry, and urinalysis), vital signs, and 12-lead electrocardiograms. Icapamespib concentration was evaluated in plasma and cerebrospinal fluid, the latter in Part 2 (multiple ascending dose) only. Forty-eight subjects in total were randomized and assessed for tolerability, pharmacokinetics, and bioavailability parameters as follows: 24 subjects in Part 1 (single ascending dose) with PU-AD 10 mg (n = 6), 20 mg (n = 6), 30 mg (n = 6), and placebo (n = 6); 16 subjects in Part 2 (multiple ascending dose) with icapamespib 20 mg (n = 6), 30 mg (n = 6), and placebo (n = 4); and 8 subjects in Part 3 (bioavailability) crossed-over between icapamespib 30 mg (tablet) and icapamespib 30 mg (oral solution). Single doses of icapamespib up to 30 mg and multiple doses of icapamespib up to 30 mg for 7 days were generally safe and well tolerated in healthy non-elderly and elderly subjects. Treatment-emergent adverse events were mild, with headache being the most common treatment-emergent adverse event. Mean icapamespib exposure (area under the curve) was dose-proportional over the dose range tested. The median time to maximum observed plasma concentration ranged from 1.00 to 2.00 h across single ascending dose, multiple ascending dose, and bioavailability groups; icapamespib exposure was 50% higher in elderly subjects compared with non-elderly subjects but was well tolerated. The study provides clinical evidence of the safety of icapamespib in healthy non elderly and elderly subjects and supports the advancement of icapamespib to Phase 2 evaluation in Alzheimer’s Disease and other neurodegenerative diseases.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9419134

Safety, Tolerability and Pharmacokinetics of Icapamespib, a Selective Epichaperome Inhibitor, in Healthy Adults

Background: Sickle cell disease (SCD) is caused by polymerization of sickle hemoglobin (HbS). Voxelotor is a first-in-class HbS polymerization inhibitor approved by the United States Food and Drug Administration for the treatment of SCD in adult and pediatric patients aged ≥4 years, and by the European Medicines Agency for the treatment of hemolytic anemia due to SCD in adult and pediatric patients aged ≥12 years as monotherapy or in combination with hydroxycarbamide. GBT021601 is a next-generation HbS polymerization inhibitor with improved pharmacokinetic (PK) properties that stabilizes Hb in the oxygenated state, thus inhibiting polymerization. GBT021601 has the potential to achieve higher Hb occupancies at lower doses than voxelotor, potentially reducing treatment burden and improving clinical outcomes for patients with SCD. Aims: To explore the safety, tolerability, PK, and pharmacodynamics of GBT021601 in healthy volunteers and patients with SCD. Methods: Two studies are in progress: (1) GBT021601-011: a phase 1, randomized, double-blind, placebo-controlled, parallel-group study of single ascending doses (SADs) and multiple ascending doses (MADs) of GBT021601 in healthy volunteers aged 18 to 55 years; and (2) GBT021601-012: a phase 1, single-arm, intrapatient, single-dose and MAD study in patients with SCD (homozygous HbS) aged 18 to 60 years. In the GBT021601-011 SAD phase, participants (n=8) were randomized 6:2 to receive a single oral dose of GBT021601 (50 to 2200 mg) or placebo. In the GBT021601-011 MAD phase, participants (n=10) were randomized 7:3 to 14 days of GBT021601 (3 days of loading doses followed by 11 days of once-daily maintenance doses) or placebo. Data from the 50 mg MAD cohort are reported in this analysis. In the GBT021601-012 study, patients with SCD (N=6) received a single 100 mg dose of GBT021601, followed by an 8-week washout, then 2 continuous MADs: once-daily maintenance doses of 50 mg (5 weeks) then 100 mg (3 weeks). Each MAD phase participant received 2 days of loading doses. Results: In the GBT021601-011 50 mg MAD cohort, blinded safety data demonstrated that GBT021601 was well tolerated. Adverse events (AEs) were predominantly grade 1 and not related to treatment. Drowsiness, headache, and constipation were the most frequent AEs. Mean (SD) Hb occupancy of GBT021601, determined via PK analysis, was 25.8% (3.9%). In GBT021601-012, patients with SCD completed treatment with no AEs leading to study discontinuation. Three vaso-occlusive crises (grades 2 and 3) occurred in 2 patients and were deemed unrelated to GBT021601. After dosing for 8 weeks, the mean (SD) Hb occupancy achieved was 32.6% (9.4%), and the mean (SD) increase in Hb was 2.3 (0.9) g/dL. Markers of hemolysis decreased, with a mean (SD) change in absolute reticulocytes of –37.4% (17.3%), reticulocyte percentage of –54.0% (11.3%), indirect bilirubin of –6.6% (119.3%), and lactate dehydrogenase of –33.1% (15.4%). The terminal elimination half-life of GBT021601 from blood averaged about 10 days. Ektacytometry scans demonstrated improvements in red blood cell (RBC) health, and blood smears showed increased counts of RBCs with improved morphology (Figure); no changes in erythropoietin levels were observed. Image:Summary/Conclusion: Multiple daily doses of GBT021601 were well tolerated in both studies. In patients with SCD, the GBT021601 100 mg maintenance dose led to a mean Hb occupancy >30%, increased Hb, reduced markers of hemolysis, and improved RBC health. These data highlight the potential of GBT021601 and support its further development. 

S268: safety, tolerability, and pharmacokinetic/pharmacodynamic results from phase 1 studies of gbt021601, a next-generation hbs polymerization inhibitor for treatment of sickle cell disease

Reduced triglycerides and LDL cholesterol from once-weekly administration of the well-tolerated novel FGF21 analogue 0499

Interleukin 2 (IL-2) signaling is essential for the development, survival, and suppressive function of T regulatory cells (Tregs). Diminished IL-2 signaling and Treg functional impairment are associated with autoimmune diseases, including systemic lupus erythematosus (SLE)[1]-[3]. XmAb564 is a potency reduced, monomeric human IL-2 heterodimeric Fc-fusion protein with extended half-life and increased binding affinity for IL-2 receptor alpha (CD25) to selectively expand Tregs, being developed for the treatment of autoimmune diseases.In this first-in-human, placebo-controlled, double-blind, single ascending-dose study, healthy adult volunteers received XmAb564 and were evaluated for safety, tolerability, pharmacokinetics (PK), and pharmacodynamic (PD) for 30-45 days.Subjects received SC doses of XmAb564 at 0.003, 0.007, 0.015, 0.025, 0.040, and 0.065 mg/kg in 6 cohorts (6 active:2 placebo per cohort). Levels of immune cell populations in whole blood were assessed by flow cytometry for total Tregs (CD4+CD25+FoxP3+) and CD25brightTregs (CD4+CD25brightFoxP3+), as well as NK (CD56+) cells, CD4+ and CD8+ T conventional cells (Tcon).A single dose of XmAb564 was well tolerated, with no dose-limiting toxicities, no Grade 3 or greater adverse events (AEs), no serious AEs, no deaths, nor clinically significant laboratory safety abnormalities. AEs attributed to XmAb564 were mainly mild to moderate self-limited injection site reactions. Asymptomatic transient elevations of peripheral eosinophils were observed in a dose-dependent manner, similar to those reported with other biologics in the class. After a single dose of subcutaneous administration, XmAb564 exposure increased in a dose-dependent manner with dose-proportional Cmaxand non-linear clearance owing to the expected increase in target receptor expression (CD25) in response to XmAb564 and dynamic target-mediated drug disposition across the range of doses studied from 0.003 to 0.065 mg/kg.The primary effect of XmAb564 was seen on total Tregs and particularly the CD25brightTreg subset (Figure 1A, B). The elevations peaked at approximately Day 12 and remained elevated for at least 21 days following drug administration. At the highest dose of 0.065 mg/kg, the mean peak increase in numbers of Tregs and CD25brightTregs were 8-fold and 117-fold above baseline, respectively. At that same 0.065 mg/kg dose level, there was a trend of mean increase of 2.6-fold, 2.3-fold, and 2.2-fold in numbers of NK, CD4+and CD8+Tcon cells, respectively.Figure 1.XmAb564 selectively induced Tregs and was well tolerated. XmAb564 PK and PD potentially supports extended multi-week dosing intervals and has a Treg induction magnitude and durability that may be competitive or superior to other candidates in clinic, providing the rationale for clinical evaluation across a broad range of inflammatory diseases.[1]Doglio et al. JACI 2022; 150: 1289[2]Lieberman et al. J Biomed Biotechnol; 2010: 740619[3]Long et al. Genes Immun; 2011: 116NIL.Raphael Clynes Shareholder of: Xencor, Employee of: Xencor, Cassandra Key Shareholder of: ICON, Employee of: ICON, Ying Ding Shareholder of: Xencor, Employee of: Xencor, Lingling Li Shareholder of: Xencor, Employee of: Xencor, Jacky Woo Shareholder of: Xencor, Employee of: Xencor, Brian Sadler Shareholder of: ICON, Employee of: ICON, Jitendra Kanodia Shareholder of: Xencor, Employee of: Xencor, Huaiyu Sun Shareholder of: Xencor, Employee of: Xencor, Ralph Zitnik Shareholder of: Xencor, Employee of: Xencor.

/pdf/pos0119-xmab564-a-novel-potency-reduced-il-2-fc-fusion-2vp0zhev.pdf

POS0119 XmAb564, A NOVEL POTENCY-REDUCED IL-2 FC FUSION PROTEIN SELECTIVELY EXPANDS REGULATORY T CELLS: RESULTS FROM A SINGLE ASCENDING DOSE STUDY IN HEALTHY ADULT VOLUNTEERS

Handle everyday research tasks with reliable, citation-backed results

Your personal Research Agent to handle research tasks with citation-backed results

Popular Tasks used by Researchers

How can I help with your research?

Meet SciSpace

Get more enhanced response by uploading the PDFs you want me to reference.

No relevant PDFs in your library

SciSpace is the AI research assistant for academics. Run systematic literature reviews on 280M+ papers, and write papers with cited sources. Trusted by 1M+ students, PhDs & researchers.

SciSpace | AI for Research

Analyze PDFs

Code & Manuscripts

Funding & Grants

Literature & Patents

Medical & Clinical Data

Systematic Review

Visualize & Present

Web & Data

Build a Google Scholar-like website for your research.

Build a website

Create charts and images for your research

Create a Chart

Write a paper for submission to a journal

Draft a manuscript

Patent Search

Design eye-catching scientific posters in minutes.

Scientific Poster Generation

Systematic Literature Review

One task is running at the moment. Your messages will be shown right after.

Drag and drop or click here to browse

Loved by <highlight>1 million+</highlight> researchers

Extract a list of specific topics and their sources from unstructured text

Topics

Compare and analyze relevant papers that matches with your search

Papers

Get insights from PDFs and bookmarked papers from your library

My library

Recent searches

Try searching for:

Catch AI-generated content in scholarly and non-scholarly content

{ai} Detector

Ai Writer

Get PDF Summaries, highlighted text explanations 

Chat with PDF

Effortlessly create in-text citations and bibliographies in APA and 2,500 other formats

Citation generator

Get explanations, summaries, and answers on academic papers

Ease up your research workflow with {scispace}'s cohort of exciting AI tools

Elevate your academic writing skills and convey your ideas the way you want

Paraphraser

Explore our range of reading and writing tools

Your file is being prepared and should be ready in a few minutes. If it's a large file, it might take a bit longer. You can close this window, and we'll email you the file when it's done.

You have reached a maximum limit of <strong>{limit}</strong> columns in the table. Remove at least <strong>1</strong> column to add or create another one.

C. Key

Author Tools

Chat about Author

Papers

Safety, Tolerability and Pharmacokinetics of Icapamespib, a Selective Epichaperome Inhibitor, in Healthy Adults

A phase I randomized, double‐blind, single subcutaneous dose escalation study to determine the safety, tolerability, and pharmacokinetics of rezafungin in healthy adult subjects

S268: safety, tolerability, and pharmacokinetic/pharmacodynamic results from phase 1 studies of gbt021601, a next-generation hbs polymerization inhibitor for treatment of sickle cell disease

Reduced triglycerides and LDL cholesterol from once-weekly administration of the well-tolerated novel FGF21 analogue 0499

POS0119 XmAb564, A NOVEL POTENCY-REDUCED IL-2 FC FUSION PROTEIN SELECTIVELY EXPANDS REGULATORY T CELLS: RESULTS FROM A SINGLE ASCENDING DOSE STUDY IN HEALTHY ADULT VOLUNTEERS