A Pilot/Phase 1b Study of Glasdegib-Based Treatment Combinations in Adult Patients With Relapsed AML Post Allogeneic Hematopoietic Cell Transplantation

This phase Ib trial evaluates the best dose and effect of glasdegib in combination with venetoclax and decitabine, or gilteritinib, bosutinib, ivosidenib, or enasidenib in treating patients with acute myeloid leukemia that has come back (relapsed) after stem cell transplantation. Chemotherapy drugs, such as venetoclax and decitabine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Glasdegib, bosutinib, ivosidenib, and enasidenib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Glasdegib inhibits the Sonic the Hedgehog gene. Venetoclax inhibits BCL-2 gene. Bosutinib is a tyrosine kinase inhibitor that inhibits BCR-ABL gene fusion. Ivosidenib inhibits isocitrate dehydrogenase-1 gene or IDH-1. Enasidenib inhibits isocitrate dehydrogenase-2 gene or IDH-2. This study involves an individualized approach that may allow doctors and researchers to more accurately predict which treatment plan works best for patients with relapsed acute myeloid leukemia.

Start Date25 Jun 2022

Sponsor / Collaborator

City of Hope National Medical Center

[+1]

NCT04093505

/ TerminatedPhase 3IIT

Randomized Phase-III Study to Compare Two Schedules of Gemtuzumab Ozogamicin as Adjunct to Intensive Induction Therapy and to Compare Intensive Postremission Therapy Double Blinded With or Without Glasdegib in Older Patients With Newly Diagnosed AML

The study is a randomized phase III trial with a 2x2 factorial design with measurable residual disease and event-free survival as primary endpoints, respectively. Patients are upfront randomized for the two induction schedules (Gemtuzumab Ozogamicin (GO)-147 versus GO-1; ratio 1:1) and for Glasdegib or Placebo (double blinded, ratio 1:1) as adjunct to consolidation therapy and as single agent 6 months maintenance therapy. Chemotherapy backbone for induction therapy is standard 7+3 with cytarabine 200mg/m² continuously day 1 to day 7, daunorubicin 60mg/m² days 1, 2 and 3 and for consolidation therapy intermediate dose cytarabine (1g/m², bi-daily, days 1,2,3). The trial is designed to gain evidence of anti-leukemic activity of GO and Glasdegib in older patients with newly diagnosed acute myeloid leukemia.

Start Date01 Apr 2021

Sponsor / Collaborator-

NCT04230564

/ WithdrawnNot Applicable

Characteristics, Treatment Patterns, and Clinical Outcomes in Non-intensive Chemotherapy Acute Myeloid Leukemia (AML) Patients - a US Real-World Study Using Electronic Medical Record Data

Among patients with a diagnosis of AML who received non-intensive chemotherapy:
Describe patient demographic and clinical characteristics
Describe treatment patterns
Describe effectiveness outcomes
Evaluate tumor response

Start Date31 Oct 2020

Sponsor / Collaborator

Pfizer Inc.

100 Clinical Results associated with Glasdegib Maleate

100 Translational Medicine associated with Glasdegib Maleate

100 Patents (Medical) associated with Glasdegib Maleate

187

Literatures (Medical) associated with Glasdegib Maleate

01 Apr 2025·INVESTIGATIONAL NEW DRUGS

Glasdegib combined with chemotherapy in the treatment of patients with acute myeloid leukemia: a comprehensive meta-analysis

Review

Author: Marey, Mohamed Mahmoud ; Mohammed, Fatma ; Hamed, Mohamed ; Saeed, Abdelrahman ; Sharabati, Israa ; Elhady, Mahmoud M ; Abbas, Ahmed W ; Awad, Abdelaziz A ; Saeed, Omar ; Shaban, Ahmed Yasser ; Abdelgawad, Hussien Ahmed H ; Abou-Shanab, Ahmed R A ; Aldemerdash, Mohamed A ; Bahnasy, Ahmed

BACKGROUND:

Acute myeloid leukemia (AML) is characterized by clonal expansion of myeloid precursors, often accompanied by poor prognostic outcomes in older populations due to molecular heterogeneity and resistance to conventional chemotherapeutic agents. Glasdegib, a potent inhibitor of the Hedgehog signaling pathway, has emerged as a targeted agent that enhances chemosensitivity and demonstrates favorable pharmacodynamic profiles in combination regimens. This systematic review evaluates the clinical efficacy and safety of Glasdegib-based therapies in the management of AML.

METHODS:

Following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, we searched four electronic databases (PubMed, Scopus, Cochrane Library, and Web of Science) to identify eligible studies reported up to August 2024. Using R version R.4.4.1, we reported outcomes as pooled proportions and confidence intervals (CIs). The survival data were extracted from Kaplan-Meier curves and reconstructed.

RESULTS:

The pooled two-year overall survival for Glasdegib plus chemotherapy was 30% (95% CI [27-34%], I² = 0%). Subgroup analysis showed rates of 36% (95% CI [30-42%], Cytarabine and Daunorubicin), 27% (95% CI [20-36%], Low-Dose Cytarabine), and 25% (95% CI [20-31%], Azacitidine. Median survival times were highest for Glasdegib plus Cytarabine and Daunorubicin at 17.6 months (95% CI [15.6-21.9]), followed by 10.4 months (95% CI [8.22-12.3]) for Glasdegib plus Azacitidine, and 7.89 months (95% CI [5.47-11.5]) for Glasdegib plus Low-Dose Cytarabine. Safety analysis revealed varied adverse event rates for Glasdegib plus chemotherapy, with febrile neutropenia (37%), nausea (47%), vomiting (32%), and QT prolongation (44%) being the most commonly reported.

CONCLUSION:

Glasdegib combined with chemotherapy demonstrates promising efficacy in improving survival outcomes for AML patients, particularly in combination with Cytarabine and Daunorubicin. While adverse events were common, they were generally manageable, supporting Glasdegib as a viable therapeutic option. Further research is warranted to optimize treatment regimens and evaluate long-term safety and quality-of-life outcomes.

24 Feb 2025·Journal of Chemical Information and Modeling

Vertex-Edge-Weighted Molecular Graphs: A Study on Topological Indices and Their Relevance to Physicochemical Properties of Drugs Used in Cancer Treatment

Article

Author: Birgin, Kahraman ; Sorgun, Sezer

Quantitative structure-property relationship (QSPR) analysis plays a crucial role in predicting physicochemical properties and biological activities of pharmaceutical compounds, aiding in drug design and optimization. This study focuses on leveraging QSPR within the framework of vertex and edge-weighted (VEW) molecular graphs, exploring their significance in drug research. By examining 48 drugs used in the treatment of various cancers and their physicochemical properties, previous studies serve as a foundation for our research. Introducing a novel methodology for computing vertex and edge weights, we highlight the importance of considering atomic properties and interbond dynamics. Statistical analysis, employing linear regression models, reveals enhanced correlations between topological indices and the physicochemical properties of drugs. Comparison with previous studies on unweighted molecular graphs highlights the enhancements achieved with our approach.

01 Feb 2025·NANO

Statistical Evaluation of Cancer Drugs by QSPR Modeling

Author: Zaman, Shahid

The prospect of discovering a cure for cancer has been present for the past two to three decades. Annually, this illness affects approximately 10 million individuals worldwide. Anticancer medications are pivotal in treating cancer and other malignant diseases. In this paper, the physical properties and chemical reactions associated with the anticancer medications of various topological indices (TIs) have been established. Additionally, we have discussed the degree-based TIs and their Quantitative Structure-Property Relationship (QSPR) analysis. In mathematical chemistry, molecular descriptors are essential, particularly for researchers investigating Quantitative Structure-Activity Relationship (QSAR) and QSPR models. The goal of the QSPR study is to establish a mathematical relationship between the properties under investigation (such as boiling point and flash point) and various descriptors related to the molecular structure of the drugs. Furthermore, we show the correlation with the physicochemical properties of anticancer medications.

News (Medical) associated with Glasdegib Maleate

08 Apr 2025

·www.prnewswire.com

TIBSOVO's Continued Success Solidifies Its Position as a Leader in IDH1 Mutant Space | DelveInsight

With its ability to specifically inhibit the mutant IDH1 enzyme, TIBSOVO addresses an unmet need in personalized cancer treatment, offering new hope for patients with limited options. As clinical evidence continues to support its efficacy and safety, TIBSOVO is positioned for strong growth in the oncology market, especially with expanding indications and global market penetration. LAS VEGAS, April 8, 2025 /PRNewswire/ -- DelveInsight's " TIBSOVO Market Size, Forecast, and Market Insight Report" highlights the details around TIBSOVO, the first and only targeted therapy approved for patients with previously treated IDH1-mutated cholangiocarcinoma. The report provides product descriptions, patent details, and competitor products (marketed and emerging therapies) of TIBSOVO. The report also highlights the historical and forecasted sales from 2020 to 2034 segmented into 7MM [the United States, the EU4 (Germany, France, Italy, and Spain), the United Kingdom, and Japan]. Servier's TIBSOVO (ivosidenib) Overview TIBSOVO (ivosidenib) is a small molecule developed by Servier, acts as an isocitrate dehydrogenase-1 (IDH1) inhibitor. It is indicated for patients with a susceptible IDH1 mutation, which is identified through an FDA-approved test. Currently, TIBSOVO is approved for the treatment of newly diagnosed acute myeloid leukemia (AML), relapsed or refractory AML, relapsed or refractory myelodysplastic syndromes (MDS), and locally advanced or metastatic cholangiocarcinoma. According to Servier's pipeline, TIBSOVO is also being actively investigated for a range of additional indications, with key areas of exploration including solid tumors and hematological malignancies. Learn more about TIBSOVO projected market size for AML, cholangiocarcinoma, and MDS @ TIBSOVO Market Potential The oncology market has experienced significant growth in recent years, driven by advances in cancer research, the development of targeted therapies, and the increasing global prevalence of cancer. As the second-leading cause of death worldwide, cancer continues to pose a major public health challenge, creating a substantial demand for innovative treatments. The market is marked by a shift toward personalized medicine, where therapies are tailored to an individual's genetic profile, allowing for more effective and less toxic treatments. Immunotherapies, such as checkpoint inhibitors, CAR-T cell therapies, and oncolytic virus therapies, are at the forefront of these advancements, offering new hope to patients with previously untreatable cancers. Moreover, the oncology market is expanding due to the growing adoption of precision oncology and molecular diagnostics, which enable earlier and more accurate detection of cancer. This has led to increased investments in research and development, especially in areas like liquid biopsies, companion diagnostics, and next-generation sequencing. The demand for more effective and accessible cancer treatments is fueling innovation in both the pharmaceutical and biotechnology sectors, with numerous new drugs and therapies entering clinical trials and moving toward commercialization. As a result, the oncology market is poised to continue growing, with significant opportunities for breakthrough therapies in immuno-oncology, targeted treatments, and gene therapies. DelveInsight has expertise in the oncology market with an experienced team handling the oncology domain proficiently. DelveInsight has released a series of epidemiology-based market reports on Acute Myeloid Leukemia, Cholangiocarcinoma, and Myelodysplastic Syndrome. These reports include a comprehensive understanding of current treatment practices, emerging drugs, market share of individual therapies, and current and forecasted market size from 2020 to 2034, segmented into 7MM [the United States, the EU4 (Germany, France, Italy, and Spain), the United Kingdom, and Japan]. Gain deeper insights into these diseases with a customized report tailored to your needs. Connect with us today—our experts are ready to assist you! Emerging Competitors of TIBSOVO TIBSOVO faces significant competition in the newly diagnosed AML market from several alternative treatments. Oral therapies like VENCLEXTA (venetoclax), which inhibits BCL-2, and DAURISMO (glasdegib), which targets the hedgehog pathway, present strong contenders. Additionally, emerging therapies such as Lisaftoclax (Ascentage Pharma), another BCL-2 inhibitor, and gilteritinib (Astellas), a kinase inhibitor, are expected to further challenge TIBSOVO in the newly diagnosed AML space. In the R/R AML market, TIBSOVO competes with several therapies, including XOSPATA (gilteritinib), IDHIFA (enasidenib), and others. Emerging therapies such as Ziftomenib (Kura Oncology) and RVU-120 (Ryvu Therapeutics) are also expected to compete with TIBSOVO upon their approval. Ziftomenib, a small molecule developed by Kura Oncology, is currently in Phase I/II trials. In the relapsed/refractory (R/R) MDS market, TIBSOVO faces competition from therapies such as RYTELO (Imetelstat), an IV injection that inhibits oligonucleotide telomerase, and REBLOZYL (Luspatercept), a subcutaneous injection, among other treatment options. In the metastatic cholangiocarcinoma market, TIBSOVO faces relatively less competition, as there are few approved therapies. One such competitor is PEMAZYRE (pemigatinib), a kinase inhibitor that was approved in the US in 2020 and in Europe in 2021. Whereas, Tyra Biosciences' TYRA-200, an FGFR1/2/3 inhibitor, is in phase I stage of development that might be a threat to TIBSOVO one approved. To know more about the number of competing drugs in development, visit @ TIBSOVO Market Positioning Compared to Other Drugs Key Developmental Activities of TIBSOVO In October 2023, Servier announced that the FDA has approved TIBSOVO (ivosidenib tablets) for the treatment of IDH1-mutated R/R MDS. In May 2023, Servier announced that the European Commission has approved TIBSOVO as a targeted therapy in two indications: in combination with azacitidine for the treatment of adult patients with newly diagnosed AML with an isocitrate dehydrogenase-1 R132 mutation who are not eligible to receive standard induction chemotherapy; as well as in monotherapy for the treatment of adult patients with locally advanced or metastatic cholangiocarcinoma with an IDH1 R132 mutation who were previously treated by at least one prior line of systemic therapy. In May 2022, Servier announced FDA approval of TIBSOVO (ivosidenib tablets) in combination with azacitidine for patients with newly diagnosed IDH1-mutated acute myeloid leukemia. In August 2021, Servier announced FDA approval for TIBSOVO (ivosidenib tablets) for the treatment of adult patients with previously treated, locally advanced, or metastatic cholangiocarcinoma with an IDH1 mutation as detected by an FDA-approved test. TIBSOVO is the first and only targeted therapy approved for patients with previously treated IDH1-mutated cholangiocarcinoma. In May 2019, Agios announced FDA approval of TIBSOVO (ivosidenib tablets) as monotherapy for newly diagnosed adult patients with IDH1 mutant acute myeloid leukemia not eligible for intensive chemotherapy. In July 2018, the FDA approved TIBSOVO (ivosidenib) for relapsed or refractory acute myeloid leukemia with an idh1 mutation. In February 2018, the FDA accepted a new drug application and granted priority review for ivosidenib in relapsed or refractory AML with an IDH1 mutation. In December 2017, Agios submitted an NDA to the FDA for ivosidenib for the treatment of patients with relapsed/refractory aml and an IDH1 mutation. TIBSOVO Patent Details TIBSOVO is a drug owned by Servier Pharmaceuticals. Currently, it is protected by 10 Orange book-listed patents filed from 2018 to 2023, out of which none have expired yet. It is also protected by ODE exclusivity for various indications. Discover how TIBSOVO is shaping the blood cancer treatment landscape @ TIBSOVO Side Effects TIBSOVO Market Dynamics In recent years, the therapeutic landscape has undergone significant changes, with promising approaches including immunotherapy, chemotherapy combined with targeted treatments, and the regulation of immune checkpoint-mediated signaling pathways. One such treatment, Ivosidenib, works by inducing the bone marrow to develop normal blood cells, helping to reduce the frequency of blood transfusions. Investment in the research and development of drugs has surged, contributing to a rich pipeline and forecasting promising opportunities in the treatment markets for AML and cholangiocarcinomas. Therapies like TIBSOVO have the potential to capture market attention due to their efficacy and innovation. As healthcare spending continues to rise globally, the pharmaceutical market is expected to expand, providing greater opportunities for market penetration by manufacturers and facilitating the development and distribution of new treatments. Despite progress in cancer treatment, significant gaps remain in understanding the full process that governs carcinogenesis and resistance to treatments, particularly in cancers like acute myeloid leukemia (AML). This highlights the need for more advanced research to address these challenges. Additionally, the limited biomarker testing for patients with the IDH1 mutation restricts the targeted patient pool, posing a challenge for therapies like TIBSOVO to achieve their expected market share. The increasing competition from emerging therapies, such as KEYTRUDA (pembrolizumab), IMFINZI (durvalumab), and the combination of Azacitidine + Venetoclax, further intensifies the pressure on TIBSOVO. Moreover, the difficulty in obtaining sufficient patient pools and diagnostic samples during disease recurrence presents significant hurdles to the effective development of translational research, potentially slowing progress in optimizing treatments. Dive deeper to get more insight into TIBSOVO's strengths & weaknesses relative to competitors @ TIBSOVO Market Drug Report Table of Contents Related Reports Acute Myeloid Leukemia Market Acute Myeloid Leukemia Market Insights, Epidemiology, and Market Forecast – 2034 report deliver an in-depth understanding of the disease, historical and forecasted epidemiology, as well as the market trends, market drivers, market barriers, and key AML companies including Agios Pharmaceuticals, Abbvie, Jazz Pharmaceuticals, Astellas Pharma, Pfizer, Novartis Oncology, Daiichi Sankyo, AstraZeneca, Astex Pharmaceuticals, Inc., Chimerix, Takeda, Rafael Pharmaceuticals Inc., Delta-Fly Pharma, GlycoMimetics Incorporated, BerGenBio ASA, MacroGenics, Syndax Pharmaceuticals, Arog Pharmaceuticals, Forma Therapeutics, Sellas Life Sciences Group, Actinium Pharmaceuticals, Clear Creek Bio Inc., CellCentric Ltd., Biosight Ltd., Astex Pharmaceuticals, Inc., Curis, Inc., NexImmune Inc., Immunomedics, Inc., Sumitomo Dainippon Pharma Co., Ltd., Incyte Corporation, Aprea Therapeutics, Immunicum, DCPrime BV, GT Biopharma, Inc., Hanmi Pharmaceutical Company Limited, Cardiff Oncology, Bio-Path Holdings, Actinium Pharmaceuticals, Aptevo Therapeutics, Synimmune GmbH, GEMoaB Monoclonals, ImmunoGen, Inc., AGC Biologics S.p.A., Precigen, Inc., Novartis Pharmaceuticals, Xencor, Inc., Novartis, Celgene, Bristol Myers Squibb, among others. Relapsed/Refractory Acute Myeloid Leukemia Market Relapsed/Refractory Acute Myeloid Leukemia Market Insights, Epidemiology, and Market Forecast – 2034 report deliver an in-depth understanding of the disease, historical and forecasted epidemiology, as well as the market trends, market drivers, market barriers, and key R/R AML companies including Agios Pharmaceuticals, Abbvie, Jazz Pharmaceuticals, Astellas Pharma, Pfizer, Novartis Oncology, Daiichi Sankyo, AstraZeneca, Astex Pharmaceuticals, Inc., Chimerix, Takeda, Rafael Pharmaceuticals Inc., Delta-Fly Pharma, GlycoMimetics Incorporated, BerGenBio ASA, MacroGenics, Syndax Pharmaceuticals, Arog Pharmaceuticals, Forma Therapeutics, Sellas Life Sciences Group, Actinium Pharmaceuticals, Clear Creek Bio Inc., CellCentric Ltd., Biosight Ltd., Astex Pharmaceuticals, Inc., Curis, Inc., NexImmune Inc., Immunomedics, Inc., Sumitomo Dainippon Pharma Co., Ltd., Incyte Corporation, Aprea Therapeutics, Immunicum, DCPrime BV, GT Biopharma, Inc., Hanmi Pharmaceutical Company Limited, Cardiff Oncology, Bio-Path Holdings, Actinium Pharmaceuticals, Aptevo Therapeutics, Synimmune GmbH, GEMoaB Monoclonals, ImmunoGen, Inc., AGC Biologics S.p.A., Precigen, Inc., Novartis Pharmaceuticals, Xencor, Inc., Novartis, Celgene, Bristol Myers Squibb, among others. Myelodysplastic Syndrome Market Myelodysplastic Syndrome Market Insight, Epidemiology, and Market Forecast – 2034 report delivers an in-depth understanding of market trends, market drivers, market barriers, and key MDS companies such as Bristol-Myers Squibb, Astex Pharmaceutical, Taiho Oncology, Fibrogen, AbbVie, Gilead Sciences, Novartis, Syros Pharmaceuticals, Takeda, Pfizer, Geron Corporation, Karyopharm Therapeutics, Antengene Corporation, BerGenBio ASA, Jazz Pharmaceuticals, Aprea Therapeutics, Sanofi, Medac, among others. Cholangiocarcinoma Market Cholangiocarcinoma Market Insight, Epidemiology, and Market Forecast – 2034 report delivers an in-depth understanding of market trends, market drivers, market barriers, and key cholangiocarcinoma companies such as AstraZeneca, Decalth Systems, Basilea Pharmaceutica, Taiho Oncology, Eisai Pharmaceuticals, TransThera Sciences, Incyte Corporation, Roche, Agios Pharmaceuticals, Servier Pharma, among others. About DelveInsight DelveInsight is a leading Business Consultant and Market Research firm focused exclusively on life sciences. It supports pharma companies by providing comprehensive end-to-end solutions to improve their performance. Get hassle-free access to all the healthcare and pharma market research reports through our subscription-based platform PharmDelve . Contact Us Shruti Thakur [email protected] +14699457679 Logo: SOURCE DelveInsight Business Research, LLP WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

Drug ApprovalImmunotherapyPhase 1Priority Review

10 Jul 2024

·synapse.patsnap.com

GPCR Family Anticancer Targets and Marketed Therapeutic Drugs (Part 3)

This article will continue to review the antitumor targets of the GPCR family and the therapeutic drugs that have been marketed. 05 SMOThe Smoothened (SMO) receptor is a key signal transduction receptor in the Hedgehog signaling pathway and belongs to the GPCR family, featuring the classical seven-transmembrane domain structure. The SMO receptor plays a vital role in the activation of the Hedgehog signaling pathway. The discovery of the Hedgehog signaling pathway dates back to 1980 when Christiane Nüsslein-Volhard and Eric Wieschaus, during their research on the embryonic development of fruit flies, identified gene mutations affecting the segmental development of the Drosophila larvae through genetic screening. These genes were later named Hedgehog genes because their mutant flies' embryos had a spiky appearance reminiscent of hedgehogs. The Hedgehog signaling pathway is highly conserved evolutionarily, playing significant roles not only in fruit flies but also in vertebrates, including in processes such as cell differentiation, cell proliferation, cellular senescence, tumorigenesis, malignant transformation, and tumor resistance. With further research, scientists have identified that the Hedgehog pathway involves a series of proteins, particularly core components that include two membrane proteins, Patched and Smoothened (SMO), along with three transcription factors (Gli1/2/3). The activity of the Hedgehog signaling pathway is regulated by multiple mechanisms, and abnormal pathway activity is associated with various diseases, including birth defects and tumors. In the absence of a Hedgehog ligand, the SMO receptor is inhibited by the Patched (PTCH) receptor, which acts as a tumor suppressor protein that restricts SMO activity and prevents signal transduction. When Hedgehog ligands such as Sonic Hedgehog (Shh), Indian Hedgehog (Ihh), or Desert Hedgehog (Dhh) bind to the PTCH receptor, this inhibition is released, leading to the accumulation and activation of SMO within the cell. Activation of SMO further triggers downstream signaling pathways, particularly the activation of the GLI (Glioma-associated oncogene) family of transcription factors. These transcription factors exist in a repressive form when the signaling pathway is inactive, and upon SMO activation, they are dephosphorylated and converted into an active form, which then enters the nucleus to activate the expression of Hedgesten target genes. Vismodegib (brand name Erivedge™), an oral SMO receptor antagonist, was developed by Genentech and approved by the FDA in January 2012 in the United States. It is primarily used for the treatment of locally advanced or metastatic basal cell carcinoma, especially in patients who are not suitable for surgery or radiation therapy. In 2009, Genentech first disclosed the early drug discovery data of the SMO receptor antagonist candidate drug GDC-0449. Researchers used mouse embryonic fibroblasts harboring a luciferase reporter gene plasmid and performed high-throughput screening downstream of Gli binding sites. When the Hedgehog signaling pathway in these cells was stimulated, the activity of luciferase could be measured optically. Hedgehog pathway antagonists reduce the strength of this signal, leading researchers to obtain lead compounds. Subsequent SAR (Structure-Activity Relationship) studies yielded the candidate drug GDC-0449. At a low dose of 12.5 mg/kg, GDC-0449 was able to completely regress tumors in an orthotopic xenograft mouse model of medulloblastoma that entirely depended on the Hedgehog signaling pathway. Between 2009 and 2012, the Genentech team published two clinical research papers consecutively in the New England Journal of Medicine, reporting the efficacy and safety of Vismodegib in treating advanced basal cell carcinoma. The results showed that among 33 patients with metastatic basal cell carcinoma, the independently assessed response rate was 30%. Among 63 patients with locally advanced basal cell carcinoma, the independently assessed response rate was 43%, with 13 patients (21%) achieving a complete response. The median duration of response for both groups was 7.6 months. In terms of safety, over 30% of patients experienced adverse reactions such as muscle spasms, hair loss, taste disturbances, weight loss, and fatigue. It was reported that 25% of patients experienced severe adverse reactions; 7 patients died due to adverse reactions. Sonidegib (NVP-LDE225), developed by the Novartis team, is a SMO receptor antagonist also used for the treatment of locally advanced, recurrent basal cell carcinoma post-surgery and radiation, or in cases unsuitable for surgery and radiation. Sonidegib works by inhibiting a mechanism known as SMO activation, thereby blocking the Hh signaling pathway and exhibiting antitumor activity across various animal models. In a transgenic mouse pancreatic tumor model, tumors in mice treated with Sonidegib were reduced by 95% compared to untreated mice. In 2014 and 2015, the Novartis team published clinical research papers detailing trial data for Sonidegib used in patients with advanced or metastatic basal cell carcinoma. In the primary efficacy analysis cohort, 20 out of 55 patients (36%) receiving 200 mg of Sonidegib achieved an objective response, and 39 out of 116 patients (34%) receiving 800 mg of Sonidegib achieved an objective response. Among the 200 mg Sonidegib group, 18 of 42 patients (43%) with locally advanced basal cell carcinoma achieved an objective response via central review, and 2 out of 13 patients (15%) with metastatic disease also achieved an objective response. In the 800 mg Sonidegib group, 35 out of 93 locally advanced patients (38%) obtained an objective response through central review, and 4 out of 23 metastatic disease patients (17%) also achieved an objective response. Compared to the 800 mg group, the 200 mg group experienced fewer adverse events leading to dose reduction or treatment discontinuation. The most common grade 3-4 adverse events were elevated creatine kinase and increased lipase levels. In the 200 mg group of 79 patients, 11 (14%) experienced severe adverse events; in the 800 mg group of 150 patients, 45 (30%) experienced severe adverse events. Overall, the benefit-risk ratio of 200 mg Sonidegib provides a new treatment option for patients with advanced basal cell carcinoma. In June 2015, the U.S. FDA approved Sonidegib for the treatment of adult basal cell carcinoma. In 2021, Sonidegib was approved for market in Mainland China, becoming the first SMO receptor antagonist approved in China. Following the market entries of Genentech's Vismodegib and Novartis's Sonidegib Phosphate, Pfizer's SMO antagonist drug, Glasdegib Maleate, was approved in 2018 for the treatment of patients with acute myeloid leukemia. The representative molecular formula for SMO antagonists is as follows: 06 TSHRThe Thyroid-Stimulating Hormone Receptor (TSHR) is a gene that encodes a GPCR controlling the metabolism of thyroid cells. This protein acts as a receptor for thyroid-stimulating hormone (TSH) and thyroxine. In addition to the thyroid, TSHR expression has also been confirmed in various tissues including the brain, bone marrow, peripheral blood, and bones. Thyroid-stimulating hormone (TSH) is a pituitary hormone that stimulates the production of thyroid hormones by the thyroid gland. TSH is primarily synthesized in the thyrotroph cells of the anterior and nodular portions of the pituitary gland. Additionally, hematopoietic cells in the bone marrow, particularly monocyte/macrophage precursors, have also been shown to be a source of TSH. TSH binds to TSHR in the thyroid, stimulating the production and release of thyroid hormones. TSH is a non-covalently linked heterodimeric glycoprotein composed of alpha and beta subunits. The alpha subunit is common with other glycoprotein hormones, such as luteinizing hormone and follicle-stimulating hormone, while the beta subunit is unique to each hormone. TSH signaling can stimulate the secretion of vascular endothelial growth factor (VEGF), leading to angiogenesis and accelerating genomic instability in thyroid cancer. The tumorigenic role of TSH in thyroid cancer has been established. Many patients with differentiated thyroid cancer undergo radioactive iodine ablation postoperatively to remove residual normal thyroid tissue. Several non-randomized studies suggest that radioactive iodine ablation can reduce mortality and recurrence rates. Thyrotropin alfa is a recombinant form of thyroid-stimulating hormone, developed by Genzyme, and was initially approved by the U.S. FDA in 1998 as a diagnostic tool for managing patients undergoing recurrence monitoring of well-differentiated thyroid cancer. This product helps to enhance the sensitivity of tests while allowing patients to avoid potential debilitating symptoms associated with thyroid hormone withdrawal. In 2008, the FDA approved a new supplementary indication for Thyrotropin Alfa for use in conjunction with radioactive iodine to ablate or destroy residual thyroid tissue in patients who have undergone thyroidectomy for cancer. A study published in the New England Journal of Medicine in 2012 demonstrated that low-dose radioactive iodine combined with thyrotropin alfa is as effective as high-dose radioactive iodine, with a lower incidence of adverse events. In the diagnosis and treatment of thyroid cancer, the use of Thyrotropin alfa enhances the uptake of radioactive iodine by these cells, thereby improving the effectiveness of radioactive iodine treatment or enhancing the clarity of imaging during radioactive iodine scans, helping physicians to more accurately assess the status of the disease. Outside of thyroid cancer, the incidence of prostate cancer, lung cancer, and colorectal cancer has been linked to low levels of TSH. For example, various mutations such as missense mutations, nonsense mutations, silent mutations, frameshift deletions, and in-frame deletions have been observed in cancers like colorectal cancer, skin cancer, and thyroid cancer. How to obtain the latest research advancements in the field of biopharmaceuticals? In the Synapse database, you can keep abreast of the latest research and development advances in drugs, targets, indications, organizations, etc., anywhere and anytime, on a daily or weekly basis. Click on the image below to embark on a brand new journey of drug discovery!

12 Apr 2021

·www.globenewswire.com

Global Acute Myeloid Leukemia (AML) Disease Analysis Report 2021: On Average, it Takes 10.8 Years from Phase I to Approval, Compared to 9.6 Years in the Overall Oncology Space

Dublin, April 12, 2021 (GLOBE NEWSWIRE) -- The "Disease Analysis: Acute Myeloid Leukemia (AML)" report has been added to ResearchAndMarkets.com's offering. AML is a type of heterogeneous hematological malignancy that originates from immature white blood cells (blasts) in the bone marrow, which may be derived from either a hematopoietic stem cell or a lineage-specific progenitor cell. "Acute" means that the leukemia may progress rapidly - AML generally spreads quickly to the bloodstream and can then spread to other parts of the body including the lymph nodes, spleen, central nervous system, and testicles.Latest Key TakeawaysThe publisher estimates that in 2018, there were 158,400 incident cases of acute myeloid leukemia (AML) worldwide and expects that number to increase to 169,000 incident cases by 2027. Approximately 60% of newly diagnosed patients are eligible for intensive chemotherapy, such as the 7+3 regimen of cytarabine and daunorubicin.Since 2017, there have been nine new drugs approved for AML in the US, dramatically changing the treatment landscape. Gone is the era where all front-line patients received either 7+3 chemotherapy or a hypomethylating agent (decitabine or azacitidine). Many of the new therapies target specific segments of AML or patients with specific mutations. As such, there is currently little competition between the new therapies, but that will change as therapies receive label expansions and new competitor therapies are approved.Two FLT3 inhibitors have been approved for FLT3-mutated AML: Rydapt for front-line patients eligible for intensive chemotherapy, and Xospata for relapsed/refractory patients. Rydapt may soon face competition in the front-line FLT3 setting as quizartinib, crenolanib, and Xospata are being evaluated in combination with standard chemotherapy and as single-agent maintenance therapies following either chemotherapy consolidation or hematopoietic stem cell transplant (HSCT). Approval in the lucrative maintenance setting would give these drugs a favorable long-term commercial outlook. Approximately 25-30% of AML patients have an FLT3 mutation.Tibsovo and Idhifa are approved in the US as oral, single-agent therapies for relapsed/refractory AML patients with IDH1 and IDH2 mutations, respectively. Tibsovo is also approved as a monotherapy for front-line patients over the age of 75 years. Both of these IDH inhibitors are now in Phase III trials in combination with standard induction (7+3) and consolidation chemotherapy and as maintenance therapy in front-line AML. Tibsovo is also being investigated in combination with azacitidine in a Phase III trial in front-line patients. Approval of Tibsovo and Idhifa in the EU will depend on these Phase III results. Tibsovo may face competition from FT-2102, an IDH1 inhibitor being evaluated in the relapsed/refractory setting in a pivotal single-arm Phase II trial. IDH1 mutations are present in 6-9% of AML, while IDH2 mutations are present in approximately 12% of cases.Mylotarg, an antibody-drug conjugate targeting CD33, is the only monoclonal antibody therapy approved for AML. Mylotarg combined with intensive chemotherapy is recommended for newly diagnosed patients with favorable cytogenetic risk (approximately 10% of patients eligible for intensive chemotherapy). Over 90% of AML patients are positive for CD33 expression.Vyxeos, a liposomal formulation of the 7+3 chemotherapy regimen, was approved in the US and EU for the treatment of newly diagnosed patients with secondary AML after showing an improvement in overall survival compared to the 7+3 regimen in patients ?60 years of age. Secondary AML accounts for approximately one third of new AML diagnoses, but most of these patients will be too frail for Vyxeos. Approximately 16% of patients eligible for intensive chemotherapy have secondary AML. Market access for Vyxeos is strengthened by positive recommendations from the US Centers for Medicare and Medicaid Services and from NICE in England and Wales.Venclexta combined with azacitidine is the new standard of care for newly diagnosed AML patients not suited for intensive chemotherapy (approximately 40% of newly diagnosed patients). A confirmatory Phase III trial evaluating Venclexta + azacitidine demonstrated a survival advantage (15 months versus 10 months) and supported regulatory submissions to European and Japanese authorities, with approvals expected in 2021. Venclexta is currently being evaluated in combination with novel agents in several trials, and a Phase III study (VIALE-M) is evaluating Venclexta combined with azacitidine as maintenance therapy for AML patients in first remission after conventional chemotherapy.Daurismo is the first and only Hedgehog pathway inhibitor approved for AML. Daurismo is approved in combination with low-dose cytarabine (LDAC) for newly diagnosed AML patients not suited for intensive chemotherapy, and will compete with Venclexta in this difficult-to-treat setting. However, in the US, hypomethylating agents are preferred over LDAC, so Venclexta may be preferred over Daurismo.Onureg, an oral formulation of azacitidine, increased overall survival and relapse-free survival in a Phase III trial and was approved in the US as a maintenance therapy following intensive chemotherapy for patients not suited for an HSCT. A European approval decision is expected in mid-2021. The maintenance setting would be a new setting for Vidaza (azacitidine) which is currently used in the EU (and off-label in the US) to treat newly diagnosed elderly AML patients.Rafael Pharmaceuticals is developing devimistat (CPI-613) as a first-in-class therapeutic targeting the altered mitochondrial metabolism present in many cancers, including AML. Devimistat's outlook will depend on the efficacy and safety results from a Phase III trial evaluating the drug in combination with high-dose cytarabine and mitoxantrone in relapsed/refractory AML patients. The first interim analysis is expected in Q2 2021.Chimerix's dociparstat sodium (DSTAT), a glycosaminoglycan analog of heparin designed to have reduced anticoagulant effects, targets the CXCR4 pathway which is involved in the homing and adhesion of AML cells to the bone marrow and is associated with resistance to systemic drugs. DSTAT is being developed in combination with intensive 7+3 chemotherapy for newly diagnosed AML, with the aim of improving the rate of durable response. A Phase III trial is enrolling patients with intermediate or unfavorable cytogenetic risk (74% of patients eligible for intensive chemotherapy).Otsuka's Inqovi is an oral formulation of decitabine that is being developed for patients with AML unsuited for intensive induction chemotherapy. In ASCERTAIN, a Phase III trial enrolling patients with MDS, Inqovi met the trial's primary endpoint of demonstrating pharmacokinetic equivalence to intravenous decitabine. ASCERTAIN has now been extended to include patients with AML in the EU, but a trial with efficacy endpoints will be needed to secure a US AML approval.Takeda's pevonedistat targets the NEDD8-activating enzyme in the ubiquitin-proteasome pathway, and is being developed in combination with azacitidine for a subpopulation of newly diagnosed, elderly AML patients categorized as low-blast count AML. Pevonedistat is also being evaluated in a randomized Phase II trial in combination with Venclexta and azacitidine in newly diagnosed AML patients unfit for intensive chemotherapy.Zeltherva is a therapeutic vaccine being developed as maintenance therapy for patients who have achieved hematologic complete remission, with or without thrombocytopenia, after second-line therapy and who are ineligible for allogeneic stem cell transplantation. Zeltherva's outlook in the specialized setting of CR2 will depend on results in REGAL, its Phase III trial. An interim analysis for safety and futility is expected in Q4 2021.Not including FLT3 and IDH inhibitors, there are five drugs in late-phase development for newly diagnosed AML patients. Dociparstat sodium and entospletinib are being developed in combination with intensive chemotherapy, while MBG453, pevonedistat, and Inqovi are being developed for elderly patients.Relapsed/refractory AML remains an area of unmet need, and new therapies are being developed. Not including FLT3 or IDH inhibitors, there are currently five late-stage therapies being evaluated for this setting (devimistat, DFP-10917, flotetuzumab, Iomab-B, and uproleselan).Key recent events include the approval of Onureg and presentation of numerical data from Venclexta's VIALE-A trial. There were Phase III failures for Helsinn's pracinostat combined with azacitidine in the newly diagnosed setting and for Roche's idasanutlin and Otsuka's guadecitabine in the relapsed/refractory setting. Other Phase III failures include trials evaluting Xospata combined with azacitidine and Daurismo combined with intensive chemotherapy in front-line AML, and an Idhifa monotherapy trial in the third- and fourth-line setting.Key upcoming catalysts for 2021 include topline results from Phase III trials for devimistat, Iomab-B, uproleselan, and Zeltherva, and a possible NDA submission for FT-2102.The overall likelihood of approval of a Phase I AML asset is 6.3%, and the average probability a drug advances from Phase III is 50%. AML drugs, on average, take 10.8 years from Phase I to approval, compared to 9.6 years in the overall oncology space. Companies Mentioned For more information about this report visit

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100 Deals associated with Glasdegib Maleate

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-	Glasdegib Maleate	L01XX63	DB11978

R&D Status

Approved

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Indication	Country/Location	Organization	Date
Acute Myeloid Leukemia	Canada	Pfizer Canada ULC	28 Apr 2020
Adult Acute Myeloblastic Leukemia	United States	Pfizer Inc.	21 Nov 2018

Developing

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Chronic Myelomonocytic Leukemia	Phase 3	Japan	Pfizer Inc.	17 May 2021
Chronic Myelomonocytic Leukemia	Phase 3	Austria	Pfizer Inc.	17 May 2021
Chronic Myelomonocytic Leukemia	Phase 3	Canada	Pfizer Inc.	17 May 2021
Chronic Myelomonocytic Leukemia	Phase 3	Czechia	Pfizer Inc.	17 May 2021
Chronic Myelomonocytic Leukemia	Phase 3	France	Pfizer Inc.	17 May 2021
Chronic Myelomonocytic Leukemia	Phase 3	Hungary	Pfizer Inc.	17 May 2021
Chronic Myelomonocytic Leukemia	Phase 3	Italy	Pfizer Inc.	17 May 2021
Chronic Myelomonocytic Leukemia	Phase 3	Mexico	Pfizer Inc.	17 May 2021
Chronic Myelomonocytic Leukemia	Phase 3	Poland	Pfizer Inc.	17 May 2021
Chronic Myelomonocytic Leukemia	Phase 3	Spain	Pfizer Inc.	17 May 2021

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT03466450 (GEINO 1602, ESMO2024) Manual	Phase 1/2	Glioblastoma First line	74	Glasdegib temozolomide	ovzlvzsmja(dagfgaaefq) = dupiaaejbu qatkakmikd (vxpspvcazm, 41.7 - 65.2) View more	Positive	15 Sep 2024
NCT01286467 (CTgov)	Phase 1	Solid tumor	23	PF-04449913 (PF-04449913 80 mg)	tzjuadqtjk = aqxlfkjckb sdrvrdjqqa (zrvjruewtm, hwcrbpcvle - qpxsjehwuj) View more	-	06 Mar 2024
				PF-04449913 (PF-04449913 160 mg)	tzjuadqtjk = wurvqvuija sdrvrdjqqa (zrvjruewtm, iegltjrnzc - yyahfwmhui) View more
NCT04842604 (CTgov)	Phase 3	Acute Myeloid Leukemia \| Chronic Myelomonocytic Leukemia \| Myelodysplastic Syndromes	14	Glasdegib+Azacitidine (Glasdegib + Azacitidine)	sqvzthfwqo = pudpfzxtkn yxwvyhnofp (hxnqhdtzdk, dtgfdtwqgs - dkmvkfywiy) View more	-	18 Dec 2023
				Placebo+Azacitidine (Placebo + Azacitidine)	sqvzthfwqo = nmqqcbzqkk yxwvyhnofp (hxnqhdtzdk, eikpatvage - wsrphzauvp) View more
EUCTR2017-002410-31-ES \| NCT03466450 (GEINO 1602, ESMO 12023 \| ESMO 22023) Manual	Phase 1/2	Glioblastoma First line	79	Glasdegib+temozolomide+radiotherapy	gidvrrprmp(pklanbgbve) = hujgibqnvl etruwmeujm (sqqelopqmf, 14 - 21.2) View more	Positive	20 Oct 2023
				Glasdegib+temozolomide+radiotherapy (MGMT methylated)	gidvrrprmp(pklanbgbve) = azhhgfssas etruwmeujm (sqqelopqmf, 16 - NR) View more
NCT03416179 (BRIGHT AML 1019, Pubmed)	Phase 3	untreated pediatric acute nonlymphocytic leukemia	730	Glasdegib plus intensive chemotherapy (cytarabine and daunorubicin)	sezmfzhbgo(jopjvijhkz) = The most common treatment-emergent adverse events were nausea, febrile neutropenia, and anemia in the intensive study and anemia, constipation, and nausea in the non-intensive study atxoywgusa (koelwgulxh ) View more	Negative	21 Aug 2023
				Glasdegib plus non-intensive chemotherapy (azacitidine)
NCT03466450 (GEINO 1602, ASCO2022) Manual	Phase 1/2	Glioblastoma First line	74	temozolomide+radiotherapy+glasdegib	hvimylyxjr(unufzrraym) = glasdegib at 75 mg/QD dose eypjssepyf (rjbiysnmou ) View more	Positive	02 Jun 2022
				temozolomide+radiotherapy+glasdegib
NCT02038777 (CTgov)	Phase 1	Acute Myeloid Leukemia \| Myelodysplastic Syndromes	48	PF-04449913 (Monotherapy Cohort: PF-04449913 25 mg)	rnjzprhbdm = brpwddfmwr jlrouukzgl (qipmskdzdg, hyikphhfuf - urmdigbqdk) View more	-	18 Mar 2022
				PF-04449913 (Monotherapy Cohort: PF-04449913 50 mg)	rnjzprhbdm = qsfhvmifiz jlrouukzgl (qipmskdzdg, rvhuaspkgo - idcohzgrxs) View more
NCT04051996 (CTgov)	Phase 2	Acute Myeloid Leukemia \| FLT3 positive Acute Myeloid Leukemia	1	Decitabine+Glasdegib (DAC5)	urefdfysyq(pnamjaghet) = opxumkoygp jxhrdpnunl (wobfhizpte, ryxxwdwmof - ionfwbojlr) View more	-	15 Oct 2021
				Decitabine+Glasdegib (DAC10)	urefdfysyq(pnamjaghet) = gxsxhhjhhq jxhrdpnunl (wobfhizpte, dtehvimmoj - tjypthxyad) View more
NCT03627754 (Pubmed) Manual	Phase 1	Liver Injury	24	Glasdegib	patyrzuosi(htdlpaqsbe): geometric mean ratios = 110.8 (90% CI, 78.0 - 157.3) View more	Positive	01 Jul 2021
				age/weight-matched controls
NCT03416179 (BRIGHT AML 1019 \| BRIGHT AML1019, CTgov)	Phase 3	Acute Myeloid Leukemia	730	Glasdegib+Daunorubicin+Cytarabine (Intensive Study: Glasdegib + Cytarabine + Daunorubicin)	bmkpcyagrq(acxuisgqbb) = qwvliqlcmo pgsutemjjs (njvocydttf, isctmjccjn - bobfgnyrgc) View more	-	25 Jun 2021
				Placebo+Cytarabine+Daunorubicin (Intensive Study: Placebo + Cytarabine + Daunorubicin)	bmkpcyagrq(acxuisgqbb) = msxevkzgnc pgsutemjjs (njvocydttf, ojcgtepujz - mnputszvtf) View more

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