| ID | Title | Body | Facebook Description | Facebook image | Facebook Title | Facebook Video | Twitter Description | Twitter Image | Twitter Title | Meta tags |
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| 501 | DEX-M74 for GNE Myopathy (Hereditary Inclusion Body Myopathy) | GNE myopathy, previously known as hereditary inclusion body myopathy, is a rare genetic disorder characterized by progressive muscle weakness that results in severe incapacitation. GNE myopathy has been traced to specific mutations in the GNE gene and the biochemical pathways this gene affects within muscle cells. There are no approved therapies for GNE myopathy, and treatment is limited to palliative care. This purpose of this project is to develop a small molecule (DEX-M74) specifically targeted to address the biochemical pathway deficits caused by the GNE mutations that lead to muscle wasting. Scientific Synopsis GNE myopathy is a rare adult-onset muscular disorder characterized by progressive muscle weakness, resulting in severe incapacitation within 10 to 20 years after onset. GNE myopathy is a genetic disorder that has been traced to mutations in the gene GNE. GNE encodes an enzyme that catalyzes the first two steps in the biosynthesis of sialic acid (SA). The subsequent deficiency of SA production is presumed to cause decreased sialylation of muscle glycoproteins, resulting in muscle degeneration. Recent studies have implicated the SA precursor N-acetyl-D-mannosamine (ManNAc, or DEX-M74) as a potential therapeutic agent for the treatment of GNE myopathy. The National Human Genome Research Institute at NIH filed a patent application on the use of ManNAc for the treatment of GNE myopathy, and it filed an Investigational New Drug application with the Food and Drug Administration (FDA) in 2007 to conduct a Phase 2/3 clinical trial testing the safety and efficacy of ManNAc in GNE myopathy patients. The FDA issued a hold on this clinical trial, citing the need for additional preclinical studies. Lead Collaborator National Human Genome Research Institute and NIH Clinical Center, Bethesda, Maryland William Gahl, M.D., Ph.D. Public Health Impact There are no FDA-approved therapies for GNE myopathy, and treatment is limited to palliative care. There is a clear, high-priority unmet medical need. NIH owns related intellectual property for the use of ManNAc to treat GNE myopathy patients and has designed a Phase 2/3 clinical trial to test its safety and efficacy. The regulatory affairs support required to move this project forward will provide important information adaptable to future TRND projects in the rare disease space. Outcomes TRND supported the completion of animal toxicology studies and generated required data on the manufacturing processes to produce the final drug product. This work allowed TRND to gain FDA approval to lift the clinical hold and initiate human trials. To gather information on the disease and enable clinical trial design, TRND scientists began a natural history study of GNE myopathy disease progression in 2011. Since the clearance from the FDA, TRND scientists have concluded a Phase 1 and Phase 2 clinical study in GNE myopathy patients at the NIH Clinical Center. In 2015, Altamira Bio, Inc. (now Escala Therapeutics) acquired a license and entered into a Cooperative Research and Development Agreement (CRADA) with NIH to continue the development of DEX-M74 for GNE myopathy, as well as other disorders characterized by decreased sialylation. Escala plans to commence a Phase 2/3 clinical trial to demonstrate efficacy of DEX-M74 in GNE myopathy patients in 2017. Publications Mutation in the Key Enzyme of Sialic Acid Biosynthesis Causes Severe Glomerular Proteinuria and Is Rescued by N-acetylmannosamine • Journal of Clinical Investigation • June 2007 Prophylactic Treatment with Sialic Acid Metabolites Precludes the Development of the Myopathic Phenotype in the DMRV-hIBM Mouse Model • Nature Medicine • June 2009 Hereditary Inclusion Body Myopathy: A Decade of Progress • Biochimica et Biophysica Acta • September 2009 Related Information News Release: Mouse Model Points to Possible New Strategy for Treating Rare Muscle Disease, Kidney Disorders News Release: New Zealand Pharmaceuticals Announces Collaboration with the NHGRI to Develop DEX-M74 as a Treatment for Hereditary Inclusion Body Myopathy (HIBM) U.S. Patent No. 60/932,451 filed 30 May 2008: N-acetyl Mannosamine as a Therapeutic Agent Huizing, M.; Gahl, W.A.; Manoli, I.; Klootwijk, E. Clinical Trial: A Phase II Study of DEX-M74 (ManNac) in Subjects with GNE Myopathy | ||||||||
| 500 | Development of the Novel Antifungal VT-1129 for Cryptococcal Meningitis | Cryptococcal meningitis (CM) results from fungal infections that are particularly prevalent in immune-compromised patients. CM is the second leading cause of HIV-related deaths in sub-Saharan Africa, with estimates of 500,000 deaths per year. Current therapies are only marginally effective. The purpose of this project is to develop a novel therapeutic that would greatly improve treatment of CM. Scientific Synopsis CM results from infection by the encapsulated yeasts Cryptococcus neoformans and Cryptococcus gattii and is observed almost exclusively in immune-compromised individuals. The enormous population of HIV-infected people in sub-Saharan Africa (estimated to be more than 20 million), with inadequate access to antiretroviral therapy, is highly susceptible to this disease. The most common drug treatment for CM in this patient population is high-dose fluconazole monotherapy, but it achieves only a 40 percent survival rate after 10 weeks of treatment. A more potent anti-fungal drug that can be given orally once a day would likely provide a significant improvement in survival for this neglected population. This project includes preclinical Investigational New Drug (IND)–enabling studies that will evaluate VT-1129 as a novel, oral, stand-alone drug candidate for the treatment of CM. Lead Collaborator Viamet Pharmaceuticals, Inc., Morrisville, North Carolina Edward Garvey Public Health Impact The global incidence of CM and the mortality rate due to CM infection are increasing. Current drugs (FLC, amphotericin and flucytosine) are marginally effective at best. This project aims to develop novel therapeutics that have the potential to save more than 100,000 lives annually. These new therapies also have the potential to be the first effective therapy for the treatment of C. gattii, an emerging and aggressive fungus that infects non-immunocompromised individuals in industrialized geographies. Outcomes TRND researchers conducted validation studies for the lead compound, VT-1129, including pharmacokinetic, efficacy, and toxicology studies in rodents and non-rodents, enabling selection of an optimal dosing regimen to balance efficacy and safety. The TRND team optimized a synthetic process for scaled-up production of drug at a low cost that will support treatment of patients in the developing world. Additional collaborative studies were completed with the Centers for Disease Control and Prevention (CDC) to test the in vitro efficacy of the molecule against 400 fungal strains from Africa. This TRND support enabled Viamet to successfully raise venture capital funding to continue development of the de-risked candidate and receive Qualified Infectious Disease Product and Fast Track designations from the Food and Drug Administration (FDA). The purpose of these FDA designations is to get important new drugs to patients more quickly by facilitating development and expediting review. Viamet successfully filed an Investigational New Drug (IND) application with the FDA to initiate clinical trials. Related Information News Release: Viamet Receives Fast Track Designation from the FDA for VT-1129 for the Treatment of Cryptococcal Meningitis (June 2016) News Release: FDA Grants QIDP Designation to VT-1129 for Treatment of Cryptococcal Meningitis (September 2015) | ||||||||
| 499 | About New Therapeutic Uses | Therapeutic development is a costly, complex and time-consuming process. The average length of time from target discovery to approval of a new drug is about 14 years. The failure rate during this process exceeds 95 percent, and the cost per successful drug can be $1 billion or more. The high therapeutic development failure rate means there are many existing therapeutic candidates that could be repurposed for use in a new disease indication. NCATS designed its New Therapeutic Uses program to align with one of its primary goals: to foster approaches that improve the translational research pipeline and ultimately accelerate the pace at which discoveries are turned into new preventions, treatments and cures for human diseases. Drug Development Collaboratory Click the image above to view the PDF. The Drug Development Collaboratory enables a partnership with the NCATS Therapeutic Development Branch to conduct IND-enabling studies and provides clinical trial funding from the NCATS Drug Development Partnership program once an IND is cleared. Repurposing Off-Patent Drugs Workshop/Drug Repurposing Toolbox In December 2019, NCATS, the U.S. Food and Drug Administration (FDA), and the Reagan-Udall Foundation held a workshop to discuss research and regulatory challenges of off-patent drug repurposing and formulate actionable solutions to those challenges. Although finding a new therapeutic use for an existing drug seems like a simple way to get more treatments to more patients more quickly, repurposing off-patent drugs generally has little potential for return on the investment made, particularly if generic forms of the drug are already on the market. As a result, despite the potential for repurposed drugs to be brought to market relatively quickly, companies have little financial incentive to invest their resources in finding new therapeutic uses for existing drugs. One recommendation that emerged from the workshop was to provide a toolbox of information for drug repurposing in general, not just focused on off-patent drugs, as a central location for people who are interested in repurposing research. Workshop participants expressed concern that many researchers may be interested in repurposing research but not know where to start, and a central hub or toolbox could serve as critically needed starting point. In response to that recommendation, NCATS established the Drug Repurposing Toolbox to provide easy access to guidance, relevant publications, information about repurposing conferences and other resources, including funding and collaboration opportunity announcements. New Therapeutic Uses Funding and Projects Information Past and currently awarded projects can be found for the following initiatives via NIH Research Portfolio Online Reporting Tools (RePORT). Search by the Funding Opportunity Announcement of interest. NIH-Industry Partnerships reporter.nih.gov/search/B9Xu1HDwMUKpl1maeyaAPg/projects?sort_field=FiscalYear%26sort_order=desc%26shared=true Computational repurposing reporter.nih.gov/search/S52kILMRz0KbcUvMRilRqg/projects?sort_field=FiscalYear%26sort_order=desc%26shared=true Urgent COVID reporter.nih.gov/search/Q8Vx2wZAHEaTEgumbIODvg/projects?shared=true Contact Christine Colvis, Ph.D. (link sends e-mail) 301-451-3903 | The New Therapeutic Uses’ program goal is to foster approaches that improve the translational research pipeline. | /sites/default/files/ntu-awards_1260x630.jpg | About New Therapeutic Uses | The New Therapeutic Uses’ program goal is to foster approaches that improve the translational research pipeline. | /sites/default/files/ntu-awards_1260x630.jpg | About New Therapeutic Uses | ||
| 498 | Deuterated Analogs of Praziquantel for Treatment of Schistosomiasis | Infection by the Schistosoma worm, called schistosomiasis, is second only to malaria as the most devastating parasitic disease, affecting more than 200 million people worldwide. Standard therapy requires high doses of praziquantel (PZQ). Standard PZQ is highly metabolized, so very high doses are required to treat each patient. The purpose of this project is to develop modified forms of PZQ that will improve potency and drug metabolism, thereby lowering the dose needed to clear infection and allowing much more widespread patient treatment, with a goal of global eradication. CoNCERT Pharmaceuticals’ platform technology to increase exposure of currently approved therapeutics could be applied to other therapeutics in the rare and neglected tropical disease areas. Scientific Synopsis Schistosomiasis, or bilharzia, is caused by parasitic Schistosoma worms and is a neglected tropical disease in need of further research and treatment efforts. Schistosomiasis is second only to malaria as the most devastating parasitic disease, and more than 200 million people are infected worldwide in Africa, South America, the Caribbean, the Middle East, southern China, and parts of Southeast Asia, Laos and the Philippines. Humans contract the parasites following exposure to contaminated fresh water through bathing, wading, swimming, and washing. The parasites mature over several weeks and reside largely in the blood vessels, releasing eggs that can travel to the intestine, liver or bladder and cause inflammation and scarring. The current standard of care for schistosomiasis is treatment with oral PZQ. It is well absorbed (80 percent) but is highly metabolized via a pronounced first-pass effect, resulting in low effective bio-availability. Over 99 percent of the dose is converted to oxidative metabolites via liver enzymes. As a result, to achieve therapeutic blood levels, patients must be dosed repeatedly with multiple 600-mg tablets of PZQ at a level of 40–60 mg/kg over one to two days. PZQ is dosed as a racemate (50:50 mixture of R and S enantiomers), but only the R enantiomer contributes to the anti-parasitic efficacy. The extreme bitter taste of the drug can lead to vomiting. Interestingly, the bitter taste is more associated with the unneeded S enantiomer than with the active R enantiomer. CoNCERT Pharmaceuticals has synthesized deuterated analogs of PZQ and has demonstrated that selective deuterium incorporation imparts significant metabolic stabilization in vitro. Based on its experience with numerous deuterium-modified drugs, CoNCERT Pharmaceuticals expects these compounds to retain the positive pharmacologic effects of PZQ while potentially enabling lower or less frequent doses. Additionally, the company has prepared R enantiomers of its analogs, which may further facilitate smaller pill sizes, fewer pills per dose and a more palatable taste profile through the elimination of the unneeded S enantiomer. By metabolically stabilizing PZQ through deuterium substitution and selectively producing the R enantiomer, the company anticipates producing a significant improvement over the current standard of care. The first proof-of-concept milestone for the Deuterated Praziquantel project was achieved via the demonstration of metabolic stabilization in vitro for deuterated analogs versus PZQ. Lead Collaborator CoNCERT Pharmaceuticals, Inc., Lexington, Massachusetts Julie Liu, Ph.D. Public Health Impact More than 200 million people worldwide are infected with schistosomiasis. The current standard of care involves multiple large doses of oral PZQ, which is highly metabolized, resulting in low effective bio-availability. PZQ also has an extreme bitter taste that can cause vomiting and negatively affects patient compliance with dosing. Outcomes TRND researchers optimized the synthesis of a deuterated R-PZQ analog and evaluated R-PZQ and deuterated analogs in in vitro and in vivo studies. These studies included metabolite identification and quantification, confirmation of relative metabolic stability in vitro, and demonstration of stabilization to metabolism in vivo. TRND researchers completed in vitro efficacy studies comparing R-PZQ and its major metabolites as well as a pilot PZQ efficacy study in vivo. During the conduct of this research, Merck KGaA, as part of the Pediatric Praziquantel Consortium, announced a commitment to develop pediatric formulations of PZQ and R-PZQ. In light of this announcement, TRND staff concluded that the medical need for developing deuterated R-PZQ to treat schistosomiasis in pediatric patients has been met. Consequently, this TRND project has been discontinued. | ||||||||
| 497 | Cyclodextrin for Niemann-Pick Type C1 Disease | Niemann-Pick disease type C1 is a fatal genetic disease characterized by a failure to metabolize and dispose of cholesterol and lipids, causing progressively impaired movement and intellectual function. It strikes in early childhood and is lethal within a decade of diagnosis. There are no therapies for Niemann-Pick disease type C1 approved by the Food and Drug Administration (FDA), but 2-hydroxypropyl-ß-cyclodextrin (HPBCD) appears to reduce the cholesterol and lipid accumulation and prolongs survival in disease animal models. The goal of this project is to generate the extensive data needed to establish safe, effective dosing for the delivery of HPBCD directly into the central nervous system of Niemann-Pick patients and to test the drug for initial safety, efficacy and biomarker reliability in patients. Scientific Synopsis At left, fibroblasts homozygous for mutations in NPC1 demonstrate an increased accumulation of red Lysotracker staining indicative of the storage disease. At right, addition of cyclodextrin rescues this lysosomal storage defect. Niemann-Pick disease type C1 is an autosomal recessive, neurodegenerative disease with a frequency of one in 120,000 live births. Approximately 95 percent of cases are caused by mutations of the NPC1 gene, and the remaining 5 percent are caused by mutations in the NPC2 gene. Mutations that produce defective NPC1 protein, a cholesterol trafficking protein, lead to accumulation of unesterified cholesterol and other lipids in lysosomes. Manifestations of the disease include neonatal jaundice, splenomegaly, ataxia, and progressive neurodegenerative impairment of motor and intellectual function. Most often, the onset of symptoms occurs in early childhood, leading to death within a decade. Currently, no therapies have been approved by the FDA for this progressively fatal neurodegenerative disease. The molecule HPBCD has been shown to reduce both cholesterol and sphingolipid storage and to prolong survival in two types of Niemann-Pick type C1 animal models. The goal of this project was to provide the preclinical studies and clinical tools needed to establish safe and effective dosing regimens for treatment of human subjects with HPBCD. Lead Collaborator Washington University in St. Louis, Missouri Daniel Ory, M.D. Public Health Impact Currently, there are no FDA-approved therapies for this disease. Miglustat, an inhibitor of glycosphingolipid biosynthesis, is approved outside the United States, but a recent controlled study and a series of case reports suggest limited efficacy in NPC. There is an unmet medical need to develop safe and more effective treatments that significantly delay the symptoms and extend the lifespan of patients with Niemann-Pick disease type C1. Outcomes TRND established an interdisciplinary project team of academic and industrial scientists from nine different organizations and received ongoing input from patient advocacy groups to accomplish the clinical evaluation of HPBCD most efficiently. TRND scientists conducted the animal toxicology studies necessary to file an Investigational New Drug (IND) application with the Food and Drug Administration (FDA) and helped support biomarker studies. TRND provided regulatory support to achieve clearance of the IND application in November 2012, and first-in-human clinical trials began in January 2013 at the NIH Clinical Center. Due to the strong preclinical and early clinical data, including the Phase 1 trial, the program was licensed to a company, Vtesse Pharma, and received the FDA’s Breakthrough Therapy Designation. This designation could accelerate approval to provide the first effective treatment for slowing the progress or stabilizing the devastating impacts of NPC in children and adolescents. The Phase 1 trial was concluded successfully, and currently, the drug is being tested in a multicenter, multinational Phase 2b/3 clinical efficacy trial sponsored by Vtesse. This TRND project is now concluded. Publications Collaborative development of 2-Hydroxypropyl-β-Cyclodextrin for the Treatment of Niemann-Pick Type C1 Disease, Current Topics in Medicinal Chemistry, 2014, 14, 1-10 Cholesterol homeostatic responses provide biomarkers for monitoring treatment for the neurodegenerative disease Niemann–Pick C1 (NPC1), Human Molecular Genetics, June 25, 2014 Development and validation of sensitive LC-MS/MS assays for quantification of HP-β-CD in human plasma and CSF, Journal of Lipid Research, May 27, 2014 Cholesterol Oxidation Products Are Sensitive and Specific Blood-Based Biomarkers for Niemann-Pick C1 Disease, Science Translational Medicine, Nov. 3, 2010 Related Information News Release: Experimental Treatment for Niemann-Pick Disease Type C1 Appears Safe, Effective (August 2017) Web Feature: NIH, Academia and Patient Advocate Collaboration Speeds Niemann-Pick Type C1 Research (March 2017) News Release: NIH teams With Industry to Develop Treatments for Niemann-Pick Disease Type C (January 2015) News Release: Leading Life Science Syndicate Commits $25 Million to Series A Funding to Launch Vtesse, Inc., the First Rare Disease Company Spun Out of Cydan Development, Inc. (January 2015) Web Feature: TRND Research Leads to NIH Trial to Test Drug for Niemann-Pick Type C1 (February 2013) News Release: NIH Clinical Trial Begins for Treatment of Rare, Fatal Neurological Disorder (January 2013) News Release: RRD Selected as Development Partner for NIH Therapeutics for Rare and Neglected Diseases Program (January 2011) From the NIH Clinical Center: NIH Bench to Bedside Award: Cyclodextrin Therapy for Niemann-Pick C1 Disease (2011) | ||||||||
| 496 | LUM-001 as a Treatment for Creatine Transporter Deficiency | Creatine serves as a crucial energy source in the brain, and it is delivered to brain tissue by a specialized transport protein. Approximately 42,000 males in the United States are affected by creatine transporter deficiency (CTD), in which creatine cannot enter the brain, resulting in profound learning disabilities, autistic behavior, recurring epileptic seizures and lifelong care needs. There are no therapies for CTD patients approved by the Food and Drug Administration (FDA). The lead collaborator has identified a creatine analog (LUM-001) that can penetrate the brain and serve the same role as creatine, even when creatine transporters are defective. The goal of this project is to develop LUM-001 into an oral therapeutic to treat CTD. Scientific Synopsis The academic colleagues of Lumos Pharma previously reported severe expressive and cognitive delays in a 6-year-old boy who has a unique creatine deficiency in the brain, which was diagnosed by proton magnetic resonance spectroscopy. They found that he has a nonsense mutation in the X-linked creatine transporter gene (CT1; SLC6A8), which resulted in the expression of a truncated (non-functional) creatine transporter protein. This condition is now known as CTD and is one of three creatine deficiency syndromes. The creatine deficiency syndromes are considered rare disorders and have autism-like features. The discovery of inborn errors of metabolism involving creatine synthesis (two other disorders are readily reversed with creatine treatment) and transport, as well as the use of creatine transporter knockouts that model the phenotype of these diseases, provide compelling evidence suggesting that the creatine/PCr/CK system plays a critical role in normal brain function. It is estimated that CTD causes between 1 and 5 percent of all X-linked mental retardation. The primary clinical manifestations of the affected males are mental retardation, severe expressive language disorder and a seizure disorder, requiring dependent care for life. Creatine transporter knockout mice were treated with LUM-001, a repurposed small molecule that was shown to be capable of (1) getting across the blood brain barrier and (2) improving brain metabolism and cognitive function of the mice. Two parallel groups of patients with brain creatine deficiency syndromes (GAMT and AGAT), which have similar clinical manifestations as CTD, show significant clinical improvement when supplemented with creatine monohydrate. Creatine monohydrate supplementation is not effective in CTD because the creatine transporter gene is defective, preventing creatine from crossing the blood-brain barrier. As a result, no clinical improvement is seen in CTD patients when supplemented with creatine monohydrate. LUM-001 has been shown to cross the blood-brain barrier, interact with creatine kinase in the brain, become phosphorylated and act in the same way as creatine as an energy buffer. Lead Collaborator Lumos Pharma, Inc., Austin, Texas Robert Davis Public Health Impact CTD is a serious lifelong medical condition that affects approximately 42,000 males. Currently, there is no treatment for CTD. A child with CTD requires dependent care for life due to varying degrees of mental retardation, lack of language development, and autism spectrum disorders. A therapy for boys with CTD would result in increased quality of life and societal productivity of patients and caregivers. Outcomes After TRND’s acceptance of the project, Lumos was able to secure additional funding from the Wellcome Trust and venture capital to speed the team’s collaborative work. TRND scientists performed pharmacokinetic studies in animal models of the disease to better understand brain uptake of LUM-001. Key toxicology, formulation development, and chemistry and manufacturing activities were completed, which enabled Lumos to successfully file an Investigational New Drug (IND) application with the Food and Drug Administration and initiate a Phase 1 safety study in healthy volunteers. To support future trials in patients, TRND began collaborating with Lumos on a prospective, multi-center natural history study, with the NIH Clinical Center as one of the sites. Lumos transferred sponsorship of the ongoing natural history study to Ultragenyx Pharmaceutical Inc. See ClinicalTrials.gov, NCT02931682. | ||||||||
| 495 | Bone Morphogenetic Protein Inhibitors to Treat Fibrodysplasia Ossificans Progressiva | Fibrodysplasia ossificans progressiva (FOP) is a rare, fatal disease marked by inappropriate growth of bone fragments within the muscles, ligaments and other connective tissues, causing pain and progressive immobility. There are no disease-modifying therapies approved by the Food and Drug Administration. This bone formation is initiated by inappropriate activation of the bone morphogenetic protein (BMP) pathway. The lead collaborator has identified a compound that inhibits this spurious activation of the BMP pathway. The purpose of this project was to develop this early-stage inhibitor compound into a drug that may be taken orally and to perform the studies needed for testing in FOP patients. Scientific Synopsis Heterotopic ossification (HO), the formation of ectopic bone in skeletal muscle and other connective tissues, is an important cause of morbidity from joint immobility and pain. FOP, a rare form of HO, is inherited as an autosomal dominant trait and is typically associated with activating mutations in Acvr1, the gene encoding the BMP type I receptor, ALK2. Individuals with FOP only have minimal skeletal abnormalities at birth, but extensive HO affecting nearly all skeletal muscles, ligaments and fascia is triggered after birth by traumatic injury or inflammation. No effective treatments currently exist for FOP patients, and disease progression results in severe restriction of joint function and premature mortality. In 2008, the principal collaborators identified the first small molecule inhibitor of BMP signaling. The compound, dorsomorphin, blocks BMP signaling by inhibiting BMP type I receptors. Dorsomorphin derivatives were developed through initial medicinal chemistry optimization. The overall objective of this research was to advance the development of a dorsomorphin derivative in preparation for clinical testing in patients with FOP. Lead Collaborator Brigham and Women’s Hospital, Boston Paul Yu, M.D., Ph.D. Public Health Impact No effective treatments currently exist for FOP patients, and disease progression results in severe debilitation, restriction of joint function and premature mortality. Moreover, this project holds the promise to deliver new therapeutic candidates for multiple, seemingly disparate, rare conditions – FOP and iron-refractory iron deficiency anemia – due to the shared molecular mechanism of hyperactivated ALK2 / BMP signaling. Outcomes The TRND researchers determined that the initial lead molecule was unsuitable for further preclinical development, requiring further optimization through medicinal chemistry, which included the evaluation of over 1000 compounds in vitro. These efforts led to the identification of two potent ALK2 inhibitors, TRND2477 and TRND9780, and attracted a new collaborative partner, Keros Therapeutics. TRND’s preclinical support enabled Keros to initiate clinical development of TRND2477 (as KER-047). KER-047 has completed Phase I clinical trials in Australia and, in June 2022, started Phase 2 clinical trials in Europe in patients with iron-refractory iron deficiency anemia. | ||||||||
| 494 | Completed TRND Projects | Click on the links below to view completed TRND projects: Aes-103 for Sickle Cell Disease Antifibrotic Therapy for the Treatment of Pulmonary Hypertension Auranofin for Chronic Lymphocytic Leukemia AVI-4038 for Treatment of Duchenne Muscular Dystrophy Bone Morphogenetic Protein Inhibitors to Treat Fibrodysplasia Ossificans Progressiva CMX001 for Treatment of Neonatal Herpes Simplex Virus Cyclodextrin for Niemann-Pick Type C1 Disease Deuterated Analogs of Praziquantel for Treatment of Schistosomiasis Development of a Therapeutic for Lassa Fever Development of Acoziborole for the Treatment of Human African Trypanosomiasis Development of Oxadiazoles as Treatment for Schistosomiasis and Hookworm Development of the Novel Antifungal VT-1129 for Cryptococcal Meningitis Development of VBP15 for Treatment of Duchenne Muscular Dystrophy DEX-M74 for GNE Myopathy (Hereditary Inclusion Body Myopathy) Gene Therapy for the Treatment of AADC Deficiency Gene Therapy for the Treatment of Pompe Disease Inhaled GM-CSF Therapy for Autoimmune Pulmonary Alveolar Proteinosis LUM-001 as a Treatment for Creatine Transporter Deficiency Novel Treatment for Hermansky-Pudlak Syndrome Pulmonary Fibrosis PAK Inhibitor for Fragile X Syndrome A Protein Replacement Drug for Friedreich’s Ataxia Repurposing an EU Therapeutic for Hemoglobinopathies Small Molecule Pharmacological Chaperone for the Treatment of Autosomal Dominant Retinitis Pigmentosa Therapy for Fuchs Endothelial Corneal Dystrophy Treatment of Acid Ceramidase Deficiency Use of Rapamycin for the Treatment of Hypertrophic Cardiomyopathy in Patients with Noonan Syndrome with Multiple Lentigines (NSML) Use of Retinal Progenitor Cells for the Treatment of Retinitis Pigmentosa | ||||||||
| 492 | A Novel Compound for Targeted Treatment of Core Binding Factor Leukemia | Core binding factor (CBF) leukemia is a rare cancer with a survival rate of less than 50 percent. Standard treatments are nonspecific chemotherapy and bone marrow transplantation, which are frequently associated with significant side effects, including life-threatening infections, bleeding, kidney dysfunction and even death. This project aims to develop a drug targeted to the specific genetic abnormality responsible for CBF leukemia that can significantly improve survival with fewer complications than current treatments. Scientific Synopsis Leukemia is a bone marrow cancer involving developing white blood cells and often is associated with specific, recurrent chromosome translocations and inversions that generate fusion genes, which play critical roles in leukemogenesis. In this project, targeted treatments are being developed for a subgroup of leukemia based on current understanding of how leukemia develops at the molecular level. The “CBF” subgroup of leukemia contains CBF fusion genes that have been shown to play critical roles in leukemia development. Current treatments for CBF leukemia are not optimal, with long-term survival at 50 percent. The research team conducted a small chemical library screen to find inhibitors that block CBF protein interactions. Through biochemical, cell culture and animal model studies, they identified three chemically related lead compounds. In particular, one of the three compounds has shown leukemia reduction capability similar to standard chemotherapy drugs in preliminary studies in a mouse CBF leukemia model. The researchers will complete efficacy studies in this mouse model, develop one or more backup compounds, optimize formulation, and perform pharmacokinetics and toxicology tests that will lead to clinical trials. Lead Collaborator National Human Genome Research Institute, Bethesda, Maryland Paul Liu, M.D., Ph.D. Public Health Impact Currently, the long-term survival rate for CBF AML is about 50 percent. Moreover, current standard care, chemotherapy and bone marrow transplantation, frequently are associated with significant side effects. The target-specific drug this project is developing may lead to significant improvement in the overall survival rate and reduce treatment-associated complications for CBF leukemias. Outcomes TRND researchers successfully optimized and demonstrated the utility of the animal disease model and showed for the first time that the initial lead compound is effective in the models as a monotherapy. TRND researchers assessed the tolerability of the lead compound in the mouse, resulting in a decision to discontinue its further development. Subsequently, the collaborator developed an improved in vitro efficacy assay, using cells extracted from bone marrow, to support the medicinal chemistry. Currently, a new the lead compound with significantly improved pharmacokinetics and tolerability after repeat dosing in mice is being evaluated in the mouse model. | ||||||||
| 489 | Active TRND Projects | Click on the links below to view active TRND projects: Development of Malaria Transmission-Blocking Drugs A Novel Compound for Targeted Treatment of Core Binding Factor Leukemia Repurposing of a Long-Acting Parathyroid Hormone Analog for the Treatment of Hypoparathyroidism A Treatment for Patients with Jansen’s Metaphyseal Chondrodysplasia | Active TRND Projects | Active TRND Projects |
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