| ID | Title | Body | Facebook Description | Facebook image | Facebook Title | Facebook Video | Twitter Description | Twitter Image | Twitter Title | Meta tags |
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| 521 | New Therapeutic Uses Funding Announcements | Current Opportunities There are no open New Therapeutic Uses funding opportunities at this time. Information about future opportunities will appear on this page. Expired Announcements These expired funding announcements include details on the application process, eligibility and timelines for the program: NOT-TR-15-008: Notice of Clarification Regarding Clinical Trial Documentation Requirements for New Therapeutic Uses Investigators PAR-14-210: Limited Competition for NIH-Industry Program: Discovering Pediatric New Therapeutic Uses for Existing Molecules (UH2/UH3) PAR-14-211: Limited Competition for NIH-Industry Program: Discovering New Therapeutic Uses for Existing Molecules (UH3) PAR-14-212: Limited Competition for NIH-Industry Program: Discovering New Therapeutic Uses for Existing Molecules (UH2/UH3) PAR-14-213: Pre-application for the NIH-Industry Program: Discovering New Therapeutic Uses for Existing Molecules (X02) NOT-TR-14-001: Notice to Solicit Compounds for Inclusion in the NIH-Industry New Therapeutic Uses Program NOT-TR-12-010: Technical Assistance Webinar for the NIH-Industry Pilot Program: Discovering New Therapeutic Uses for Existing Molecules Limited Competition RFA-TR-12-004 (UH2/UH3) and RFA-TR-12-005 (UH3) NOT-TR-12-008: Clarification for the NIH-Industry Pilot Program: Discovering New Therapeutic Uses for Existing Molecules PAR-12-203 (X02) Pre-Application, and Limited Competition RFA-TR-12-004 (UH2/UH3) and RFA-TR-12-005 (UH3) PAR-12-203: A Pre-application for the NIH-Industry Pilot Program: Discovering New Therapeutic Uses for Existing Molecules (X02) RFA-TR-12-004: Limited Competition for NIH-Industry Pilot Program: Discovering New Therapeutic Uses for Existing Molecules (UH2/UH3) RFA-TR-12-005: Limited Competition for NIH-Industry Pilot Program: Discovering New Therapeutic Uses for Existing Molecules (UH3) | ||||||||
| 520 | New Therapeutic Uses Funding Information | Therapeutic/Indication Pairing Strategies NCATS has released a set of funding opportunities to explore a potential new use of an existing investigational therapy, Food and Drug Administration-approved drug, or licensed biologic. Through the Bench-to-Clinic Repurposing initiative, NCATS will support preclinical studies, clinical feasibility studies or proof-of-concept clinical trials to test the utility of an independent crowdsourcing effort or computational algorithm to predict new uses of a drug or biologic. Current Opportunities NCATS has released the following funding opportunity announcements: Collaborations on Late-Stage Preclinical Through Early-Stage Clinical Trials PAR-20-301: Drug Development Collaboratory (UG3/UH3 Clinical Trial Required) Q&A (PDF - 1.47MB) Expired Announcements These expired funding announcements include details on the application process, eligibility and timelines for the program: NOT-TR-21-006: Notice of Special Interest (NOSI): Repurposing Existing Therapeutics to Address the 2019 Novel Coronavirus Disease (COVID-19) PAR-18-462: Clinical Trial Planning: Therapeutic/Indication Pairing Strategies (U34) (Clinical Trial Not Allowed) NOT-TR-20-027: Notice to Extend the Expiration Date for PAR-18-462 "Clinical Trial Planning: Therapeutic/Indication Pairing Strategies (U34) (Clinical Trial Not Allowed)" PAR-18-332: Clinic Testing Therapeutic/Indication Pairing Strategies (U01 Clinical Trial Required) RFA-TR-20-003: Urgent Phase I/II Clinical Trials to Repurpose Existing Therapeutic Agents to Treat COVID-19 Sequelae (U01 Clinical Trial Required) PAR-18-910: Limited Competition for NIH-Industry Program: Discovering New Therapeutic Uses for Existing Molecules (U01 Clinical Trial Required) NOT-TR-21-004: Notice of Early Termination of PAR-18-910, Limited Competition for NIH-Industry Program: Discovering New Therapeutic Uses for Existing Molecules (U01 Clinical Trial Required) NOT-TR-19-008: Notice of Correction to Revise Application Due Dates for PAR-18-910 Limited Competition for NIH-Industry Program: Discovering New Therapeutic Uses for Existing Molecules (U01 Clinical Trial Required) PAR-18-909: Pre-application for the NIH-Industry Program: Discovering New Therapeutic Uses for Existing Molecules (X02 Clinical Trial Not Allowed) NOT-TR-21-003: Notice of Early Termination of PAR-18-909, Pre-application for the NIH-Industry Program: Discovering New Therapeutic Uses for Existing Molecules (X02 Clinical Trial Not Allowed) NOT-TR-18-032: Notice of Change to Receipt Date on Pre-application for the NIH-Industry Program: Discovering New Therapeutic Uses for Existing Molecules (X02 Clinical Trial Not Allowed) (PAR-18-909) PAR-17-465: Bench Testing Therapeutic/Indication Pairing Strategies (UG3/UH3) NOT-TR-20-025: Notice to Extend the Expiration Date for PAR-17-465 "Bench Testing Therapeutic/Indication Pairing Strategies (UG3/UH3)" NOT-TR-18-016: Notice of Change in Bench Testing Therapeutic/Indication Pairing Strategies (UG3/UH3) (PAR-17-465) NOT-TR-17-022: Notice of Modification to PAR-17-465 "Bench Testing Therapeutic/Indication Pairing Strategies (UG3/UH3)" PAR-18-462: Clinical Trial Planning: Therapeutic/Indication Pairing Strategies (U34) (Clinical Trial Not Allowed) NOT-TR-20-027: Notice to Extend the Expiration Date for PAR-18-462 "Clinical Trial Planning: Therapeutic/Indication Pairing Strategies (U34) (Clinical Trial Not Allowed)" PAR-18-332: Clinic Testing Therapeutic/Indication Pairing Strategies (U01 Clinical Trial Required) NOT-TR-20-026: Notice to Extend the Expiration Date for PAR-18-332 "Clinic Testing Therapeutic/Indication Pairing Strategies (U01 Clinical Trial Required)" RFA-TR-17-001: Pre-application for the NIH-Industry Program: Discovering New Therapeutic Uses for Existing Molecules (X02) RFA-TR-17-002: Limited Competition for NIH-Industry Program: Discovering New Therapeutic Uses for Existing Molecules (UG3/UH3) NOT-TR-17-014: Changes to RFA-TR-17-002 "Limited Competition for NIH-Industry Program: Discovering New Therapeutic Uses for Existing Molecules (UG3/UH3)" RFA-TR-17-003: Limited Competition for NIH-Industry Program: Discovering Pediatric New Therapeutic Uses for Existing Molecules (UG3/UH3) NOT-TR-17-013: Changes to RFA-TR-17-003: Limited Competition for NIH-Industry Program: Discovering Pediatric New Therapeutic Uses for Existing Molecules (UG3/UH3) NOT-TR-17-015: Changes to FOA RFA-TR-17-001 "Pre-application for the NIH-Industry Program: Discovering New Therapeutic Uses for Existing Molecules (X02)" RFA-TR-16-015: Bench Testing Therapeutic/Indication Pairing Strategies (UH2/UH3) PA-16-183: Limited Competition: Rare Diseases Clinical Research Network (RDCRN) Project Supplements for Clinical Trials to Repurpose Drugs in Collaboration with E-Rare Awardees (Admin Supp) RFA-TR-16-001: Preclinical Research Based on Existing Repurposing Tools (R21) NOT-TR-15-008: Notice of Clarification Regarding Clinical Trial Documentation Requirements for New Therapeutic Uses Investigators PAR-14-210: Limited Competition for NIH-Industry Program: Discovering Pediatric New Therapeutic Uses for Existing Molecules (UH2/UH3) PAR-14-211: Limited Competition for NIH-Industry Program: Discovering New Therapeutic Uses for Existing Molecules (UH3) PAR-14-212: Limited Competition for NIH-Industry Program: Discovering New Therapeutic Uses for Existing Molecules (UH2/UH3) PAR-14-213: Pre-application for the NIH-Industry Program: Discovering New Therapeutic Uses for Existing Molecules (X02) NOT-TR-14-001: Notice to Solicit Compounds for Inclusion in the NIH-Industry New Therapeutic Uses Program NOT-TR-12-010: Technical Assistance Webinar for the NIH-Industry Pilot Program: Discovering New Therapeutic Uses for Existing Molecules Limited Competition RFA-TR-12-004 (UH2/UH3) and RFA-TR-12-005 (UH3) NOT-TR-12-008: Clarification for the NIH-Industry Pilot Program: Discovering New Therapeutic Uses for Existing Molecules PAR-12-203 (X02) Pre-Application, and Limited Competition RFA-TR-12-004 (UH2/UH3) and RFA-TR-12-005 (UH3) PAR-12-203: A Pre-application for the NIH-Industry Pilot Program: Discovering New Therapeutic Uses for Existing Molecules (X02) RFA-TR-12-004: Limited Competition for NIH-Industry Pilot Program: Discovering New Therapeutic Uses for Existing Molecules (UH2/UH3) RFA-TR-12-005: Limited Competition for NIH-Industry Pilot Program: Discovering New Therapeutic Uses for Existing Molecules (UH3) | ||||||||
| 519 | Development of VBP15 for Treatment of Duchenne Muscular Dystrophy | Duchenne muscular dystrophy (DMD) affects approximately 10,000 patients in the United States and 40,000 worldwide. Characteristic muscle deterioration results in confinement to wheelchairs by age 12 and death by age 30 due to cardio-respiratory failure. Current therapy, glucocorticoid steroid injection, acts in a nonspecific manner to lessen the severity of symptoms but does not treat the muscle-specific effects of DMD. Glucocorticoids can be used only for a short time due to serious toxic side effects, including bone fragility, suppression of the immune system and suppression of growth hormone production. The purpose of this project is to develop a modified steroid treatment that will be specific to the muscles, potentially avoiding the toxic side effects of current therapy. Scientific Synopsis Chronic treatments with glucocorticoids are considered the standard of care for DMD and result in improved strength and prolonged ambulation. However, side effects, such as bone fragility and stunted growth, can be serious. Accumulating evidence suggests that side effects are mediated by drug/receptor interactions, whereas efficacy is mediated by non-receptor mechanisms. Delta 9,11 derivatives of steroids were developed to retain efficacy but eliminate side effects. Intellectual property on methods of use has been filed in multiple countries and assigned to Validus BioPharma (since renamed ReveraGen BioPharma). Funding to date has been provided by MDA Venture Philanthropy, the Department of Defense Congressionally Directed Medical Research Programs, the Foundation to Eradicate Duchenne and NIH. A lead compound, VBP15, has been selected, and in vitro and in vivo efficacy was shown in muscular dystrophy and asthma mouse models. Pharmacokinetic/absorption, distribution, metabolism, and excretion (PK/ADME) studies have been completed, and VBP15 shows excellent features. The goal of the TRND project is to complete Investigational New Drug (IND)–enabling toxicology to enable first-in-human trials in DMD. The timeline includes acute and chronic GLP toxicology studies, formulation studies, and submission of an IND in a 14- to 16-month time frame. Lead Collaborator ReveraGen BioPharma, Inc., Rockville, Maryland Erica Reeves, Ph.D. Public Health Impact DMD is a rare disease caused by mutations in the X-linked dystrophin gene, resulting in loss of function of the dystrophin protein in skeletal muscle, heart, smooth muscle, and some neurons and glia. Disease incidence is about one in 3,500 live-born males, and approximately 8,000 males are affected in the United States. Current standard therapy, glucocorticoids, can be used only for a short period due to associated serious toxicities, such as bone fragility, adrenal suppression, immune suppression and mood changes. This project aims to develop novel compounds that provide DMD patients with tissue-selective treatment. Potential tissue-selective glucocorticoids can benefit larger patient populations in the United States. Outcomes After TRND’s acceptance of the project, ReveraGen was able to secure supplemental funding from the Muscular Dystrophy Association to speed the team’s collaborative work. TRND completed confirmatory studies demonstrating the effectiveness of the candidate molecule in both cell-based assays and animal models of DMD disease, and successfully designed and executed a novel synthetic route for manufacturing the candidate molecule for human testing under Food and Drug Administration (FDA) guidelines. TRND prepared for and participated in a pre-IND meeting with the FDA in early fiscal year 2014 to receive guidance regarding clinical endpoints and other regulatory issues. TRND support generated the data package necessary for filing an IND application for VBP15, allowing clinical trials to begin. | ||||||||
| 518 | Development of Oxadiazoles as Treatment for Schistosomiasis and Hookworm | Schistosomiasis and hookworm are parasitic diseases responsible for significant mortality and morbidity in developing countries, together infecting more than 1 billion people worldwide. They can cause serious chronic illnesses, resulting in organ damage, cancer, and impaired growth and cognitive development in children. Current standard-of-care therapies for these diseases are not effective in all patients, and there are concerns about developing drug resistance. The purpose of this project is to develop a novel class of drugs with potent anti-parasitic activity. Scientific Synopsis Schistosomes and hookworms are parasites responsible for significant mortality and morbidity in developing countries. They can cause serious chronic illnesses resulting in organ damage, cancer, and impaired growth and cognitive development in children. The current standard-of-care therapies for schistosomiasis (praziquantel) and hookworm (albendazole) are effective in most but not all patients. Due to the high infection rate, these drugs must be administered on an annual or semi-annual basis. Additionally, there are concerns about the development of drug resistance due to widespread treatment of very large populations. A previous collaboration between NIH grantee David Williams, Ph.D., and the NCATS Chemical Genomics Center identified a potential class of drugs for the treatment of schistosomiasis. Researchers screened several libraries for compounds that could inhibit the schistosome redox pathway, which is involved in the defense against free radical damage. They identified several classes of compounds active against this pathway, including phosphinic amides and oxadiazole 2-oxides. Follow-up studies on these compounds showed that oxadiazole 2-oxides effectively killed schistosomes in infected mice at all intramammalian life cycle stages and with little toxicity to the mice. Lead Collaborator Rush University Medical Center, Chicago David Williams, Ph.D. Public Health Impact Schistosomiasis and hookworm infection affect more than one billion people worldwide but are generally neglected because they primarily affect developing countries. These infections can cause serious chronic illnesses resulting in organ damage, cancer, and impaired growth and cognitive development in children. Outcomes TRND scientists supported additional medicinal chemistry optimization and evaluation of the target anti-parasitic compounds, as well as studies of drug efficacy in animal models of the diseases. Despite considerable effort, milestones of pharmacokinetics and in vivo efficacy were not met, and TRND discontinued this project in November 2011. This project is complete. Publications Structure Mechanism Insights and the Role of Nitric Oxide Donation Guide the Development of Oxidiazole-2-Oxides as Therapeutic Agents against Schistosomiasis • Journal of Medicinal Chemistry • Oct. 22, 2009 Synthesis of Oxadiazole-2-oxide Analogues as Potential Antischistosomal Agents • Tetrahedron Letters • April 2009 Identification of Oxadiazoles as New Drug Leads for the Control of Schistosomiasis • Nature Medicine • April 2008 Quantitative High-Throughput Screen Identifies Inhibitors of the Schistosoma mansoni Redox Cascade • PLoS Neglected Tropical Diseases • Jan. 2, 2008 A 1,536-Well-Based Kinetic HTS Assay for Inhibitors of Schistosoma mansoni Thioredoxin Glutathione Reductase • ASSAY and Drug Development Technologies • August 2008 Related Information News Release: Scientists Identify New Leads for Treating Parasitic Worm Disease (March 2008) U.S. Patent Application No. 13/057,667 filed 13 Aug 2009: Treatment of Schistosomiasis Using Substituted Oxadiazole 2-Oxides Thomas, C. J.; Maloney, D. J.; Bantukallu, G. R.; Sayed, A. A.; Simeonov, A.; Williams, D. L. | ||||||||
| 517 | PAK Inhibitor for Fragile X Syndrome | Fragile X syndrome (FXS) is the most common inherited cause of mental impairment and the most common known single-gene cause of autism. The disease is caused by mutations in a gene on the X chromosome and affects about one in 3,000 to 4,000 males. Current therapies include anti-psychotics, anti-depressants or other stimulants to manage disease symptoms, but there are no FDA-approved treatments for FXS itself. A specific protein, p21-activated kinase (PAK), has been shown to play a role in the nerve cell defects seen in FXS patients. The purpose of this project is to develop the first therapy directly targeting this FXS-related biological pathway. Scientific Synopsis FXS is an X-linked genetic disorder. Clinical manifestations of FXS include developmental delays, cognitive defects, hyperactivity and autistic behaviors in affected males. In collaboration with Afraxis, Inc., a San Diego-based biotechnology company, TRND researchers aim to develop the first disease-modifying FXS treatment by directly addressing the defects in synaptic function that are thought to be the cause of cognitive and behavioral deficits associated with FXS. Analysis of brain samples from FXS patients show characteristic defects in dendritic spines, which are the post-synaptic structure in most glutamatergic synapses. Specifically, brain samples from FXS patients show an increased number of "immature" dendritic spines and decreased number of functional, or "mature," dendritic spines. It is hypothesized that the defects in synaptic function and plasticity observed in rodent models of FXS are a direct consequence of the defects in dendritic spines. Afraxis, Inc. proposes that reversing the defects in dendritic spine morphology in humans will reverse synaptic function defects associated with FXS and positively affect cognition and behavior in patients. By targeting p21-activated kinase (PAK), a protein kinase that is a critical regulator of dendritic spine morphology, the researchers on this project aim to develop a disease-modifying therapy for FXS. Lead Collaborator Afraxis, Inc., La Jolla, California David Campbell, Ph.D. Public Health Impact There are no treatments for FXS approved by the Food and Drug Administration (FDA), and off-label medications, such as antipsychotics, antidepressants and stimulants, are used to manage disease symptoms rather than address the underlying pathology of the disease. There is a clear unmet medical need for new therapies for FXS. Outcomes The project team has developed a series of novel and selective compounds that target the desired molecular pathway underlying the disease. Structure-activity relationship (SAR) studies have been conducted to aid the selection of lead compounds that have the properties required for development as a drug. Due to Afraxis’ business priority changes, this TRND project was terminated in January 2013. | ||||||||
| 516 | Small Molecule Pharmacological Chaperone for the Treatment of Autosomal Dominant Retinitis Pigmentosa | Autosomal dominant retinitis pigmentosa (adRP) is a rare genetic disease of the eye, characterized by the loss of the light-sensing cells of the retina. Most patients have night blindness in their early teens, typically progressing to legal blindness by age 40. There are no approved treatments for adRP. Researchers have investigated many genes associated with adRP. The most common genes have changes in the protein opsin. The lead collaborator for this project has identified and begun developing compounds that correct abnormal forms of opsin. The purpose of this project is to fully develop one of these candidate compounds into a drug that may be taken orally and to perform the studies needed for testing in adRP patients. Scientific Synopsis adRP is an orphan genetic disease of the eye, affecting about 75,000 patients worldwide. Nearly 15,000 patients carry the class II (misfolded opsin) mutation. The disease is characterized clinically by the loss of rod photoreceptor cells, followed by cone cell degeneration. The most common adRP-associated mutations affect opsin, a protein integral to the function of the visual cycle. Opsin combines with the pigment 11-cis-retinal to form rhodopsin in the rod cells. In adRP with class II mutations, mutant opsin does not traffic normally to the outer segment but rather aggregates in the photoreceptor cell’s endoplasmic reticulum, causing toxicity, cell death and retinal degeneration. As rod function degenerates due to proteotoxicity, decreased night vision appears as the first symptom. When rod photoreceptors die, cone photoreceptors destabilize, resulting in loss of visual acuity and color/central vision. The principal investigators have identified several series of small molecule pharmacological chaperones that promote the correct folding of mutant forms of human opsin. The lead molecule was confirmed in vitro to be a pharmacological chaperone that induces normal rhodopsin conformation, enabling its translocation to the plasma membrane of the retinal rod cell. The lead molecule is effective in transgenic mouse models representative of the human disease after oral administration, preserving rod photoreceptor cell viability and function. It has progressed successfully through a battery of non-clinical de-risking studies, and the collaborators seek the resources and expertise of TRND to complete the preclinical course and achieve a successful Investigational New Drug filing with the Food and Drug Administration. Lead Collaborator BIKAM Pharmaceuticals, Inc., Cambridge, Massachusetts William F. Brubaker, Ph.D. Public Health Impact There are no approved treatments for adRP. The disease typically results in legal blindness by age 40. Outcomes TRND confirmed the chaperone activity of the lead molecule in cells and significantly improved the throughput of the key assay which can be applied to the screening for new lead compounds. TRND contributed to de-risking the lead molecule by completing a dose range-finding toxicology study to support a future IND filing. After completion of these activities, BIKAM Pharmaceuticals was acquired by Shire Pharmaceuticals to continue the development of the de-risked lead molecule for the treatment of adRP. | ||||||||
| 515 | Development of a Therapeutic for Lassa Fever | Lassa fever is a viral, hemorrhagic (causes bleeding) disease found in tropical regions of Africa. Each year, an estimated 300,000 people are infected, and severe cases can be fatal. Symptoms include fever and damage to multiple organs and the circulatory system. Current treatment options are inadequate, relying primarily on supportive care. The purpose of this project is to develop an antiviral drug to treat and prevent Lassa fever. Scientific Synopsis Lassa fever is one of a group of viral hemorrhagic fevers (VHFs). Several VHFs are caused by arenaviruses, a family of enveloped RNA viruses. Five of these arenaviruses are classified as Category A Priority Pathogens by the Centers for Disease Control and Prevention and the National Institute of Allergy and Infectious Diseases. Arenavirus VHFs are found in tropical regions of South America and Africa, and Lassa fever is endemic to countries in West Africa (Nigeria, Sierra Leone, Liberia and Guinea). Current treatment by intravenous ribavirin has shown some efficacy against Lassa fever when administered early in the course of the disease, but toxicities limit its use. The goal of this project is to develop a small molecule inhibitor able to treat and prevent Lassa fever as well as other arenavirus VHFs. Lead Collaborator Kineta, Inc., Seattle Sean Amberg, Ph.D. Public Health Impact Lassa fever affects an estimated 300,000 people annually in the developing world, resulting in about 5,000 deaths. With the exception of an Argentina-licensed vaccine for Junín virus, no approved vaccines or therapeutics are available for diseases caused by arenaviruses. This project represents an important step toward developing an effective drug to treat and prevent a number of related neglected tropical diseases. Outcomes TRND scientists completed a gap analysis and created a preclinical development plan that identified a set of critical experiments and milestones for the project. During the planning phase, the lead collaborator established a new business alliance, enabling Kineta to use internal corporate resources to continue development and not enter into a collaboration agreement with TRND. This TRND project is complete. | ||||||||
| 514 | Auranofin for Chronic Lymphocytic Leukemia | Approximately 15,000 people in the United States are diagnosed each year with a rare blood cancer called chronic lymphocytic leukemia (CLL). Patients ultimately become resistant to current chemotherapies, and their disease recurs — leading to death. Working with the NCATS Chemical Genomics Center, the lead investigator found that the drug auranofin selectively kills CLL cells. Auranofin was previously approved by the Food and Drug Administration (FDA) as a treatment for rheumatoid arthritis. The goals of this TRND project are to develop auranofin as a treatment for refractory CLL and to develop a novel collaborative paradigm that is broadly applicable to repurposing drugs for rare diseases. Scientific Synopsis The Institute for Advancing Medical Innovation at the University of Kansas, the Leukemia & Lymphoma Society (LLS), and the NCATS TRND program have formed a collaboration known as The Learning Collaborative (TLC). The goal of this collaboration is to identify new drug therapies for patients with rare blood cancers such as CLL. CLL is a blood and bone marrow disease that usually occurs in middle-aged adults and progresses over a long period. Currently, therapeutic options for CLL patients are limited and few therapies are under development. There is an important need for new medical treatments. To find compounds that selectively kill CLL cells versus normal donor lymphocytes, TLC carried out a high-throughput screen of a library of known drugs using a cell proliferation assay. The arthritis drug auranofin was identified as a potent, selective cytotoxic agent. A cooperative research and development agreement (CRADA) has been established to conduct the necessary preclinical and clinical proof-of-concept studies to determine the potential benefit of auranofin in treating individuals with relapsed CLL. The development strategy for repurposing the therapeutic use of auranofin for CLL capitalizes on available preclinical and clinical experience with a known, previously approved, therapeutic drug to accelerate clinical testing of the same drug for a new medical indication (CLL). The goal is to complete preclinical through clinical trial studies, at which time an industry partner will be engaged. Lead Collaborator University of Kansas Medical Center, Kansas City Scott Weir, Pharm.D., Ph.D. Public Health Impact Approximately 15,000 people in the United States are diagnosed with CLL each year. Currently, CLL is treated with various chemotherapies, but patients eventually become resistant to this treatment and can die as a result. There is an unmet medical need to develop novel therapies for chemotherapy-resistant disease. In addition, whereas traditional chemotherapy can be quite toxic, auranofin has received previous regulatory approval and was demonstrated to be reasonably safe and effective in the treatment of arthritis. Outcomes A unique collaboration called The Learning Collaborative (TLC) was established among TRND, the University of Kansas, and the nonprofit Leukemia & Lymphoma Society. Each organization has contributed expertise and funding to the development of auranofin for CLL. The team completed all preclinical studies necessary to support an Investigational New Drug (IND) application to the FDA in less than a year after initiation of the auranofin collaboration. The IND was cleared by the FDA, and auranofin underwent Phase I–IIa clinical trials in patients at three sites (NIH, the University of Kansas and Ohio State University). In the past several months, four quite promising new treatments for CLL have been introduced. As such, the perceived unmet medical need for this blood cancer is much less than when the TLC team embarked on this project. As a partnership, TLC has decided to close the ongoing CLL clinical trial evaluating auranofin. The TRND/TLC project now is concluded. | ||||||||
| 513 | Aes-103 for Sickle Cell Disease | Sickle cell disease (SCD) is a genetic blood disorder that alters red blood cells. The disease affects millions worldwide and about 80,000 patients in the United States, in particular, one in every 500 African American births. A defect in hemoglobin (a protein that helps the cells carry oxygen through the body) causes red blood cells to become rigid and take on a crescent (sickle) shape, blocking small blood vessels and causing decreased blood flow, inflammation, pain and strokes in children. To date, the only drug approved by the Food and Drug Administration (FDA) to treat SCD is hydroxyurea, an anticancer drug that is indicated for use only in adults. Hydroxyurea is only moderately effective and has undesirable side effects that limit its use. The purpose of this project is to develop Aes-103 as an effective treatment for adults and children with SCD. Scientific Synopsis Sickle cell disease (SCD) is a recessive, genetic (i.e., inherited) blood disorder affecting the hemoglobin of red blood cells. Deoxygenation of the abnormal hemoglobin leads to formation of polymers, which causes the red blood cells to become rigid and take on a crescent (sickle) shape. These rigid, sickle-shaped cells can block small blood vessels, decreasing blood flow, which can result in significant and permanent damage to tissues and can be fatal. Although SCD was first described in the medical literature more than 100 years ago (James Herrick, 1910) and was the first disease determined to be of genetic origin (Linus Pauling, 1949), no drugs have been developed specifically for the treatment of SCD. A number of agents have been studied, but the only drug approved for use in treating SCD patients is the anticancer agent hydroxyurea. A sickle-shaped red blood cell. Hydroxyurea is approved for use only in adults, but as an anticancer drug it is only moderately effective against SCD and has undesirable side effects — all of which have limited its use in SCD patients. The novel compound Aes-103 is the first drug candidate to directly target the underlying cause of SCD by maintaining the abnormal hemoglobin molecule in a conformation that does not undergo polymerization and sickling. Lead Collaborator AesRx, LLC, Newton, Massachusetts Stephen Seiler Collaborator National Heart, Lung and Blood Institute, Bethesda, Maryland Gregory Kato, M.D. Public Health Impact SCD affects millions worldwide, including approximately 80,000 patients in the United States. It affects 1 in every 500 African American births. With no approved therapies for use in children, there is a high-priority medical need. Outcomes Less than a year after signing the collaborative agreement with AesRx, TRND completed the preclinical toxicology, chemistry, manufacturing, controls and regulatory studies necessary to support an Investigational New Drug (IND) application to the FDA were completed, and the IND was filed. Upon clearance from the FDA, Aes-103 was moved into Phase I clinical trials in both healthy volunteers and SCD patients. TRND has established a project team that includes TRND staff, AesRx and a leading SCD clinical researcher at NIH’s National Heart, Lung, and Blood Institute. After adoption into the TRND portfolio, AesRx obtained a Massachusetts Life Sciences Center Accelerator Loan to support additional studies needed to complete clinical development of Aes-103. In July 2014, the biopharmaceutical company Baxter International acquired Aes-103 for further clinical development — the first time a company has acquired a drug candidate developed in part by TRND researchers. Publications 5-hydroxymethyl-2-furfural Modifies Intracellular Sickle Haemoglobin and Inhibits Sickling of Red Blood Cells • British Journal of Haematology • February 2005 Structural Basis for the Potent Antisickling Effect of a Novel Class of Five-Membered Heterocyclic Aldehydic Compounds • Journal of Medicinal Chemistry • Sept. 9, 2004 Related Information News Release: First Drug Candidate from Innovative NIH Program Acquired by Biopharmaceutical Company (July 2014) News Release: Baxter Acquires AesRx, LLC, Including Its Investigational Sickle Cell Disease Treatment (July 2014) News Release: AesRx Announces Collaboration With National Institutes of Health (NIH) to Develop Aes-103 for Sickle Cell Disease (November 2010) | ||||||||
| 512 | AVI-4038 for Treatment of Duchenne Muscular Dystrophy | Duchenne muscular dystrophy (DMD), which affects approximately 10,000 patients in the United States and 40,000 worldwide, is a rare genetic disorder affecting one in every 3,500 live male births. Mutations in the dystrophin gene result in loss of the dystrophin protein, which causes deterioration of muscle cells. Patients are confined to wheelchairs by age 12 and can die by age 30 due to cardio-respiratory failure. Sarepta Therapeutics has developed an injectable drug that allows the DNA-RNA machinery to effectively “skip over” the mutated portion of the dystrophin gene so that the body can produce functional dystrophin protein. The purpose of this project is to develop this technology into a potential disease-modifying, lifesaving therapy. The technology being developed for this DMD project may be applicable to many other rare genetic disorders, amplifying the project’s impact. Scientific Synopsis DMD results from mutations in the dystrophin gene that disrupt the mRNA translational reading frame, preventing production of dystrophin, an essential protein that maintains the integrity of muscle cell membranes. Absence of dystrophin leads to severe muscle wasting and affected individuals may succumb to cardio-respiratory failure. This project exploits the mechanism of exon skipping in which a phosphorodiamidate morpholino oligomer (PMO) binds to dystrophin pre-mRNA such that the targeted exon is skipped in the spliced mRNA. This process bypasses the mutation and restores translation of internally truncated but partially functional dystrophin protein. In recent clinical trials, intravenous injections of the Sarepta Therapeutics PMO-based drug AVI-4658 resulted in production of dystrophin in muscles of treated patients. In this project, another PMO drug candidate targeting a different mutation within the dystrophin gene will be tested for safety in a series of preclinical studies mandated by the Food and Drug Administration (FDA). If the compound is found to be safe, clinical trials will commence. Successful conclusion of all trials would result in an exon-skipping drug that benefits a separate group of DMD patients from those targeted by AVI-4658. Together, the two compounds would suggest that other compounds of this class may also be safe, facilitating development of PMO-based drugs for additional DMD mutations and expanding the number of patients benefiting from the treatment. Lead Collaborator Sarepta Therapeutics, Inc., Bothell, Washington Peter Sazani, Ph.D. Public Health Impact Currently, there is no disease-modifying treatment for DMD, a disease that invariably kills patients before they reach 30 years of age. Existing treatments are palliative and do not change the course of disease. Exon-skipping PMOs, if successful in the clinic, can bring potential lifesaving medications to various DMD patient subpopulations. Outcomes The project team performed preclinical efficacy studies to select the candidate molecule for development. After TRND confirmed the lead molecule, Sarepta reclaimed full control of the project, utilizing internal corporate resources to continue development. This TRND project is complete. |
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