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DUBLIN, OH, United States

Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 165.92K | Year: 2014

DESCRIPTION (provided by applicant): Navidea Biopharmaceuticals (Navidea) is seeking SBIR FastTrack grant support to investigate the clinical utility, safety, and efficacy of its new product, 99mTc-tilmanocept, to identify sentinel lymph nodes (SLNs) during surgeries to remove early stage cervical cancers with the intent of improving patient outcomes and reducing post-surgical morbidities in patients undergoing these operations. Cancer patients can frequently be cured of their illnesses by surgeries that remove their tumors. To be successful, these surgeries must remove all of a patient's cancer. Residual tumor tissue in patients after surgery can result in potentially life threatening disease recurrences. It is very common that the first places to which a cancer may spread (metastasize) beyond the primary tumor are to lymph nodes that are immediately downstream from the tumor in the lymphatic flow, the SLNs. Previously and/or currently, it is/was standard of care in cervical cancer surgeries to remove e

Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 321.84K | Year: 2015

DESCRIPTION provided by applicant Navidea Biopharmaceuticals is seeking support to progress efforts designed ultimately to determine if its diagnostic imaging agent mTc tilmanocept can be used to improve upon the identification of atherosclerotic plaques that are at high risk for near term rupture High risk atherosclerotic plaques are referred to as vulnerable plaques or thin cap fibroatheromas TCFA Rupture of a TCFA causes thrombus blood clot formation leading to blockage of arterial blood flow Such ruptures are the leading cause of myocardial infarctions heart attacks and sudden cardiac death Such TCFA ruptures also contribute significantly to the incidence of strokes Atherosclerosis is a chronic and progressive inflammatory syndrome that develops slowly over the course of many years or decades to generate atherosclerotic plaques in the walls of arteries Individuals infected with HIV experience much accelerated rates of atherosclerosis development even if they are being successfully treated with antiretroviral therapies Generally atherosclerosis is asymptomatic until a TCFA ruptures and the patient experiences a potentially catastrophic cardiovascular disease CVD event A large portion of the population has atherosclerotic plaques to some degree Most of these plaques are stable and are relatively unlikely to precipitate a major CVD event In this application Navidea and its collaborators Dr Steven Grinspoon et al at Massachusetts General Hospital are addressing the need for a more efficacious means to identify TCFA and differentiate TCFA from stable atherosclerotic plaques in cardiovascular imaging studies The potential public health benefit of this project is that asymptomatic persons with high risk TCFA could be placed on currently available therapies which will significantly lower their chances of experiencing a TCFA rupture and a major and potentially life threatening CVD event Many lives may be saved and the lives of many patients could be greatly improved mTc Tilmanocept was purposely designed to bind to the macrophage mannose receptor CD CD expressing macrophages populate tumor associated lymph nodes facilitating accumulation and retention of mTc tilmanocept in SLN Recently it has been observed that CD expressing macrophages densely populate TCFA but not other kinds i e stable atherosclerotic plaques Thus patients injected with mTc tilmanocept may accumulate this imaging agent specifically in TCFA should they occur Visualization of retained mTc tilmanocept in TCFA may possible with SPECT CT thereby identifying patients at high risk for near term CVD events The proposed study has two specific aims The first involved an examination of plaque tissue from both HIV infested and uninfected individuals to confirm the infiltration of CD expressing macrophages specifically in TCFA The second specific aim involves a limited RDRC approved clinical study of individuals with andamp without aortic atherosclerotic plaques and with andamp without HIV infections This study will provide needed information about the feasibility of mTc tilmanocept to better identify patients with TCFA PUBLIC HEALTH RELEVANCE The proposed efforts seek to determine the feasibility of using Navidea Biopharmaceuticalandapos s diagnostic imaging agent mTc tilmanocept to better identify asymptomatic patients with vulnerable atherosclerotic plaques that are at high risk of near term rupture and resulting precipitation of myocardial infarctions sudden cardiac death and strokes accumulatively the leading cause of death in the US If successful this project could facilitate the delivery of life sparing treatments to individuals at risk for major cardiovascular disease events before these events have inflicted their catastrophic tolls

Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 232.46K | Year: 2016

DESCRIPTION provided by applicant Kaposi sarcoma KS is a potentially life threatening consequence of immunosuppression in patients that are infected with human herpes virus HHV Most KS occurs in patients with acquired immunodeficiency syndrome AIDS Current KS therapies have limited efficacy and serious off target toxicities Navidea has been developing mTc tilmanocept r a wholly synthetic molecular construct that binds with very high affinity and specificity to the macrophage mannose receptor CD The first commercial application for mTc tilmanocept is as an intraoperative lymphatic mapping ILM agent for identifying sentinel lymph nodes SLNs during cancer surgeries to remove solid tumors After a broad range of preclinical studies and highly successful clinical trials the FDA and European regulators approved mTc tilmanocept for ILM and identification of SLNs Navidea has learned that KS tumor cells and also tumor associated macrophages TAMs in most types of cancer highly express CD In this grant application Navidea is seeking support to evaluate a tilmanocept like drug delivery construct MT which is intended to deliver doxorubicin to CD expressing cells Doxorubicin is an important therapy for KS in AIDS patients but its efficacy is limited due primarily to its off target cardiotoxicity Heart muscle cells do not expres CD The central concept of this proposal is that MT could concentrate doxorubicin in CD expressing cells such as KS cells and their TAMs while sequestering away this cardiotoxic drug from other tissues and especially from heart muscles This would enhance the effectiveness of the drug while reducing or virtually eliminating its cardiotoxicity An important feature of CD andapos s interactions with its ligands is that after CD ligand binding the complex is internalized into endosomes inside the cell Endosomes become acidified causing CD to release its ligand allowing CD to recycle to the cell surface Navidea has developing acid labile linkers which are part of MT These will permit MT to release its doxorubicin payload only once they are in the endosomes of the targeted cells Navideaandapos s has shown that a MT like prototype molecule specifically kills CD expressing cells It also kills KS cells and their TAMs in KS biopsy explants maintained in culture while sparing cells that do not express CD This Fast Track SBIR application requests support to complete a series of in vitro cell culture based and preclinical animal studies to evaluate the likely safety and efficacy of MT for the treatment of KS The information from these studies will be combined with other information concerning chemical manufacturing controls CMC and synthesis optimization in an investigational new drug IND application that will be submitted to the FDA requesting permission to begin testing MT in human KS patients We anticipate that this project will bring an effective and life sparing new therapy to KS patients who are in desperate need for such a new treatment We also believe that given the data to date this project will be a powerful gateway to a new class of anti TAM therapies directed at solid tumors generally PUBLIC HEALTH RELEVANCE Kaposi sarcoma KS is a serious and potentially life threatening illness in persons infected with the human immunodeficiency virus HIV the causative agent of acquired immunodeficiency syndrome AIDS Tumor associated macrophages TAMs constitute an important tumor component for most types of cancer including KS that contributes to tumor growth and protection from immune responses Navidea is developing a receptor targeted drug construct that may be able to effectively treat KS and could contribute to effective immunotherapy for a wide variety of cancers generally

Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase II | Award Amount: 538.13K | Year: 2015

DESCRIPTION provided by applicant After an interim period of inactivity based on a select alternative commercial focus and after consultation with the FDA Neoprobe Corporation is rapidly reinitiating efforts to develop and commercialize Iodine labeled HuCC CH anti Tumor Associated Glycoprotein TAG monoclonal antibody construct as an aid to cancer surgeons who are operating on patients to remove liver tumors that have spread or metastasized from adenocarcinomas of the colon or rectum TAG is an adenocarcinoma specific product with both notable production in the tumor center and strong tumor margin definition HuCC CH binds to TAG with very high affinity and specificity When I HuCC CH binds to TAG it emits a radioactive signal that can be detected a handheld gamma detection probe utilized by the surgeon This signal defined in real time during the surgery informs the surgeon as to the location and extent of the cancer that the surgeon is trying to remove This will assist the surgeon in two ways that will provide benefit to the patient and improve their quality of care First it will help the surgeon remove the entire tumor from the liver and avoid leaving small amounts of cancer at the margins of the surgical resection Second it will permit surgeons identify small difficult to identify or occult tumors that may hav spread beyond the liver especially to nearby or perihepatic lymph nodes that drain the tumor area To complete the development and commercialization of I HuCC CH for the intended use described Neoprobe must complete a preclinical testing bridging study packet and two human clinical trials The product studies involving validation of chemistry manufacturing and controls CMC studies have already been initiated and are near completion The FDA does require a bridging packet of preclinical animal studies The purpose of these preclinical animal studies is to show that the current production lots of I HuCC CH are equivalent to the lots of diagnostic drug used previously After the CMC and preclinical studies are completed Neoprobe will perform an FDA requested standardization clinical trial that will examine product safety and will train surgeons on the use of I HuCC CH for the intended use in radioimmunoguided surgery RIGS and harmonize surgical procedures This standardization trial will set the stage for a pivotal Phase clinical trial of the product demonstrating the safey and efficacy of the I HuCC CH RIGS system and will support an NDA application to the FDA seeking permission to market the product for use in liver metastases of adenocarcinomas of the colon and rectum Neoprobe is seeking SBIR Fast Track grant support for part of the required preclinical animal study effort and for the standardization clinical trial Neoprobe is developing an I labeled HuCC CH humanized monoclonal antibody construct as an aid to cancer surgeons in the identification and removal of liver metastases in colorectal patients This product will significantly improve the quality and effectiveness of these surgeries with specific focus on tumor margins and perihepatic lymph node involvement the two key components of resection failure and thus provide significantly better patient outcomes

Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 224.99K | Year: 2015

DESCRIPTION provided by applicant Navidea Biopharmaceuticals is seeking SBIR Fast Track grant support for preclinical animal studies and a regulatory phase clinical study of the ability of mTc tilmanocept to identify skeletal joint inflammation due to rheumatoid arthritis RA RA is a chronic progressive systemic autoimmune disease characterized by skeletal joint inflammation If not treated successfully RA can lead to disability disfigurement and premature death Recently antirheumatic drugs DMARDs have dramatically improved outcomes for many RA patients Three problems persist DMARDs are most effective when RA symptoms first appear which is problematic for current RA diagnostics monitoring the effectiveness of DMARD therapy is challenging and a significant portion of RA patients respond poorly or not at all to current DMARDs Therefore there are significant unmet medical clinical needs for a more accurate RA diagnostic especially for early stage RA and for more effective RA therapies With this application Navidea is initiating efforts intended to address these clinically pivotal needs mTc Tilmanocept is a wholly synthetic molecule designed specifically to bind with high affinity to macrophage mannose receptors CD The original intended use for mTc tilmanocept was for imaging sentinel lymph nodes during cancer surgeries an indication for which mTc tilmanocept has received FDA approval mTc Tilmanocept binds to CD displayed on macrophages residing in tumor associated lymph nodes In RA large numbers of CD expressing macrophages infiltrate into the synovial spaces of inflamed joints An animal study with a mouse model of RA showed that mTc tilmanocept can be injected intravenously and thereafter accumulates specifically in RA inflamed joints In an ex vivo test of human synovial aspirates Cy tilmanocept strongly differentiated RA from osteoarthritis and healthy control tissue In this application additional animal studies are proposed to ensure the safety of injecting mTc tilmanocept intravenously Then in a clinical study mTc tilmanocept will be injected intravenously into four types of study participants participants with active RA participants with recent development of polyarthralgia PAT healthy arthritis free individuals over the age of and patients with painful joints not caused by RA PAT may have many causes of which RA is only one About of PAT patients are expected to progress to frank RA in yr It is the RA patients among these patients that would benefit m o s t from early diagnosis so that they can receive DMARD therapy when it is most effective Participants injected with mTc Tc tilmanocept will be imaged by single photon emission computed tomography SPECT This study will investigate the ability of mTc tilmanocept to identify RA inflamed joints and to identify early RA patients among those with PAT Follow on studies will investigate if tilmanocept can also target delivery of therapeutics to RA inflamed joints thus enabling better therapies PUBLIC HEALTH RELEVANCE This project seeks to significantly improve patient outcomes and quality of care for patients with rheumatoid arthritis by providing these patients with an innovative targeted agent tilmanocept that provides more accurate and more timely earlier diagnosis of their illnesses This will enable currently available therapeutics to be more effectiv and may make possible the development of new and even more effective therapies based on the targeted diagnostic

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