Phase II year
2016
(last award dollars: 2017)
Phase II Amount
$1,500,000
Navidea Biopharmaceuticals is seeking SBIR Fast Track grant support for preclinical animal studies and a regulatory phase 1/2 clinical study of the ability of 99mTc-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: 1 ] DMARDs are most effective when RA symptoms first appear, which is problematic for current RA diagnostics; 2 ] monitoring the effectiveness of DMARD therapy is challenging; and 3 ] 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. 99mTc- Tilmanocept is a wholly synthetic molecule designed specifically to bind with high affinity to macrophage mannose receptors (CD206). The original intended use for 99mTc-tilmanocept was for imaging sentinel lymph nodes during cancer surgeries, an indication for which 99mTc-tilmanocept has received FDA approval. 99mTc-Tilmanocept binds to CD206 displayed on macrophages residing in tumor associated lymph nodes. In RA, large numbers of CD206 expressing macrophages infiltrate into the synovial spaces of inflamed joints. An animal study with a mouse model of RA showed that 99mTc-tilmanocept can be injected intravenously and thereafter accumulates specifically in RA-inflamed joints. In an ex vivo test of human synovial aspirates, Cy3-tilmanocept strongly differentiated RA from osteoarthritis and healthy control tissue. In this application, additional animal studies are proposed to ensure the safety of injecting 99mTc-tilmanocept intravenously. Then in a clinical study, 99mTc-tilmanocept will be injected intravenously into four types of study participants: 12 participants with active RA, 30 participants with recent development of polyarthralgia (PAT), 12 healthy, arthritis free individuals over the age of 50, and 12 patients with painful joints not caused by RA. PAT may have many causes, of which RA is only one. About 2/3 of PAT patients are expected to progress to frank RA in =1 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 99mTc Tc-tilmanocept will be imaged by single-photon emission computed tomography (SPECT). This study will investigate the ability of 99mTc-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 Statement: 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.
NIH Spending Category: Aging; Arthritis; Autoimmune Disease; Clinical Research; Diagnostic Radiology; Rheumatoid Arthritis
Project Terms: Address; Affinity; Age; Animals; Antirheumatic Agents; Arthritis; arthritis therapy; Aspirate substance; Autoantibodies; Autoimmune Diseases; Automobile Driving; base; Binding; Biological Products; Blood Tests; cancer surgery; Cessation of life; Chronic; Clinical; Clinical Protocols; Clinical Research; Complement; Confusion; Contracts; Deformity; Degenerative polyarthritis; design; Development; Diagnostic; Diagnostic Imaging; disability; Disease-Modifying Second-Line Drugs; Dose; Early Diagnosis; effective therapy; Effectiveness; Elbow; Enrollment; Ensure; Evaluation; FDA approved; follow-up; Grant; Hand; Health; Human; Image; imaging agent; improved; improved outcome; in vivo; Individual; Infiltration; innovation; Institutional Review Boards; intravenous administration; intravenous injection; Joints; Knee; Laboratories; Lead; lymph nodes; Lymphatic; macrophage; Malignant Neoplasms; mannose receptor; Maps; Medical; Minority; Molecular; Monitor; mouse model; novel therapeutics; Ohio; Pain; Participant; Pathology; Patient-Focused Outcomes; Patients; performance site; Peripheral; Pharmacotherapy; Phase; Physical Examination; Physicians; Polyarthralgias; pre-clinical; preclinical study; premature; prevent; protocol development; Quality of Care; Radiopharmaceuticals; Research Design; research study; Resources; Rheumatoid Arthritis; Safety; Sentinel Lymph Node; Shoulder; Site; skeletal; Small Business Innovation Research Grant; Staging; Swelling; Symptoms; Synovial Fluid; systemic autoimmune disease; targeted agent; targeted delivery; Testing; Therapeutic; therapy outcome; TimeLine; Tissues; Tomography, Emission-Computed, Single-Photon; Toxic effect; Training; tumor; Ultrasonography; Universities; Work; Wrist; X-Ray Computed Tomography
