Navidea Biopharmaceuticals, Inc. (NYSE American: NAVB) (“Navidea” or the “Company”), a company focused on the development of precision immunodiagnostic agents and immunotherapeutics, today announced enrollment of the 50^th participant in the Company’s pivotal NAV3-33 Phase 3 clinical trial titled “Evaluation of Tc 99m Tilmanocept Imaging for the Early Prediction of Anti-TNFα Therapy Response in Patients with Moderate to Severe Active Rheumatoid Arthritis (RA)” (ClinicalTrials.gov Identifier: NCT05246280).

This Phase 3 trial will establish the ability of Tc99m tilmanocept imaging to serve as an early predictor of treatment response in rheumatoid arthritis (“RA”) patients switching to an anti-TNFα therapy, addressing a large unmet medical need. Overall trial size will range from 198-672 patients, with enrollment targeted to achieve a minimum of 100 clinical responders to anti-TNFα therapy and 98 non-responders.

Rheumatoid arthritis is a serious and potentially debilitating disease. The standard practice of treating RA is to monitor patients starting new RA therapies over a course of three to six months and, in those patients for which the new therapies prove to be ineffective, to change their treatments to an alternative therapy. This trial-and-error process of appropriate treatment selection may take several months to more than a year to arrive at an adequate treatment for any RA patient. Imaging with Tc99m tilmanocept, a synthetic molecule with high affinity to CD206 receptors expressed on activated macrophages, offers the potential to provide an early predictor of clinical response by providing an objective, quantifiable readout of changes in macrophage density in the joints of patients undergoing initiation or change of therapy. These macrophage density changes may be observable weeks before disease modification can be detected with standard clinical assessments. Additionally, in patients with a low-macrophage type of RA who have been shown to be less responsive to anti-TNFα therapy, an initial baseline scan alone could point their physicians to another therapy type that has a better chance of success than an anti-TNFα.

The data from the Company’s completed NAV3-31 Phase 2B trial demonstrated that Tc99m tilmanocept can provide robust, quantitative imaging in both healthy controls and in patients with active RA, and that this imaging is reproducible and can define joints with and without RA-involved inflammation. The Phase 2B trial also provided evidence in support of the hypothesis that Tc99m tilmanocept can provide an early prediction of treatment efficacy in patients switching to an anti-TNFα therapy, with an overall accuracy of early treatment response prediction of 90% at 12-week follow up and 86% at 24 weeks.

The design of the Phase 3 trial is built upon data from this completed Phase 2B study, as well as input from the End of Phase 2 Type B meeting with the FDA. The NAV3-33 Phase 3 trial involves Tc99m tilmanocept imaging in participants with RA who are about to begin anti-TNFα therapy. Planar (two-dimensional) images of the hands and wrists are taken at baseline prior to initiation of therapy and at week 5 following start of therapy. These images are quantitatively evaluated to assess changes in Tc99m tilmanocept signal localization, if any, in order to predict treatment response or non-response as determined by standard clinical assessments at three and six months post therapy start.

Dr. Michael Rosol, Chief Medical Officer for Navidea, said, “This is an important milestone in our RA program and for the Company as a whole. Throughout this program’s development, we have worked closely with expert rheumatologists, nuclear medicine specialists, and the FDA, and we are confident we are on the right path to bringing a valuable tool forward to meet a large unmet medical need in patients with RA.” Dr. Rosol continued, “Success would mean that we can provide rheumatologists and those suffering with RA a noninvasive, quantifiable, early indicator of whether an anti-TNFα treatment is working. This could bring enormous benefit to these patients by assisting physicians in putting them on the right course of treatment earlier than is possible today. We continue to be excited about the level of progress we are making with this trial, the benefits that it could provide to those suffering from RA, and the value a successfully completed trial would create for our shareholders.”

About Navidea

Navidea Biopharmaceuticals, Inc. (NYSE American: NAVB) is a biopharmaceutical company focused on the development of precision immunodiagnostic agents and immunotherapeutics. Navidea is developing multiple precision-targeted products based on its Manocept platform to enhance patient care by identifying the sites and pathways of disease and enable better diagnostic accuracy, clinical decision-making, and targeted treatment. Navidea’s Manocept platform is predicated on the ability to specifically target the CD206 mannose receptor expressed on activated macrophages. The Manocept platform serves as the molecular backbone of Tc99m tilmanocept, the first product developed and commercialized by Navidea based on the platform. Navidea’s strategy is to deliver superior growth and shareholder return by bringing to market novel products and advancing the Company’s pipeline through global partnering and commercialization efforts. For more information, please visit www.navidea.com.

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