- What makes Navidea Biopharmaceuticals, Inc. unique?
We have a proprietary FDA- and EMEA-approved delivery system that targets a receptor expressed only on activated macrophages.
- Why should I care?
The activated macrophage is critical to both fighting disease and, when improperly activated, causes and/or potentiates many of the most important diseases such as many forms of cancer or autoimmune diseases.
- Cancer – potentiating the immune system’s support of the tumor via production of VEGF, numerous checkpoint inhibitor ligands, proteases crucial for metastasis etc.
- Autoimmune diseases - via production of TNF alpha, superoxide’s, IL-12, increase T1’s and many other pro-inflammatory chemokines and cytokines)
- What evidence exists that activated macrophages are an important target?
Many published studies in animals demonstrate that preventing activation of macrophages or depleting macrophages when functioning inappropriately results in significant efficacy in treating diseases ranging from Cancer, Atherosclerosis, NASH, lipid storage diseases, etc.
- Why haven’t any drugs been developed then that address this problem?
No one has been able to target solely the activated macrophages in isolation without some non-activated macrophages getting included. (See liposomes, CSF inhibitors, CCL2, CCL5 inhibitors)
- What evidence exists that Navidea or Macrophage Therapeutics has addressed this problem?
Published data in The Journal of Immunology, confirms the fact that the Manocept technology can target only the activated state of the macrophage and not the non-activated state. Animal data with a variety of therapeutic constructs confirm the selectivity of the technology. Data generated at the University of Pennsylvania confirm the very high Kd’s on the order of 10-11 to 10-13 achievable with various therapeutic constructs of the Manocept technology. Animal results in NASH confirm the therapeutic efficacy of targeting only the disease-causing macrophages in the liver while leaving intact the tissue resident non-activated macrophages, called Kuepffer cells, which represent roughly 30% of the liver.
- How big is the addressable market?
Auto-immune disease represents the largest therapeutic segment among pharmaceuticals. Humira™, the highest-selling drug in the world, inhibits the activity of just one of the many chemokines and cytokines produced by inappropriately-activated macrophages known as TNF alpha. Newer agents such as JAK’s inhibitors and IL4/IL13 inhibitors block other compounds produced by disease-causing macrophages.
It is estimated that ~1% of the western world is on steroids at any given time. Glucocorticoids are unquestionably the most potent anti-inflammatory products available but are limited in their use due to their severe toxicity. Glucocorticoids work by converting pro-inflammatory macrophages (M1’s) to the anti-inflammatory phenotype (M2). Unfortunately, many cells in addition to activated macrophages have glucocorticoid receptors limiting the use of these highly efficacious but extremely toxic agents. MT has developed an exquisitely targeted glucocorticoid to JUST the activated macrophage potentially enabling the extended safe use of this highly efficacious therapeutic.
In cancer, it is becoming broadly accepted that the role of the tumor microenvironment is key to the progression of disease and thus targeting the microenvironment is critical to maximizing the success in therapy. It is estimated that roughly 30% of a tumor’s volume is tumor cells with the rest stroma and immune cells. Tumor associate macrophages, TAMs, are considered high value targets for enhancing radiation, chemo or immunotherapy. All major pharmaceutical and biotech companies are evaluating approaches to targeting the tumor’s microenvironment confirming the high scientific consensus of the role of TAM’s in supporting the tumor.
- What attributes of the Manocept technology have been demonstrated and why are they important?
Our Manocept platform is protected by issued patents and the fact that a product utilizing this technology has been FDA- and EMEA-approved confirms the fact that the product is:
- effective at targeting its receptor
- safe when dosed at a dose that is effective at targeting its receptor and
- the manufacturing stability and related concerns have been successfully addressed with at least one compound.
The half life of the system has been demonstrated in humans providing clear road maps for developing other agents with the system. The short half life of the existing agent provides significant advantages over competing delivery systems, namely antibodies.
Existing drugs targeting specific “outputs” of disease-causing macrophages have very long half-lives and thus suppress critical components of the immune system for weeks at a time, exposing patients to the risk of infections and cancer.
The newer JAKs inhibitors are oral and have shorter half-lives but also suppress multiple critical components of the immune system for extended durations thus also exposing patients to the risk of infections and cancer.
Finally, some of the newer agents in clinical development are being designed to inhibit the activation of macrophages, thus providing for improved efficacy, as this will inhibit all products of activated macrophages but this will also subject the patients to greater risks, resulting from their essentially being immuno-compromised, as they can no longer activate their immune system as needed so long as they remain on these agents.
We have demonstrated in numerous animal models that we can 1. selectively deplete or convert the disease-causing macrophages with a short acting agent to comprehensively treat the disease by eliminating all the disease-causing agents but in a highly selective manner so that we do not 2. Suppress or in any way diminish the immune system from reacting as needed to normal immunological stimuli.
- Why can’t someone develop an antibody to do the same thing?
Theoretically an antibody should be able to target the same receptor and we do not have IP to prevent that approach. In practice, an antibody lacks the required specificity to accomplish what we can do with our agents. A really well-designed antibody maxes out at a Kd of 10-9 while we can achieve 100- to 10,000-fold better affinities with our product. This enables much lower dosages of our agents which reduces toxicity and enhances dosing formulation degrees of freedom. In addition the cost of goods of our agents are orders of magnitude less that antibodies. We have been told by at least one major pharmaceutical company that they have tried to develop antibodies to M1 macrophages and have been unsuccessful. We have generated human data confirming our ability to target M1 macrophages with both subcutaneous (SC) and intravenous (IV) dosing.
- How will Navidea/Macrophase advance this technology?
We are pursuing the drug delivery model. This means Navidea will continue to develop the core technology and focus our efforts on providing potential partners, who will fund and manage the commercialization efforts for specific applications of interest to them, with products designed to maximize the performance and value for specific indications. For example, oral or topical formulations for chronic inflammatory conditions. For CNS indications, products that cross the blood brain barrier. For cancer, longer-acting more-powerful agents. Our plan is to partner the existing imaging agents and to continue to develop new indications using existing funds, grants and partner payments. For therapeutics, we plan to spin out Macrophage Therapeutics and raise venture capital funding to enable expanded IP and product development for acute indications and orphan diseases while continuing to expand partnering discussions for larger indications.