An already validated approach with Navidea Biopharmaceuticals Inc.'s radioimaging agent for rheumatoid arthritis (RA) might have presaged the victory, but that didn't stop Wall Street from rewarding the shares handsomely, and the stock (NYSE:NAVB) closed Tuesday at $1.10, up 32 cents or almost 41.5%, having traded as high as $1.36.

"We feel our diagnostic is going to revolutionize the industry," CEO Jed Latkin told BioWorld. He predicted that, if approved, the test will be used routinely "for everybody who has RA, because it will be the only one out there that can objectively tell you whether or not the [prescribed] drug is working" and tell ahead of time whether it's likely to. "All the politicians are hammering on the very high cost burden of health care to society," he said. "If there's a tool out there that can tell you whether your $40,000-$60,000-a-year drug is working or not working, [payers are] going to insist that you do that." Today, insurers "try to get patients to come in every six months to be monitored," which doesn't always happen. He said Navidea's test will incentivize visits to the doctor because patients "can see the map of their body, they can see the joints" and the state of progress, so that the drug can be continued or switched.

The Dublin, Ohio-based firm offered the first interim analysis from the successful NAV3-31 phase IIb study with Tc99m-tilmanocept, or Tc-Til, which combines a radioactive marker (technetium [Tc] 99m) with a ligand (tilmanocept) for the CD206 receptor found on activated macrophages. Tc-Til can image the concentration of activated macrophages, known to be heavily involved in inflammation. In 2014, the FDA approved Lymphoseek, designed to deploy the same technology for sentinel lymph node mapping as a way of detecting metastatic spread in cancer, noted Maxim analyst Jason McCarthy. Commercial rights for Lymphoseek were bought by Cardinal Health Inc. in March 2017. Navidea collected about $83 million at closing, with terms that mean it could earn up to $227 million in contingent consideration based on certain milestones through 2026, with $17.1 million of that amount guaranteed over the three years following the deal.

RA is the second-largest drug category globally and affects more than 1.5 million people in the U.S., but "despite the large market and $39 billion impact on the U.S. economy, diagnostic options remain limited with current methods often relying on subjective analysis," McCarthy pointed out in a report, noting the "lack of approved biomarkers to guide treatment selection, which creates an unmet need, considering the premium pricing of anti-inflammatory therapies, and [considering] that only 20%-50% of patients will respond" to any particular therapy. He started coverage over the summer with a buy rating and a 12-month price target of $2, saying that Tc-Til has the potential to "change the diagnostic paradigm across several larger therapeutic areas," including RA. The product is also undergoing investigation in cardiovascular disease (phase II), Kaposi sarcoma (phase II, grant-funded) and nonalcoholic steatohepatitis (phase II-ready).

It was Maxim's McCarthy who asked about Navidea's partnering prospects during the conference call on earnings in early August. Latkin said the firm is "looking at some of the larger diagnostic players who might not have any exposure to the RA space right now but have the necessary funds to get there. It's important that when we launched Lymphoseek, we had built up a sales force. That's something we're not going to look to do at this juncture. What we'd really like to do is find a partner that has financial muscle. Even if they don't have the client-established RA platform, they have what it would take to build up an RA sales force and hit all the rheumatologists. But I can assure you that the people that we're talking to are all larger diagnostic players that do have enough of a presence and enough of a financial backing" to get the job done, he said.

'Mind-boggling' industry gap

McCarthy also pointed to "a bit of a buzz in the RA space around the new anti-inflammatory drugs, specifically Janus kinase (JAK) inhibitors for patients who are no longer responding to tumor necrosis factor [TNF] drugs. How are you expecting the presence of this newer, later class of drugs to impact the need for something like Tc-Til?" Chief Medical Officer Michael Rosol acknowledged the JAK inhibitors and others, such as anti-GM-CSF agents that work to inhibit the promotion of macrophage activity. Some "fit exactly into the wheelhouse of what our imaging readout provides. For example, [with] the anti-macrophage kind of stimulating factor therapeutics, we could have a significant impact on determining if [a tested] patient would or would not benefit from those. One of our indications that we're going for in the phase III is to potentially help give an imaging readout that can point towards the subtype of RA that the patient has. There are three subtypes of RA and two of them, the lymphomyeloid and myeloid, are macrophage enriched, and both have different levels of macrophage involvement. And then the third type, the fibroid types, don't involve macrophages much at all. With our readout focusing on macrophages, it actually might be that [with] those folks who have the fibroid subtype, our scan should be able to give us information on that at baseline. If the scan looks relatively like the healthy control – and we'll learn through the course of our study if this is true or not – then those folks may be that subtype, [which] won't benefit from the anti-TNF alphas. That subtype may indeed benefit from the JAK inhibitors or some of these other ones," he said.

The trial has three arms. One consists of healthy subjects, another of patients with active, moderate to severe RA who are on stable therapy, and the third is a pilot arm of the upcoming phase III trial to judge the Tc-Til's ability to provide an early indicator of efficacy of anti-TNF alpha treatment in RA patients. That interim analysis was designed to examine data from arms one and two in order to confirm the repeatability, reproducibility and stability of Tc-Til, as well as to further establish the quantitative determinants of healthy joints vs. those with RA-involved inflammation. A total of 30 subjects were included, 18 healthy controls and 12 patients with RA. Whole-body and hand/wrist planar gamma camera images were obtained at multiple time points within the same day (both arms of the trial) and on an additional day (arm two) to measure imaging stability and variability, i.e., any change from one image set to the next and from one day to another.

Images from patients with active RA show the same localization patterns on images taken a week apart, Navidea said. Notable agreement turned up between qualitative and quantitative assessment of joint-specific localization across all time points. Data gathered from the interim analysis plus the remainder of NAV3-31 arms one and two will provide the necessary input to establish quantitative "cut points" to differentiate between joints with and without the inflammation seen in RA, the company said. The findings will also serve to establish the quantitative metrics that will enable the detection of change in disease status in patients with RA – that's how doctors can learn if a given drug is working.

"The fact that [such a test has] never been available is really mind-boggling," CEO Latkin said. "We had a product – we still do, but we've sublicensed it – that is the best beta-amyloid imaging agent in the world. We can tell you if you have beta-amyloid in your brain, which is a very good indication that you have Alzheimer's disease [AD]. But the next question is, so what? There's no treatment, no therapy." The scenario is much different in RA, where treatments abound sans objective diagnostics beyond needle biopsies, which come with their own problems.

In AD, the situation may change, given Cambridge, Mass.-based Biogen Inc.'s decision to file for approval early next year of beta-amyloid-targeting aducanumab in AD based on fresh analysis of a bigger phase III dataset. In 2017, Navidea agreed to sublicense to Boston-based Cerveau Technologies Inc. the worldwide rights to conduct research using NAV-4694 in AD and provided an exclusive license for the development and commercialization of the product in Australia, Canada, China and Singapore. (See BioWorld, Oct. 3, 2019.)

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