Navidea Biopharmaceuticals Inc. CEO Jed Latkin said positive findings from the second interim analysis of the phase IIb study called NAV3-31 “were certainly better than what we were looking for” and will “make our partnering discussions a lot more interesting.”

NAV3-31’s findings in the trial’s third arm – designed to provide a “snapshot” of the phase III work to come, Latkin said – reinforce the company’s claim that Tc99m tilmanocept (Tc-Til) can provide robust, quantitative imaging in healthy controls and in patients with active rheumatoid arthritis (RA).

Shares of the Dublin, Ohio-based firm (NYSE:NAVB) closed May 22 at $2.43, up $1.16, or 91.3%, after trading as high as $3.11.

Tc-Til combines a radioactive marker (technetium 99m) with a ligand (tilmanocept) for the CD206 receptor found on activated macrophages. Arm one of NAV3-31 consists of healthy subjects, arm two comprises patients with active, moderate to severe RA who are on stable therapy, and arm three is a pilot arm of the upcoming phase III experiment testing the ability of Tc-Til to provide an early indicator of efficacy of anti-TNF-alpha treatment in RA patients. The interim checkup evaluated the magnitude of change of Tc-Til signal localized to RA-involved joints in patients before and after treatment with an anti-TNF-alpha therapy, also examining whether that change in localization, if any, can serve as an early, quantifiable predictor of treatment efficacy.

Fifteen subjects with active moderate to severe RA were included in the latest analysis, each of which was set to begin a new or first-time treatment regimen with an anti-TNF-alpha therapy. Whole body and hand/wrist planar gamma camera images were obtained at baseline prior to initiation of new treatment, again at five weeks post-therapy start, and then again at 12 weeks on eight of the 15 subjects. The remaining seven subjects had received baseline and five-week scans only at the time of this analysis. A panel of established clinical assessments was performed at each time point as well, in order to compare imaging results with clinical standards over the 12-week time course.

Results show that Tc-Til imaging from baseline to the fifth week was predictive of clinical outcome at 12 weeks in seven out of eight subjects with 12-week clinical assessment available. The one subject who did not demonstrate concordance of signal quantification and clinical assessment had undergone a change in treatment regimen while enrolled in the trial that may have skewed the trajectory of the clinical response, Navidea said.

Combined data from all 15 subjects in arm three suggest a wide dynamic range of more than one order of magnitude (>10-fold) for calculated global Tc-Til uptake values in joints with RA-involved inflammation. In the subjects with 12-week follow-up data available, global Tc-Til signals declined by an average of 58% from baseline to week five in those who responded significantly to anti-TNF alpha treatment by week 12. In those subjects who did not have a significant clinical response to anti-TNF alpha treatment by week 12, Tc-Til signals increased by an average of 79% from baseline to five weeks. The results indicate that marked changes in Tc-Til global uptake values by the fifth week are in agreement with clinical efficacy evaluations made at week 12.

The wide dynamic range of global Tc-Til signal readout combined with the low variability of imaging signal quantification established in the first two arms of the trial means that clinically meaningful changes in signal localization can be detected by the product, Navidea said, and the phase III trial will start later this year. Wainwright analyst Vernon Bernardino said in a May 15 report that interim results from the first two arms were “very positive,” with low variability in imaging.

Lymphoseek to accelerate in Europe?

Michael Rosol, Navidea’s chief medical officer, said during a conference call with investors that Navidea believes Tc-Til “can be employed longitudinally, so patients not only can have an early predictor of their response, but they can be followed over time. You can consistently image patients every so often during the course of the year to see if their disease is still responding to the drug. We know from experience that most subjects will actually need to switch drugs over the course of their disease in RA, unfortunately, and they'll have to do this several times, unless you happen to catch them very early on in the disease,” he said. The latter scenario, which lets physicians “sometimes beat [RA] into submission,” is “not true for the majority of people. They're going to be cycling through medications for their lives, at least in the current landscape of treatments available.”

In 2013, the FDA granted first approval for Navidea’s Lymphoseek, designed to deploy the same technology as Tic-Til but for sentinel lymph node mapping as a way of detecting metastatic spread in cancer. Commercial Lymphoseek rights were bought by Cardinal Health Inc. in March 2017. Navidea collected about $83 million at closing, with terms that provided up to $227 million more in contingent payouts based on certain milestones through 2026.

Lymphoseek is approved in Europe, too, for imaging and intraoperative detection of sentinel lymph nodes draining a primary tumor in adult patients with breast cancer, melanoma or localized squamous cell carcinoma of the oral cavity. Earlier this month, Navidea regained all Lymphoseek rights and intellectual property there from privately held Norgine BV, of Amsterdam, which was not able to pull off a strong launch, having priced the product at three times its U.S. cost. The deal dated from March 2015. Bernardino likes the current setup with the compound as well, saying in a report that “with pricing now stable and recent tenders for the product, we look for growth to continue and potentially accelerate once there is widespread recovery in the European health care system, potentially by the end of 2020.”

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