2nd gen radiotracers and Alzheimer's diagnosis in the age of early-intervention trials
On July 19, the Alzheimer’s Association International Conference (AAIC) issued a press release highlighting anticipated advances in the ability to diagnose Alzheimer’s disease (AD) at earlier stages.
According to the AAIC, “Most Alzheimer’s clinical trials have been conducted among individuals in the dementia phase of the disease. More recently, trials have been initiated during an earlier phase, known as mild cognitive impairment (MCI), where people have a significantly increased risk of progressing to Alzheimer’s disease (AD) dementia. For more than a decade, these trials have been unsuccessful in identifying new Alzheimer’s medications. A few clinical trials have recently been initiated among individuals in the preclinical phase of the disease. However, there is limited data on which to base the selection of individuals for a clinical trial in the preclinical phase; there is a great need for better tools for earlier detection and cognitive assessment to identify these individuals and track their progress.”
Companies, such as Navidea Biopharmaceuticals, based in Ohio, are at the forefront of efforts to develop more precise diagnostic tools. Their radiotracer, NAV4694, is currently in a phase III, end-of-life validation trial---and results thus far have been promising. Biopharma Dive spoke to Dr. Michael Tomblyn, Chief Medical Officer, and David Colburn, VP Clinical Operations, at Navidea to learn more about their technology and their outlook on AD diagnostics, as well as their goal to find a partner for the last critical stages of product development.
Biopharma Dive: According to research conducted by Eli Lilly, at least 20% of people diagnosed with AD are misdiagnosed. This not only leads to misuse of medication (as high as 67% according to a sensitivity analysis) but can compromise the results of clinical trials designed to evaluate AD treatments. What are some of the steps being taken to address this?
Navidea: We know that researchers are developing improved methods to better identify suspected Alzheimer’s patients and patients at risk for developing AD---while avoiding those suffering from other forms of dementia---by verifying the presence of beta amyloid utilizing advanced technology for brain imaging along with clinical assessment. In addition, by finding patients earlier in the disease process, researchers may be better able to measure a drug’s impact before the disease becomes too advanced.
Biopharma Dive: What role does NAV4694 play in providing diagnostic support for clinical trials?
Navidea: Currently NAV4694 is an investigational product being evaluated as a diagnostic agent in phase II and III clinical studies. It is not currently being used in support of any therapeutic AD clinical trials. However, we believe that NAV4694 represents the potential to be the best-in-class PET amyloid imaging agent, which could be critically important in identifying appropriate patients for clinical trials of emerging, promising therapies.
Biopharma Dive: Why is PIB-C, which is considered the gold standard, not more widely used?
Navidea: The first PET tracer used clinically for visual and quantitative assessment of β‑amyloid deposition in the brain was [11C] Pittsburg B compound or [11C] PIB, a radioactive carbon. Several groups have assessed the rate of progression to AD in [11C]-PIB-positive MCI subjects compared with subjects with a [11C]-PIB-negative PET scan. In all published studies, a higher progression rate to AD was observed in subjects with signs of [11C]-PIB‑uptake in their brain, although the yearly progression rates varied considerably in these studies from 30%, to 47%, to over 60% per year.
A study published in the June 2013 issue of The Journal of Nuclear Medicine by Christopher C. Rowe, MD et al, notes that the radiotracer [11C] PiB has been proven effective for amyloid PET imaging and has outperformed many F-18 bound biomarkers. However, expanded use of [11C] PiB is limited by production logistics. Due to its radioactive half-life of 20 minutes, [11C] PiB requires an on-site cyclotron, whereas F-18 radiotracers have a 110 minute half-life and are much more conducive for commercialization and distribution. Navidea’s PET radiotracer NAV4694 displays binding characteristics nearly identical to that of [11C] PiB with all the logistical benefits of a fluorine-based agent.
Biopharma Dive: Do you see AD treatments being approved along with companion diagnostics?
Navidea: Objective tools, such as amyloid PET imaging, in addition to clinical assessment may eventually become a more routine part of a physician’s diagnostic evaluation of patients with cognitive decline to help physicians not only define the stage of disease, but also assist in earlier development of the appropriate treatment approach for their patients, especially as new treatment options become available.
Biopharma Dive: Considering the fact that sales of first-generation of radiotracers are relatively low, do you anticipate strong uptake for NAV4694 assuming approval?
Navidea: We believe NAV4694 represents the potential to be the best-in-class PET amyloid imaging agent. Comparative studies like the one done by Dr. Christopher Rowe demonstrate that NAV4694 displays imaging characteristics nearly identical to those of [11C] PiB, the gold standard, but with a more practical distribution profile including the longer half-life of 18F, making NAV4694 commercially feasible where [11C] -PiB is not.
If approved, NAV4694 could certainly be used in clinical trials similar to the current Lilly trial (evaluating salanezumab) to ensure subjects meet certain inclusion criteria . Moreover, in the case of disease-modifying treatment trials, with its sensitivity and low white matter binding NAV4694 may be able to be used to monitor disease progression.
From a patient perspective, research is indicating that earlier treatment intervention may lead to better patient outcomes. NAV4694 may offer the potential to play an increasingly important role in clinical practice allowing for earlier diagnosis and therefore earlier therapeutic intervention.
Biopharma Dive: What's next?
Navidea: If approved, we believe the commercial potential for NAV4694 is bright as AD treatments and disease modifying therapies make their way to market. However, Navidea has made the strategic decision to narrow its focus to its CD206 targeting platform of imaging agents and therapeutics and is currently looking to partner or divest the final stages of development and commercialization of NAV4694.
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