Avid Radiopharmaceuticals

Avid Radiopharmaceuticals
Type	Private
Founder	Dr. Daniel Skovronsky
Headquarters	Philadelphia, Pennsylvania , United States
Parent	Eli Lilly and Company
Website	http://www.avidrp.com

Last updated April 23, 2022

Avid Radiopharmaceuticals is an American company, founded by Dr. Daniel Skovronsky, and based at the University City Science Center research campus in Philadelphia, Pennsylvania. The company has developed a radioactive tracer called florbetapir (¹⁸F). Florbetapir can be used to detect beta amyloid plaques in patients with memory problems using positron emission tomography (PET) scans, making the company the first to bring to market an FDA-approved method that can directly detect this hallmark pathology of Alzheimer's disease.

Detection of Alzheimer's disease

Since the disease was first described by Alois Alzheimer in 1906, the only certain way to determine if a person indeed had the disease was to perform an autopsy on the patient's brain to find distinctive spots on the brain that show the buildup of amyloid plaque. Doctors must diagnose the disease in patients with memory loss and dementia based on symptoms, and as many as 20% of patients diagnosed with the disease are found after examination of the brain following death to not have had the condition. Other diagnostic tools, such as analysis of cerebrospinal fluid, magnetic resonance imaging scans looking for brain shrinkage and PET scans looking at how glucose was used in the brain, had all been unreliable.^[2]^[3]

Avid built on research done by William Klunk and Chester Mathis who had developed a substance called Pittsburgh compound B as a means of detecting amyloid plaque, after analyzing 400 prospective compounds and developing 300 variations of the substance that they had discovered might work. In 2002, a study performed in Sweden on Alzheimer's patients was able to detect the plaque in PET brain scans. Later studies on a control group member without the disease did not find plaque, confirming the reliability of the compound in diagnosis. While the tool worked, Pittsburgh compound B relies on the use of carbon-11, a radioactive isotope with a half-life of 20 minutes that requires the immediate use of the material prepared in a cyclotron.^[2]

Dr. Skovronsky established Avid Radiopharmaceuticals in July 2005 with the goal of finding a dye that could be injected into the body, would cross the blood–brain barrier and attach itself to amyloid protein deposits in the brain.^[4] The firm raised $500,000 from BioAdvance, the Biotechnology Greenhouse of Southeastern Pennsylvania, as seed funding.^[5] Once they found a candidate dye, they attached the positron-emitting fluorine-18, a radioactive isotope with a half-life of nearly two hours that is used annually in two million PET scans and that can last for as long as a day when prepared in the morning by cyclotron. The dye had been developed and patented by the University of Pennsylvania and was licensed by Avid.^[2]^[3]

Initial tests in 2007 on a patient at Johns Hopkins University Hospital previously diagnosed with symptoms of Alzheimer's disease detected plaque in a PET scan in areas where it was typically found in the brain. Further tests found that the scans detected plaque in patients with Alzheimer's, didn't find it in those without the diagnosis and found intermediate amounts in patients with early signs of dementia. The tests found amyloid plaque in 20% of its test patients over age 60 that had been in the normal range, but had performed worse than a control group on tests of mental acuity.^[2]

Validation by autopsy

In order to confirm if the dye was accurate in detecting Alzheimer's, an advisory committee at the Food and Drug Administration demanded that the team of Avid, Bayer and General Electric perform a study to test their method. Avid established a study with a group of 35 hospice patients, some that had been diagnosed with dementia and others that had no memory problems. The participants and their families agreed that they would undergo the PET scans and would have their brains autopsied after their death by pathologists. After the study was conducted, Avid received confirmation in May 2010 that the results of the test were successful in distinguishing between those with Alzheimer's and those without the disease.^[2]

In results presented in July 2010 to an international conference on Alzheimer's disease held in Hawaii, the company showed that for 34 out of the 35 hospice patients who had been scanned, the initial scan results were confirmed when pathologists counted plaque under a microscope and when a computerized scan of the plaque was performed on material from the autopsied brain.^[6] The findings will require review by the FDA to confirm its reliability as a means of diagnosing the disease. If confirmed, the technique would provide a means to reliably diagnose and monitor the progress of Alzheimer's and would allow potential pharmaceutical treatments to be evaluated.^[2]

In a study published in January 2011 in the Journal of the American Medical Association , Avid reported on the results of further studies conducted based on 152 test subjects who had agreed to receive the company's PET scans and to have their brains analyzed after death for definitive determination of the presence of amyloid plaques. Of the patients included in the study, 29 who died had autopsies performed on their brains and in all but one the brain autopsy results matched the diagnosis based on the PET scan taken before death. Avid's technique is being used to test the efficacy of Alzheimer's disease treatments being developed by other pharmaceutical firms as a means of determining the ability of the drugs to reduce the buildup of amyloid protein in the brains of living subjects.^[7]

On January 20, 2011, an FDA advisory committee unanimously recommended that Avid's PET scan technique be approved for use. The advisory committee included a qualification requiring the firm to develop clear guidelines establishing when the tests had spotted enough of the amyloid plaque in order to make a diagnosis of Alzheimer's, a task that Avid CEO Skovronsky stated could be resolved in several months.^[8]^{[ needs update ]}

Other Radiopharmaceuticals

Avid is sponsoring clinical trials of [¹⁸F]AV-133 (or [¹⁸F]Fluoropropyl-(+)-DTBZ) to identify subjects with dopaminergic degeneration.^[9]

Related Research Articles

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Positron emission tomography (PET) is a functional imaging technique that uses radioactive substances known as radiotracers to visualize and measure changes in metabolic processes, and in other physiological activities including blood flow, regional chemical composition, and absorption. Different tracers are used for various imaging purposes, depending on the target process within the body. For example, ¹⁸
F-FDG is commonly used to detect cancer, NaF¹⁸
F is widely used for detecting bone formation, and oxygen-15 is sometimes used to measure blood flow.

Vascular dementia (VaD) is dementia caused by problems in the supply of blood to the brain, typically a series of minor strokes, leading to worsening cognitive abilities, the decline occurring step by step. The term refers to a syndrome consisting of a complex interaction of cerebrovascular disease and risk factors that lead to changes in brain structures due to strokes and lesions, resulting in changes in cognition. The temporal relationship between a stroke and cognitive deficits is needed to make the diagnosis.

Single-photon emission computed tomography Nuclear medicine tomographic imaging technique

Single-photon emission computed tomography is a nuclear medicine tomographic imaging technique using gamma rays. It is very similar to conventional nuclear medicine planar imaging using a gamma camera, but is able to provide true 3D information. This information is typically presented as cross-sectional slices through the patient, but can be freely reformatted or manipulated as required.

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Amyloid plaques are extracellular deposits of the amyloid beta (Aβ) protein mainly in the grey matter of the brain. Degenerative neuronal elements and an abundance of microglia and astrocytes can be associated with amyloid plaques. Some plaques occur in the brain as a result of senescence (aging), but large numbers of plaques and neurofibrillary tangles are characteristic features of Alzheimer's disease. Abnormal neurites in amyloid plaques are tortuous, often swollen axons and dendrites. The neurites contain a variety of organelles and cellular debris, and many of them include characteristic paired helical filaments, the ultrastructural component of neurofibrillary tangles. The plaques are highly variable in shape and size; in tissue sections immunostained for Aβ, they comprise a log-normal size distribution curve with an average plaque area of 400-450 square micrometers (µm²). The smallest plaques, which often consist of diffuse deposits of Aβ, are particularly numerous. The apparent size of plaques is influenced by the type of stain used to detect them, and by the plane through which they are sectioned for analysis under the microscope. Plaques form when Aβ misfolds and aggregates into oligomers and longer polymers, the latter of which are characteristic of amyloid. Misfolded and aggregated Aβ is thought to be neurotoxic, especially in its oligomeric state.

Cerebral amyloid angiopathy (CAA), is a form of angiopathy in which amyloid beta peptide deposits in the walls of small to medium blood vessels of the central nervous system and meninges. The term congophilic is sometimes used because the presence of the abnormal aggregations of amyloid can be demonstrated by microscopic examination of brain tissue after staining with Congo red. The amyloid material is only found in the brain and as such the disease is not related to other forms of amyloidosis.

Pittsburgh compound B (PiB) is a radioactive analog of thioflavin T, which can be used in positron emission tomography scans to image beta-amyloid plaques in neuronal tissue. Due to this property, Pittsburgh compound B may be used in investigational studies of Alzheimer's disease.

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The biochemistry of Alzheimer's disease, the most common cause of dementia, is not yet very well understood. Alzheimer's disease (AD) has been identified as a proteopathy: a protein misfolding disease due to the accumulation of abnormally folded amyloid beta (Aβ) protein in the brain. Amyloid beta is a short peptide that is an abnormal proteolytic byproduct of the transmembrane protein amyloid-beta precursor protein (APP), whose function is unclear but thought to be involved in neuronal development. The presenilins are components of proteolytic complex involved in APP processing and degradation.

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Alzheimer's Disease Neuroimaging Initiative (ADNI) is a multisite study that aims to improve clinical trials for the prevention and treatment of Alzheimer’s disease (AD). This cooperative study combines expertise and funding from the private and public sector to study subjects with AD, as well as those who may develop AD and controls with no signs of cognitive impairment. Researchers at 63 sites in the US and Canada track the progression of AD in the human brain with neuroimaging, biochemical, and genetic biological markers. This knowledge helps to find better clinical trials for the prevention and treatment of AD. ADNI has made a global impact, firstly by developing a set of standardized protocols to allow the comparison of results from multiple centers, and secondly by its data-sharing policy which makes available all at the data without embargo to qualified researchers worldwide. To date, over 1000 scientific publications have used ADNI data. A number of other initiatives related to AD and other diseases have been designed and implemented using ADNI as a model. ADNI has been running since 2004 and is currently funded until 2021.

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Florbetapir (¹⁸F), sold under the brand name Amyvid, is a PET scanning radiopharmaceutical compound containing the radionuclide fluorine-18 that was approved for use in the United States in 2012, as a diagnostic tool for Alzheimer's disease. Florbetapir, like Pittsburgh compound B (PiB), binds to beta-amyloid, however fluorine-18 has a half-life of 109.75 minutes, in contrast to PiB's radioactive half life of 20 minutes. Wong et al. found that the longer life allowed the tracer to accumulate significantly more in the brains of people with AD, particularly in the regions known to be associated with beta-amyloid deposits.

Florbetaben, a fluorine-18 (18F)-labeled stilbene derivative, trade name NeuraCeq, is a diagnostic radiotracer developed for routine clinical application to visualize β-amyloid plaques in the brain. It is indicated for Positron Emission Tomography (PET) imaging of β-amyloid neuritic plaque density in the brains of adult patients with cognitive impairment who are being evaluated for Alzheimer's disease (AD) and other causes of cognitive impairment. β-amyloid is a key neuropathological hallmark of AD, so markers of β-amyloid plaque accumulation in the brain are useful in distinguishing AD from other causes of dementia. The tracer successfully completed a global multicenter phase 0–III development program and obtained approval in Europe, US and South Korea in 2014.

Flutemetamol (¹⁸F) is a PET scanning radiopharmaceutical containing the radionuclide fluorine-18, used as a diagnostic tool for Alzheimer's disease.

Flortaucipir (¹⁸F), sold under the brand name Tauvid, is a radioactive diagnostic agent indicated for use with positron emission tomography (PET) imaging to image the brain.

Julie C. Price American physicist and professor of radiology

Julie C. Price is an American medical physicist and professor of radiology at Massachusetts General Hospital (MGH), Harvard Medical School (HMS), as well as the director of PET Pharmacokinetic Modeling at the Athinoula A. Martinos Center at MGH. Price is a leader in the study and application of quantitative positron emission tomography (PET) methods. Prior to this, Price worked with Pittsburgh colleagues to lead the first fully quantitative pharmacokinetic evaluations of ¹¹C-labeled Pittsburgh compound-B (PIB), one of the most widely used PET ligands for imaging amyloid beta plaques. As a principal investigator at MGH, Price continues work to validate novel PET methods for imaging biological markers of health and disease in studies of aging and neurodegeneration, including studies of glucose metabolism, protein expression, neurotransmitter system function, and tau and amyloid beta plaque burden.

References

↑ Staff. "Lilly Snags Avid Radiopharma", Forbes , November 8, 2010. Accessed November 8, 2010.
1 2 3 4 5 6 Kolata, Gina. "Promise Seen for Detection of Alzheimer’s", The New York Times , June 23, 2010. Accessed June 23, 2010.
1 2 Staff. "Avid Radiopharmaceuticals Initiates First Phase II Trial Of Novel Compound For Imaging Alzheimer's Disease", Medical News Today , June 11, 2008. Accessed June 23, 2010.
↑ Staff. "Phila. start-up developing a way to test for Alzheimer's, Avid Radiopharmaceuticals has raised $26 million in new venture financing. Seeking a test for Alzheimer's", The Philadelphia Inquirer , May 9, 2007. Accessed June 23, 2010.
↑ Staff. "Avid Radiopharmaceuticals Selected to Receive Seed Funding from BioAdvance; Funds to Be Used to Develop Molecular Imaging Tools for Alzheimer's Disease.", Business Wire , January 5, 2005. Accessed June 23, 2010.
↑ Kolata, Gina. "New Scan May Spot Alzheimer’s", The New York Times , July 12, 2010. Accessed July 14, 2010.
↑ Kolata, Gina. "Two Tests Could Aid in Risk Assessment and Early Diagnosis of Alzheimer’s", The New York Times , January 18, 2011. Accessed January 19, 2011.
↑ Kolata, Gina. "F.D.A. Sees Promise in Alzheimer’s Imaging Drug", The New York Times , January 20, 2011. Accessed January 20, 2011.
↑ "A Trial of 18F-AV-133 Positron Emission Tomography (PET) Imaging to Differentiate Subjects With Parkinson's Disease (PD) From Other Movement Disorders". Clinical Trials. U.S. National Institutes of Health. Retrieved 20 July 2015.

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[1] Staff. "Lilly Snags Avid Radiopharma", Forbes , November 8, 2010. Accessed November 8, 2010.

[NYT2010-2] 1 2 3 4 5 6 Kolata, Gina. "Promise Seen for Detection of Alzheimer’s", The New York Times , June 23, 2010. Accessed June 23, 2010.

[MNT-3] 1 2 Staff. "Avid Radiopharmaceuticals Initiates First Phase II Trial Of Novel Compound For Imaging Alzheimer's Disease", Medical News Today , June 11, 2008. Accessed June 23, 2010.

[4] Staff. "Phila. start-up developing a way to test for Alzheimer's, Avid Radiopharmaceuticals has raised $26 million in new venture financing. Seeking a test for Alzheimer's", The Philadelphia Inquirer , May 9, 2007. Accessed June 23, 2010.

[5] Staff. "Avid Radiopharmaceuticals Selected to Receive Seed Funding from BioAdvance; Funds to Be Used to Develop Molecular Imaging Tools for Alzheimer's Disease.", Business Wire , January 5, 2005. Accessed June 23, 2010.

[NYT20100712-6] Kolata, Gina. "New Scan May Spot Alzheimer’s", The New York Times , July 12, 2010. Accessed July 14, 2010.

[7] Kolata, Gina. "Two Tests Could Aid in Risk Assessment and Early Diagnosis of Alzheimer’s", The New York Times , January 18, 2011. Accessed January 19, 2011.

[8] Kolata, Gina. "F.D.A. Sees Promise in Alzheimer’s Imaging Drug", The New York Times , January 20, 2011. Accessed January 20, 2011.

[9] "A Trial of 18F-AV-133 Positron Emission Tomography (PET) Imaging to Differentiate Subjects With Parkinson's Disease (PD) From Other Movement Disorders". Clinical Trials. U.S. National Institutes of Health. Retrieved 20 July 2015.

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