18F-Fluciclovine, marketed under the brand name Axumin®, is a radiopharmaceutical used in positron emission tomography (PET) imaging for the detection and localization of recurrent prostate cancer. It is a synthetic amino acid analog labeled with the radioactive isotope fluorine-18, which allows it to be detected and visualized in the body using PET scanning technology.
Prostate cancer is one of the most common cancers in men, and accurate detection of recurrent disease is crucial for treatment planning and monitoring. 18F-Fluciclovine PET imaging works by targeting the increased amino acid transport in prostate cancer cells, which is often elevated in recurrent or metastatic disease. By visualizing the uptake of 18F-Fluciclovine in prostate cancer cells, PET scans can help identify the presence and location of recurrent tumors.
18F-Fluciclovine PET imaging is particularly useful in patients with biochemical recurrence of prostate cancer, where prostate-specific antigen (PSA) levels rise after initial treatment. It can help differentiate between local recurrence, distant metastases, and benign lesions, guiding further management decisions. 18F-Fluciclovine PET scans provide important information about tumor location, extent, and metabolic activity, helping clinicians optimize treatment strategies and improve patient outcomes.
Axumin® (18F-Fluciclovine) has been approved by regulatory agencies for clinical use in the United States and other countries for the imaging of recurrent prostate cancer. It is considered safe and well-tolerated, with minimal side effects reported in patients undergoing imaging with this radiopharmaceutical.
Overall, 18F-Fluciclovine PET imaging with Axumin® plays a valuable role in the management of patients with recurrent prostate cancer, offering important insights into disease localization and progression. It complements other imaging modalities and biochemical markers in the assessment of prostate cancer, providing clinicians with valuable information to guide treatment decisions and improve patient care.
Description
18F-Fluciclovine (Axumin®, 18F-anti-1-amino-3-fluorocyclobutane-1-carboxylic acid, 18F-FACBC, and 18F-GE-148, 18F-NMK36) is a synthetic L-leucine analogue developed for the imaging of tumor proliferation. This tracer, discovered in 1994, initially developed at Emory University, Atlanta GA, was part of the pipeline of GE Healthcare (actually sublicensed from Nihon MediPhysics (NMP) as NMP has been granted a world-wide exclusive right from Emory University to make, use, and sell FACBC as a diagnostic imaging agent) since 2008. Rights in Western countries were acquired by Blue Earth Diagnostics Ltd in March 2014. The product was covered by patents until 2017. In May 2015, Blue Earth came to an agreement with Siemens PETNET Solutions for the future production and distribution of 18F-Fluciclovine in the US.
In July 2015, 18F-Fluciclovine was granted Orphan Drug Status from both the EMA and the FDA in the diagnosis of glioma. By end of May 2016, FDA approved 18F-Fluciclovine for marketing as a new agent for diagnosis of recurrent prostate cancer based on elevated PSA that occur after primary treatment and it is sold under the brand name Axumin®. Axumin obtained its MA from the EMA in May 2017. An agreement was signed between Blue Earth Diagnostics and AAA for the exclusive distribution and non-exclusive manufacturing of Axumin in France, Italy, Germany, Spain and Portugal (announcement May 2017).
Blue Earth Diagnostic was acquired by Bracco in 2019.
Nihon Medi-Physics Co., Ltd which still detains the worldwide rights to 18F-Fluciclovine continues the development in Asia and in particular in Japan. Under this agreement, NMP signed an agreement in June 2019 with DuChemBio, Ltd., which will become the exclusive supplier of FACBC in Korea. In 2019, NMP granted distribution rights for 18F- Fluciclovine to GMS in Taiwan.
Clinical applications
18F-Fluciclovine is a tracer allowing the evaluation of the L-amino acid transport (LAT) system. This agent is preferentially accumulated by tumor cells but unlike naturally occurring amino acids, this non-natural amino acid-analogue radiotracer is not metabolized. Accordingly, 18F-Fluciclovine accumulates in tumor cells and can potentially be used to image these tumors. The tracer has low native urinary excretion, avoiding superimposition with bladder accumulation. 18F-Fluciclovine is not indicated for prostate cancer diagnosis (lower sensitivity in the case of small tumors) but is useful in staging and restaging. It was approved in the USA and EU for diagnosis of recurrent prostate cancer based on elevated PSA that occur after primary treatment.
18F-Fluciclovine can be synthesized with yields higher than 24% (decay corrected) and is used in clinical trials at about 10 mCi doses.
The tracer was clinically explored in prostate (staging and restaging) and breast cancer, but also in non-invasive imaging of lung nodules, Head and Neck cancer, gliomas andparathyroid adenomas. For disease detection in the prostate bed, 18F-Fluciclovine- PET/CT had greater sensitivity than 111In-Capromab pendetide (Prostascint)-based SPECT/CT (89% versus 69%), along with better specificity (67% versus 58%) and better accuracy (83% versus 67%). In the detection of extraprostatic recurrence, 18F-Fluciclovine showed sensitivity of 100% and 100% accuracy, compared with only 10% sensitivity and 47% accuracy for SPECT/CT with 111In-Capromab pendetide based SPECT/CT. Both modalities turned in specificity of 100%. Superiority over 11C-Choline was also demonstrated.
A Lancet Oncology publication provided results of a prospective, single-center, open- label, single-arm comparative study done at University of California Los Angeles between 18F-Fluciclovine and 68Ga-PSMA-11. The study concluded that PSMA should be the PET tracer of choice when PET-CT imaging is considered for subsequent treatment management decisions in patients with prostate cancer and biochemical recurrence after radical prostatectomy and low PSA concentrations (≤2·0 ng/mL).
In December 2018, Blue Earth Diagnostics filed a supplemental new drug application form for the use of 18F-Fluciclovine in detecting brain metastases following a late-stage trial showing that PET/MRI with Axumin yielded improved glioma diagnosis as opposed to MRI alone. So far (2021), the official indication for Axumin has not been extended beyond prostate cancer.
Additional development
By end of 2014, more than 1,000 patients had already been screened with this tracer in diverse clinical trials. A clinical study intended to demonstrate the diagnostic advantage of 18F-Fluciclovine in the treatment with 223Ra-Chloride (Xofigo) has been filed in Quarter I, 2015. A new study in Head and Neck cancers had also been launched in 2013.
In January 2015 a new retrospective observational study was initiated to collect data from 800 patients imaged with 18F-Fluciclovine. The NDA dossier was filed and approved for review by the FDA in December 2015 and the MA was obtained in May 2016.
The tracer is undergoing several Phase II trials in breast cancer patients (completed in 2014) and entered (2014) in exploratory clinical studies in H&N cancer. The tracer is also presently being studied for potential applications in parathyroid adenomas, lung tumors and brain tumors (gliomas). These brain studies were performed in comparison with 18F-FLT or 11C-Methionine. Most of the studies were performed at Emory University, Atlanta GA, or at the MSKCC, New York, NY. A large Phase II/III study is presently running in prostate cancer.
Results from Phase I/II explorative data in patients with recurrent gliomas were published in May 2020. The tracer proved superior to MRI and equivalent to the established brain tumor imaging agent 11C-Methionine, but providing significantly higher image contrast.
Availability and price
Production of 18F-Fluciclovine can take place in any site that is also producing 18F-FDG. Blue Earth Diagnostics had to find several networks of production and to come to agreements for manufacturing and distribution. In the USA, the tracer is available from PETNET (Siemens) at a price of about US$ 3,600 per dose.
Competition
Prostate cancer imaging methods are numerous. They are based on conventional imaging modalities such as transrectal ultrasound (TRUS), computed tomography (CT), high- resolution magnetic resonance imaging (HR-MRI), ultrasound Doppler alone or combined with microbubble contrast agent, three-dimensional stereotactic US (3D-US), higher- resolution 3T MRI, endorectal coils MRI, dynamic contrast enhanced MRI (DCE-MRI), diffusion weighted MRI (DW-MRI) and MR spectroscopy (MRS). Nuclear medicine imaging has access to 111In-ProstaScint (expensive) or prostate-specific membrane antigen (PSMA) imaging labeled either with 18F, 99mTc, 89Zr or 68Ga (all under development). For advanced metastasized cancer, bone scans (99mTc or 18F-sodium fluoride) are used for detecting and staging the disease. PET with FDG is not really useful as prostate cancer is a slow progressing cancer.
The area of tracers under development for imaging of prostate cancer is very crowded. The list of products under clinical development includes 11C-Methionine, 18F- Fluoroacetate, 18F-Fluorocholine, 18F-Fluoroethylcholine, 61Cu and 64Cu-ATSM, 68Ga-Bombesin (BAY86-7548), 89Zr-Df-IAB2M, 99mTc-Bombesin, 99mTc-MIP-1404, 123I-MIP-1072, and 177Lu-TLX591 (priority given to therapy for this last one). However, the tracer with the presently fastest development is the generic 68Ga-PSMA-11 which competes with other 68Ga-labeled PSMA peptides such as 68Ga-PSMA-THP or 68Ga-PSMA-R2.
At this stage, direct competition with marketed tracer will only take place locally in presence of available 11C-Choline in the US and 18F-Fluorocholine in Europe.
Comments
Recent data have shown that both 68Ga-PSMA and 18F-Fluciclovine are shown to be more accurate in the detection of recurrent disease as compared with radiolabeled 11C/18F- choline PET/CT. As both 18F- and 68Ga-PSMA analogues have obtained their marketing authorizations at least in the USA, , it will be interesting to observe the evolution of the sales of 18F-Fluciclovine. There are great risks that PSMA-targeting tracers will substitute for Fluciclovine (at least in the prostate cancer indication).