Gadopiclenol (Elucirem™) for Contrast-Enhanced MRI

Magnetic resonance imaging (MRI) is an important imaging technique necessary for disease diagnosis and treatment. Contrast agents are products used to improve the visibility of internal body structures in MRI and the most commonly used compounds for contrast enhancement are gadolinium-based.

Gadolinium chelates are hydrophilic and are thus useful for enhancing lesions and tumours where the blood-brain barrier (BBB) is compromised. Clinically harnessed since 1988 and engined by water proton relaxation catalyst properties, gadolinium-based contrast agents (GBCA) are considered to be safe and are preferred to iodinated intravenous contrast used in computed tomography (CT).1 GBCAs improve the contrast between lesions and surrounding tissues by accelerating the relaxation of protons thanks to the interaction with gadolinium atoms.2 GBCAs can be divided into two groups based on the type of ligand. Linear agents have an elongated organic molecular ligand that wraps around the ion. Macrocyclic agents form a cage-like ligand structure with the ion trapped in a preformed central cavity, which is considered to be more stable as they have lower dissociation constants.3,4

In September 2022, following a priority review, the US FDA granted regulatory approval to Gadopiclenol (Elucirem™), a new macrocyclic GBCA for use in adults and children aged 2 years and older, for contrast-enhanced MRI.5 The priority review designation is assigned to applications for drugs that provide significant improvements in the safety or effectiveness of the treatment, diagnosis, or prevention of serious conditions compared to available therapies. The product is used to detect and visualize lesions with abnormal vascularity in the central nervous system (CNS; brain, spine and associated tissues) and the body (head and neck, thorax, abdomen, pelvis and musculoskeletal system). 

Regulatory approval was primarily based on data from two global Phase III trials – the PICTURE trial for CNS MRI (NCT03996447) and the PROMISE trial for body MRI (NCT03986138).6,7 The trials recruited a total of 1,047 patients with doses ranging from 0.025mmol/kg to 0.3mmol/kg and met its endpoints in terms of the diagnostic benefit of injecting Gadopiclenol (0.05 mmol/kg) during MRI examinations, based on: 

1. The superiority of the examination with Gadopiclenol compared to the examination with no contrast agent; and
2. The non-inferiority of Gadopiclenol (0.05 mmol/kg) at half the gadolinium dose of gadobutrol (0.1 mmol/kg), another GBCA, as assessed in 3 lesion visualization co-primary criteria: border delineation, internal morphology and contrast enhancement.6,7 In the PICTURE trial, readers preferred the quality of visualization obtained with a half dose of Gadopiclenol compared to a full dose of gadobutrol.

Gadopiclenol, the active substance of Elucirem, is designed with two sites for water molecule exchange which enables twice as much interaction, resulting in the highest relaxivity among all non-specific GBCAs. This consequently permits its use at half the conventional gadolinium dose of existing non-specific GBCAs and addresses existing clinical concerns about gadolinium exposure. No major safety signals were reported during the development of Gadopiclenol, and the adverse reactions reported during the two-Phase III studies were similar for both products administered.  The most common adverse reactions (incidence >0.2%) in patients who received Gadopiclenol were injection site pain, headache, nausea, injection site warmth and coldness, dizziness, and localized swelling.

Market authorization of Gadopiclenol comes at a critical time as the toxicity, pharmacokinetics, and pharmacodynamics of GBCAs have been placed under increasing scrutiny by a concatenation of studies that highlight its potentially toxic effects.2,8 A linear relationship has been observed between insufficient excretion of GBCAs in reno-compromised patients and nephrogenic systemic fibrosis (NSF) due to the retention of dissociated gadolinium. This risk was found to vary with the structure of each GBCA, being much higher in the case of non-ionic linear chelates than the relatively biostable macrocyclic GBCAs owing to the rapid deceleration of the former.2 More recently, reports have also suggested that despite normal hepatobiliary function and an intact BBB, patients receiving GBCAs remain at risk of gadolinium deposition in the neuronal cells.9 While its long-term implications have not been explicated, the risk also appears to vary with the structure of each GBCA used. 

At present, clinical consensus on mitigating approaches is to minimize the dose of GBCAs, in acknowledgement of the significant dose-dependent neuronal accumulation of gadolinium observed in the studies. The use of GBCAs should only be reserved for when clinically indicated in consideration of indications and dosing regimens, and the use of macrocyclic GBCAs in lieu of linear GBCAs if indicated, due to concerns about potential free gadolinium toxicity. Additionally, patient education and clinician consideration of retention characteristics when choosing GBCAs for patients at higher risk of gadolinium retention is also urged.1,10 

References

1. Gadolinium-Based Contrast Agent Use, Their Safety, and Practice Evolution – PMC. Accessed October 10, 2022. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8378745/
2. Ranga A, Agarwal Y, Garg KJ. Gadolinium-based contrast agents in current practice: Risks of accumulation and toxicity in patients with normal renal function. Indian J Radiol Imaging. 2017;27(2):141-147. doi:10.4103/0971-3026.209212
3. Cowling T, Frey N. Macrocyclic and Linear Gadolinium Based Contrast Agents for Adults Undergoing Magnetic Resonance Imaging: A Review of Safety. Canadian Agency for Drugs and Technologies in Health; 2019. Accessed October 10, 2022. http://www.ncbi.nlm.nih.gov/books/NBK546000/
4. Rogosnitzky M, Branch S. Gadolinium-based contrast agent toxicity: a review of known and proposed mechanisms. Biometals. 2016;29(3):365-376. doi:10.1007/s10534-016-9931-7
5. Accessed October 10, 2022. https://www.accessdata.fda.gov/
6. Guerbet. Efficacy and Safety of Gadopiclenol for Central Nervous System (CNS) Magnetic Resonance Imaging (MRI). clinicaltrials.gov; 2021. Accessed October 6, 2022. https://clinicaltrials.gov/ct2/show/NCT03996447
7. Guerbet. Efficacy and Safety of Gadopiclenol for Body Magnetic Resonance Imaging (MRI). clinicaltrials.gov; 2021. Accessed October 6, 2022. https://clinicaltrials.gov/ct2/show/NCT03986138
8. Davies J, Siebenhandl-Wolff P, Tranquart F, Jones P, Evans P. Gadolinium: pharmacokinetics and toxicity in humans and laboratory animals following contrast agent administration. Arch Toxicol. 2022;96(2):403-429. doi:10.1007/s00204-021-03189-8
9. Guo BJ, Yang ZL, Zhang LJ. Gadolinium Deposition in Brain: Current Scientific Evidence and Future Perspectives. Front Mol Neurosci. 2018;11:335. doi:10.3389/fnmol.2018.00335
10. Royal College of Radiologists. Guidance on gadolinium-based contrast agent administration to adult patients BFCR(19)4 -2019.