Mangoral ™ is an investigational new drug for diagnostic use as a MRI contrast agent for enhancement of the liver tissue. The candidate drug is being developed for detection of liver metastases in patients where use of gadolinium based contrast agents may be medically inadvisable or cannot be administered.
Metastasis to the liver often occurs in progressive cancer disease and is associated with substantially reduced survival. In fact, the liver is one of the most frequent – and often the first – site of metastasis. About 50% of all patients with colorectal cancer will develop liver metastases at some point in their lifetime, and one-third of these will have metastases confined only to the liver. Early detection and localization of liver metastases is critical for optimal patient management.
Mangoral is the first contrast agent in the world to obtain Orphan Drug Designation by the FDA for use in liver MRI in patients where use of gadolinium-based contrast agents may be medically inadvisable or where gadolinium-based contrast agents cannot be administered.
Mangoral is orally administered and consists of manganese combined with absorption promoters to increase manganese absorption in the small intestine, a prerequisite for a high uptake of manganese into the liver tissue, which is the optimal condition for obtaining high imaging quality. Manganese is a natural trace element and after absorption from the gastrointestinal tract it is efficiently taken up by normal liver cells, known as hepatocytes. Due to the retention of manganese in the hepatocytes and its paramagnetic properties, the contrast agent clearly enhances the liver tissue in MR imaging whilst the liver metastases do not accumulate manganese. Therefore, the liver metastases will become clearly detectable against the enhanced liver tissue on the MR image. From the liver the manganese is excreted via the bile. Mangoral’s route of administration, uptake and excretion means that only very small amounts of manganese reaches the systemic blood circulation.
The currently used MRI contrast agents are based on gadolinium and have been associated with Nephrogenic Systemic Fibrosis in patients with severely impaired kidney function. Consequently, regulatory authorities have contraindicated or warned against the use of these contrast agents in patients with eGFR <30 ml/min/1.73 m2 as well as in Acute Kidney Injury patients. These patients are candidates for Mangoral.
To date, Mangoral has been studied in six completed clinical trials in healthy volunteers (N=52, in which two received placebo) and patients with known liver metastases or suspected liver lesions (N=75). One Phase I clinical study in healthy volunteers (Study No. CMC-P001), one Phase II clinical study in healthy male and female volunteers (Study No. CMC-P010) and four Phase II clinical studies in patients with liver metastases or suspected liver lesions (Study No. CMC-P002, CMC-P003, CMC-P004 and CMC-P005) have been completed (see Table below). In addition, Mangoral has been used in a compassionate use program.
The efficacy of Mangoral as a contrast agent in MRI of the liver and gastrointestinal tract was evaluated by means of both objective and subjective assessments in the individual clinical studies. Overall, the results from the efficacy analyses show that diagnostic quality scores improved after use of Mangoral. However, the results indicated a more efficient contrast enhancement of the liver than of the biliary tract and other parts of the gastrointestinal tract. MR images of the liver taken after administration of Mangoral showed improvement in terms of visualization of the liver, signal intensity in the liver, delineation of focal liver lesions, number of detected metastases, delineation and visualization of the size of liver metastases, delineation of the liver blood vessels and overall image quality, compared to MR images taken before Mangoral administration. A dose-dependency was observed for some of the efficacy variables assessed, with the 800 mg dose giving the best balance between safety and efficacy. The results did also suggest that MRI should be performed 2 to 6 hours after Mangoral administration.
Note: Study CMC-P005 was not published. With regards to the primary objective of the study, the results showed no difference in visualisation of the bile ducts between 2,5 hours and 4 hours after administration of Mangoral or between 800 mg and 1600 mg of Mangoral. The efficacy on liver visibility and focal liver lesions (which was a secondary objective) was better after Mangoral administration, and the safety results was also in line with what was shown in the other Phase II Mangoral studies performed, i.e. no safety concerns were identified and the product was regarded as safe and well tolerated.