FDA Issues Complete Response Letter for Orviglance in Liver Imaging

The FDA has issued a complete response letter (CRL) for the new drug application (NDA) of manganese chloride tetrahydrate (Orviglance) for improving the detection and visualization of focal liver lesions on MRI in patients with severely impaired kidney function, according to a news release from the developer, Ascelia Pharma.¹ The agency stated it is currently unable to approve the application in its present form and has requested additional clinical data and product documentation. The developer plans to request a Type A meeting with the FDA as soon as possible to better understand the issues raised.

The NDA was supported by the phase 3 SPARKLE trial (NCT04119843), a global, multicenter study that enrolled 85 patients across 32 sites in the US, Europe, and Latin America, with known or suspected focal liver lesions and severe kidney impairment, defined as an estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m².^2,3 Orviglance is administered orally before MRI; after absorption in the small intestine, manganese is taken up by normal liver tissue, causing it to appear bright on imaging, while metastases and tumors, which take up less manganese, appear comparatively dark, making lesions easier to identify.

The SPARKLE trial met its primary end point, with Orviglance significantly improving the visualization of focal liver lesions compared with unenhanced MRI. The primary end point was evaluated independently by 3 blinded radiologists, who also assessed secondary efficacy endpoints; results reached statistical significance (P <.001) for all 3 readers, with reliability described as “strong and conclusive”.² Secondary end points included quantitative image improvement and safety.

Common adverse events in this population were consistent with prior Orviglance studies, most frequently being mild-to-moderate nausea; no serious adverse drug reactions were observed. Across the full development program of 9 clinical studies in 286 patients and healthy volunteers, safety and efficacy findings were consistent.

“We remain confident in Orviglance and are committed to making it available to patients,” said Magnus Corfitzen, chief executive officer of Ascelia Pharma, in the release.¹ “Our focus now is to work with the FDA to identify an expedited path forward. We will provide further updates when appropriate.”

To be eligible for the SPARKLE trial, patients were 18 years and older with known or suspected focal liver lesions based on medical history and previous laboratory and/or imaging examinations, and severe renal impairment. Those with simple liver cysts, any investigational drug or device given within 6 weeks of baseline visit, and any MRI contrast media within 6 weeks prior to baseline visit were among those ineligible for trial enrollment.

Orviglance, also known by the development code ACE-MBCA and formerly as Mangoral, has been granted orphan drug designation by the FDA. It would be the first contrast agent developed specifically for liver MRI in adults with severely impaired kidney function.

The FDA accepted the NDA for review in November 2025 and had set a Prescription Drug User Fee Act (PDUFA) action date of July 3, 2026.⁴

The liver is the second most common site of metastasis after the lymph nodes, and 5-year survival can increase from 6% to 46% when liver metastases are detected early enough to be surgically removed. Patients with severely impaired kidney function are currently limited to unenhanced MRI, since the gadolinium-based contrast agents used in standard liver imaging carry Black Box warnings in this population due to the risk of nephrogenic systemic fibrosis (NSF), a rare but potentially fatal condition causing progressive skin thickening, joint contractures, and multi-organ fibrosis. Orviglance was developed as a gadolinium-free alternative intended to give this population access to contrast-enhanced imaging.

References

1. Ascelia Pharma provides update on the Orviglance NDA. News release. Ascelia Pharma. July 3, 2026. Accessed July 6, 2026. https://tinyurl.com/yf4bhz25
2. Orviglance. Ascelia Pharma. Accessed July 6, 2026. https://tinyurl.com/msxavc8t
3. Safety and diagnostic efficacy of Mangoral in participants with focal liver lesions and reduced kidney function. ClinicalTrials.gov. Updated February 6, 2025. Accessed July 6, 2026. https://tinyurl.com/y4k246a8
4. Ascelia Pharma announces FDA acceptance of Orviglance New Drug Application for review. News release. Ascelia Pharma. November 15, 2025. Accessed July 6, 2026. https://tinyurl.com/49cubecv