From the Journals

Amyloid depleter/antibody duo reduces systemic amyloidosis severity

 

Key clinical point: A combination of an amyloid-depleting agent and immunotherapeutic antibody appears effective and safe in patients with systemic amyloidosis.

Major finding: A 2,000-mg dose of dezamizumab reduced amyloid load in the liver and/or spleen in five of seven patients.

Data source: Open-label, nonrandomized clinical trial of 23 adults with various subtypes of systemic amyloidosis.

Disclosures: GlaxoSmithKline funded the study. Three of the coauthors are GSK employees and stockholders. Prof. Pepys is the inventor on patents for miridesap and miridesap plus anti-SAP antibody.

Source: Richards D et al. Sci. Transl. Med. 2018;10:eaan3128.


 

FROM SCIENCE TRANSLATIONAL MEDICINE

A one-two combination consisting of a drug to deplete amyloid fibrils from circulation and a monoclonal antibody to mop up residual amyloid protein appears to be safe and shows promising activity against systemic amyloidosis in an early clinical trial.

High magnification micrograph of senile cardiac amyloidosis. Congo red stain. Autopsy specimen. The micrograph shows amyloid (extracellular washed-out red material) and abundant lipofuscin (yellow granular material). ©Nephron/Wikimedia Commons/CC BY SA 3.0
High magnification micrograph of senile cardiac amyloidosis. Congo red stain. Autopsy specimen. The micrograph shows amyloid (extracellular washed-out red material) and abundant lipofuscin (yellow granular material).
“Clearance of amyloid from the liver was associated with improved liver function, firmly establishing the relationship between the presence and amount of amyloid and the pathogenesis of organ dysfunction. There was no change in proteinuria or renal function through the 6-week study follow-up; additional dosing and longer follow-up will be required to ascertain preservation or restoration of renal function,” they wrote. The report was published in Science Translational Medicine (Sci. Transl. Med. 2018. doi: 10.1126/scitranslmed.aan3128).

Systemic amyloidosis is caused by extracellular deposition of amyloid fibrils coated with serum amyloid P component (SAP), a normal plasma protein. Miridesap has been shown to deplete levels of circulating SAP, but fails to clear SAP lingering in amyloid deposits. Dezamizumab is a fully humanized immunoglobulin G1 antibody that is directed against SAP and provokes immune system clearance of residual protein.

The investigators enrolled 23 adults with systemic amyloidosis into an open-label, nonrandomized trial of safety, pharmacokinetics, and dose responses to up to three cycles of miridesap followed by dezamizumab. They used scintigraphy with radiolabeling to measure amyloid burden, equilibrium MRI to measure organ extracellular volume, and transient elastography to evaluate liver stiffness.

They found that a 2,000-mg dose of dezamizumab reduced amyloid load in the liver and/or spleen in five of seven patients, and that liver stiffness, a sensitive marker for hepatic amyloid load, initially increased in some patients, but then fell “substantially,” suggesting amyloid clearance and resolution of cellular infiltrates. Progressive dose-related clearance of amyloid in the liver was also associated with improvements in liver function tests.

In addition, 7 of 11 patients had reductions in renal amyloid burden, with the greatest benefit seen in patients treated with higher doses of the antibody.

The trial cohort also included six patients with clinical cardiac amyloidosis: three with monoclonal immunoglobulin light-chain amyloidosis (AL), and three with ATTR (transthyretin) amyloidosis. Although the investigators had excluded patients with cardiac amyloidosis in the first part of the study out of safety concerns, there were no new arrhythmias and no increases in cardiac troponin T or creatine kinase concentrations. One patient had a 17% reduction in left ventricular mass, suggesting a reduction in cardiac amyloid burden.

Patients tolerated the treatment, with self-limiting, early-onset rashes after higher antibody doses being the most frequent adverse event.

“However, the identified and potential risks of the intervention are considered manageable, and thus acceptable, in relation to the demonstrable clinical benefits of removing amyloid from vital organs,” the investigators wrote.

GlaxoSmithKline funded the study. Three of the coauthors are GSK employees and stockholders. Prof. Pepys is the inventor on patents for miridesap and miridesap plus anti-SAP antibody.

Source: Richards D et al. Sci. Transl. Med. 2018. doi: 10.1126/scitranslmed.aan3128.

Next Article: