Recombinant Human LCAT Raises HDL in Rare Lipoprotein Disorder

Shelley Wood

June 05, 2013

LYON, France — Researchers have, for the first time, successfully replaced the enzyme found in familial lecithin cholesterol acyltransferase (LCAT) deficiency using recombinant human LCAT ACP-501 (Alphacore Pharma). Familial LCAT deficiency, caused by mutations of the LCAT gene, is exceedingly rare, with only 125 known cases worldwide; there are no other treatments for the disorder.

Dr Robert Shamburek (National Heart, Lung, and Blood Institute, Bethesda, MD) presented the single case involving a 53-year-old patient here at the European Atherosclerosis Society 2013 Congress .

LCAT is a liver-derived enzyme that transfers a fatty acid from lecithin to cholesterol to form cholesteryl esters. The company developing the product is also testing the agent in patients with very low HDL and coronary artery disease, demonstrating some early success. As Shamburek put it during his late-breaking presentation, "If this is working in low HDL patients with CAD, what about a patient with no HDL?"

In fact, the patient treated in this first-in-human case had HDL cholesterol <5 mg/dL [0.13 mmol/L]), as well as corneal opacity, stage 4/5 renal disease, anemia, atrial arrhythmias, and splenomegaly.

For the study, the patient, treated under a compassionate-use protocol, was given increasing doses of ACP-501 infusions over a two-week period, followed by 9-mg/kg infusions every one to two weeks.

According to Shamburek, LCAT levels rose after each dose and remained elevated after four days of treatment. After the seventh infusion, plasma HDL levels had increased by 80%, reaching 24 mg/dL (0.62 mmol/L). Biomarkers of renal function BUN and cystatin C improved by 30% and 17%, respectively. Hemoglobin and hematocrit both increased by 25%.

The patient had no infusion-related adverse events and no infusion-site reactions but did have recurrent atrial fibrillation that was deemed unrelated to treatment. Asked about this during the Q&A, Shamburek explained that the patient had two brothers who do not have LCAT deficiency and who both also suffer from recurrent atrial fibrillation. "I'm presuming it's not related [to treatment]," Shamburek said. "There is potentially a connection, but the family history in this case throws it off."

Commenting on the study for heartwire , Dr Børge Nordestgaard (University of Copenhagen, Denmark) called the case report "promising."

"From what was presented, it seemed like there were no serious side effects. But even if there are some minor long-term side effects, you can still live with those if the benefit outweighs the harms, and that's what these early data look like."

Having a therapy for such a rare and devastating disease would be "fantastic," he said.

Whether an HDL-raising agent of this sort can succeed where other recent efforts have failed in a wider group of patients with low HDL is a bigger question.

"That's what you always dream about, that you find something that works in a very rare situation and you can then apply it to a more general population with low HDL. But that needs a lot more science before you can say anything serious about it, and the whole idea of HDL-cholesterol raising, that this will be beneficial, that [theory] has had a lot of blows lately."

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