Genzyme's Mipomersen: Liver Side Effects Could Limit a Promising Cholesterol Drug
Genzyme's mipomersen, a promising new cholesterol drug, could offer new hope for patients who don't respond to existing lipid-lowering drugs such as statins. But there are also troubling questions about a potential long-term, adverse effect of mipomersen on the liver.
Mipomersen is an antisense inhibitor of apo-B protein synthesis, the first drug of its type. Genzyme (GENZ) intends to first seek approval in the U.S. and Europe for mipomersen in those patients with homozygous familial hypercholesterolemia (HoFH), a rare genetic disorder affecting one in a million people, in the first half of 2011. HoFH patients have extremely high cholesterol levels (greater than 500 mg per deciliter) and exhibit early signs of cardiovascular disease in all major arterial beds (including the neck, heart, and legs), resultant from defective low-density lipoprotein (LDL-c) receptors in the liver that are unable to remove LDL-c from circulation.
In a pivotal late-stage clinical trial of patients with HoFH, mipomersen reduced plasma LDL-c levels by almost 25 percent compared to placebo when added to existing lipid-lowering drugs (although most patients failed to reach targeted LDL goals).
Study investigators, led by Frederick J Raal, concluded in their findings, which are found online in Lancet, that "mipomersen could be a valuable addition to the drugs used in the management of homozygous familial hypercholesterolemia and should prove useful in the management of other forms of severe refractory hypercholesterolemia."
Results, however, also raised questions about mipomersen's safety and tolerability, as 76 percent and 12 percent of patients in the mipomersen group had injection-site reactions and increased liver enzymes of three times or more the upper limit of normal (with MRI findings of increased intra-hepatic fat content too).
Most experts concur with study investigators that mipomersen appears to offer a viable option for patients with severe, refractory hypercholesterolemia. In an editorial accompanying the Lancet article, R. Dermot Neely and Margaret F. Bassendine (of the Royal Victoria Infirmary and Newcastle University, England), said: "This new treatment paradigm appears to offer patients who would otherwise be dependent on weekly LDL apheresis a less onerous alternative." LDL apherisis is a blood-filtering procedure that removes the "bad" cholesterol in a method similar to dialysis, and can cost upwards of $100,000 per year.
However, Neely judiciously noted, too, that hepatic fat increases were only measured (MRI) in the four folks with abnormally high ALT readings. Consequently, he concluded that longer studies with greater numbers of participants will be needed to provide reassurance that more significant fat accumulation and progression to non-alcoholic, irreversible liver damage does not occur -- especially if mipomersen treatment is extended to common lipid disorders with more heterogeneous underlying causes (such as co-morbid diseases like diabetes).
Pharmacology studies evaluating the enzyme activities of mipomersen provide evidence that supports the use of mipomersen in combination with oral lipid-lowering agents. For example, mipomersen exhibited no clinically relevant pharmacokinetic interactions with the disposition and clearance of Zocor (simvastatin), ezetimibe, or the combination of the two, marketed as Vytorin (simvastatin/ezetimibe). Moreover, mipomersen did not inhibit any of the major hepatic enzymes involved in metabolizing lipid-lowering, psychotropic or other classes of drugs requiring "first-pass" through the liver to be converted to their active compounds.
If not drug interference, what is the causation behind mipomersen-related liver issues? In email correspondence, Dermot Neely elucidated the mechanism by which hepatic fat is increased with mipomersen:
Fat in the liver can be burned, stored or exported to other parts of the body. The mode of action of mipomersen is to reduce production of the carrier protein (apolipoprotein B) required for the export of fat (and cholesterol) from liver cells. Therefore if the liver continues to produce fat (from sugars, etc.) or receive deliveries of fat (e.g. released from fat stores) and is unable to burn this off in the production of energy (fat oxidation), fat stored in the liver will increase, resulting in an increase in transaminases [liver enzymes].In addition, Drs. Neely and Bassendine cautioned that injection-site reactions occurred in most of the mipomersen-treated patients (76 percent), to the extent that such side-effects could have confounded the blinding of treatment. Of greater concern, could these events be immune-mediated reactions? To date, (in all studies) no antibodies to mipomersen have been detected so far, but the doctors prudently suggest longer-term monitoring will be necessary to ensure patients do not develop treatment resistance or autoimmunity.
John J Kastelein, (Chairman of the Department of Vascular Medicine at the Academic Medical Centre Amsterdam), and who has clinically investigated the effect of apo-B synthesis inhibition on liver triglyceride contents in FH patients, told me hat "it shouldn't be entirely unexpected that treated patients showed a trend towards an increase in intra-hepatic fat content (due to mode of action)."
Moreover, liver fat is not to be confused with liver toxicity -- nor elevations of liver enzymes. In fact, most obese individuals have more liver fat -- and for decades -- than any of the guys in our mipomersen studies.Kastelein did concur, however, with Neely that it would be prudent to have more long-term studies on the observed effects of mipomersen on hepatic function, as the affect of prolonged and profound reductions in apo-B on intra-hepatic fat content is unknown.
This risk assessment ought not be taken lightly, in my opinion. In the future likely candidates for adjunctive mipomersen injections -- if Genzyme has its way -- would include the broader range of at-risk patients already on maximal doses of statin therapies, but with circulating LDL still above recommended Adult Treatment Panel guidelines (not due to FH). A cohort of such study candidates should include those dyslipidemic patients with co-morbid diseases like diabetes, obesity, and/or pro-thrombotic states like advanced vascular disease -- patients whose livers are likely already "stressed-out" (as assessed by ALT levels). Consequently it is critical to collect as much observable data as possible to help assess the risk-reward benefit of adjunctive treatment in such patients.
So there's the rub, the folks who need the drug the most are at greatest risk for increases in stores of hepatic fat and elevated liver enzymes.
Without lipid-lowering therapy, hoFH patients rarely live beyond age 30. That statistic in mind, Kastelein finds no reason to refute claims by study investigators, too, that the additional 25 percent mean reduction in circulating LDL-c brought about by mipomersen could offer major clinical benefits to patients with HoFH. "Mipomersen heralds a new age of DNA-based therapies that can truly change the course of disease in these unlucky folks with mutated alleles resulting in severely high cholesterol levels," he said.
Genzyme has a significant head start on other anti-sense competitors, with few even beyond animal or "proof-of-concept" studies. A company spokeswoman said two ongoing Phase 3 trials evaluating mipomersen in high-risk, high cholesterol patients are both incorporating comprehensive MRI measurements of hepatic fat content. Initial results are expected this summer, and will hopefully provide additional data on liver safety issues.
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