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In separate trials, two monoclonal antibodies each lowered low density lipoprotein (LDL) cholesterol in people with a particularly refractory form of familial hypercholesterolemia (FH), researchers reported at the (ACC).

The drugs -- one already on the market, the other still in clinical trials -- appeared effective against homozygous FH, in which patients have . The condition responds even less well to current therapies than heterozygous FH. It's also extremely rare, with an estimated 1,300 patients total in the U.S.

In the , treatment with the currently marketed PCSK9 inhibitor alirocumab (Praluent) lowered LDL cholesterol an average of 26.9% from baseline over 12 weeks in homozygous FH patients, versus an 8.6% LDL increase with placebo (P<0.0001).

And in a separate study, treatment with the investigational agent evinacumab, which targets angiopoietin-like 3 (ANGPTL3) protein, reduced LDL levels by 47.1% after 24 weeks while a placebo group had an average increase of 1.9%.

Alirocumab

The lead investigator of the ODYSSEY HoFH trial, Dirk Blom, MD, PhD, of the University of Cape Town in South Africa, said, "The addition of alirocumab on top of maximally tolerated lipid lowering therapy helps patients get closer to their LDL cholesterol goal."

The trial randomized 45 patients with homozygous FH to alirocumab and 24 to placebo. Baseline LDL in these groups averaged 295 and 260 mg/dL, respectively. Treatments were given every 2 weeks.

"LDL cholesterol percent reduction with alirocumab is less pronounced in patients with homozygous familial hypercholesterolemia than in other forms of hypercholesterolemia, as homozygous familial hypercholesterolemia is characterized by severely impaired LDL receptor function," Blom said at an ACC press conference. Nevertheless, he said, "Substantial and significant absolute reductions in LDL-cholesterol were observed with alirocumab."

In commenting on the trial, Eileen Handberg, PhD, of the University of Florida in Gainesville, said, "The findings of this PCSK9 inhibitor is similar to what we have seen with other agents. We may be able to use this information in trying to guide therapy. This population is very difficult to treat."

Alirocumab is currently approved to treat heterozygous FH, but not the homozygous form.

Evinacumab

In targeting ANGPTL3, evinacumab -- a fully human monoclonal antibody -- is designed to reduce LDL independent of whether patients have functioning LDL receptors. Frederick Raal, PhD, of the University of Witwatersrand in Johannesburg, South Africa, who presented the trial findings, said that people with poorly functioning receptors respond weakly or not at all to drugs such as statins and PCSK9 inhibitors.

The trial enrolled 43 patients to receive evinacumab in an intravenous dose of 15 mg/kg every 4 weeks and 22 patients given intravenous placebo infusions.

Raal said evinacumab worked just as well in people with homozygous familial hypercholesterolemia who had some functioning receptors as those without those receptors. In fact, the map of their effectiveness overlapped.

In the trial, none of the patients on placebo experienced any serious adverse effects; there were two in the evinacumab patients – a bout of urosepsis, and an unsuccessful suicide attempt. Neither were considered treatment related. "Evinacumab safety is being further assessed in the 24-week open-label treatment period of the trial," Raal said.

He noted that the effect of evinacumab was evident as early as 2 weeks into treatment, showing about a 40% reduction in LDL-cholesterol at that clinic visit. After 24 weeks, "the mean absolute decrease in LDL-cholesterol was 132 mg/dL, which is remarkable," he said.

"Evinacumab may provide an effective treatment for patients with homozygous familial hypercholesterolemia who are unable to reach target LDL-cholesterol despite multiple conventional lipid-lowering therapies with or without apheresis."

Handberg commented, "I think this is groundbreaking in terms of this population through this alternate mechanism that can help people who cannot make use of PCSK9 inhibitors."

"The reduction in LDL was quite impressive," she said. "The fact that the reduction occurred so rapidly and remained reduced over the course of therapy is extremely important. I agree with the investigators that long-term safety of this compound is extremely important since they will have to be taking medication over the course of their lifetime."

Handberg also expressed concerns over the drug's likely high cost, which would add to all the other medications these patients need to take.

Drugmaker Regeneron is also developing evinacumab for other forms of refractory hypercholesterolemia and severe hypertriglyceridemia. In reporting topline results from the homozygous FH trial last August, the company said it sometime in 2020.