Alirocumab Successfully Reduces LDL Cholesterol in Homozygous FH: ODYSSEY HoFH

In patients with homozygous familial hypercholesterolemia (FH)—a rare genetic condition characterized by LDL receptor loss-of-function mutations that is difficult to treat with traditional lipid-lowering medications—alirocumab (Praluent; Sanofi/Regeneron) can reduce LDL cholesterol by as much as one-third over 12 weeks, according results from the randomized ODYSSEY HoFH study presented at last week’s American College of Cardiology (ACC) 2020 Scientific Session.

These findings follow the publication of the TAUSSIG study in February showing that the other available PCSK9 inhibitor, evolocumab (Repatha; Amgen), can reduce LDL cholesterol in patients with homozygous FH by 21.2% at week 12 and 24% at week 216. And in the same ACC 2020 session as ODYSSEY HoFH, another study showed that the novel angiopoietin-like protein 3 (ANGPTL3) inhibitor evinacumab (Regeneron), can impart substantial LDL cholesterol-lowering in this complex group of patients.

“Treating patients with alirocumab can certainly gain a clinically meaningful further reduction in LDL cholesterol in this difficult to treat cohort of patients,” said Dirk Blom, MBChB, PhD (University of Cape Town, South Africa), who presented ODYSSEY HoFH. “We’re not getting most patients to goal, but we’re certainly getting them close to goal. And so, a lot of patients will need further therapies that don't rely on functional LDL receptors such as ANGPTL3 inhibition, lomitapibe, or apheresis depending on what's available.”

“ODYSSEY HoFH is a very important trial because it expands our knowledge about the importance of PCSK9 inhibitors in reducing LDL cholesterol in these patients,” said Raul Santos, MD, PhD (University of São Paulo Medical School Hospital and Hospital Israelita Albert Einstein, Brazil), primary investigator of TAUSSIG, when discussing the trial after its presentation.

Significant Decrease in LDL Cholesterol

For the study, Blom and colleagues enrolled 69 patients 18 years or older with homozygous FH on lipid-lowering therapy and/or apheresis and a baseline LDL-cholesterol level of at least 70 mg/dL. Following an optional 4-week run-in period and a 2-week screening period, patients were randomized to treatment with alirocumab 150 mg (n = 45) or placebo injection (n = 24) every 2 weeks for 12 weeks. After the study period, all patients were given alirocumab for another 12 weeks.

More than one-third of the total population had a history of coronary heart disease, and the mean patient age was in the early 40s. About 40% were null/null carriers of the homozygous mutation, and slightly more than one-quarter were carriers of the compound heterozygous mutation.

At baseline, more than 95% of participants were on statins (more than 85% on high-intensity statins), more than two-thirds were on ezetimibe, and about 10-15% each on lomitapibe and apheresis. Despite these treatments, baseline LDL cholesterol was 295 and 260 mg/dL, respectively, for the alirocumab and placebo groups.

After 12 weeks of treatment, those treated with alirocumab saw a 26.9% drop in LDL cholesterol, equivalent to a mean reduction of 62.8 mg/dL, while the placebo arm reported an increase of 8.6%, or a mean increase of 8.9 mg/dL (mean difference -35.6%; P < 0.0001). More than one-quarter of patients in the alirocumab arm saw at least a 50% reduction in LDL cholesterol, as compared to none in the placebo arm (P = 0.0017).

Blom explained that there was some variability in response to alirocumab with some patients seeing upwards of 60% reductions and others reporting much smaller effects. Additionally, all patients with null/null mutations, with the exception of one, saw “very little or no response,” he said.

The lone patient with a single null mutation allocated to alirocumab had an increase in LDL cholesterol, but whether this was because of poor compliance or other factors remains unknown. “In the patients with more variable genetic diagnoses, we see even more variability, but in general a somewhat better response,” Blom added.

Overall, other atherogenic lipids including total cholesterol, apolipoprotein B, non-HDL cholesterol, and lipoprotein(a) were all reduced by alirocumab compared with placebo by more than 25% (P < 0.0001 for all).

Alirocumab was considered safe, with 44.4% of patients in the study arm and 50% of the placebo arm reporting treatment-emergent adverse events. One patient treated with alirocumab reported a local injection site reaction, but no serious adverse events, deaths, or discontinuations were observed due to the study drug.

Similar to Evolocumab

“Homozygous FH is classically known for its refractory lipid profile—even if you use statins and ezetimibe, very rarely do we obtain adequate LDL-cholesterol levels,” Santos said. “However, even despite the refractoriness of treatment, these patients might get 10-15 extra years free of cardiovascular events. Even so, these patients do persist at extremely high risk and other therapies to reduce LDL are needed.”

While lomitapibe and apheresis have been options, “unfortunately these treatments are expensive [and] not available universally, so we need other treatments,” he explained. “This is the second study with a PCSK9 inhibitor. We already knew that evolocumab, another drug from this class, reduced LDL on average by 20-25% but with huge variability on the response.”

Santos said these results look very similar and perhaps “a little better” than those with evolocumab, perhaps due to the fact that TAUSSIG included many patients with heterozygous FH with a severe phenotype.

He suggested trying to increase the dose of alirocumab for homozygous FH patients to potentially reduce LDL-cholesterol levels even further and reduce variability going forward. “Residual LDL was high, but as you saw, there’s a huge variability in response,” Santos said. “Certainly, PCSK9 inhibitors should be a next step after statins and ezetimibe to check how much cholesterol could be reduced.”

Additionally, he said future studies of PCSK9 inhibitors are needed in children with this genetic condition. “It’s going to be very important to expand these treatments to younger people with homozygous FH because we have to start very early,” Santos concluded. “Finally, we have to guarantee access to these treatments for homozygous FH patients because they really can make the difference.”

During a press conference, Eileen Handberg, PhD, ARNP-BC (University of Florida, Gainesville), commented that the study “moves it forward in terms of this population that's very difficult to treat who are desperately looking for opportunities. It will be helpful to have both agents on board and hopefully this will, with such substantial reductions in LDL, allow for maybe more access to these drugs. This has been an ongoing issue in this population for sure, and so I think that’s an important sequalae of getting more drugs and hopefully the costs will continue to go down and there'll be better access.”