ORION 2: Sustained LDL Reduction With Inclisiran in Homozygous FH

Liam Davenport

May 29, 2019

MAASTRICHT, The Netherlands — Patients with homozygous familial hypercholesterolemia (hoFH), for which there are currently no ideal treatments, may have substantial and sustained low-density-lipoprotein (LDL)-cholesterol lowering with inclisiran (ALN-PCSsc, Alnylam Pharmaceuticals/The Medicines Company), suggests a pilot study.

Inclisiran is a novel small interfering RNA-based therapy that acts by preventing proprotein convertase subtilisin/kexin type 9 (PCSK9) production in hepatocytes.

As reported by theheart.org | Medscape Cardiology, the ORION 1 trial showed that the drug offered long-lasting reductions in LDL-cholesterol levels of up to 41.9%, suggesting that it could be given just once every 6 months.

This was followed by a secondary analysis showing that it also substantially reduced levels of non-high-density (HDL) cholesterol, apolipoprotein B, and lipoprotein(a).

Moreover, the majority of patients met guideline-recommended targets for non-HDL cholesterol and apolipoprotein B.

Now, data presented here at the European Atherosclerosis Society (EAS) 2019 Congress show the impact of inclisiran in patients with hoFH.

The ORION 2 pilot study examined four hoFH patients already receiving intensive lipid-lowering therapy with statins and ezetimibe, who were administered inclisiran 300 mg and then followed for 180 days.

Three patients had substantial reductions in LDL-cholesterol levels that were maintained out to 180 days, with the largest reduction of 43% in one patient on day 120.

Lead author Frederick Raal, MD, PhD, University of the Witwatersrand, Johannesburg, South Africa, told delegates that there were also reductions in atherogenic factors, such as apoliprotein B and lipoprotein(a), with no safety concerns.

Describing the study as a "proof of concept," Raal said that inclisiran has been shown to be "effective in homozygous FH at the sort of usual dose that's been used in the clinical development program."

Emphasizing that the dose did not need to be escalated during the study, he said that the results have formed the basis of the phase 3 ORION 5 trial, which will recruit 45 hoFH patients to test the treatment further.

Raal noted, however, that, as has been seen with monoclonal antibody therapy against PCSK9, two of the patients with an identical mutation "had very different responses to the medication, so there must be other reasons why some patients do not respond as well as others."

Alberico L. Catapano, MD, PhD, professor of pharmacology, University of Milan, and past president of the EAS, who was not involved in the study, told theheart.org | Medscape Cardiology that any additional impact that lowering PCSK9 can have on top of that seen with intensive lipid-lowering therapy depends on the degree of expression of the LDL receptor.

"If the defect is that you still have a sizeable amount of LDL receptors, then the efficacy of lipid-lowering will be higher, no matter if you block PCSK9 or not, but there is no possibility to stimulate further in people who have very little expression of the receptor," Catapano explained.

"You can drop PCSK9 levels but the amount of receptor they can express is limited, so these patients will have less reduction of LDL. It’s not a one-to-one relationship; it depends on two steps."

Nevertheless, Catapano believes that inclisiran, if proven to be safe in hoFH, will offer a "big advantage" in terms of compliance.

"The drug effect will last at least 3 months, people think 6 months is doable, so that will make things much easier, especially because those patients often have to be referred to a specialized center, which may not be close to home," he said.

"That will make it much easier on the patient and will make the patient be compliant with the treatment on a strict basis."

Although Catapano underlined that the benefit seen with inclisiran will depend on an individual's LDL-receptor expression, "it might really prove useful in lowering perhaps the dose of other drugs."

As such, he sees it as "an adjunct to the armamentarium we have for homozygous FH," as these patients are difficult to treat.

Rare, Life-threatening Disorder

Raal said that hoFH is a rare, life-threatening disorder in which high-intensity statin therapy achieves a 10% to 25% reduction in LDL-cholesterol levels, with ezetimibe increasing that by only 10% to 15%.

Lomitapide achieves greater reductions in LDL cholesterol but at the cost of an increased risk for hepatotoxicity, which is also seen with the injectable agent mipomersen.

To investigate the effectiveness and safety of inclisiran in this hard-to-treat population, the researchers included patients 12 years and older with genetically or clinically confirmed hoFH. They also had to have been stable on maximum-tolerated lipid-lowering therapy for at least 4 weeks.

Patients were excluded if they had either active liver disease or uncontrolled diabetes, and/or had experienced a major adverse cardiovascular event within 3 months of enrolment.

After a screening period of 28 days, patients were injected with inclisiran 300 mg and followed for 180 days, with another injection on day 90, or on day 104 if mean serum PCSK9 levels were not suppressed by more than 70%.

The patients then underwent extended follow-up out to day 300, as long as they continued to have an LDL-cholesterol level reduction that was at least 20% of that seen between baseline and day 90.

Four patients, two of them female, and all white and 23 to 50 years of age, were enrolled in the study. Their body mass index ranged from 23 to 44 kg/m2.

Three of the patients had established atherosclerotic cardiovascular disease and all four were receiving intensive lipid-lowering therapy.

Two patients were true homozygotes for FH, whereas two were compound heterozygotes. Regardless, all of them had defective overall LDL-receptor function.

After inclisiran treatment, three patients experienced a reduction in LDL-cholesterol levels of 11.7% to 33.1% on day 90 and 17.5% to 37.0% on day 180.

The largest reduction was 43.0%, which was seen in one patient on day 120.

The fourth patient, however, had an increase in LDL-cholesterol levels after treatment, by 14.3% on day 90 and 3.3% on day 180.

Despite this, all patients experienced marked decreases in PSCK9 levels of 48.7% to 83.6% on day 90 and of 40.2% to 80.5% on day 180.

Raal also showed that inclisiran was associated with lower apolipoprotein B levels, at reductions of 14.2% to 46.1% on day 90 and 6.8% to 38.6% on day 180.

The pattern for lipoprotein(a) levels was less consistent, with one patient having an increase in levels on day 90 but a substantial decrease by day 180, and another patient had increased levels at both timepoints.

He said that this was overall similar to the pattern of response seen with monoclonal antibodies against PCSK9.

Finally, Raal said that there were no drug-related events or event-related discontinuations, no injection-site reactions, and no clinically relevant laboratory abnormalities.

During the postpresentation discussion, session cochair Alexandros D. Tselepis, MD, PhD, director of the Atherothrombosis Research Centre, University of Ioannina, Greece, said he would have expected to see greater PCSK9 reductions with inclisiran than with monoclonal antibodies.

Raal said that because monoclonal antibodies "mop up" all the PCSK9 within the circulation, "you're going to get a 90%+ reduction."

"Inclisiran works in the liver but there are other sites of some PCSK9 production, probably from the intestines, possibly the kidney, so you reduce PCSK9 by about 80% with the use of this targeted therapy against the liver; you don’t get complete suppression."

Raal said, however, that the advantage of this approach is the prolonged reduction with a single injection, "as opposed to monoclonal antibody therapy, which has to be given fortnightly or monthly."

The study was funded by funded by The Medicines Company. Raal reports research grants and honoraria from Amgen, Regeneron, Sanofi, The Medicines Company. No other potential conflicts of interest reported.

European Atherosclerosis Society (EAS) 2019 Congress: Abstract EAS19-1122. Presented May 27, 2019.

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