ORION-1: Novel PCSK9 Inhibitor Provides Durable LDL-C Reduction

Susan Jeffrey

November 23, 2016

NEW ORLEANS, LA — A novel method of inhibiting proprotein convertase subtilisin kexin type 9 (PCSK9) synthesis, called RNA interference, provides a durable     reduction in LDL cholesterol, preliminary studies suggest.

Interim analysis of ORION-1, a phase 2 study looking at various doses of a long-acting RNA     interference agent called inclisiran (ALN-PCSsc, Alnylam Pharmaceuticals/the Medicines Company) showed a single injection of the 300-mg dose reduced LDL-C     up to 51% at 90 days, and two doses reduced LDL-C by 57% at 180 days[1].

"It appeared to be well tolerated, with no material safety issues, and it offers us the potential for bi- or triannual dosing," lead author Dr Kausik K     Ray (Imperial College, London, UK) told a press conference.

The results support the move to phase 3 outcomes trials, he added.

"I want to leave you with one key message," he concluded. "The efficacy, safety, and dosing profile of inclisiran are likely to ensure significant and     durable reductions in LDL-C and thus could potentially impact cardiovascular outcomes."

The study was presented here at the American Heart Association 2016 Scientific Sessions. Cursory top-line results were released in October, as reported by heartwire from Medscape.

RNA Interference

Antibody-based agents that reduce LDL-C by blocking PCSK9 are already commercially available, Ray noted. However, they are expensive and have a short     duration of effect, requiring injections once or twice a month.

The method they are investigating approaches PCSK9 from a different direction, using a synthetic double-stranded oligonucleotide (PCSK9si) to block genes     that regulate PCSK9 in the liver. The molecule consists of 21 to 23 base pairs, with a two base-pair overhang, a modification that allows specific uptake     into the liver by asialoglycoprotein receptors, Ray noted, "thus limiting its toxicity to other tissues."

Once in the liver, it engages in a natural process called RNA-induced silencing complex, which allows it to cleave messenger RNA that encodes PCSK9.     Treatment in early studies has produced LDL-C reductions that last several months.

Results of a phase 1 study of inclisiran were also presented at the AHA meeting and published in     the New England Journal of Medicine[2].

Healthy volunteers with an LDL-C of at least 100 mg were randomized in a 3:1 ratio to receive subcutaneous injection of inclisiran or placebo in single or     multiple ascending-dose arms. The single ascending-dose arm included 18 patients who received 25-, 100-, 300-, 500-, or 800-mg doses, and six placebo     patients.

The multiple ascending-dose arm received inclisiran 125 mg weekly for four doses, 250 mg every other week for two doses, or 300 or 500 mg monthly for two     doses, with (four placebo, nine inclisiran) or without (eight placebo, 24 inclisiran) concurrent statin therapy.

The researchers, led by first author Dr Kevin Fitzgerald (Alnylam Pharmaceuticals, Cambridge, MA), reported no serious adverse events with inclisiran. Investigators attributed one     instance of grade 3 elevation in gamma-glutamyltransferase levels to statin therapy. The most common adverse events were     cough, musculoskeletal pain, nasopharyngitis, headache, back pain, and diarrhea.

As for LDL-C reduction, they found doses of 300 mg or more, as single or multiple doses, reduced LDL-C by about 50% for 6 months or longer.

At the meeting, Ray presented results from an ongoing phase 2 study of inclisiran. Although the primary end point was percentage change in LDL-C from     baseline to day 180, they prespecified an interim analysis at 90 days to assess percentage changes in PCSK9 and LDL-C, as well as safety and tolerability     end points.

Patients eligible for inclusion had atherosclerotic cardiovascular disease or high-risk primary-prevention features, including diabetes and familial     hypercholesterolemia, and LDL-C greater than 100 mg/dL on maximum-tolerated statin treatment.

As of October 25, 497 patients had been followed out to 90 days, and 186 out to 180 days. Four patients did not receive drug. Doses chosen for a single     injection were placebo, 200, 300 and 500 mg of inclisiran, and doses for a second injection at 90 days were placebo, 100, 200, and 300 mg of inclisiran.

The average age of participants was 60 years, and most had cardiovascular disease (68%), were male (67%), and on lipid-lowering     treatment (82%), mainly statins (72%).

Baseline LDL-C in the placebo and treatment groups was about 125 mg/dL, similar to previous monoclonal PCSK9 trials, but baseline PCSK9 was higher, about     420 vs 360 mg in the current vs monoclonal trials, Ray noted.

Safety findings at 90 days show no difference in treatment-emergent adverse events (TEAE), either overall or classified as serious, severe, or treatment     related.

There was one death in the 500-mg group, Ray noted. "This was somebody with an over 20-year history of cardiovascular disease and multiple MIs, who died     suddenly in a restaurant."

Events reported with more than 2% frequency included myalgia, headache, fatigue, nasopharyngitis, back pain, hypertension, diarrhea, and dizziness.

ORION-1: Treatment-Emergent Adverse Events (TEAE) at Day 90

End point Placebo (n=127),
           n (%)
Pooled (n=370),
           n (%)
Inclisiran 100 mg (n=61),
           n (%)
Inclisiran 200 mg (n=122),
           n (%)
Inclisiran 300 mg (n=122),
           n (%)
Inclisiran 500 mg (n=65),
           n (%)
Any TEAE
           
69 (54) 198 (54) 38 (62) 64 (52) 68 (56) 28 (43)
Serious TEAE 5 (4) 22 (6) 8(13) 6 (13) 6 (5) 2 (3)
Severe TEAE 5 (4) 12 (3) 3 (5) 3 (2) 4 (3) 2 (3)
Related TEAE 24 (19) 67 (18) 11 (18) 20 (16) 27 (22) 9 (14)
Death 0 (0) 1 (0.3) 0 (0) 0 (0) 0 (0) 1 (0.3)

There was no dose-dependent relationship between treatment and biological or biochemical abnormalities, he said. There was no increase in bilirubin in any     group. Increases in alanine aminotransferase (ALT) and aspartate aminotransferase greater than three times the upper limit of normal each occurred in one     patient (0.3%), both in the 300-mg group, and alkaline phosphatase greater than two times the upper limit of normal occurred in three patients (0.8%), one     in the 100-mg and two in the 300-mg group. The increase in ALT improved with down-titration of statins, and the other abnormalities "resolved     spontaneously without intervention," Ray said.

"Importantly, there was no difference in myalgia between the groups," he added, reported in six placebo patients (4.7%) and 21 treated patients (5.7%).

Injection-site reactions occurred in 12 (3.2%) first injections and lasted more than 4 hours in nine (2.4%).

In terms of efficacy, Ray said, "a single injection of inclisiran sustained or reduced PCSK9 by day 15 and achieved a maximal level by day 30 that was     sustained through to 90 days."

With respect to LDL-C reduction, the single dose reduced LDL-C by up to about 50%, reaching a maximum at 60 days, and appeared to be maintained through day     90. "There's not a lot of difference between the 300-mg and 500-mg dose," he noted.

Both PCSK9 and LDL-C reductions were significant (P<0.0001). There was a "modest" decrease in triglycerides and increase in HDL cholesterol.     Other lipid parameters were also reduced.

When they followed patients out to day 180, the maximum nadir in LDL-C occurred at about day 60, increasing again after day 90.

"Now, with a second injection given at day 90, you get a further 10%  reduction, and that seems to be maintained to about 57% at day 180," Ray  noted.

Looking at individual patient data at day 180, in the 300-mg group  who received two doses of inclisiran, the mean absolute reduction in  LDL-C from baseline     was 64 mg/dL, ranging from 26 mg/dL to 122  mg/dL. "Everybody basically responded," he noted.

ORION-1: Lipid Parameters by Treatment Group at 90 Days

Lipid Measure Placebo (n=124) Inclisiran 100 mg (n=61) Inclisiran 200 mg (n=122) Inclisiran 300 mg (n=122) Inclisiran 500 mg (n=65)
Total cholesterol mean, % (SD) -1 -22 (12) -26 (14) -28 (15) -30 (11)
Triglyceride median, % 3 1 -11 -10 0
HDL-C mean, % (SD) -2 (14) 5 (11) 8 (12) 9 (16) 8 (15)
Non-HDL-C, mean, % (SD) 0 (20) -30 (13) -37 (18) -40 (19) -42 (15)
Apo-B mean, % (SD) -2 (16) -28 (12) -34 (15) -37 (16) -40 (13)
Lp(a), median, % -1 -18 -21 -23 -22
SD=standard deviation

Intra- vs Extracellular PCSK9

Invited discussant Dr Borge Nordestgaard (University of Copenhagen and Copenhagen University Hospital, Denmark) noted differences between the antibody     approach to PCSK9 inhibition and the new RNA interference method, principally that although monoclonals inhibit extracellular PCSK9, the RNA method blocks     both intracellular and extracellular PCSK9. However, "whether the difference has any meaning, we don't know at this stage," he said.

"Of course, my job is to have a critical voice, but I still want to praise," Nordestgaard said wryly. "This inhibition of PCSK9 synthesis by RNA     interference had a 50% to 60% reduction over 3 to 6 months, and treatment only two to three times per year looks really encouraging, I must say, so the     balance of effect vs side effect seems to be tipped."

For now, the only side effects are injection-site reactions, but adverse effects similar to statins could eventually appear, such as myalgia, and effects     on platelets, intolerance, or neurocognition, he said.

"But in the long term, phase 3 trials looking at end points are really important," Nordestgaard said.

"I think the key question is whether LDL-C reduction, which now is very impressive, is sustainable over time. And then of course, whether this will lead to     cardiovascular disease benefit or even lead to a mortality benefit in a very long trial."

        Both studies were funded by Alnylam Pharmaceuticals and the Medicines Company. Ray reports receiving honoraria from Takeda, Boehringer Ingelheim,         Cipla, Algorithm, Kowa, Sanofi, Amgen, Pfizer, AstraZeneca and AbbVie. He had been a consultant or participated in advisory boards for Sanofi,         Regeneron, Amgen, the Medicines Company, AstraZeneca, Cerenis Therapeutics, Ionis Pharmaceuticals, AbbVie, Resverlogix. He had received research grants         from Sanofi, Regeneron, Pfizer, MSD. Nordestgaard reports he has consulted for or given talks sponsored by AstraZeneca, Omthera Pharmaceuticals,         Sanofi, Regeneron, Ionis, Aegerion, Dezima Pharma, Fresenius, B Braun, Kaneka, Amgen, Kowa, and Denka Seiken.    

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