Novel Anti-PCSK9 Fusion Protein Slashes LDL-C Levels

Liam Davenport

June 03, 2019

MAASTRICHT, The Netherlands — A novel antiproprotein convertase subtilisin/kexin type 9 (PCSK9) recombinant fusion protein that offers a more convenient dosing regimen than anti-PCSK9 monoclonal antibodies substantially decreases low-density-lipoprotein (LDL)-cholesterol levels on patients already taking maximally tolerated statins, results of a phase 2 trial show.

LIB003 combines a PCSK9-binding domain with human serum albumin in a recombinant fusion therapeutic agent derived from a mammalian cell line.

The binding domain blocks the interaction between PCSK9 and the LDL-cholesterol recepto, and the albumin linkage increases the half-life to 12 to 15 days, allowing low-volume injections to be given every 4 weeks.

Following on from promising phase 1 data, the team conducted a phase 2 study in which 81 patients were randomized to 150 mg, 300 mg, or 350 mg of LIB003 or placebo for 12 weeks.

Evan Stein, MD, founder, LIB Therapeutics, and Metabolic & Atherosclerosis Research Center, Cincinnati, presented the results here at the European Atherosclerosis Society 2019 Congress. LIB Therapeutics funded the study.

He showed that the 300 mg dose was associated with an average reduction in LDL-cholesterol levels of 77% over 12 weeks, compared with baseline, whereas free PCSK9 levels decreased by 88%.

Interestingly, there was no additional lipid- or PCSK9-lowering benefit seen with the highest dose of LIB003, although it was associated with more moderate and severe treatment-related adverse events.

Stein said that, although all doses of LIB003 "induced a rapid, sustained, and significant mean reduction in LDL cholesterol and free PCSK9," the "longest, stablest, maximum reductions were observed with the 300 mg cohort."

He continued: "There was no additional reduction with 350 mg, indicating that once we achieved maximum suppression of PCSK9, there's no additional benefit in terms of LDL reduction, which we've known for some time with monoclonal antibodies."

Stein added: "Based on these results, the 300 mg dose has been selected for the open-label extension, on which these patients have been on now for about 6 months, and phase 3 development."

Danilo Norata, PhD, professor, Department of Pharmacological and Biomolecular Sciences, University of Milan, was not involved in the study.

He told theheart.org | Medscape Cardiology that LIB003 offers a new approach to targeting PCSK9, with a mechanism of action similar to that of monoclonal antibodies and directed to circulating PCSK9 but an improved pharmacokinetic profile with a longer half-life.

Norata said that "additional clinical trials in different patient cohorts are warranted to confirm a decrease in LDL cholesterol, similar to that presented in this phase 2 trial."

If this reduction, "which appears to be similar to that of anti PCSK9 monoclonal antibodies," is indeed maintained, he believes that there could be a space in the market for LIB003, "and drug costs will become an important point."

He also stressed that it should be borne in mind that the way in which PCSK9 inhibitors are designed can result in large differences in efficacy.

Referencing the withdrawal of the partially murine monoclonal antibody bococizumab (Pfizer) due to the generation of antidrug antibodies that attenuated the LDL-cholesterol lowering effect, Norata said that it is unlikely that LIB003 will fall victim to the same problem.

He pointed out that "the way the compound is formulated reduces the chances that this will be recognized by the immune system, and therefore you would not expect loss of efficacy."

Norata added: "But we have to wait for these data, as well as to evaluate the efficacy in different types of patients."

For the study, patients had or were at high risk for, asymptomatic cardiovascular disease, or had homozygous familial hypercholesterolemia, with LDL-cholesterol levels above 80 mg/dL on maximally tolerated statin therapy.

They were randomized to LIB003 150 mg (n = 21), 300 mg (n = 19), or 350 mg (n = 21), or placebo (n = 20) injections every 4 weeks for 12 weeks, followed by a 4-week washout and monitoring period and an optimal longer-term extension of 12 weeks.

The groups were generally well balanced in terms of their baseline characteristics.

Patients in the LIB003 300 mg group tended to be slightly younger, were less likely to be white, and had a lower cardiovascular disease risk than those in the other groups, whereas those in the placebo group were more likely to be female, white, and never smokers than other patients.

There was a wide range in the proportion of patients receiving high-intensity statin therapy, from 31.6% to 61.9%; current ezetimibe use ranged from 14.3% to 30.0%.

Baseline LDL-cholesterol levels were comparable across groups regardless of the method used to calculate them.

All but one patient in the LIB003 150 mg group and one in the LIB003 350 mg group completed the study.

Calculating the percentage change in LCL-cholesterol levels from baseline, the team found that, whereas all three active treatment groups achieved significant reductions on an intention-to-treat analysis, the largest was seen with the 300 mg dose.

Compared with a rise in LDL-cholesterol levels of 6.4% with placebo at week 12 over baseline, patients taking the 150 mg dose of LIB003 achieved a 33.5% reduction (P < .0001).

In contrast, the 300 mg dose was associated with 77.3% reduction in LDL-cholesterol levels, and the 350 mg dose was associated with a reduction of 70.1% (P < .0001 for both).

Waterfall plots underlined that all patients given the 300 mg dose of LIB003 achieved a reduction in LDL-cholesterol levels of more than 30%, with no greater gain seen with the 350 mg dose.

Moreover, the reductions were consistent regardless of the whether the Friedewald or Hopkins formulas or ultracentrifugation were used to calculate LDL-cholesterol levels.

When the researchers turned their attention to PSCK9 levels, all three LIB003 doses, as expected, were associated with marked reductions in from baseline to week 12.

For the 150 mg dose, the mean reduction was 46.6%, increasing to 88.2% with the 300 mg dose and 94.3% with the 350 mg dose. This was compared with a mean reduction of just 4.1% in the placebo group.

Again, waterfall plots showed that all patients given the 300 mg dose of LIB003 achieved a reduction in PCSK9 levels of more than 30%, with no additional gain with the larger dose.

Compared with placebo, LIB003 was also associated with significant reductions in apoliprotein B at week 12 at all three doses (P < .0001 for all), as well as significant reductions in lipoprotein(a) levels with the 300 mg and 350 mg doses (P < .001 for both).

A small but significant increase in high-density lipoprotein-cholesterol levels was also observed with the 300 mg dose of LIB003 (P < .02).

In terms of safety, the LIB003 150 mg dose was associated with an adverse-event profile similar to that seen with placebo.

Although the 300 mg and 350 mg doses were associated with higher event rates, there appeared to be a plateau effect with increasing doses comparable to that seen with the efficacy analysis.

However, the highest dose was associated with more than twice as many moderate and severe treatment-related adverse events than the medium dose, at 23.8% vs 10.5% for moderate severity events and 14.3% vs 5.3% for severe events.

Stein said that, nevertheless, none of the LIB003 doses was associated with proven drug-related adverse events over and above those seen with placebo.

There were also no safety signals in terms of liver or renal function, glucose parameters.

Two patients developed antidrug antibodies, but there were no instances of neutralizing antibodies and there was no pharmacodynamic effect on LDL cholesterol or PCSK9.

In the post-=presentation discussion, session cochair Alexandros D. Tselepis, MD, PhD, director, Atherothrombosis Research Centre, University of Ioannina, Greece, asked about the potential benefit with LIB003 compared with monoclonal antibodies.

"I saw the data are almost similar...so can you comment on this: What should we expect from the use of this protein as compared to the monoclonal antibodies?"

Stein replied that the "big difference" is that with LIB003, patients receive an approximately 1 mL injection every 4 weeks, which could be fitted into an autoinjector.

He continued that, in comparison, the equivalent dose with a monoclonal antibody would typically require either three 1 mL injections or an infusion device delivering 3.5 mL.

"In addition...the drug is now stable at ambient temperature, up to about 9 months, so it may be more patient friendly, in that distribution doesn't have to be from the pharmacy to the patient, and patients wouldn't have to keep the drug refrigerated either at home or in their travel," Stein said.

Session cochair François Mach, MD, PhD, head of cardiology, Geneva University Hospital, countered that his patients "don't care" if they have three injections a month or need a fridge.

"They have fridges," he said, adding that the more important question is: "Will it be cheaper?"

Stein replied that "having looked at monoclonal antibodies for many years, the real cost at which they sell it is not the cost."

He said the situation is similar to statins, in that "they used to cost the same to produce as they do today, [but] now they sell for $3 a month when they used to sell for $300 a month."

When Mach described that as "an elegant nonanswer," Stein added that the cost of production of LIB003 is "probably going to be competitive or lower than a monoclonal antibody."

"But that doesn't translate into what people sell the drugs for. They spend more on marketing than they do on the cost of producing the drug."

The study was funded by LIB Therapeutics. Stein is founder and a partner in LIB Therapeutics; reports consulting fees related to the development of PCSK9 inhibitors from Amgen, Regeneron/Sanofi, Genentech, The Medicines Company, and BMS; reports fees relating to other LDL drugs from AstraZeneca, Catabasis, CymaBay, and Gemphire; and is on the Lipid Advisory Panel for CVS/Caremark.

European Atherosclerosis Society (EAS) 2019 Congress: Abstract EAS19-1100. Presented May 27, 2019.

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