PCSK9 Inhibition and Other New Therapies for Lipid Modification: Good News and Bad

NEW ORLEANS, LA—A late-breaking clinical trial session devoted to newly approved and investigational compounds for the treatment of lipids highlighted the end of a once promising therapy for low HDL cholesterol and a number of studies showing positive surrogate-endpoint findings for drugs that improve lipid parameters. 

In GLAGOV, an IVUS study of evolocumab (Repatha, Amgen), statin-treated patients with coronary artery disease who received the PCSK9 inhibitor for 18 months had dramatic reductions in LDL cholesterol levels, down from 93 mg/dL at baseline to 36.6 mg/dL. Some patients, such as those who started with an LDL cholesterol less than 70 mg/dL, had on-treatment LDL cholesterol levels as low as 24 mg/dL.

Presenting the results of GLAGOV today at the American Heart Association Scientific Sessions 2016, Steven Nissen, MD (Cleveland Clinic, OH), reported that evolocumab-treated patients had a significant reduction in IVUS-measured percent atheroma volume (PAV) compared with patients who received statin monotherapy. Approximately two-thirds of treated patients had a regression of coronary atherosclerosis.

Cardiovascular events “trended in the right direction,” Nissen said during a morning press conference, but he noted that the study was not designed as a morbidity and mortality trial, being far too small and too short in duration.

“Clearly, IVUS is a useful measure, but the critical determination of benefit and risk is going to come from the outcome trials,” he said. “We are very humble about this. We know we have a surrogate endpoint—we think this is a signal that suggests there may be benefits at really low LDL [cholesterol] levels, but the definitive studies will come hopefully next year.” 

“We are very humble about this. We know we have a surrogate endpoint.” Steven Nissen

Stephen Nicholls, MBBS (University of Adelaide, Australia), lead author of GLAGOV, which was published simultaneously in the Journal of the American Medical Association, said he believes the -0.95% reduction in PAV observed in the evolocumab-treated patients is “clinically significant.”

To TCTMD, Daniel Rader, MD (Perelman School of Medicine at the University of Pennsylvania, PA), who was not involved in the GLAGOV trial, said he is a proponent of the “lower is better” hypothesis and expects the results of FOURIER—the large cardiovascular outcomes trial testing evolocumab—to be positive. According to Rader, there is likely some point where additional LDL lowering does not provide cardiovascular risk protection, but the point of diminishing returns is lower than 70 mg/dL, once the recommended target for LDL cholesterol lowering.

In addition to data on evolocumab, Kausik Ray, MD (Imperial College, London, England) presented interim results on the PCSK9 synthesis inhibitor known as inclisiran (Medicines Company/Alnylam Pharmaceuticals), an investigational RNA-interference therapy that lowers LDL cholesterol levels. Inclisiran differs from the newly approved PCSK9 inhibitors in that patients receive a subcutaneous injection as little as twice per year.   

In the 90-day interim analysis of the phase II dose-ranging study, investigators observed “significant and durable” reductions in LDL cholesterol after a single injection, with the 300-mg dose reducing LDL cholesterol 51% at day 90. For patients who received a second injection of inclisiran at day 90, there was a 57% reduction in LDL from baseline by day 180. Injection-site reactions were infrequent, occurring in 3.2% of patients.

Focusing on HDL Cholesterol  

Turning away from LDL cholesterol to focus on HDL, Nicholls presented final data from the MILANO-PILOT trial, a study in patients with acute coronary syndrome who received weekly injections of a recombinant apoA-1 Milano/phospholipid complex over a 5-week period.

Although apoA-1 was once hailed as “liquid Drano” for the coronary arteries, the MILANO-PILOT studied showed no meaningful effect on coronary atherosclerosis as assessed by IVUS when compared with patients who received a placebo injection. The Medicines Company is discontinuing the development of MDCO-216, as the drug is known, opting to focus on inclisiran, their PCSK9 synthesis inhibitor.  

For Rader, an expert in HDL cholesterol, the completion of MILANO-PILOT is the end for the compound. “I think we can probably write the obituary for apoA-1 Milano, even though it’s never been studied in cardiovascular outcomes,” he commented.

“I think we can probably write the obituary for apoA-1 Milano.” Daniel Rader

Still, he holds out hope for other compounds, including CSL112, a reconstituted, plasma-derived human apoA-1 shown to be safe and well tolerated in the AEGIS-1 trial, which was also presented during the late-breaking clinical trial session. Lead investigator C. Michael Gibson, MD (Beth Israel Deaconess Medical Center, Boston), said CSL112 is designed to increase cholesterol capacity, the first step in reverse cholesterol transport. Tested in ACS patients, CSL112 did not appear to cause any clinically significant changes in kidney or liver function in the phase IIb AEGIS-1 study.       

Rader believes these other wild-type apoA-1 products should continue clinical development. These compounds differ in structure and function from apoA-1 Milano, he noted. “I don’t know if [the CSL112] approach is going to work,” said Rader. “But I don’t think we can extrapolate the results from apoA-1 Milano to wild-type apoA-1.” Whether or not these other HDL-raising compounds can yield cardiovascular risk protection remains a big question mark for the field, said Rader.

Finally, Sotirios Tsimikas, MD (Ionis Pharmaceuticals/University of California, San Diego), presented data from IONIS-ANGPTL3-LRx, a trial testing an antisense inhibitor to angiopoietin-like protein 3 (ANGPTL3), which is a “genetically validated lipid and metabolic target.” Tsimikas said genetic variations in ANGPTL3 are associated with low LDL cholesterol and triglyceride levels. Treatment with the antisense inhibitor reduced triglycerides, LDL cholesterol levels, and total cholesterol levels, but also lowered HDL cholesterol levels.   

Michael O’Riordan is the Managing Editor for TCTMD. He completed his undergraduate degrees at Queen’s University in Kingston, ON, and…

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  • Ray K, et al. Inhibition of PCSK9 synthesis via RNA interference: 90 day data from ORION-1 – a multicenter, phase 2 randomized trial. Presented at: American Heart Association Scientific Sessions 2016. November 15, 2016. New Orleans, LA.

  • Nicholls SJ, Puri R, Anderson T, et al. Effect of evolocumab on regression of coronary disease in statin-treated patients: GLAGOV randomized clinical trials. JAMA. 2016; Epub ahead of print.

  • Gibson CM, Korjian S, Tricoci P, et al. Safety and tolerability of CSL112, a reconstituted, infusible, plasma-derived apolipoprotein A-1, after acute myocardial infarction. Circulation. 2016; Epub ahead of print.

  • Tsimikas S, et al. Ionis-angptl3-Rx, an antisense inhibitor to angiopoietin-like protein 3 (angptl3) reduces plasma angptl3 and lipids in healthy volunteers with elevated triglycerides. Presented at: American Heart Association Scientific Sessions 2016. November 15, 2016. New Orleans, LA.

  • Nicholls S, et al. Impact of infusion of ApoA-1 Milano HDL mimetic on regression of coronary atherosclerosis in acute coronary syndrome patients: the MILANO-PILOT study. Presented at: American Heart Association Scientific Sessions 2016. November 15, 2016. New Orleans, LA.

  • Nissen reports consulting for many companies and conducting clinical trials on behalf of Abbvie, Amgen, AstraZeneca, Cerenis, Eli Lilly, Esperion, Takeda, Novo Nordisk, The Medicines Company, and Pfizer (honoraria is paid to charity and no reimbursement is accepted for trial participation).
  • Nicholls reports consulting for AstraZeneca, Amgen, Anthera, Boehringer Ingelheim, CSL Behring, Eli Lilly, Esperion, Merck, Takeda, Roche, Kowa, LipoScience, Novartis, Sanofi-Regeneron. He conducts clinical trials on behalf of Amgen, Anthera, AstraZeneca, Eli Lilly, Novartis, Cerenis, The Medicines Company, Resverlogix, InfraReDx, Roche, Sanofi-Regeneron, and LipoScience.
  • Gibson is a consultant to Amarin Pharma, Amgen, Boston Clinical Research Institute, Cardiovascular Research Foundation, CSL Behring, Eli Lilly and Company, Gilead, Novo Nordisk, Pfizer, Pharma Mar, Roche Diagnostics, St. Francis Hospital, St. Jude Medical, The Medicines Company, and Web MD. He has present research or grant funding from Angel Medical Corporation, Bayer Corp, CSL, Inc., Ikaria, Inc., Janssen Pharmaceuticals, Johnson & Johnson Corporation, Portola Pharmaceuticals, Stealth Peptides, Inc., St. Jude Medical.
  • Tsimikas is a co-inventor and receives royalties from patents held by UCSD on oxidation-specific antibodies and is an employee of Ionis Pharmaceuticals (in addition to his posting at UCSD).
  • Ray did not disclose any conflicts of interest.