Effects of Concomitant Lipid Modifying Therapy on the LDL-C Lowering Efficacy of PCSK-9 Inhibition

838 treatments targeting or up-regulating the LDLR. Results of studies in LDL-R -/- mouse models and in humans carrying loss-of-function mutations in the ANGPTL3 (angiopoietinlike protein 3) gene suggest that blockade of ANGPTL3 may have beneficial LDL-C lowering effects in HoFH. Objective/Purpose: To evaluate the efficacy and safety of evinacumab, a human mAb inhibitor of ANGPTL3, in HoFH patients on various background lipid therapies. Methods: This is a fully-enrolled, ongoing, single-arm, open label, proof-of-concept study involving 9 HoFH patients. HoFH diagnosis was genetically and phenotypically confirmed. Patients entered the trial on high doses of statins in combination with a variety of background LLTs. Current LLT was maintained from 4 weeks before baseline through the 26-week treatment and observation period. Evinacumab was initially dosed as a single 250 mg SC injection at baseline and subsequently as 15 mg/kg IV at week-2. Two patients further received 450 mg SC at weeks 12, 13, 14, and 15. The primary endpoint was mean percent change in LDL-C from baseline to week-4. Results: Evinacumab reduced LDL-C from baseline (mean 376.0 mg/dL) to week-4 (mean 218.7mg/dL) in the 9 patients: mean reduction was 49.2% (range 24.7%90.1%). Among the three null/null patients (baseline: 596.8 mg/dL), mean percent (absolute) reduction in LDLC was 37.3% (215.8 mg/dL) at week-4. Over the course of weeks 4-8 of treatment, mean LDL-C reduction from baseline was 41.7% (range 25.9%-59.5% among the 3 null/null patients). At week-4, four (44.4%) patients achieved an LDL-C ,100 mg/dL. Similar and consistent reductions were observed in apoB (-45.9%), non-HDL-C (-48.9%) and total cholesterol (-47.0%) at week-4. There was one serious adverse event (coronary artery disease, not related to treatment) and no adverse events leading to discontinuations. The most common drug-related events were injection-site reaction and hot flush. Conclusions: Evinacumab produced clinically meaningful reductions in LDL-C in all HoFH patients in this study, even in the subset of patients with null/null mutations in the LDL-R. These initial results are indicative of an add-on contribution of evinacumab, through inhibition of ANGPTL3, in the treatment of HoFH.

205 Bempedoic Acid Reduces LDL-C and is Well-Tolerated in Patients Receiving Atorvastatin 80 mg Background Therapy Mary McGowan, MD, Diane MacDougall, MS, Jeffrey Hanselman, MS, Sharon Watling, PharmD, Narendra Lalwani, PhD, (Ann Arbor, MI)

Lead Author’s Financial Disclosures: Employed by Esperion Therapeutics, Inc. Study Funding: None

Journal of Clinical Lipidology, Vol 11, No 3, June 2017

Background/Synopsis: Bempedoic acid (ETC-1002) is an investigational oral drug currently in Phase 3 of clinical development that lowers LDL-C by inhibiting ATPcitrate lyase and upregulating the LDL receptor. Bempedoic acid added to low- and moderate-dose statin background therapy lowers LDL-C by 20-22% compared to placebo. The effect of adding bempedoic acid to high-dose statin background therapy was unknown. Objective/Purpose: To assess the efficacy, pharmacokinetics (PK) and safety of bempedoic acid versus placebo in patients receiving atorvastatin 80 mg background therapy, LDL-C and atorvastatin PK (co-primary endpoints), hsCRP, other lipids, and safety were assessed. Methods: Statin-treated patients began receiving openlabel atorvastatin 80 mg during a 4-week run-in period. Randomized patients received (2:1) double-blind bempedoic acid or placebo. Efficacy and safety were assessed 4 weeks post randomization; PK for atorvastatin and its metabolite were assessed pre- and 2 weeks post randomization. Results: Sixty-eight patients on background atorvastatin 80 mg were randomized to receive bempedoic acid 180 mg (n545) or placebo (n523) daily for 4 weeks; 64 patients completed treatment. Baseline LDL-C was 71 mg/dL and 86 mg/dL for bempedoic acid and placebo groups, respectively. Treatment with bempedoic acid significantly decreased LDL-C by 22% (mean placebo-adjusted; 95% confidence interval [CI], -36.4, -7.96; p5 0.0028) with change from atorvastatin treated baseline of -13% for bempedoic acid and +9% for placebo. Additionally, hsCRP was significantly decreased from baseline by 35% for bempedoic acid versus an increase of 1% for placebo; total cholesterol, non-HDL-C and apolipoprotien B were also significantly decreased. Maximum concentrations (Cmax) of atorvastatin and its metabolite, ortho-hydroxy atorvastatin, were unchanged with corresponding bempedoic acid administration and area under the curve (AUC24h) showed minimal changes of +29% and +22%, respectively. Adverse events and safety laboratories were balanced across treatment arms. Conclusions: Bempedoic acid 180 mg is a complementary, oral, once-daily LDL-C lowering option for patients with hypercholesterolemia inadequately treated with highdose statin.

206 Effects of Concomitant Lipid Modifying Therapy on the LDL-C Lowering Efficacy of PCSK-9 Inhibition Arnold Abud, MS, Paul Ziajka, MD, (Orlando, FL)

Lead Author’s Financial Disclosures: None Study Funding: None

Abstracts

Background/Synopsis: The onset of PCSK-9 inhibitors have provided clinicians with new tools for lowering the LDL-C levels in those patients who were previously thought to be drug intolerant or who have not reached desired LDL-C levels on standard drug therapies. While the lipid lowering efficacy of PCSK-9 inhibitors has been well established, little research has been done to identify what effects concomitant lipid modifying therapy with statins, ezetimibe or colesevelam has on PCSK-9 inhibition. Objective/Purpose: This retrospective study was designed to determine the effects of PCSK-9 Inhibitors and concomitant lipid-modifying therapy on LDL-C values in patients with dyslipidemia. Methods: 96 charts of patients on PCSK-9 Inhibitors (alirocumab or evolocumab) were reviewed at a Florida private practice lipid clinic. 60 patients were identified as being on concomitant therapy with a PCSK-9 inhibitor and either a statin, ezetimibe or colesevelam. The 48 patients on a statin and a PCSK-9 inhibitor were compared to 56 patients on a PCSK-9 inhibitor without a statin. The 9 patients treated with ezetimibe and a PCSK-9 inhibitor and the 3 patients being treated with colesevelam and a PCSK-9 inhibitor had %LDL-C change measured before and after stopping concomitant therapy. Results: Mean %LDL-C reduction was significantly greater in patients on PCSK-9 inhibitors with a statin (62.10% +/-18.02 %LDL reduction, n548) compared to those on a PCSK-9 Inhibitor without a statin (49.01% +/-19.92 %LDL reduction, n556), (two-sample t-test, p,0.001). A trend noted in the group of patients on ezetimibe and a PCSK-9 Inhibitor who stopped ezetimibe, shows a 71.5% +/- 86.33 LDL mean increase (n59, N.S). A 40% +/- 37.68 LDL mean increase was noted in patients initially on colesevelam and a PCSK9 inhibitor who subsequently discontinued colesevelam therapy (n53; N.S). Conclusions: The use of statins plus a PCSK-9 Inhibitor significantly increases the efficacy of LDL-C reduction. The use of concomitant therapy of ezetimibe and a PCSK-9 Inhibitor or colesevelam and a PCSK-9 Inhibitor seem to improve the LDL lowering efficacy of PCSK-9 Inhibition, but larger studies are needed.

207 Treating Hypercholesterolemia with PCSK9 Inhibitors in a Real-World Setting: Twenty Month Experience with Ninety Patients Glenn Huth, MD, Ann Mayer, RN, Jessie Collar, RMA, (Appleton, WI)

Lead Author’s Financial Disclosures: None Study Funding: None Background/Synopsis: Experience of a Lipidologist in a real-world setting prescribing PCSK9 inhibitors has not

839 been described in the literature. The approval of alirocumab and evolocumab has been met with optimism among Lipidologists, given the limited options available for treating patients with Familial Hypercholesterolemia and patients with high risk coronary heart disease plus statin intolerance. While 40 to 60% reductions in LDL-C along with a low incidence of adverse drug events are reported in clinical trials with these monoclonal antibodies, experience in private Lipidology practice has yet to be described. Furthermore, there is a perception that the high cost of injection therapy will limit the availability of these two medications for a patient with hypercholesterolemia referred to a Lipidologist. Objective/Purpose: The purpose of this study is to describe the early experience with PCSK9 inhibitors in patients treated by a Lipidologist in practice with a group of fourteen Cardiologists and two Thoracic Surgeons. Methods: A prospective Microsoft Access database is used to track patients on PCSK9 inhibitor therapy. The first patient was prescribed alirocumab on August 29, 2015. The most recent start that has been approved by the patient’s insurer was on November 17, 2016. Results: Starting August 29, 2015 through January 3, 2017 ninety patients have been prescribed and have obtained insurance coverage for therapy with a PCSK9 inhibitor. Additional work required by the Lipidologist to obtain insurance coverage included twenty-four appeal letters and six conference calls. One patient needed genetic testing to document the LDLR gene mutation as a requirement for insurance coverage. The genetic analysis on an oral rinse sample was performed by GeneDx The most common indication for PCSK9 inhibitor therapy was for secondary prevention in 52 patients having statin intolerance. Twenty-seven patients had high risk coronary