Mipomersen, a First-in-Class Apolipoprotein B Synthesis Inhibitor, Lowers Lipoprotein (a) in Patients with Homozygous Familial Hypercholesterolemia

Abstracts 146 Mipomersen, a First-in-Class Apolipoprotein B Synthesis Inhibitor, Lowers Lipoprotein (a) in Patients with Homozygous Familial Hypercholesterolemia William C. Cromwell, MD, Raul D. Santos, Dirk J. Blom, David A. Marais, Robin H. Lachmann, Daniel Gaudet, Ju L. Tan, Scott Chasan-Taber, Diane L. Tribble, JoAnn Flaim, Frederick J. Raal, Min-Ji Charng, (Raleigh, NC) Synopsis: Despite available lipid-lowering therapy (LLT), adequate treatment of patients with homozygous familial hypercholesterolemia (HoFH) remains an unmet medical need. Mipomersen (ISIS301012) is an apolipoprotein A (apoB) synthesis inhibitor based on antisense oligonucleotide technology. In lipoprotein (a) (Lp[a]) transgenic mice, the use of mipomersen reduced Lp(a) levels without having an impact on apo(a) synthesis. Reductions in Lp(a) also were observed in a pilot study in 3 patients with HoFH. Purpose: The purpose of this study was to examine the effect of mipomersen on Lp(a), a proposed independent risk factor for CVD in FH patients, in a larger clinical trial. Methods: This was a double-blind, placebo-controlled, phase 3 study in patients with HoFH randomized to 200 mg of mipomersen (n 5 34) or placebo (n 5 17), administered subcutaneously weekly for 26 weeks. Results: The majority of patients (13/17 placebo; 32/34 mipomersen) had Lp(a) levels (.20 mg/dL) at baseline (BL). Lp(a) levels (mg/dl, median, range, BL and after treatment, respectively) were placebo: 58 (3–164) and 53 (3–150); mipomersen: 56 (10–176) and 33 (4–133), reflecting a median percent reduction from BL (prespecified tertiary end point) by mipomersen of 32% (P 5 .001 vs placebo), exceeding that for all other lipids examined. A total of 8 of 34 (24%) of mipomersen-treated patients had Lp(a) reductions greater than 50%. Median absolute reduction in Lp(a) was 20.5 mg/dL (P 5 .002 vs placebo). We previously reported that mean BL low-density lipoprotein cholesterol (LDL-C) values were 400 mg/dL (placebo) and 439 mg/dL (mipomersen) and that mipomersen produced a 25% reduction in LDL-C from BL (primary end point), with a mean absolute reduction of 113 mg/dL (both P , .001 vs placebo). Significant reductions also were observed for secondary end points (apo B [27%], total cholesterol [21%], nonHDL-C [24%], all P , .001 vs placebo). A total of 45 of 51 patients completed treatment; 6 mipomersen patients withdrew from treatment because of an injection-site reaction (n 5 2), or (n 5 1 each) rash, ALT elevation, noncompliance, and withdrawal of consent. The most common adverse event was injection-site reaction on 1 or more occasions (26/34 mipomersen patients). ALT increased to $3X ULN in 4/34 mipomersen patients without clinically significant bilirubin elevations. Conclusions: High Lp(a) has been treated by targeting reductions in LDL, a key component of the Lp(a) particle, with statins 6 other LLT, or with niacin, but these agents

221 are only modestly effective. The present results suggest that mipomersen represents an effective therapeutic option for use in conjunction with existing LLT to improve management of Lp(a), in patients with high LDL-C and Lp(a) levels.

147 Change Heart and Vascular Risk with Attitude, Nutrition, Goals, and Exercise (CHANGE) Edward Mark Goldenberg, MD, Elisabeth Bradley, Deanna Hoosty, Bernadette Baker, Catherine Johnson, Melissa Steward, Dionne Thompson, Penny Vigneau, (Newark, DE) Synopsis: Cardiovascular disease is the number one cause of death in the United States. Traditional risk factors account for more than 90% of the risk of an initial heart attack. Forty-four percent of the reduction in death from heart disease in recent decades is attributed to risk factor modification. Many individuals are aware of their risk factors; however, they are not aware of their treatment goals. Low-risk individuals identified by the Framingham risk score account for the majority of cardiovascular events. Identification of lifetime risk rather than Framingham risk identifies individuals appropriate for early aggressive risk factor management. Purpose: A Cardiovascular Prevention Program was developed by Christiana Care Health System in January 2008 with the goal of improving management of cardiovascular risk factors and reducing the lifetime cardiovascular risk of community members. Methods: The multidisciplinary team included the Medical Director, Advanced Practice Nurse, Cardiovascular Nurses, Behavioral Health Specialist, Vascular Lab, Marketing, and Heart and Vascular Administration. Through a promotional campaign, community members were invited to visit the Christiana Care Website to complete an online cardiovascular risk assessment. Individuals identified with any cardiovascular risk were invited to come for a free comprehensive on-site screening with a cardiovascular nurse. This included a full lipid profile, blood sugar, body mass index, waist circumference, blood pressure, carotid auscultation, assessment of sex-specific and psychosocial risk factors, and triple vascular screening. Personalized risk factor counseling was provided with an emphasis on patient goals and educating and empowering patients with knowledge. In addition to Framingham risk, the patient’s lifetime risk for cardiovascular disease was determined during a multidisciplinary team review, and best-practice recommendations provided to the patient and Primary Care Physician. Results: Key outcomes from 289 patients seen in 2008 reflected risk factor profiles consistent with national statistics. Although 70% met traditional lipid goals, only 18% met lipid goals for lifetime risk of cardiovascular disease. A