disease by preventing their formation. Together with Genzyme, we completed a randomized, double-blind,
placebo-controlled trial in HoFH patients. In this multi-center trial, KYNAMRO significantly further reduced
LDL-C and all other measured endpoints when added to a treated baseline. In this trial, four patients (11 percent)
treated with KYNAMROwithdrew due to adverse events. Consistent with other studies evaluating KYNAMRO,
commonly observed adverse events included mild to moderate injection site reactions and flu-like symptoms, as
well as elevations in liver transaminases.
Familial Hypercholesterolemia
Physicians diagnose patients as having FH if they have very high cholesterol, are at high cardiovascular risk
and cannot reduce their LDL-C sufficiently with currently available lipid-lowering therapies. FH is a genetic
disease that causes elevated LDL-C levels and family patterns of premature heart disease and heart
disease-related death. FH patients have inherited abnormalities in liver cells that are responsible for clearing LDL
particles from the blood. FH is autosomal dominant, which means that all first-degree relatives of FH patients
have a 50 percent chance of having the disease as well, making early detection through early screening critically
important. Patients with untreated heterozygous FH have a 50 percent mortality rate by age 60.
HoFH is a severe form of FH. People with HoFH have inherited mutations that limit the body’s ability to
clear cholesterol. HoFH is extremely rare: it is believed to occur in only one out of every one million persons.
As with other rare diseases, the true prevalence of HoFHmay be underestimated because of inadequate data and
under-diagnosis. Today, it is estimated that HoFH affects about 6,000 people globally. Medical literature includes
different criteria for making the diagnosis of HoFH. There are multiple diagnostic criteria, which may include:
•
DNAevidence confirming the presence of specific gene mutations associated with a genetic diagnosis
of HoFH. However, DNAevidence is generally not necessary for diagnosis and genetic analysis may
be inconclusive;
•
Family history, if known, of premature coronary heart disease and hypercholesterolemia;
•
Presence of premature heart disease;
•
Elevated plasma levels of total cholesterol and LDL-C;
•
Physical examination for signs of cholesterol deposits, including xanthomas on the backs of hands,
fingers, face and other areas of the skin. Xanthomas may not be present in every patient; and
•
Suboptimal response to lipid lowering therapy.
In addition to lipid-lowering medications, current standard-of-care for HoFH patients can include apheresis,
a two to four hour process administered two to four times a month. Apheresis mechanically removes LDL-C
from the blood and until recently it has been the primary therapy available on top of maximally tolerated
lipid-lowering therapy.
Clinical Development
In conjunction with Genzyme, we evaluated KYNAMRO in a Phase 3 study in patients with HoFH. The
randomized, double-blind, placebo-controlled, multi-center study enrolled 51 HoFH patients ages 12 to 53 years,
including seven patients ages 12 to 16 years, who were maintaining a regimen of maximally tolerated
lipid-lowering medications. Treatment with KYNAMRO further reduced LDL-C levels by an average of
113 mg/dL, or 25 percent, from a treated baseline of 439 mg/dL, and further reduced all measured endpoints for
atherogenic particles. InMarch 2010, these data were published in The Lancet by Professor Raal of the
University of theWitwatersrand in SouthAfrica.
Together with Genzyme, we also conducted three additional Phase 3 studies in patients with severe
hypercholesterolemia, in patients with HeFH and in patients with high cholesterol at high risk for cardiovascular
disease. In all three Phase 3 studies, treatment with KYNAMRO lowered LDL-C and reduced other atherogenic
lipids, including apo-B, total cholesterol, non-HDL-cholesterol, and lipoprotein a, or Lp(a). These key lipids are
generally accepted risk factors for cardiovascular disease. Data from these studies were published in Circulation,
PLoS One and the Journal of theAmerican College of Cardiology.
Safety data for KYNAMRO are based on pooled results from the four Phase 3 studies noted above with a
total of 390 patients. In these four Phase 3 studies, 261 patients received weekly subcutaneous injections of
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